SMASH USMLE Step 1

High Yield Review

(First Edition)

ADELEKE ADESINA, DO

Founder Smashusmle Reviews

Board Certified Emergency Medicine
Houston Methodist Hospital, Houston, Texas
Copyright © 2020 by Adeleke Adesina in the United states of America. All right reserved. No part
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Adeleke Adesina

SMASH USMLE Step 1 High Yield Review (First Edition)/ By Adeleke Adesina

ISBN13: 978-1-7353452-0-8

The First Edition, July 2020

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SMASH USMLE Step 1 High Yield Review

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 SmashUSMLE ReviewsTM

SMASH USMLE Step 1

High Yield Review

First Edition

Adeleke Adesina, DO
Board Certified, Emergency Medicine
Founder, Smashusmle reviews
Department of Emergency Medicine
Houston Methodist Hospital
Houston, Texas

Sulaiman I S Abuhaiba, M.D

Smashusmle Reviews Clinical Content Writer
Senior Clinical Researcher in Clinical Neuro-electrophysiology
Lecturer at University of Coimbra,
Faculty of Medicine, Coimbra Institute for Biomedical
Imaging and Translational Research

Mohamed Edfawy, Hussien, M.Sc., Ph.D.

Smashusmle Reviews Clinical Content Writer
Neuronal Circuits and Behavior Lab, 2nd floor (205b)
Center for Neuroscience and Cell Biology
Faculty of Medicine
-This book is dedicated to the Almighty God, the Master physician, entrepreneur, author and finisher of
my faith.

- To my wife, Olufunmilayo Adesina for supporting me through all the tough years of medical school and
beyond and believing in my visions to become a doctorpreneur.

To my sons, Olamide and Oluwadamola, for always keeping a smile on my face and making me proud of
you.

And to my dad and mom, thank you for encouraging me to think big and discover my true worth.
About Smashusmle reviews
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 Table of Contents

Chapter 1: Biochemistry............................................................................................................. 1
Chapter 2: Microbiology .......................................................................................................... 68
Chapter 3: Immunology ......................................................................................................... 147
Chapter 4: Behavioral Sciences .............................................................................................. 182
Chapter 5: Basic Pathology .................................................................................................... 206
Chapter :6 Basic Pharmacology.............................................................................................. 235
Chapter 7: Cardiology ............................................................................................................ 256
Chapter 8: Endocrinology ...................................................................................................... 335
Chapter 9: Gastroenterology................................................................................................... 371
Chapter 10: Hematology and oncology................................................................................... 435
Chapter 12: Neuroscience ...................................................................................................... 571
Chapter 13: Psychiatry ........................................................................................................... 640
Chapter 14: Renal .................................................................................................................. 668
Chapter 15: Fluids and Electrolytes ........................................................................................ 709
Chapter 16: Reproductive system ........................................................................................... 716
Chapter 17: Pulmonary system ............................................................................................... 741
About the author ..................................................................................................................... 771
 Chapter 1:

Biochemistry

1
Introduction to Nucleic Acids • Nucleic acids are long chain polymers of
nucleotides joined by 3′, 5′-phosphodiester bonds;
that is, a phosphate group links the 3′ carbon of a
sugar to the 5′ carbon of the next sugar in the chain
• Each strand has a distinct 5′ end and 3′ end, and
thus has polarity
• Sequence is always specified as 5′→3′
DNA structure properties
• The two strands are antiparallel (opposite in
Overview:
direction).
• Nucleic acids (DNA and RNA) are assembled
• The two strands are complementary. A always
from nucleotides, which consist of three
pairs with T (two hydrogen bonds), and G always
components:
pairs with C (three hydrogen bonds)
• Nitrogenous base (Purines, Pyrimidines)
• Five- carbon sugar (pentose) Ribose or Comparison between DNA and RNA
Deoxyribose Comparison DNA RNA
• Phosphate. Found in Nucleus Nucleus and
Cytoplasm
• Nucleic acids are classified according to pentose Pentose Deoxyribose Ribose
sugar If the pentose is ribose, the nucleic acid is Nitrogenous base Adenin- Thymin Adenine-Uracil
RNA (ribonucleic acid); if the pentose is Guanin- Cytocin Guanin- Cytocin
deoxyribose, the nucleic acid is DNA Shape Double strand Single strand
Types Messenger 8mRNA)
(deoxyribonucleic acid). Transfer (tRNA)
• There are two types of nitrogen-containing bases Ribosomal (rRNA)
commonly found in nucleotides:
A-purines:
• The two purines commonly found in nucleic acids
are adenine (A) and guanine (G); both are found in
DNA and RNA.
• Contain 2 rings in their stricture
B-pyrimidines
• Cytosine (C) is present in both DNA and RNA.
Thymine (T) is usually found only in DNA,
whereas uracil (U) is found only in RNA.
• Pyrimidines have only one ring.

• The bases attached to each other due to hydrogen

bonds
• Guanine binds to cytosine with three hydrogen
bonds
• Adenine binds thymine with two hydrogen bonds
• Nucleotides are formed when one or more
phosphate groups is attached to the 5′ carbon of a
nucleoside (Nucleoside di- and triphosphates are
high energy compounds because of the hydrolytic Polymerase enzyme:
energy associated with the acid anhydride bonds • Polymerases are enzymes that catalyze the
synthesis of DNA or RNA polymers whose

2
 sequence is complementary to the original • The parental strand is used as a template for this
template process
• It adds nucleotides to the 3´ end and synthesized
from the 5´ ends to the 3´ ends

• DNA
polymerases has A 3´→ 5´ proofreading feature. It Formation of replication fork:
allows the enzyme to check each nucleotide during • Helicase breaks the hydrogen bonds holding the
DNA synthesis and excise mismatched nucleotides base pairs together. This allows the two parental
in the 3´ to 5´ direction. strands of DNA to begin unwinding and forms two
Helicase enzyme: replication forks
• Helicases are enzymes that bind and unwinds the • SSB protein binds the complex to stabilize ssDNA
DNA Primer synthesis
• Primase synthesizes a short (about 10 nucleotides)
RNA primer in the 5′→3′ direction, beginning at
the origin on each parental strand.
• RNA primers are required because DNA
polymerases are unable to initiate synthesis of
DNA and can only extend a strand from the 3′ end
of a preformed “primer.”
Leading strand synthesis
• There are DNA and RNA helicases. • DNA polymerase III begins synthesizing DNA in
• DNA helicases are essential during DNA the 5′→3′ direction, beginning at the 3′ end of each
replication because they separate double-stranded RNA primer. The newly synthesized strand is
DNA into single strands allowing each strand to be complementary and antiparallel to the parental
copied strand used as a template. This strand will move
Ligase into the replication fork (Leading strand synthesis).
• Used to join DNA fragments by catalyzing the Lagging strand synthesis
formation of phosphodiester bonds between 5' • Many DNA fragments are synthesized sequentially
phosphate and 3' hydroxyl termini in double- on the DNA template strand in the 5′→3′ direction.
stranded DNA using ATP as a coenzyme These DNA fragments called Okazaki fragments
• Each Okazaki fragment is initiated by the synthesis
of an RNA primer by primase, and then completed
by the synthesis of DNA using DNA polymerase
III
• RNA primers on Okazaki fragments are digested
by enzyme RNAase
• The gaps are filled by DNA polymerase I in in the
5′→3′ direction
Endonuclease • DNA ligase seals the “nicks” between Okazaki
• Enzyme that breaks down a nucleotide chain into fragments, converting them to a continuous strand
two or more shorter chains by cleaving the of DNA.
phosphodiester bonds linking nucleotides Termination
• (DNA topoisomerase II) removes positive
DNA replication supercoils ahead of advancing replication forks
DNA replication
• DNA replication: Synthesis of daughter DNAs
using parental DNAs as template

3
Summary of DNA replication steps Split site involves either insertion or Protein function might be altered
Replication step deletion results in one or more
introns remaining in mature mRNA
Origin of replication (ori) One ori site per chromosome
Trinucleotide repeat expansion Protein product becomes longer than
normal
Unwinding of DNA double helix Helicase
Example: Huntington disease
Stabilization of unwound template strands Single-strand DNA-binding
protein SSB Lac Operon
Synthesis of RNA primers Primase Function
Synthesis of leading, lagging strands DNA polymerase III • The lac operon (Lactose Operon) is required to
(Okazaki fragments) transport and metabolism of Glucose in
Removal of RNA primers DNA polymerase I
Escherichia coli
• The lac operon allows the effective digestion of
Joining of Okazaki fragments DNA ligase lactose when glucose is not available through the
Removal of positive supercoils ahead of DNA topoisomerase II
activity of beta-galactosidase
advancing replication forks • During low glucose levels- Increase adenylate
cyclase activity- Increase generation of cAMP
DNA mutations from ATP and consequently lead to activation of
Overview catabolite activator protein (CAP) and eventually
• One of the common types of mutation is a single enhance transcription.
base alteration or point mutation • In case of high lactose leads to unbinds repressor
• Transition a point mutation in which purine- protein from repressor/operator site and eventually
pyrimidine base is replaced with pair with a enhance transcription.
different purine-pyrimidine base pair
• Example: A-T base pair becomes a G-C base pair.
• Transversion a point mutation that replaces a
purine-pyrimidine base pair with a pyrimidine-
purine base pair
• Example: A-T base pair becomes a T-A or a C-G
base pair.
• The severity of damage classified as follow silent
<< missense < nonsense < frameshift.

Common types of mutations in protein structures

Three genes associated with Lac operon

1. Lac Z codes for B-galactosidase and help breaks

down glucose into glucose and galactose

2. Lac y codes for galactose permease which found in

E.Coli cytoplasmic membrane which help
transport lactose into the cells

3. Lac a code for Galactoside acetyltransferase an

Type of mutation Effect on protein enzyme that transfers an acetyl group from acetyl-
Silent: New codes for the same None CoA to β-galactosides.
amino acid
Missense: New codes BUT specifies Possible decrease in function
different amino acid Example: Sickle cell disease Element Function
(substitution of glutamic acid with Operator (lac O) Binding site for repressor
valine). Promotor (lacP) Binding site for RNA polymerase
Repressor Binds to DNA at the operator and blocks binding of
Nonsense: New codon results in stop Usually nonfunctional RNA polymerase at the promotor
codon (UAG, UAA, UGA) Lac I Controls production of the repressor protein
Frameshift/ in-frame: addition or Protein function might be altered
deletion of bases resulting in Example: Duchenne muscular
misreading of all nucleotides dystrophy
downstream Tay-Sachs disease.

4
Summary of different scenarios of glucose and lactose
abundance

Regulation of gene expression

Overview: Several steps in gene expression process may be
• Regulation of gene expression is an essential modulated
feature in maintaining the functional integrity of a 1. Transcription
cell. 2. RNA splicing
• It involves several mechanisms that are used by 3. Translation
the cells to increase or decrease the production of 4. Post-translation modification
specific gene products (protein or RNA)
• It also regulates the rate of transcription by the Regulation of gene expression divided into
help of activator and repressor proteins 1. Positive regulation
• The regulatory proteins bind to either enhancer or 2. Negative regulation
silencer elements associated with eukaryotic gene
regions •
When the expression of genetic information is
• Gene regulation in prokaryotes is one of the quantitatively increased by the presence of a
methods of conservation of cell resources by specific regulatory element, regulation is said to be
turning OFF and ON of genes transcribing. positive
• Regulations of prokaryotic genes are done in units • when the expression of genetic information is
called as Operons. decreased by the presence of a specific regulatory
element, regulation is said to be negative.
• The operon is a unit of gene expression and
regulation which typically includes structural • The element or molecule mediating negative
genes for enzymes involved in a specific regulation is said to be a negative regulator,
biosynthetic pathway whose expression is a silencer or repressor; that mediating positive
coordinately controlled. regulation is a positive regulator,
an enhancer or activator.
• Operator sequence: DNA sequence that regulates
Lac operon
transcription of the structural genes and regulatory
gene whose products recognize the control • The lac operon (Lactose Operon) is required to
elements, for example a repressor which binds to transport and metabolism of Glucose in
and regulates an operator sequence. Escherichia coli
• The lac operon allows the effective digestion of
Promotor: lactose when glucose is not available through the
• DNA region that initiates transcription of a activity of beta-galactosidase
particular gene. • During low glucose levels- Increase adenylate
• Promoters are located near the transcription start cyclase activity- Increase generation of cAMP
sites of genes, on the same strand and upstream on from ATP and consequently lead to activation of
the DNA (towards the 3' region of the anti-sense catabolite activator protein (CAP) and eventually
strand). enhance transcription.
• In case of high lactose leads to unbinds repressor
protein from repressor/operator site and eventually
enhance transcription.

Three genes associated with Lac operon

1. Lac Z codes for B-galactosidase and help breaks
down glucose into glucose and galactose

5
 2. Lac y codes for galactose permease which found in mRNA splicing
E.Coli cytoplasmic membrane which help
transport lactose into the cells
3. Lac a code for Galactoside acetyltransferase an
enzyme that transfers an acetyl group from acetyl-
CoA to β-galactosides.
Lac Repressor
• Encoded by lacI gene, which is active as a
tetramer of identical subunits. •
• In the absence of lactose, the repressor occupies mRNA splicing: Protein involved in the process by
the operator-binding site. Both the lac repressor which nonsense sequences or intervening
and the RNA polymerase can bind simultaneously sequences (introns) are removed from pre-mRNA
to the lac promoter and operator sites. to generate a functional mRNA (messenger RNA)
Induction that contains only exons.
• In the presence of lactose an inducer molecule like • Pre-mRNA is processed into a messenger RNA
Allolactose, which is an isomer of lactose, binds to (mRNA)
a specific site on the lac repressor causing a • A 5' cap is added to the beginning of the RNA
conformational change which leads to dissociation transcript, and a 3' poly-A tail is added to the end.
of repressor from the operator. • During splicing, introns are removed accomplished
• β galactosidase molecule in E. coli converts by spliceosomes (also known as an snRNP), which
lactose into allolactose. are complexes of snRNA and protein. Meanwhile,
mRNA splicing exons are joined together to assemble the coding
Overview region of the mature mRNA.
• Genetic information is transferred from genes to • The mature mRNA molecule is transported to the
the proteins via RNA cytoplasm, where it is translated to form a protein.
• Most genes have their protein-coding information • In some cases, alternative splicing might occur
interrupted by non-coding sequences called leading to the production of different mRNA
“introns”. The coding sequences are then called molecules
“exons”
• Proteins have a non-coding sequence called introns
and a coding sequences called exons
• Introns are removed by a process called RNA
splicing

• Spliceosome: Help remove the introns from pre-

mRNA molecules
• Spliceosome composed of 5 small
ribonucleoproteins snRNPs
• The RNA components of snRNPs interact with the
intron and are involved in the catalysis
• Spliceosome acts by formation of complex E, A,
B, C

6
Introns VS Exons

Comparison between Introns and Exons

Introns Exons

Non-coding region Coding region for protein

Sequence changed over the time Conserved sequence

Found in eukaryotes Found in both prokaryotes and eukaryotes

Considered as the bases located between two exons Considered as the bases which encode an amino acid sequence of a protein

Stay in the nucleus by splicing out from mRNA Exit the nucleus to the cytoplasm after mRNA production

RNA types
Ribosomal RNA (rRNA) ● Most abundant RNA
● With ribosomal proteins, makes up the ribosomes, the organelles that translate the mRNA.
Transfer RNA (tRNA) ● Brings amino acids to ribosomes during translation.
mRNA Messenger RNA ● Carries the information specifying the
amino acid sequence of a protein to the ribosome
● The only translated form of RNA
snRNA small nuclear RNA ● Involved in splicing of mRNA (Removal of introns)

MicroRNAs
• MicroRNAs constitute a recently discovered class
of non-coding RNAs that play key roles in the
regulation of gene expression.
• microRNAs play an integral role in numerous
biological processes, including the immune
response, cell-cycle control, metabolism, viral
replication, stem cell differentiation and human
development.
• microRNA expression or function is significantly
altered in numerous diseases including cancer and
fibrosis, as well as CNS, metabolic and
inflammatory disorders

tRNA structure and Function

Overview

tRNA structure
● 70 to 80 nucleotides in length, that serves as the
physical link between the mRNA and the amino
acid sequence of proteins.
● Cloverleaf secondary structure
●
Transcription is the first step in the expression of tRNA composed of
genetic information starting from the base ● 5-terminal phosphate group
sequence of double-stranded DNA molecules to ● Amino acid acceptor arm at the 3’
form single-stranded molecule of RNA ● Site for amino acid attachment
● DNA molecule is considered the template strand ● D arm composed of stem and loop with
and through which RNA is synthesized in the 5-3 dihydrouracil
direction using RNA polymerase ● D arm serve as recognition site for aminoacyl-
● However, RNA polymerase moves in 3-5 direction tRNA synthetase that activate the amino acid
through DNA template therefore, RNA product
will be antiparallel and complementary to the
templateRNA types
7
 ● TΨ C arm composed of stem and loop where Ψ is
pseudouridine a modified uridine

Anticodon loop
● Composed of stem and loop
● Recognize mRNA codon and binds to it
● Anticodon complementary and antiparallel to
codon in mRNA

Variable arm
● Located between anticodon loop and T Ψ C loop
● Helps stability of tRNA
tRNA function
● During translation, the codons for each amino acid Protein Synthesis
in the is transcribed from DNA to mRNA. Overview
● tRNAs serve as adapter molecules that couple the • Protein synthesis occurs by peptide bond
codons in mRNA with the amino acids, they each formation between successive amino acids whose
specify, thus aligning them in the appropriate order is specified by a gene and thus by an mRNA.
sequence before peptide bond formation • Protein synthesis is carried out through 2 important
● In the cytoplasm, tRNA joins its cognate amino molecules ribosomes and tRNA
acid in a process called amino acid activation • Each end at tRNA contain a sequence of three
● Aminoacyl tRNA synthetase activate amino acids, nucleotides (Anticodon) that could bind to specific
then transfer the activated amino acid to the 3’ end mRNA codon
of RNA • During translation, the amino acids are attached to
● Next, the amino acid binds to tRNA with high the 3′ ends of their respective tRNAs.
energy bond that is sufficient enough to make a • The aminoacyl–tRNAs are situated in the P and A
peptide bond linking the amino acid into a protein. sites of the ribosome
● Each tRNA has an anticodon sequence that allows • Ribosome is the backbone where polypeptides are
it to pair with the codon for its cognate amino acid built
in the mRNA. Because base pairing is involved, • Each ribosome has two subunits, a large one (50S)
the orientation of this interaction will be and a small one (30S)
complementary and antiparallel. • The ribosome has three active sites: The A site, the
● Note: Aminoacyl tRNA synthetases have self- P site, and the E site.
checking functions to prevent incorrectly paired 1. The A site (Acceptor site), binds to the aminoacyl
aminoacyl tRNAs from forming. tRNA
2. The P site is where the peptidyl tRNA is formed in
the ribosome.
3. The E site function as threshold which holds
empty tRNA as it exits
Protein Synthesis
• Occur in three steps initiation, elongation and
termination
• GTP is required as a source of energy
• Special protein factors are required for initiation
(IF), elongation (EF), and termination (release
factors)

8
Initiation
• The small ribosomal subunit binds to the mRNA
• The charged initiator tRNA becomes bound to the
AUG start codon on the message through base

Cell Cycle
• Overview

pairing with its anticodon

• The large subunit binds to the small subunit,
forming the completed initiation complex
Elongation
• Occurred through three steps cycle, each cycle
consumes 4 energy bounds
• The mRNA is read one codon at a time, and the
amino acid matching each codon is added to a C
growing protein chain.
• During elongation, the ribosome moves in the 5′ to Overview:
3′ direction along the mRNA, synthesizing the Role of cell division:
protein from amino to carboxyl terminus • Reproduction
• Growth and development
1. A charged tRNA binds in the A site. The particular • Renewal and repair
aminoacyl–tRNA is determined by the mRNA
codon aligned with the A site. Cell Cycle phases:
2. Peptidyl transferase catalyzes peptide bond • The M phase (mitosis) is the time in which the cell
formation, transfers growing polypeptide to amino divides to form two daughter cells
acid in A site (The bond linking the growing
• Mitosis consists of 5 phases:
peptide to the tRNA in the P site is broken
1. Prophase
3. The ribosome moves exactly three nucleotides 2. Prometaphase
(one codon) towards 3’ end of mRNA. This moves
3. Metaphase
the growing peptidyl–tRNA into the P site and
4. Anaphase
aligns the next codon to be translated with the
5. Telophase
empty A site.
• Cytokinesis: Division of the cytoplasm
• Interphase is the term used to describe the time
between two cell divisions or mitoses
• During Interphase, gene expression take place
Interphase is divided into
G1 phase (gap 1)
• Period of cellular growth preceding DNA
synthesis.
• Cell is metabolically active
S phase (DNA synthesis)
• period of time during which DNA replication
occurs
G2 phase (gap 2)
Termination • Continuation of cell growth after DNA synthesis
• The stage in which the release factors recognize but preceding mitosis
stop codon (UAG, UAA, or UGA) that eventually G0
stop translation • Exit from cell cycle – Non dividing cell such as
• Completed polypeptide is released from its tRNA muscle and nerve cells, are said to be in a special
moving out of the ribosome state called G0
Factors that control the cell cycle

9
 • Control of the cell cycle is done by checkpoints Cell Types
between the various phases
• Checkpoints ensure that cells will not enter the Definition Examples
Permanent Cannot reproduce Neurons, skeletal and
next phase of the cycle until the molecular events themselves after birth cardiac muscle, RBCs.
in the previous cell cycle phase are concluded. (Remain in G0)
Stable Don´t replicate normal but Hepatocytes, lymphocytes,
maintain the capacity of PCT, periosteal cells.
Cyclin dependent kinases: proliferation
• They are also involved in regulating transcription, Labile Continuous proliferation
Bone marrow, gut
mRNA processing, and the differentiation of nerve through life (Never go to G0)
epithelium, skin, hair
Affected by chemotherapy
follicles,
cells germ cells.
• Constitutive and inactive
Cyclin-CDK complexes: Cell organelles
• Activates other proteins in the presence of cyclins Endoplasmic reticulum
such as Maturation promoting factor (MPF) • Endoplasmic reticulum composed of:
• When the cyclins and CDKs that are expressed in a • Rough ER (RER) is involved in some protein
specific phase are bonded and activated, they production, protein folding, quality control and
phosphorylate the specific serine and threonine despatch.
residues of a target protein. • It is called ‘rough’ because it is studded with
ribosomes
Cyclins • Smooth E R (SER) is associated with the
• Control the progression of cells through the cell production and metabolism of fats and steroid
cycle by activating cyclin-dependent kinase (CDK) hormones. It is ‘smooth’ because it is not studded
enzymes with ribosomes and is associated with smooth
• There are two main groups of cyclins: slippery fats.
• G1/s cyclins • Smooth ER also plays a large part in detoxifying a
• G2/M cyclins number of organic chemicals converting them to
safer water-soluble products
Tumor Suppressors Peroxisome
• Tumor suppressor genes encode proteins that Peroxisome Function:
regulate and suppress cell proliferation by • Known as microbody
inhibiting progression of the cell through the cell • Involved in catabolism of, branched fatty acids,
cycle. methanol and aminoacids
• DNA repair may not occur properly when certain • Beta oxidation of very long chain fatty acids
tumor suppressor genes have been inactivated • Reduction of reactive oxygen species (H2O2)
through mutation or deletion • Production of Plasmalogens (for brain and lung
• The p53 gene encodes a protein that prevents a cell development)
with damaged DNA from entering the S phase. • Synthesis of cholesterol, bile acids
• p21 represents a major target of P53 activity and
thus is associated with linking DNA damage to Diseases associated with Peroxisome dysfunction
cell cycle arrest Zellweger Syndrome
• Inactivation or deletion associated with Li • Autosomal recessive disorder
Fraumeni syndrome and many solid tumors. • Occur due to genetic mutation in any gene
• The retinoblastoma protein (RB): prevent involved in peroxisomes biogenesis such as PEX1,
excessive cell growth by inhibiting cell cycle PEX2
progression until a cell is ready to divide. • Characterized by:
• When the cell is ready to divide, Rb is
phosphorylated to pRb inactivating the protein 1. Accumulation of very long chain fatty acid and
which allows cell cycle progression branched fatty acids
• Growth factors (eg, insulin, PDGF, EPO, EGF) 2. Impaired neuronal migration and brain
bind tyrosine kinase receptors to transition the cell development
from G1 to S phase 3. Deficiency in myelin production
(Hypomyelination)
4. Deficiency in Plasmalogens (important for brain
and lung function)

10
Clinical presentations: • Mannose-6-phosphate (M6P) is a key targeting
• Hepatomegaly signal for acid hydrolase precursor proteins that
• Vision problems are destined for transport to lysosomes.
• Abnormal muscle tone • The M6P-tagged lysosomal enzymes are shipped
• Decrease brain development to the late endosomes via vesicular transport
• Infants usually die within their first year. • Endosomes provide an environment for material to
Refsum disease be sorted before it reaches the degradative
• Autosomal recessive disorders due to lysosome
accumulation of phytanic acid in cells and tissue • Molecules are also transported to endosomes from
due to impaired alpha-oxidation of branched fatty the trans- Golgi network and either continue to
acid lysosomes or recycle back to the Golgi
Characterized by: • Lysosomes: Organelles whose major function is to
• Cataracts digest materials that the cell has ingested by
• Shortening of 4th toe endocytosis.
• Ataxia • Lysosomes contain multiple enzymes that,
• Epiphyseal dysplasia. collectively, digest carbohydrates (glycosylases),
• Scaly skin lipids (lipases), and proteins (proteases).
• Treatment: Diet, Plasmapheresis. Signal recognition particles (SRP)
Adrenoleukodystrophy • Abundant, cytosolic ribonucleoprotein that traffics
• X-linked recessive disorder of β-oxidation results proteins from the ribosome to the endoplasmic
in results in the accumulation of very long chain reticulum
fatty acid in adrenal gland • Disfunction associated with SRP leads to
• Lead to destruction of myelin sheath of the nerves accumulation of proteins in the cytosol
resulting in seizures and hyperactivity
Signs and symptoms: Vesicular trafficking proteins
Adrenomyeloneuropathy (AMN) phenotype symptoms: COPI:
• Walking and balance problems • Specific coat protein complex that initiates the
budding process on the cis-Golgi membrane.
• Pain, numbness, or tingling in the legs
• Function as coating vesicles transporting proteins
• Urinary problems or incontinence and bowel
urgency or incontinence from the cis end of the Golgi complex back to the
rough endoplasmic reticulum (ER), where they
• Sexual dysfunction, or the inability to obtain or
were originally synthesized.
maintain an erection.
Proteasome • This type of transport is termed as retrograde
transport
• Protein complexes which degrade or damaged
COPII:
proteins by proteolysis (ubiquitin-proteasome
• Transport proteins from Endoplasmic reticulum to
system UPS)
the Golgi-complex
• Deregulation of the UPS has been implicated in
the pathogenesis of many neurodegenerative • This type of transport is termed as anterograde
transport
disorders like Alzheimer's disease, Parkinson's
diseases, Huntington disease, Prion-like lethal
disorders, in the pathogenesis of several genetic
diseases including cystic fibrosis, Angelman's
syndrome and Liddle syndrome and in many
cancers.

Cell trafficking
Cell trafficking components:
• The Golgi apparatus is involved in the sorting
and trafficking of proteins produced within a cell.
• Proteins translated within the rough endoplasmic
reticulum are transferred to the Golgi. From there Clathrin
they are modified and packaged into vesicles for • key molecules in the process of clathrin-mediated
distribution. endocytosis, which is used for the specific uptake

11
 of large extracellular molecules such as proteins, Microtubules
membrane-localized receptors, and ion channels. • Function: Involved in movement and cell division
• Examples: Cilia, flagella, mitotic spindle, axonal
I –cell disease: trafficking and centrioles
• When cargo arrive in the Golgi apparatus, specific
mannose residues located in their N-linked Intermediate filaments
oligosaccharide chains are phosphorylated by N- • Elements that connect cells and tissue together
acetylglucosamine- 1 phosphotransferase, forming • Examples: Vimentin, desmin, cytokeratin, lamins,
a critical mannose-6-phosphate in the glial fibrillary acidic protein (GFAP),
oligosaccharide chain neurofilaments.
• Genetic defects affecting this phosphorylation
produce I-cell disease in which lysosomal enzymes
are released into the extracellular space, and
inclusion bodies accumulate in the cell,
compromising its function.

Clinical Presentations:
• Coarse facial features, gingival hyperplasia,
macroglossia Cilia
• Craniofacial abnormalities, joint immobility, • Cilia contain 9 peripheral pairs of microtubules
clubfoot, claw-hand, scoliosis and 2 central microtubules.
• Psychomotor retardation, growth retardation • Composed of Basal body, intermediate junction,
• Cardiorespiratory failure, death in first decade Microvillus and Occluding junction
• Bone fracture and deformities • Basal body (base of cilium below cell membrane)
• Mitral valve defect consists of 9 microtubule triplets B with no central
• Secretion of active lysosomal enzymes into blood microtubules.
and extracellular fluid • The microtubules convey motility to cilia through
the ATPase dynein
Cilia Structure • They also form the core of the flagella, the motile
Cytoskeleton tail of sperm cells

Diseases associated with Cilia dysfunction

Kartagener syndrome
• Due to an absence of dynein that is required for
flagellar motility
• Characterized by:
• Immotile spermatozoa that lead to male infertility
• Cytoskeleton is a cellular structure that helps cells • Dysfunction fallopian tube cilia which increase
maintain their shape and internal organization ectopic pregnancy
• It also provides mechanical support that enables • Chronic respiratory chronic respiratory infections
cells to carry out essential functions like cell- because of similar defects in cilia of respiratory
division, anchorage and movement. epithelium
• Cytoskeleton composed of: • Conductive hearing loss and situs inversus
1. Microfilaments
2. Intermediate filaments
3. Microtubules

Microfilaments
• Function: Reinforcing cytoskeletal elements,
muscle contraction and cytokinesis
• Examples: Fibers of actin subunits, Microvilli

12
Microtubules
• Composed of helical array of polymerized
heterodimers of α- and β-tubulin
• Microtubules form the mitotic spindle during
mitosis and meiosis.
• Provide intracellular transport of vesicles and
molecules specially through the axons
• Transport requires specific ATPase motor
molecules
• Dynein drives retrograde transport and kinesin
drives anterograde transport
• Microtubules are found in true cilia and flagella,
and utilize dynein to convey motility to these
structures
• Drugs that acts on microtubules:

1. Mebendazole (anthelminthic)
2. Griseofulvin (antifungal)
3. Colchicine (antigout)
4. Vincristine/Vinblastine (anticancer)
5. Paclitaxel (anticancer) • Because the hydroxylase enzymes that perform
these reactions require vitamin C as a cofactor, a
Collagen and Elastin synthesis and structure long-term deficiency in this vitamin results in
Overview impaired collagen synthesis and scurvy
• Collagen is the most abundant protein in the
human body, found in the bones, muscles, skin, C-Glycosylation
and tendons. • Selected hydroxylysines are glycosylated.
• Collagen forms a scaffold to provide strength and • Three pro-α chains assemble to form a triple
structure. helical structure (procollagen) via hydrogen and
• Collagen is an example of a protein that undergoes disulfide bond
several important co- and posttranslational • At this point, procollagen can now be transferred
modifications to the Golgi.
• Composed of a repeating tripeptide Gly-X-Y-Gly- • Modification of oligosaccharide continues in the
X-Yetc. Golgi.
• X and Y are proline and lysine D-Exocytosis
• Procollagen is secreted from the cell.
Collagen Synthesis
• Hydroxyproline is an amino acid unique to E-proteolytic processing
collagen. • The propeptides are cleaved from the ends of
• The hydroxyproline is produced by hydroxylation procollagen by proteases to form collagen
of prolyl residues at the Y positions in procollagen molecules (also called tropocollagen).
chains as they pass through the RER.
A-Synthesis Cross-Linking
• Preprocollagen-α chains containing a hydrophobic • Collagen molecules assemble into fibrils. Cross-
signal sequence are synthesized by ribosomes linking involves lysyl oxidase, an enzyme that
attached to the RER. requires O2 and copper.
B-Hydroxylation • Fibrils aggregate and cross-link to form collagen
• Selected prolines and lysines are hydroxylated by fibers.
prolyl and lysyl hydroxylases.
Disorders of collagen biosynthesis
Ehlers-Danlos (ED) Syndromes
• Autosomal dominant or recessive disease caused
by mutations in the gene for type-3 procollagen
• Example of Locus heterogeneity

13
 • Represent a collection of defects in the normal
synthesis and processing of collagen
Clinical presentations
• Hyperextensible, fragile skin
• Hypermobile joints
• Dislocations
• Varicose veins
• Ecchymoses,
• Berry and aortic aneurysms
• Classical type associated with joint instability
(Mutation in type V collagen) Such as COL5A1,
COL5A2
• Vascular type III associated with arterial,
intestinal, or uterine rupture; and easy bruising

Menkes disease
• Menkes disease Deficient cross-linking secondary
to functional copper deficiency
• Impaired Menkes protein (ATP7A)
Clinical presentations
• Depigmented hair (Brittle and kinky hair)
• Growth retardation
• Osteoporosis
• Anemia
• Arterial tortuosity
Osteogenesis imperfecta
• Mutations in genes encoding type 1 collagen affect Scurvy
the coding of one of the two genes (COL1A1 and • Scurvy is caused by a prolonged dietary deficiency
COL1A2), accounting for approximately 80% of vitamin C
cases. • Risk factors for vitamin C deficiency:
• The mutations result in the production of a mixture A. Babies who are fed only cow's milk or plant-based
of normal and mutant collagen chains. beverages during the first year of life
• Substitution of a larger amino acid (eg, cysteine or B. Alcoholic individuals
alanine) for glycine results in abnormal helix C. Elderly individuals who eat a tea-and-toast diet
formation D. Economically disadvantaged persons, who tend to
• Arise from autosomal dominant mutations not purchase foods high in vitamin C (eg, green
Clinical presentations vegetables, citrus fruits)
• Blue sclerae due to the translucent connective E. Cigarette smokers
tissue over choroidal veins F. Pregnant and lactating women and those with
• Triangular facies thyrotoxicosis: These individuals require an
• Macrocephaly increased intake of vitamin C because of increased
utilization
• Hearing loss (abnormal ossicles)
• Defective dentition (due to lack of dentin) G. People with anorexia nervosa or anorexia from
other diseases such as AIDS or cancer
• Barrel chest
H. People with type 1 diabetes have increased vitamin
• Scoliosis
C requirements, as do those on hemodialysis and
• Limb deformities peritoneal dialysis
• Fractures Elastin Synthesis
• Joint laxity • Elastin is the main protein of elastic fibers and
• Growth retardation confers the property of elastic recoil to the tissues
such as arteries, lung, elastic cartilage
• The major protein component of the blood vessels
is elastin. Therefore, the loss of elastin may cause

14
 atherosclerosis. The loss of elastin in lungs causes `
emphysema.
• Elastin is mainly produced in the fetus. It is no
longer produced after puberty.
• Elastin is an insoluble protein polymer
• Synthesized from a precursor, tropoelastin
• Rich in non-hydroxylated proline, glycine, and
lysine residues
• α1-antitrypsin plays an important role in elastin
degradation
• It inhibits the activity of trypsin synthesized by the
pancreas
• Inhibit neutrophil elastase
• Elastase is a powerful protease that is released into
the extracellular space by neutrophils

Collagen- Osteogenesis imperfecta & Ehler-Danlos

Syndrome
Types of Collagen

Type Example Function

Type I Most common-bone, skin, tendon, Provide tensile strength
dentin, fascia, cornea, late wound to connective tissue
repair
Type II Cartilage (including hyaline), Provide tensile strength
vitreous body, Nucleus pulposus to connective tissue
Type III Reticulin, Skin, blood vessels, Provide structural
Marfan disorders uterus, fetal networks of spleen,
• Spectrum of disorders caused by a heritable tissue, granulation tissue. (early
wound healing)
Liver, Lymph nodes,
smooth muscle and
genetic defect of connective tissue Associated with Ehlers-Danlos adipose tissue
• The defect itself has been isolated to Syndrome
Type IV Basement membrane, basal lamina, Associated with Alport
the FBN1 gene on chromosome 15, which codes lens syndrome and
for the connective tissue protein fibrillin. Hearing loss, vision loss, renal Goodpasture syndrome
• Abnormalities in this protein cause a myriad of disease
distinct clinical problems, of which the
musculoskeletal, cardiac, and ocular system
problems predominate • Goodpasture syndrome (GPS), also known as anti-
Clinical presentations glomerular basement membrane disease, is a rare
autoimmune disease in which antibodies attack the
• Craniofacial characteristics
basement membrane in lungs and kidneys, leading
• Thumb and wrist signs
to bleeding from the lungs and kidney failure.
• Pectus carinatum
• Alport syndrome is a genetic condition
• Severe hindfoot valgus characterized by kidney disease, hearing loss, and
• Subluxation of lenses, typically upward and eye abnormalities.
temporally • Characterized by progressive loss of kidney
• Hypermobile joints; long, tapering fingers and toes function. Almost all affected individuals have
(arachnodactyly) blood in their urine (hematuria), which indicates
• Cystic medial necrosis of aorta abnormal functioning of the kidneys.

15
Ehlers-Danlos (ED) Syndromes • Inhibit neutrophil elastase
• Autosomal dominant or recessive disease caused • Elastase is a powerful protease that is released
by mutations in the gene for type-3 procollagen into the extracellular space by neutrophils
• Example of Locus heterogeneity
• Represent a collection of defects in the normal Polymerase chain reaction (PCR)
synthesis and processing of collagen Principle:
Clinical presentations
• Hyperextensible, fragile skin
• Hypermobile joints
• Dislocations
• Varicose veins
• Ecchymoses,
• Berry and aortic aneurysms
• Classical type associated with joint instability • A common laboratory technique used to make
(Mutation in type V collagen) Such as COL5A1, many copies (millions or billions!) within a few
COL5A2 hours of a selected region of a chromosome
• Vascular type III associated with arterial, • The main goal of PCR is to make enough DNA
intestinal, or uterine rupture; and easy bruising that can be used for many application
Osteogenesis imperfecta • only a small amount of DNA is available e.g. drop
• Mutations in genes encoding type 1 collagen affect of blood, Semen strains, Single hair, vaginal swabs
the coding of one of the two genes (COL1A1 and etc.
COL1A2), accounting for approximately 80% • The region of a chromosome to be amplified by a
cases. PCR is referred to as the target sequence and may
• The mutations result in the production of a mixture be an area containing a suspected mutation, a short
of normal and mutant collagen chains. tandem repeat (STR, or microsatellite sequence),
• Substitution of a larger amino acid (eg, cysteine or or really any area of interest.
alanine) for glycine results in abnormal helix • This technique involves repeating different heating
formation and cooling cycles over and over again, as many as
• Arise from autosomal dominant mutations 35 or more times.
• Each complete cycle doubles the amount of DNA
Clinical presentations present, so in just 20 cycles there are over one
• Blue sclerae due to the translucent connective million (220) copies of that specific segment of
tissue over choroidal veins DNA.
• Triangular facies
• Macrocephaly PCR components:
• Hearing loss (abnormal ossicles)
• Defective dentition (due to lack of dentin)
• Barrel chest
• Scoliosis
• Limb deformities
• Fractures
• Joint laxity
• Growth retardation
• For PCR there are five chemical components
• Elastin is mainly produced in the fetus. It is no needed, including:
longer produced after puberty. • DNA template: Contain the fragments needed to
• Elastin is an insoluble protein polymer be amplified
• Synthesized from a precursor, tropoelastin • MgCl2: Essential cofactor for Taq DNA
• Rich in non-hydroxylated proline, glycine, and polymerase
lysine residues • Taq DNA polymerase: Enzyme that helps catalyze
• α1-antitrypsin plays an important role in elastin the polymerization of the deoxynucleotides into a
degradation DNA strand
• It inhibits the activity of trypsin synthesized by the • Primers: A primer is a strand of nucleic acid that
pancreas serves as a starting point for DNA replication. Two

16
 primers are needed to amplify the target DNA Elongation
fragment • Elongation Taq polymerase binds to the template
• DNTPs Nucleotides: the building blocks from DNA and starts adding nucleotides that are
which the DNA polymerase synthesizes a new complementary to the first strand.
DNA strand • This happens at 72°C as it is the optimum
• Reaction buffer: providing a suitable chemical temperature for Taq Polymerase.
environment for optimum activity and stability of
the DNA polymerase PCR applications:
The reaction is commonly carried out in a volume of • Comparing DNA samples in forensic cases
10–200 μL in small reaction tubes (0.2–0.5 mL • Paternity testing
volumes) in a thermal cycler. • Direct mutation testing
Detailed steps of PCR • Diagnosing bacterial and viral infections
1. Add the sample containing DNA to be amplified. • HIV testing in situations where antibody tests are
2. Add excess amounts of primers complementary to uninformative (importantly, infants whose mothers
both 3′ flanks of the target sequence. This selects are HIV positive)
the region to be amplified. Crisper Cas9
3. Add a heat-stable DNA polymerase (Taq DNA Principle:
polymerase) and deoxyribonucleotides (dNTPs) • Genome editing is a group of technologies that
for DNA synthesis. give scientists the ability to change an organism's
4. Heat the sample to melt the DNA (convert dsDNA DNA.
to ssDNA).
• Different genome editing techniques include:
5. Cool the sample to re-anneal the DNA. Because
• ZFNs (Zinc Finger Nucleases)
the ratio of primers to complementary strands is
extremely high, primers bind at the 3′ flanking • TALENs (Transcription Activator Like Effector
Nucleases)
regions
6. Heat the sample to increase the activity of the Taq • CRISPR
DNA polymerase. • Crisper Cas9 Is an RNA- guided DNA
7. Primer elongation occurs, and new complementary endonuclease enzyme associated with the
strands are synthesized CRISPR.
• It catalyzes site-specific cleavage of double
stranded DNA.
• CRISPR are sections of genetic code containing
short repetitions of base sequences followed by
spacer DNA segments.
• It was identified in a prokaryotic defense system.
• It is associated with the CRISPR adaptive
immunity system in Streptococcus pyogenes,
among other bacteria.
• Considered as a tool for genome engineering. By
replacing the endogenous RNA with the sequence
Major PCR steps of a target gene the endonuclease component (Cas)
Initiation can be induced to cleave almost any DNA
• In this step the samples are heated to 94-96 C with sequence.
the main purpose to activate taq DNA polymerase
Mechanism of CRISPR/Cas9-mediated gene disruption.
Denaturation
• DNA strands are separated by heating to 95°C.
• The Hydrogen bonds between the two strands
breaks down and the two strands separates.
Annealing
• The process of allowing two sequences of DNA to
form hydrogen bonds.
• The annealing of the target sequences and primers
is done by cooling the DNA to 55°C.
• Time taken to anneal is 45 seconds.

17
 1. A single guide RNA (sgRNA), consisting of a • This technique is based on the principle of
crRNA sequence that is specific to the DNA target, separation of DNA fragments by gel
and a tracrRNA sequence that interacts with the electrophoresis and identified by labelled probe
Cas9 protein hybridization.
2. Next, sgRNA will bind to a recombinant form of • Basically, the DNA fragments are separated on the
Cas9 protein that has DNA endonuclease activity. basis of size and charge during electrophoresis.
3. The resulting complex will cause target-specific Separated DNA fragments after transferring on
double-stranded DNA cleavage. nylon membrane, the desired DNA is detected
4. The cleavage site will be repaired by the using specific DNA probe that is complementary
nonhomologous end joining (NHEJ) DNA repair to the desired DNA.
pathway, an error-prone process that may result in • A hybridization probe is a short (100-500bp),
insertions/deletions (INDELs) that may disrupt single stranded DNA. The probes are labeled with
gene function. a marker so that they can be detected after
hybridization.

Applications of CRISPR/Cas9

Blotting procedures
Blotting:
• Blotting is a technique used to separate DNA,
Northern blot
RNA and proteins.
• Northern blotting is used to detect RNA.
• Blotting is generally done by letting a mixture of
• Cells can be broken open to release their RNA.
DNA, RNA or protein flow through a slab of gel.
• Northern blotting may reveal how a disease is
• This gel allows small molecules to move faster
working at the level of RNA production.
than bigger ones.
• Probe remains DNA
Southern blot: Western blot
• Western blotting is a common technique for
separating proteins by size using electrophoresis
• After separation, proteins are transferred to an
appropriate blotting matrix such as PVDF
membrane
• Western blotting uses specific antibodies to
identify proteins that have been separated based on
size
• Visualization is done using secondary antibodies
and detection reagents.
• Western blot is a confirmatory test in a presumed
HIV infection

•
Southern blotting is a hybridization technique for
identification of particular size of DNA from the
mixture of other similar molecules.
Western blot procedure
18
 • Up to
thousands of particles per second can be analyzed
as they pass through the liquid stream.

Composition of Flow Cytometry:

• Flow cell
• Measuring system
• Detector
• Amplification system
• Computer for analysis of the signals

Southwestern blot
• Used to investigate DNA-Protein interaction
• Used for proteins that regulate transcription
• It provides information regarding the molecular Basic
weight of unknown protein factor. principle of flow cytometry
• This method combines the features of Southern • When a cell suspension is run through the
and Western blotting techniques, Separation of cytometer
proteins is done first by electrophoresis, followed • Light scattered from the cells or particles is
by transferring the proteins to a membrane detected as they go through the laser beam.
support, the membrane-bound proteins are • A detector in front of the light beam measures
renatured and incubated with a (32)P-labeled forward scatter (FS) and several detectors to the
double-stranded oligonucleotide probe of specific side measure side scatter (SS).
DNA sequence • Fluorescence detectors measure the fluorescence
emitted from positively stained cells or particles.
Flow Cytometry
Overview Different types of light used in a flow cytometry
• Flow cytometry measures various properties of experiment.
single particles flowing in a single file in a stream
of fluid Forward scattered light Side scattered light
• Light scattering at different angles can distinguish
differences in size and internal complexity, • Detected by a • Detected by a
whereas light emitted from fluorescently labeled sensor in the light sensor that is
antibodies can identify a wide array of cell surface path orthogonal to the
and cytoplasmic antigens original light
• Used to detect the path.
size of the object in • used to make a
the light path. determination

19
 • Larger objects will regarding
produce more the granularity
forward scattered and
light than smaller complexity of the
objects, and larger cell in the light
cells will have a path.
stronger forward • Highly granular
scatter signal cells with a large
amount of
internal
complexity, like
neutrophils, will
produce more •
side-scattered DNA microarrays is known as DNA chips, gene
light, and a chips, DNA arrays, gene arrays and biochips
higher side-
scatter signal Principle (Indirect assessment of mRNAs)
than cells with a • mRNA carries the genetic information from the
low-granularity cell nucleus to the cytoplasm for protein synthesis.
and complexity. • These mRNAs synthesize the corresponding
protein by translation.
• So, indirectly by assessing the various mRNAs, we
Applications of flow cytometry can assess the genetic information or the gene
• Basic research: Cell counting and Cell sorting expression.
• Protein engineering: Identify cell surface protein • This helps in the understanding of various
variants processes behind every altered genetic expression.
• Medicine: used in transplantation, oncology, Thus, mRNA acts as a surrogate marker. Since
hematology and genetics mRNA is degraded easily, it is necessary to
• Marine biology convert it into a more stable cDNA form. Labeling
• Diagnosis of health disorders such as blood of cDNA is done by fluorochrome dyes Cy3
cancers (green) and Cy5 (red).
• Biomarker detection

Microarray (Microchips)
Outline:
• Overview
• Principle
• Component of DNA microarray
• Application of DNA microarray

Overview:
• DNA microarrays used to measure the expression
levels of large numbers of genes simultaneously or
to genotype multiple regions of a genome.
• Used to compare differences in gene expression
between two mRNA samples. For example, up or
down-regulation of certain genes could highlight
the implication of certain genes in diseases and
might help identify possible therapeutic targets • The principle of DNA microarrays lies on the
hybridization between the nucleotide.
• Using this technology, the presence of one
genomic or cDNA sequence in 1,00,000 or more
sequences can be screened in a single
hybridization.

20
 • The property of complementary nucleic acid • The enzyme-linked immunosorbent assay
sequences is to specifically pair with each other by (ELISA) is an immunological assay commonly
forming hydrogen bonds between complementary used for serological analysis
nucleotide base pairs. • Used to measure antibodies, antigens,
proteins and glycoproteins in biological samples.
1. First, mRNA is extracted from the ‘normal’ • Efficient technique allows measuring several
sample, and a fluorescent labeled cDNA samples at once using 96 well plate
probe is produced, representing all of the Principle
genes expressed in the reference sample.
2. A second cDNA probe is generated using a
different-colored fluorescent label and mRNA
extracted from the ‘affected’ cells (tumor cells
or cells exposed to drugs).
3. The two fluorescent probe samples are mixed
and applied to a single microarray chip, where
they react with the arrayed cDNA molecules.
4. Each well of the microarray is scanned for the
fluorescence intensity of each probe, the
intensity of which is proportional to the
expression level of that gene in the sample.
5. The ratio of the two fluorescent intensities • ELISA relies on antigen-antibody interaction,
provides a highly accurate and quantitative where an antigen must be immobilized on a solid
measurement of the relative gene expression surface and then complexes with an antibody that
level in the two cell samples. is linked to an enzyme
• Detection is observed through evaluation of
Components of DNA microarray conjugated enzyme activity upon substrate
• DNA Chip addition
• Target Sample (Fluorescently labelled) • One of the key aspects of ELISA technique is the
specificity of antigen-antibody interaction
• Enzymes
• Each ELISA measures a specific antigen, and kits
for a variety of antigens are widely available.

Applications of ELISA
• Diagnosis of HIV infection
• Pregnancy tests
• Serum antibody concentration
• Detection of potential food allergens
Cystic fibrosis

Overview:
• Cystic fibrosis (CF) is the most common lethal
genetic disorder in Caucasians.
• Fluorescent dyes • Autosomal recessive disorder
• Probes • Cystic fibrosis transmembrane conductance
• Scanner regulator (CFTR) is highly expressed in
epithelial cells of airways, GIT (pancreas) and
Applications of DNA microarray sweat glands
• Gene expression analysis • CFTR regulate epithelial chloride channel, sodium,
• Diagnosis of certain diseases potassium and bicarbonate ions
• Drug discovery
Detection of IDs of organisms in food and mycoplasma in Pathophysiology
cell culture • Cystic fibrosis occurs due to a mutation in CFTR
gene which is located on chromosome 7 and most
ELISA commonly has been damaged by a deletion of the
Overview amino acid phenylalanine at position 508 (ΔF508).

21
 • Normal CFTR increases the reabsorption of • Chest Wheezing
chloride ion and enhance the reabsorption of • Chronic cough
sodium ions • Hemoptysis,
• The alteration in chloride transport is associated • Digital clubbing
with production of abnormally thick secretions in • Pansinusitis and nasal polyps
glandular tissues (hypertonic salty sweat) • Reticulonodular pattern on CXR
• In Lung, GIT and Pancreas: Mutated CFTR • Opacification of sinuses
decreases the secretion of Chloride ion and
augments the reabsorption of Sodium ion (with Bronchiectasis: is an abnormal permanent airway
passive Water reabsorption) that lead to hyper dilatation due to chronic necrotizing inflammation.
concentrated “dehydrated” viscid secretions Clinical findings include cough, fever, malodorous
• In cystic fibrosis the apical Cl channels do not purulent sputum, and dyspnea.
open.
• Failure of water transport results in thickening of • In the GIT, thick secretions may cause:
the mucous layer covering the epithelia • intestinal obstruction (meconium ileus) (10-15% of
• The lung bronchioles and pancreatic ducts are newborns with CF)
primarily affected, often resulting in progressive • Meconium peritonitis
destruction of these organs • Rectal prolapse
• Cystic fibrosis entails 2 mutations: • In the pancreas, CF may cause
• G551D mutation (4-5 %), in which the amino • Plugging of pancreatic ducts resulting in atrophy
acid glycine (G) in position 551 is replaced and fibrosis
with aspartic acid (D). • Pancreatic insufficiency leading to fat
• G551D is characterized by a dysfunctional CFTR malabsorption
protein on the cell surface. • Malodorous steatorrhea (frequent, bulky, greasy,
• In the case of G551D, the protein is trafficked to large, foul-smelling stools)
the correct area, the epithelial cell surface, but • Deficiency of fat-soluble vitamins (A, D, E and K)
once there the protein cannot transport chloride
• In the liver, plugging of the biliary canaliculi may
through the channel.
result in biliary cirrhosis, portal hypertension
• F508del mutation, the most common CF mutation,
• In the male reproductive system,
is primarily considered to be a processing
• CF may be associated with absence or obstruction
mutation.
of the vas deferens and epididymis, which often
• The F508del mutation removes a single amino acid
leads to male infertility
from the CFTR protein.
• CF is also associated with secondary amenorrhea,
dry skin, salty taste to skin and failure to thrive
• The 3 most common pulmonary infections are S.
Aureus (infancy), H. influenzae, and P. aeruginosa
(adolescence)

Diagnosis
• Sweet chloride test (elevated NaCl)
• Due to improved therapies, some patients live into
their forties, but with this increase in longevity
there has been an increase in liver disease.
• Prenatal diagnosis:
1. fetus with hyperechogenic fetal bowel
2. Increase immunoreactivity trypsinogen
• Radiography: chest x-ray reveals bronchiectasis
and pulmonary arterial enlargement
Clinical Presentations:
• Signs and symptoms entail several organs include
Treatment:
• In the lungs, CF may cause:
• Ivacaftor is a "potentiator" of CFTR, meaning it
• Recurrent pulmonary infections increases the probability that the defective channel
• chronic bronchitis will be open and allow chloride ions pass through
• Bronchiectasis the channel pore (less thick mucus)

22
 • Chest physiotherapy
• Hypertonic saline to enhance mucus clearance
• Bronchodilators: albuterol, aerosolized dornase
alfa (DNase)
• Azithromycin
• Ibuprofen
• N-acetyl cysteine
• Pancreatic enzymes
• High protein diet
• Combination therapy is recommended in case of
patients with Phe508 deletion (lumacaftor+
ivacaftor)
• N.B Cystic fibrosis (heterozygote resistance to
typhoid fever)
Modes of inheritance
Mitochondrial Inheritance: • Because
affected individuals must receive a disease-causing
gene from an affected parent, the disease is
typically observed in multiple generations of a
pedigree
• The recurrence risk is thus 50%, and half the
children, on average, will be affected with the
disease.
• If both parents are heterozygous, the recurrence
risk is 75%.

Autosomal dominant disorder:

• Familial hypercholesterolemia (LDL receptor
deficiency)
• Huntington disease
• Neurofibromatosis type 1
• • Marfan syndrome
Mitochondrial DNA is inherited exclusively • Acute intermittent porphyria
through females.
• Diseases are transmitted only from affected Autosomal Recessive Inheritance
females to their offspring
• Both males and females are affected.
• All offspring of an affected female are affected.
• None of the offspring of an affected male is
affected.

Clinical presentations
• Leber hereditary optic neuropathy
• MELAS: mitochondrial encephalomyopathy
• Lactic acidosis
• Stroke-like episodes
• Myoclonic epilepsy with ragged red muscle fibers
• Occur only when
Autosomal Dominant Inheritance two copies of the mutated gene are inherited.
• Due to a defect in a single copy of autosomal gene • If one gene is defective whereas the other inherited
• Because these genes are located on autosomal gene is normal, the individual is simply a carrier of
gene, both males and females are affected the gene, and does not suffer from the disease.
• Autosomal recessive diseases are typically seen in
only one generation of a pedigree

23
 • Males and females are affected in roughly equal • Common to occur in fragile X syndrome and
frequencies. Alport syndrome
• With Heterozygous parents, 25 % of children will
be affected (homozygous), 50% will be carrier and
25% will be neither affected nor carrier

Autosomal Recessive disorders

• Sickle cell anemia
• Cystic fibrosis
• Phenylketonuria (PKU)
• Tay-Sachs disease (hexosaminidase A deficiency)
X linked dominant
• Due to mutations in genes located on the X
chromosome
• An X-linked dominant disorder arises when a
single copy of the gene leads to expression of the
abnormal protein. X-linked recessive
• Most common in females • Due to a single copy of defective gene on the X-
• A characteristic of X-linked disorders is that an chromosome
affected father does not pass on the defect to sons, • They are more common in males
since sons inherit X-chromosome from their • An affected female will always pass on the
mothers. condition to her sons.
• Mothers transmit to 50% of daughters and sons • Skipped generations are commonly seen because
an affected male can transmit the disease-causing
X linked dominant disorders mutation to a heterozygous daughter, who is
• Coffin Lowry syndrome unaffected but who can transmit the disease-
• X-linked hypophosphatemia (familial vitamin d- causing allele to her sons.
resistant rickets)
• Rett syndrome
• Giuffrè-Tsukahara syndrome
• Danon disease (glycogen storage disease type IIb)

Hypophosphatemic rickets

X-linked recessive disorders

• Duchenne muscular dystrophy
• Glucose-6-phosphate dehydrogenase deficiency
• Hemophilia A and B
• Red-green color blindness
• Menke’s disease
• Defective intestinal absorption of calcium
• Ornithine transcarbamoylase (OTC) deficiency
resulting in decreased proximal renal tubular
• SCID (IL-receptor γ-chain deficiency)
resorption of phosphate, resulting in renal
X inactivation
phosphate wasting and hypophosphatemia
• Occurs in the blastocyst during the development of
• Characterized by rickets or Osteomalacia
female embryos when an X chromosome is
unresponsive to vitamin D
inactivated, its DNA is not transcribed into
mRNA, and the chromosome is visualized under

24
 the microscope as a highly condensed Barr body in chromosome contains an imprinted region or a
the nuclei of interphase cells mutation
• X inactivation characterized by: • Prader-Willi syndrome caused by maternal
1. Random, fixed, permanent and incomplete uniparental disomy of chromosome 15
• Examples: Turner syndrome • Angelman syndromes caused by paternal
uniparental disomy of chromosome 15.
Conclusion
Prader-Willi Syndrome
• Caused by loss from the paternal chromosome of
an imprinted locus mapping to 15q11-13 that
includes the gene SNRPN.
• This gene, normally active from the paternal copy
of chromosome 15

Clinical presentations
• Affects males and females
• Neonatal hypotonia
• Poor feeding in neonatal period
• Behavior problems
• Moderate mental and developmental retardation
• Hypogonadism, underdeveloped genitalia
• Hyperphagia (overeating) and obesity by ages 2–4
years
Imprinting: • Small hands and feet
• Small number of genes are transcriptionally active • Deletion from paternal 15q
only when transmitted by one of the two sexes. • Very low recurrence risk
• The homologous locus in the other parent is
rendered transcriptionally inactive Angelman Syndrome
• In cases of imprinting, it is normal to have only the • Occur due to a deletion of 15q11-13 from the
maternal (for some loci) active, or only the maternal chromosome.
paternal • The locus imprinted in the maternal chromosome
(for other loci) active. includes a gene involved in the ubiquitin pathway
• On rare occasions, the transcriptionally active known as UBE3A, for which the maternal gene is
gene may be deleted from the chromosome, hence, normally expressed while the paternal gene is
the offspring won´t have any active gene at that silenced
locus
“The gene from one parent is Inactive due to Clinical presentations
imprinting, and the gene from the other parent • Affects males and females
deleted by a mutation” • Severe mental retardation
• Examples: Prader-Willi syndrome and Angelman • Seizures
syndromes • Ataxia
• Puppet-like posture of limbs
Uniparental disomy • Happy disposition
• Rare condition in which a person receives two • Deletion from maternal 15q
copies of a chromosome, or of part of a
chromosome, from one parent and no copy from
the other parent
• UPD can be the result of heterodisomy: in which
a pair of non-identical chromosomes are inherited
from one parent (due to meiosis I error) or
isodisomy, in which a single chromosome from
one parent is duplicated (due to meiosis II error).
• Most common UDP results in no phenotypical
abnormalities but it may cause problems if the

25
 Genetic terminology:
• p = frequency of allele 1 (conventionally the most
common, normal allele)
• q = frequency of allele 2 (conventionally a minor,
disease-producing allele)
• p2 = frequency of genotype 1-1 (conventionally
homozygous normal)
• 2pq = frequency of genotype 1-2 (conventionally
heterozygous)
• q2 = frequency of genotype 2-2 (conventionally
homozygous affected)
• The frequency of an X-linked recessive disease in
males = q and in females = q2

Linkage disequilibrium:
• linkage disequilibrium may exist between alleles at
different loci without any genetic linkage between
A. Loci normally imprinted on chromosome 15 them and independently of whether or not allele
B. Deletion causing Prader-Willi syndrome frequencies are in equilibrium
C. Deletion causing Angelman syndrome Genetic terms
Locus:
• Location of a gene on a chromosome
Hardy-Weinberg population genetics Allele:
Population genetics: • Different forms of a gene
• Study of distributions and changes of allele Homozygous
frequency and interaction of alleles in a population • If the individual has the same allele on both
• Hardy-Weinberg law explain that a population is homologs (homologous chromosomes) at that
undergoing NO evolutionary changes locus.
• Hardy-Weinberg law assumptions include: Heterozygous
• If the individual has different alleles on the two
1. No mutation occurring at the locus homologs (homologous chromosomes) at that
2. Natural selection is not occurring locus
3. Completely random mating Dominant
4. No net immigration • Requires only one copy of the mutation to produce
disease
• The results could be explained based on the theory Recessive
of probability if p and q are the frequencies of • Requires two copies of the mutation to produce
separate alleles, then disease

• The probability of receiving the Gene A from both

parents P x P= P2
• Also, the probability of receiving the gene a from Codominance:
both parents will be q X q= q2 • Pattern of gene expression in which the phenotype
• The probability of being heterozygous will be P q+ of a heterozygous individual is intermediate
p q= 2 p q between those of the parents (both alleles in a
heterozygous organism are expressed)
26
 • Examples: the DNA site leading to reduced levels
1. Blood groups A, B, AB of gene activation
2. α1-antitrypsin deficiency
3. HLA groups Mosaicism
Incomplete penetrance: • Mosaicism is defined as the presence of ≥2
• Some individuals will not express the trait even populations of cells within an individual
though they carry the allele • Causes of Mosaicism:
• % penetrance x probability of inheriting genotype 1. Chromosomal mutation during development
= risk of expressing phenotype. 2. X inactivation
• Examples: 3. Structural abnormalities of chromosome
• Familiar breast cancer due to mutation in BRCA1
Somatic Mosaicism Gonadal Mosaicism
gene
Loss of heterozygosity: • Mutation arises from • Mutation only in egg or
• loss of one normal copy of a gene or a group of mitotic errors after sperm cells
fertilization and
genes. In some cases, loss of heterozygosity can propagates through Examples:
contribute to the development of cancer. multiple tissues or • Osteogenesis imperfecta
• Indicate the absence of tumor suppression gene, Examples:
organs. • Ovarian dysgenesis
hence, the complementary allele must de deleted • Cancer
before cancer development (colorectal cancer and • Down syndrome
small-cell lung cancer) • Lines of Blaschko
Example:
• Retinoblastoma and two hit hypothesis ( that McCune-Albright Syndrome
most genes require two mutations to cause
• Disorder that affects the bones, skin, and several
a phenotypic change)
hormone-producing (endocrine) tissues due to
Pleiotropy: mutation in G- protein signaling gene (GNAS)
• Pleiotropy exists when a single disease-causing Clinical presentations:
mutation affects multiple organ systems
• polyostotic fibrous dysplasia (PFD)
• Examples:
• Café-au-lait skin pigmentation
1. Marfan syndrome (a mutation in the gene that
• Autonomous endocrine hyperfunction (eg,
encodes fibrillin, a key component of connective
gonadotropin-independent precocious puberty).
tissue)
Heteroplasmy
2. Untreated phenylketonuria (light skin, intellectual
disability, and musty body odor) • When a specific mutation occurs in some of the
Variable expression: mitochondria, this mutation can be unevenly
distributed
• Most genetic diseases vary in the degree of
phenotypic expression: Some individuals may be • into daughter cells during cell division
severely affected, whereas others are more mildly • Some cells may inherit more mitochondria in
affected. which the normal DNA sequence predominates,
Examples: while others inherit mostly mitochondria with the
mutated, disease-causing gene
• Patients with neurofibromatosis might show
different signs and symptoms
Allelic heterogeneity
Dominant negative mutations: • Different mutations at the same locus lead to the
• A mutation whose gene product adversely affects same or very similar phenotypes
the normal, wild-type gene product within the Examples:
same cell. • Alkaptonuria
• The product can still interact with the same • Albinism
elements as the wild-type product, but block some • Achondroplasia
aspect of its function • Phenylketonuria
Examples: • B-thalassemia
• Mutation in a transcription factor that removes Locus heterogeneity
the activation domain, but still contains • Mutations in genes at different chromosomal loci
the DNA binding domain. Examples:
• This product can then block the wild- • Retinitis pigmentosa
type transcription factor from binding • Hypertrophy cardiomyopathy
27
 • Familiar hypercholesterolemia
Gene expression modifications

Conditional Knockout
• Deletion od specific gene in certain tissue or cell
types
• Temporal suppression of a certain gene at a given
time-point post-natal or in adult animals

Knockout:
• Potent and irreversible means to inactivate a gene.
• Gene knockout methods are used for the
identification of a specific gene function by
inhibiting the function of the particular gene
• Knockout models carried out through several
methods include:
• Homologous recombination
• Site specific nucleases
• Zinc-finger nucleases
• TALENS
• Crisper/ cas9

Knock in
• Exogenous DNA sequence can be inserted into
the target locus in the zygote using genome editing Conditional knockout strategy is carried out by
technology Cre-lox system, where The Cre recombinase
• Useful for evaluating endogenous gene recognizes the loci of recombination loxP that
expressions and functions in vivo causes a deletion of the gene between the two loxP
sites.
Gene targeting: RNA interference:
• Genetic technique uses homologous recombination • RNA interference (RNAi) is a mechanism
to modify endogenous gene that inhibits or activates gene expression at the
stage of translation or by hindering the
• Gene trapping involve random insertion of a
transcription of specific genes.
cassette while gene targeting involves specific
gene
Cloning
Constitutive knockout
• A constitutive Knockout mouse, also referred to
as a conventional or whole-body Knockout (KO),
defines a mouse model in which the target gene is
permanently inactivated in the whole animal, in
every cell of the organism.

28
 • Application of DNA cloning • Bacteria that took up the plasmid can
be selected on nutrient plates containing the
Principle: antibiotic. Bacteria without a plasmid will die,
• DNA cloning refers to the process by which while bacteria carrying a plasmid can live and
recombinant DNA molecules are produced and reproduce.
transformed into a host organism, where they are
replicated.
• A target gene is inserted into a circular piece
of DNA called a plasmid.
• The insertion is done using enzymes that “cut and
paste” DNA called restriction enzyme
• DNA cloning reaction is typically comprised of the 3. Growing the plasmid carrying bacteria to extract
following two components: protein and purify it
1. The DNA fragment of interest to be replicated
2. A vector/plasmid backbone that contains all of the
components for replication in the host

Plasmids contain four components:

1. Origin of replication
2. multiple cloning site where the restriction enzymes
cleave Applications of DNA cloning:
3. Antibiotic resistance gene (selectable marker) • Synthesis of vitamins, hormones and antibiotics
4. Promotor region • Genome sequencing
• Production of friendly insecticides
DNA cloning Composed of three major steps • Gene therapy
• Production of recombinant proteins
1. Insertion of DNA fragment into plasmid using
restriction enzymes (which cut DNA) and DNA Fluorescence in situ hybridization
ligase (which joins DNA) Principle:
• In situ is a Latin word means in place
• In situ hybridization was the first technique
developed to detect target mRNAs in individual
cells.
• It involves the hybridization of a labeled RNA or
single-stranded DNA probe with a specific target
nucleic acid within a cell
• In situ hybridization is a means of identifying
where mRNAs are present in fixed tissue samples,
while immunohistochemistry identify protein in
fixed tissue.

2. Insertion of the plasmid into bacteria. Use

antibiotic selection to identify the bacteria that
took up the plasmid.
• Plasmids can be introduced into bacteria, such as
the harmless E. coli used in a process
called transformation.
• During transformation, bacterial cells are given a
shock (such as high temperature 42 C) that
encourages them to take up foreign DNA.

29
Methodology

International system for human cytogenetic

nomenclature
• Each area of the chromosome given number
• Lowest number closest (Proximal) to centromere
• Highest number distal to centromere
Advantages of FISH: • Each arm divided into sub-regions and identified
• FISH can be used to identify genetic changes that by a number
are too small to be detected under a microscope, • Example- 1q2.4
does not require cell culture • The first chromosome, long arm, region of the
• FISH analysis is useful in identifying genetic chromosome, the band of that sub-region
abnormalities undetectable by conventional
chromosomal analysis
Karyotyping
Overview
• Chromosomes contain the genetic material
inherited from the parents.
• They’re composed of DNA and determine the way
every human develops.
• The karyotype is the complete chromosomal set
of the nucleus of the cell which provide a genome-
wide snapshot of an individual´s chromosome
• Karyotype considered as a photograph of all of an
How to read chromosomes
organism chromosome
• Size: This is the easiest way to tell chromosomes
• The cells are usually feezed at the metaphase,
apart.
when the chromosomes are easily isolated and
stained • Banding pattern: The size and location of Giemsa
bands make each chromosome unique.
• Considered as a reference for the analysis of
mutations and help to determine if any • Centromere position: Centromeres appear as a
chromosomes are missing or damaged. constriction. They have a role in the separation of
chromosomes into daughter cells during cell
division (mitosis and meiosis).
• Using these key features, scientists can identify all
46 chromosomes one set of 23 from each parent

Sample preparation for karyotyping

• Blood sample
• Bone marrow biopsy Centrosomes:
• Amniocentesis
30
 • Required during chromosome separation during
cell division
• Each chromosome has only one centromere.

• During cell division, microtubules attach to

centromeres and pull the chromosomes to opposite
ends of the cell.
• Chromosome number can be identified through the
position of the centromere relative to the ends
• Metacentric chromosomes, the centromere lies Methodology
near the center of the chromosome.
• Submetacentric chromosomes have a centromere
that is off-center, so that one chromosome arm is
longer than the other. The short arm is designated
"p" (for petite), and the long arm is designated "q"
(because it follows the letter "p").
• Acrocentric chromosomes, the centromere is
very near one end.
Chromosome banding
• Treating the chromosome with a dye to identify
each chromosome and to diagnose chromosomal
aberrations, breakage or duplication Clinical Applications
Types of chromosome banding • Gender identification
• G banding: uses a stain called Giemsa stain. • Pre-birth diagnosis of genetic diseases
• G-banding gives you a series of light and dark • Detect aneuploidy
stripes along the length of the chromosome • Detection of chromosomal aberration
• For staining metaphase chromosome • Identify chromosomal abnormalities (Extra-
• Prepared by pretreating chromosomes with salt or Missing chromosome)
Chromosomal abnormalities detected by karyotype

Rett Syndrome
Overview
• Sporadic disorder associated with autism spectrum
disorder
• More common among females 1: 10,000
proteolytic enzyme • Associated with male lethality
• Q banding: uses a stain called quinacrine. Q- Pathophysiology
banding yields a fluorescent pattern. It is similar in • Mutation in MECP2 gene (X chromosome)
pattern to G-banding but glows yellow. • MECP2 plays important role in nerve maturation
• C banding: Only stains centrosomes • Turning off or silencing other genes
• R banding: Stains non-centromeric regions. Clinical presentations:
• Q banding: Fluorescent pattern obtained using • Patients are born with very hard to find signs of a
Quinacrine for staining disorder, but after about six months to a year and
• T banding half, speech and motor function capabilities start to
• Silver Banding decrease
• Spectral Karyotyping
• Digital Karyotyping

31
 • Signs and symptoms include cognitive •Muscular hypotonia; broad short neck;
impairment, seizures, repetitive or stereotypical •Single palmar crease
behavior and social interaction deficits •Gap between 1st 2 toes
Down Syndrome (Trisomy 21) •Atrioventricular septal defect
Overview: •Duodenal atresia (“double-bubble” sign)
• Hirschsprung disease; increased risk (15–20 fold)
of acute lymphoblastic leukemia (ALL)
• Alzheimer disease (by age 40) since chromosome
21 codes for amyloid precursor protein
• Congenital heart disease
• Increased nuchal translucency and hypoplastic
nasal bone
• Atlantoaxial instability (AAI)
• Hypothyroidism (High TSH, decrease T3 and T4)
Diagnosis
• Pregnancy screening test:
Disorder involving an extra autosome • Blood test: Abnormal levels of PAPP-A and HCG
• It is a chromosomal disorder caused by an error in may indicate a problem with the baby.
cell division resulting in the presence of an • Ultrasound Nuchal translucency test: When
additional third chromosome 21 or trisomy 21. abnormalities are present, more fluid than usual
• Nondisjunction is the usual cause of aneuploidies tends to collect in this neck tissue.
including Down, Edward, and Patau syndromes, as • Down syndrome can also be screened by assaying
well as Turner and Klinefelter syndromes. maternal serum levels of α-fetoprotein, chorionic
• Nondisjunction is more likely with increasing gonadotropin, and unconjugated estriol. This so-
maternal age (woman age>45) called triple screen can detect approximately 70%
• Incidence ratio 1:700 with Median life expectancy of fetuses with Down.
is 47 years. • Decrease alpha fetoprotein
• The most common karyotype is 47, XX, +21 • Decrease Estriol
• The problem occurs sometime shortly after • Increase B-hcG
fertilization; during the phase when cells are • Increase inhibin A
dividing rapidly.
Edwards Syndrome (Trisomy 18)
Pathogenesis Overview
• The pathogenesis involves: • Edwards syndrome (trisomy 18) is caused by
1. meiotic nondisjunction (95%) nondisjunction.
2. Robertsonian translocation (4%)
• The risk increases with maternal age with
3. Mosaicism due to mitotic nondisjunction during
incidence ration 1:8000
embryogenesis (1%).
• 2nd most common autosomal trisomy resulting in
live birth (most common is Down syndrome).

Clinical Presentations
• Mental retardation
Clinical presentations
• Mongoloid facial features (flat face, low-bridged
• Infant with microcephaly
nose, and epicanthal folds)
• Rocker-bottom feet
• Brush field spots (speckled appearance of the iris)
• Clenched hands

32
 • Structural heart defect Pregnancy screen
• Prominent occiput • Decrease free β-hCG
• Intellectual disability • Decrease PAPP-A
• Low-set ears • Increased nuchal translucency
• Micrognathia (Small jaw) Vitamin A
• There is a very poor prognosis due to severe Overview:
congenital malformations. • Vitamin A is the name of a group of fat-soluble
• Death usually occurs by age 1. retinoids, including retinol, retinal, and retinyl
esters
Patau syndrome Physiological functions of Vitamin A:
Overview: • Vitamin A also supports cell growth and
differentiation of epithelial cells into pancreatic
cells and mucus-secreting cells
• Considered as am major component of rhodopsin,
a protein that absorbs light in the retinal receptors
• Vitamin A (retinal, β-carotene) is present within
the retina’s rods and cones in the form of retinal.
• Antioxidant

Sources of Vitamin A:
• Vitamin A is highly enriched in liver, fish oils
milk, eggs, leafy green vegetables, orange, yellow
• Rare genetic disorders caused by having additional vegetables, tomato products, fruits, and some
copy of chromosome 13 (nondisjunction) vegetable oils
Clinical applications of Vitamin A:
• Nondisjunction: The failure of homologous
chromosome to separate probably during meiosis
• Incidence 1: 15,000
• Common in Puberty and the risk increases with
maternal age
• Babies with trisomy 13 have many abnormalities,
involving nearly every organ system in the body,
as well as developmental delay.
• It is difficult to predict the life expectancy of a
baby with trisomy 13.
• Acute
myelogenous leukemia M3 (AML) which might
Clinical findings
progress to disseminated intravascular coagulation
• AML M3 could be diagnosed by Auer rods (
lumps of azurophilic granular material that form
elongated needles seen in the cytoplasm of
myeloid leukemia blasts)
• Treatment of measles caused by paramyxovirus
and characterized by cough, conjunctivitis, coryza
and Kolpik spots
• Isotretinoin used to treat Acne not to pregnant
woman
• Mechanism of action (Decrease sebum
• Severe mental retardation production under the skin, decrease fatty acid
• Microcephaly synthesis)
• Microphalamia (abnormally small eyes) • Contraindication in pregnant woman lead to
• Holoprosencephaly (cleft palate, cardiac abnormalities) Isotretinoin is
• Polydactyly (Many fingers) teratogenic
• Cleft lip/palate • Contraceptive drugs should be used to avoid
• Congenital heart disease pregnancy during drug administration

33
Vitamin A deficiency: • Psychosis
• Night blindness • Cerebral damage
• Dry skin • Ophthalmoplegia
• Corneal degeneration • Nystagmus
• Immunosuppression
Vitamin A toxicity Beriberi syndrome
• Headache, papilledema, cerebral edema lead to • Mainly due to malnutrition
benign intracranial hypertension • Associated with wet and dry phenotypes

Signs of vitamin A toxicity: Wet Dry

Dilated cardiomyopathy polyneuritis
• Arthralgias, alopecia, sore throat, headache, Edema Loss of sensation
fatigue, cerebral edema, papilledema Congestive heart failure Peripheral neuropathy
Vitamin B1 (Thiamine) Wasting, difficulty walking and paralysis
Overview:
• Found in thiamine pyrophosphate (TPP), a Treatment:
cofactor for several dehydrogenase enzyme • Vitamin B1 supplements
reactions. Vitamin B6 (pyridoxine)
Physiological Functions: Overview:
• Thiamine plays an essential role for ketoglutarate • Vitamin B6 are primarily metabolized in liver to
dehydrogenase (Krebs cycle) and pyruvate pyridoxal 5'-phosphate (PLP)
dehydrogenase (glycolysis) activities. • PLP is a cofactor crucial for the functioning of
• In HMP (Hexose Monophosphate) Shunt, many enzymes involved in amino acid
Transketolase needs thiamine for the conversion metabolism.
of ribulose 5 phosphate to fructose 6 phosphate. • Liver disorders (elevated levels of ALT& AST) is
• Branch chain AA dehydrogenase commonly associated with vitamin B6 deficiency

Role of vitamin B6 in homocysteine pathway:

Homocysteine

cystathionine β-synthase Vit B6

Cystathionine

cystathionine gamma lyase Vit B6

Vitamin B1 deficiency
Cysteine
Wernicke Korsakoff syndrome
• Associated with alcoholics and malnutrition Homocystinuria (cystathionine beta synthase deficiency)
patients due to dietary deficiency or reduced • Abnormal accumulation of homocysteine and its
absorption of thiamine metabolites (homocystine, homocysteine–cysteine
• Wernicke-Korsakoff syndrome is associated with complex, and others) in blood and urine.
atrophy of the mammillary bodies • Caused due to the absence of activity of
cystathionine β-synthase, an enzyme often
Signs and symptoms: responsive to vitamin B6 (pyridoxine)
• Neurological symptoms:
Signs and symptoms of homocystinuria
• Amnesia
• Mental retardation
• Hallucinations
• Tall stature
• Confabulation or exaggerated storytelling
• Lens subluxation
34
 • Atherosclerosis (stroke, MI)- damage to carrier for CO2 in a multistep reaction.
endothelial walls due to homocysteine

Role of vitamin B6 in other pathways

Vit B6
Tryptophan Niacin (vit B3)
Vit B6
Histidine Histamine
Gluconeogenesis in liver
Vit B6 • Pyruvate carboxylase (PC) catalyzes the
Porphyrin formation of oxaloacetate from pyruvate, a step
Glycine important in the TCA cycle, gluconeogenesis and
Glutamate Glutathione Hemelipogenesis; lack of this function can lead to
hypoglycemia, ketosis, and lactic acidosis.
Fatty acid synthesis (citrate shuttle)
Vit B6
GABA
DOPA
Vit B6 NE E
Tyrosin Acetyl-CoA
carboxylase
Phenylalanine e
Vitamin B6 deficiency
• Sideroblastic anemia
• Convulsions, seizures
• Hyperirritability
• INH- Isoniazid- causes hepatotoxicity and Vitamin
B6 level depletes causing peripheral
• neuropathy •
• Oral contraceptive pills • Dopami
Vitamin B7 ne
• Acetyl-CoA carboxylase is expressed mainly in
liver and adipose tissue where it generates the
malonyl CoA that is required for lipogenesis (fatty
Overview: acid synthesis)
• Biotin is a coenzyme involved in the metabolism
of:
1. Fatty acids, a type of molecule found in fats and
oils
2. Gluconeogenesis, the synthesis of glucose from
molecules that are not carbohydrates, for example,
amino and fatty acids
• Biotin is a coenzyme for carboxylase enzymes,
involved in the synthesis of fatty acids
• Biotin assists in various metabolic reactions
involving the transfer of carbon dioxide
Propionate metabolism
Physiological Functions of Vitamin B7 • Propionyl-CoA carboxylase (PCC) catalyzes the
• Biotin functions as a coenzyme in carboxylation conversion of propionyl CoA to methylmalonyl
reactions involving lipid, glucose and amino acid CoA, which in turn isomerizes to succinyl CoA,
metabolism. and enters the TCA (Kreb's) cycle.
• There are 5 biotin-dependent carboxylases each of • PCC is important in the metabolism of odd-chain
which exists as an inactive form. fatty acids, and the amino acids isoleucine, valine,
• In all 5 carboxylases, biotin functions as a methionine, and threonine.
coenzyme or prosthetic group that serves as a

35
 • In case of B7 deficiency can cause high levels of Note: Serum folate levels tend to be increased in
propionyl CoA, while B12 deficiency cause patients with vitamin B12 deficiency, because of
megaloblastic anemia impairment of the methionine synthase pathway and
accumulation of methyltetrahydrofolate, the principal
Vitamin B7 deficiency form of folate in the serum
• Occur rarely, but include • Neural tube defects
• Dermatitis o It is recommended that all women of
• Alopecia or hair loss childbearing age who are planning a
• Enteritis pregnancy take a daily supplement as it is
• Biotin deficiency from excessive of raw eggs difficult to achieve through diet alone
ingestion because raw eggs have avidin that binds o Adequate folic acid intake helps to prevent
to biotin and leads to vit b7 deficiency neural tube defects (e.g. spina bifida) in
• Antibiotics might be associated with Vit b7 babies.
deficiency Folate deficiency is common in:
Overview: o Patients with insufficient diet – Elderly
patients (Tea and Toast diet)
• Vitamin B9, also called folate or folic acid
o Alcoholic individuals: Alcoholic drinks
• Folic acid is the synthetic version of vitamin B9,
contain high caloric contents; hence they
which is what is found in fortified foods and
don´t eat properly
supplements.
o Patients with prolonged use of antibiotics
• Vitamin B9 plays an essential role in:
o Several drugs: phenytoin, sulfonamides,
1. Production and maintenance of DNA methotrexate (inhibit folic acid
2. producing red blood cells — which carry oxygen metabolism)
around your body Clinical features of folate deficiency:
• The most common sources of vitamin B9 is dark o Megaloblastic anemia (MCV 100)
green leafy vegetables, beans, lentils, asparagus, o Macrocytic RBS
wheat germ, yeast, peanuts, oranges, and o Stomatitis, glossitis
strawberries.
• Folate is stored in the liver, but stored for a short Treatment:
period (3 months), yet B12 stored for 3 years o Oral folic acid supplement
o Continuous monitoring of homocysteine,
• Converted to tetrahydrofolic acid (THF), a methylmalonic acid levels
coenzyme for 1-carbon transfer/methylation o For prophylaxis, folate supplement for pregnant
reactions. women and patients with chronic hemolysis
(Sickle cell disease)

Vitamin B12
• Causes of Vitamin B12 deficiency
• Signs and symptoms of cobalamin deficiency
• Diagnosis

Overview
• Vitamin B12 is a water-soluble vitamin that is
naturally present in some foods
• Vitamin B12 is required for proper red blood cell
formation, neurological function, and DNA
synthesis
• Vitamin B12 functions as a cofactor for
Folate deficiency leads to methionine synthase and L-methylmalonyl-CoA
• Macrocytic (megaloblastic) anemia: mutase.
o Abnormal DNA synthesis, due to vitamin B12 or • Methionine synthase catalyzes the conversion of
folate deficiencies homocysteine to methionine
o Results in delayed nuclear development,
characterized by hypersegmented neutrophils and
large erythrocytes (MCV 100)

36
 Absorption of vitamin B12
• When humans eat animal foods, the B12 is
protein-bound.
• When the protein-B12 complex reaches the
Functions of Vitamin B 12 stomach, the stomach secretes acids and enzymes
Cofactor for L-methylmalonyl-coenzyme A mutase that detach the B12 from the protein.
• R-protein (aka cobalophilin, haptocorrin, and
transcobalamin I pick up the B12 and transports it
through the stomach and into the small intestine.
• The stomach cells also produce a protein called
intrinsic factor (IF), which travels to the small
intestine where it attaches to cobalamins.
• Intrinsic factor then carries the cobalamins to the
last section of the small intestine, the ileum.

• 5-Deoxyadenosylcobalamin is required by
the enzyme that catalyzes the conversion of L-
methylmalonyl-coenzyme A to succinyl-coenzyme
A (succinyl-CoA), which then enters the citric acid
cycle .
• Succinyl-CoA plays an important role in:
• production of energy from lipids and proteins
• Required for the synthesis of hemoglobin, the
oxygen-carrying pigment in red blood cells
• Required for Krebs cycle
• Production of myelin

Cofactor for methionine synthase

• Vitamin B12 is required for the function of the
folate-dependent enzyme, methionine synthase.
• This enzyme is required for the synthesis of
the amino acid, methionine, from homocysteine.
• It receives the methyl group from N5-
methyltetrahydrofolate thus regenerating
tetrahydrofolate to participate in other one- carbon
transfers in purine metabolism or pyrimidine
remodeling

37
Causes of Vitamin B12 deficiency • Prolonged deficiency lead to irreversible nerve
damage.
• Positive Babinski sign

Diagnosis:
• Peripheral blood smear with:
1. Megaloblastic anemia MCV >100
2. Macrocytic red blood cells
3. Hypersegmented neutrophils
• Serum vitamin B12 levels less than 100 pg/ml
• Increased Methylmalonic acid and Homocysteine
levels
• Bone marrow analysis to detect megaloblastic cells
• Schilling test (helps determine the site of the
metabolic defect that led to deficiency)
• IF and parietal cell antibody levels are helpful in
• Deficiency mainly due to impaired reabsorption or diagnosing pernicious anemia.
malabsorption • The Schilling test is a medical procedure used to
• Pernicious anemia: Insufficient B12 absorption determine whether you’re absorbing vitamin B-12
caused by a deficiency of intrinsic factor (usually properly
owing to an autoimmune disease) The test composed of 2 main stages:
• Partial or complete gastrectomy or gastric • A normal patient will show a normal level of
reduction surgery- damage of parietal cells which cobalamin in urine upon administration of the
lead to deficiency of intrinsic factor oral dose. If the urine level is abnormal, it can be
• Poor diet: strike to vegetarian food from either an absorption defect in the terminal
• Fish tap warm (Diphyllobothrium latum) ileum or a lack of intrinsic factor.
• Bacterial overgrowth • If the abnormal result of stage 1 improves with
• Absence of terminal ileum (surgical resection, e.g. administration of Intrinsic factor, it means that the
for Crohn disease) The Normal Mechanisms and Defects of Absorption of Vitamin B12
patient has intrinsic factor deficiency (Pernicious
Signs and symptoms of cobalamin deficiency: anemia).
• Megaloblastic anemia due to stopped DNA • If the patient still has a low urine level of
synthesis become big cells macrocytosis stuck in cobalamin, it means that there is an absorption
G2 phase defect in the terminal ileum and further tests
• Neuropathy due to impaired myelin synthesis in should be done to investigate.
spinal cord that include:
• Demyelination of the cervical and thoracic dorsal Stage 1
and lateral columns of the spinal cord
• The patient is given radiolabeled vitamin B12
• Occasional demyelination of cranial and peripheral
orally, following an intramuscular (IM) dose of
nerves, and demyelination of white matter
unlabeled vitamin B12 one hour later to saturate
all the receptors. The injection is given to ensure
o Dorsal column dysfunction leads to decreased
that none of the radioactive B12 binds to any
proprioception and vibratory sensation.
vitamin B12 depleted tissues, for example, the
o Lateral column dysfunction leads to weakness of
liver.
the legs, arms, and trunk (with tingling).
o Dorsal column involvement leads to loss of • A 24-hour urine collection monitors the absorption
vibratory and position senses and the excretion.
• Plasma levels can be also monitored

Stage 2

• If the previous stage provides an abnormal result,

stage 2 can be done to assess whether there is a
• Ataxia deficiency of intrinsic factor.
• loss of deep tendon reflexes • Stage 1 is repeated along with an oral dose of
intrinsic factor.

38
 • A 24-hour urine collection is carried out to assess
the level of vitamin B12.

Stage 1 Stage 2 Diagnosis

Normal - Normal or dietary vitamin
B12 deficiency
Low Normal Problems with intrinsic factor
production, e.g. Pernicious anemia
Low Low Malabsorption (terminal ileum)

Comparison of Folate and Vitamin B12 deficiency

Folate deficiency Vitamin B12 (Cobalamin)

deficiency
• Megaloblastic anemia • Megaloblastic anemia
• Macrocytic • Macrocytic
• MCV >100 • MCV> 100
• PMN • PMN
• Homocysteinemia with • Homocysteinemia with
risk for cardiovascular risk for cardiovascular
disease disease
• Deficiency develops in • Methylmalonic aciduria
3-4 months • Progressive peripheral
neuropathy • Required for synthesis of Dopamine,
• Deficiency develops in Noradrenaline and adrenaline
Risk factors for deficiency: years
• Pregnancy (neuronal Risk factors for deficiency:
tube defects in fetus • Methylmalonic aciduria
may result) • Risk factors for
• Alcoholism deficiency
• Severe malnutrition • Pernicious anemia
• Gastric or terminal • Gastric resection
ileum resection • Chronic pancreatitis
• Severe malnutrition
• Vegan
• Infection with D. latum
• Bacterial overgrowth

Vitamin C /Ascorbic acid

Overview:
• Vitamin C is water soluble vitamin
• Act as antioxidant
• Help uptake of iron in GIT
• Involved in formation of active form of folic acid
• Ascorbic acid is naturally found in fresh fruits and
vegetables

Functions of Vitamin C
• Synthesis of collagen, responsible for generation
of connective tissues and cartilage
• Facilitate the absorption of dietary iron from the
• Cofactor for proline and lysine hydroxylases intestine through the reducing property of vitamin
which are required for post synthetic modification C (keep iron in ferrous state)
of procollagen to collagen
• These hydroxylation reactions require reducing Vitamin C deficiency
agent Vitamin C • Due to malnutrition, decrease dietary intake of
• Important for wound repair and healthy gum vitamin C
• Boost the immune system Scurvy:
• Impairment in collagen synthesis
• Impair wound healing
• Tooth loss
• Bone fractures

39
 • Fragile capillaries resulting in abnormal bleeding • Dihydroxycholecalciferol and is also called as
and gum decay calcitriol
o Prolong bleeding time, but normal PT&PTT • Cholecalciferol is first hydroxylated by a specific
• Deteriorated immune response hydroxylase present in liver Vitamin D3-25
• Bruising, petechiae, hemarthrosis hydroxylase to form 25-hydroxy-cholecalciferol as
• Impaired E, NE production that might predispose a major storage form
depression • In the kidney, 1- hydroxylase enzyme manage to
Vitamin C Toxicity produce 1,25 dihydroxy cholecalciferol
• Occur through iron transfusion in anemic patients
(caution for hemochromatosis) Calcitriol has 2 final pathways
• Signs includes Nausea, vomiting, diarrhea, fatigue, • Bone, osteoclasts: Ca+2 mineralization or
calcium and oxalate nephrolithiasis mobilization with PTH
Vitamin D • Intestine: Increase calcium uptake from intestine
Overview:
• The production of vitamin D in the skin is directly Vitamin D and parathyroid glands mutual relationship
proportional to the exposure to sunlight and • Parathyroid hormone (PTH) regulates serum
inversely proportional to the pigmentation of skin calcium and phosphate, which in return regulate
• Vitamin is not secreted by breast milk, should give PTH.
orally • kidney produces vitamin D’s active form, which is
called 1,25(OH)₂D
Forms of Vitamin D: • 1,25(OH)₂D helps you absorb calcium and also
• Vitamin D2 (Ergocalciferol) inactive form - Plants keeps your PTH levels in check.
• Vitamin D3 (Cholecalciferol) (Milk, under sun • During hypocalcemia, parathyroid glands
exposed skin) start secreting PTH.
• Active form • PTH starts pulling calcium from your bones and
• Storage form into your blood.
• PTH initiate the kidneys to start making more
Functions of Vitamin D 1,25(OH)₂D.
• Increase intestinal absorption of calcium and • When the kidney starts producing 1,25(OH)₂D, it
phosphate helps the gut absorb more calcium than usual, to
make sure you get enough calcium into your body.
• When 1,25(OH)₂D increases and helps your body
get to the right calcium balance, it tells the
parathyroid to stop making so much PTH and stop
pulling calcium from the bones.

Vitamin D pathway
• During cholesterol synthesis 7-dehydro cholesterol
is formed as an intermediate product
• On exposure to sunlight, 7-dehydrocholesterol is
converted to cholecalciferol (Vit D3) in the skin
(dermis and epidermis)

40
Vitamin D deficiency Physiological functions of Vitamin E
• Can be caused by low dietary intake
• low sunlight exposure
• Chronic kidney disease or renal failure patients
develop secondary hyperparathyroidism- renal
osteodystrophy
• Alcoholic with liver cirrhosis prohibited to take
D2, D3 due to improper metabolization
• Exacerbated due to chronic sun exposure and
premature birth

• Antioxidant- Cardioprotective effect

• Antioxidants protect cells from the damaging
effects of free radicals.
• Free radicals damage cells and might contribute
to the development of cardiovascular disease and
cancer
Clinical signs and symptoms • Vitamin-E–replete endothelial cells lining the
• Rickets in children (deformity due to incomplete interior surface of blood vessels are better able to
mineralization) resist blood-cell components adhering to this
• Osteomalacia in adults (bone pain and muscle surface
weakness) • Vitamin E also increases the release of
• Enlargement and softening of bones prostacyclin from the endothelium, which, in turn,
• Delay in teeth formation dilates blood vessels and inhibits platelet
• Tetany (carpopedal spasm) due to hypocalcemia aggregation
• Biochemical findings: • Prevent atherosclerosis by inhibiting the oxidation
• Decreased serum calcium levels of low-density lipoprotein (LDL).
• Decreased plasma phosphorous levels
Vitamin E deficiency
Vitamin D Toxicity • Occurs rarely in humans, only reported in two
• Hypercalcemia situations
• Hypercalciuria 1. Malnutrition- Fat malabsorption
• Loss of appetite 2. Premature infants
• Sarcoidosis (epitheloid macrophages are activated)
Signs and symptoms:
Vitamin E • Hemolytic anemia due to oxidative damage to red
Overview: blood cells (Acanthocytosis)
• Naturally occurring vitamin E exists in eight • Neuromuscular dysfunction due to disruption of
chemical forms (alpha-, beta-, gamma-, and delta- myelin sheath in axons in adults and children,
tocopherol and alpha-, beta-, gamma-, and delta- observed as:
tocotrienol) o muscle weakness
o posterior column
Sources of Vitamin E: o spinocerebellar tract demyelination
• Nuts, seeds, and vegetable oils are among the best o Peripheral neuropathy
sources of alpha tocopherol o Ataxia
• Green leafy vegetables, fortified cereals soybean, o Loss of position
canola, corn, and other vegetable oils and food o Vibration sense
products. • Retinitis pigmentosa

41
 • These symptoms might overlap with other IX Plasma Yes
disorders such as Friedreich Ataxia or vitamin B12 thromboplastic
deficiency component
• Vitamin E toxicity associated with enterocolitis in X Stuart Factor Yes
children XI Plasma No
Vitamin K thromboplastin
Overview: antecedent
• Required for the production of blood clotting XII Hageman factor No
factors, essential for coagulation XIII Fibrin stabilizing No
• Stored in the liver factor
• Activated by epoxide reductase to the reduced
form
• The reduced form function as coenzyme for
carboxylation of glutamic acid residues
• Necessary for the maturation of clotting factors II,
VII, IX, X, and proteins C and S.

Vitamin K Deficiency

• Occur in the newborn due to deficiency in sterile

intestinal flora
• To avoid neonatal hemorrhage, intramuscular
injection of vitamin K following delivery
• Small quantities of vitamin K crossing the
placental barrier from maternal circulation
• Linked to impaired absorption caused by biliary
obstruction
• Prolonged administration of antibiotics might
destroy bacterial flora (natural source of vitamin
K)

Clinical features
•  PT,  PTT
• Normal bleeding time
• Measurement of PT is an indication of liver
function
• Warfarin is vitamin K antagonist used for
treatment of thrombosis after myocardial infarction

Note: Vitamin K isn´t found in breast milk, should be

injected immediately after birth

Coagulation factors dependent of vitamin K

c Common Synonym Dependent of
Vitamin K
I Fibrinogen No
II prothrombin Yes
III Tissue No Vitamin K deficiency Vitamin C deficiency
thromboplastin Easy bruising, bleeding Easy bruising, bleeding
IV Calcium No Normal bleeding time Increased bleeding time
V Proaccelerin No Increased PT Normal PT
VII Proconvertin Yes Hemorrhagic disease • Gum hyperplasia,
VIII Antihemophilic No inflammation,
factor loss of teeth

42
 • Skeletal • Decreased visceral protein leads to
deformity in hypoalbuminemia
children
• Poor wound Marasmus
healing • Muscle wasting (Body weight less than 60% than
• Anemia expected)
Associated with Associated with • Energy malnutrition skinny arms and skinny legs
• Fat • Deficient in citrus and loss of subcutaneous fat
malabsorption fruit, green • Complete starvation
• Prolonged vegetables • Absence of edema
antibiotic
administration
• Breast-fed
newborns
• Infants exposed
to anticonvulsant
through the
mother during
pregnancy

Malnutrition
Kwashiorkor:

• Starvation resulting from inadequate intake of all

nutrients
• More common in developing countries (found in
countries where there is drought and famine).
Characterized by:
• Skin lesions with late healing (hyperkeratosis,
dyspigmentation)
• Edema
• Decrease protein content
• Decrease hydrostatic pressure
• Liver malfunction because of the fatty change
• Anemia
• Big belly with thin arms
• Swollen legs
• Decreased protein intake leads to decreased
synthesis of visceral proteins

43
Ethanol Metabolism • Increased NADH/NAD+ ratio in liver favor the
Ethanol toxicity: formation of:
1. Lactate from pyruvate
2. Malate from OAA in the cytoplasm
3. Glycerol 3-phosphate from DHAP
• Accumulation of cytoplasmic NADH and glycerol
3-P may also contribute to lipid accumulation in
alcoholic liver disease (Hepatosteatosis).
• In the presence of high glycerol 3-P, fatty acids are
inappropriately stored in the liver as triglyceride

Ethylene glycol and Methanol toxicity:

Treatment of Ethanol toxicity:

Signs of Ethylene glycol toxicity:
• Disulfiram used to prevent alcohol abuse, blocks • CNS depression
acetaldehyde dehydrogenase to cause a buildup of
• Acidosis
acetaldehyde when drinking leads to unpleasant
• Nephrotoxicity
side effects such as flushed skin, tachycardia, and
nausea and vomiting
Signs of Methanol toxicity:
• Retinal damage (Blindness)
• Antizol (fomepizole) Injection is a competitive
inhibitor of alcohol dehydrogenase for Ethylene
glycol and methanol toxicity

Introduction to metabolism
Overview:
• Metabolism: All the chemical reactions that occur
in the body
• A metabolic pathway begins with a specific
molecule and ends with a product
• These reactions are catalyzed by enzymes
Ethanol elimination: Metabolic sites
• Ethanol elimination follows zero order kinetics, Cytoplasm:
Because the enzymes responsible for ethanol • Glycolysis
metabolism become saturated after the average • Fatty acid synthesis
individual consumes 1-2 drinks, the rate at which it • Hexose monophosphate shunt pathway
is cleared or eliminated from the body change
from first order to zero order kinetics Endoplasmic reticulum:
• Protein Synthesis occur in rough surface
Alcoholics and diabetes
• Steroid synthesis occurs in smooth surface
• Alcoholics are very susceptible to hypoglycemia.
• Alcohol is metabolized to acetate (acetyl-CoA), Mitochondria
the high amounts of cytoplasmic NADH formed
• Beta oxidation of fatty acids
by alcohol dehydrogenase and acetaldehyde
• Acetyl CoA production
dehydrogenase interfere with gluconeogenesis.
• TCA cycle

44
 • Oxidative phosphorylation

Both mitochondria and cytoplasm

• Heme synthesis
• Urea cycle
• Gluconeogenesis
Enzymes:
• Enzymes help speed up chemical reactions in the
body
Kinases:
• Involved in phosphorylation where
the substrate gains a phosphate group and the high-
energy ATP molecule donates a phosphate group.

• Throughout glycolysis, four phosphorylation’s

reactions are involved, two that create ATP from
ADP and two that use ATP and converting it into
ADP. • Dehydrogenase: oxidizes a substrate by a
Examples: reduction reaction
• Phosphofructokinase, catalyzes the conversion of • Examples: Pyruvate dehydrogenase
fructose-6-phosphate to fructose-1,6-bisphosphate
and is an important point in the regulation of • Carboxylase: allow the production of new carbon-
glycolysis. carbon bonds by introducing HCO3- or CO2 into
target molecules
• Examples: Acetyl CoA carboxylase is the first
enzyme of fatty acid synthesis
• The carboxylation of acetyl CoA
involves biotin which acts as a carrier for
“activated CO2”

Glycolysis
Overview:
• Glycolysis involves the oxidation of glucose and
occurs in the cytosol of all cells.

•
phosphorylases catalyze the addition of a
phosphate group from an inorganic
phosphate (phosphate + hydrogen) to an acceptor
• Glycogen phosphorylase

• Phosphatase: removes a phosphate group from the •

phosphorylated amino acid residue of its substrate Glycolysis can be either aerobic or anaerobic.
protein. • If a cell has mitochondria and oxygen, glycolysis
is aerobic

45
 • If either mitochondria or oxygen is lacking, 1. Glucokinase/hexokinase
glycolysis may occur anaerobically 2. PFK-1
• Anaerobic glycolysis occurs in anoxic tissues, red 3. Pyruvate kinase
blood cells, and skeletal muscle during intense
exercise. Hexcokinase:
• In a few tissues, most importantly red blood cells, • Glucose entering the cell is trapped by
glycolysis represents the only energy-yielding phosphorylation using ATP
pathway available • widely distributed in tissues
• Glycolysis is a cytoplasmic pathway that converts • During high carbohydrate meal (excessive
glucose into two pyruvates, and net production of glucose), Glucose-6- phosphate inhibit Hexokinase
2 ATP in the liver through negative feedback
• In the liver, glycolysis is part of the process by
which excess glucose is converted to fatty acids Glucokinase
for storage • Glucokinase is found only in hepatocytes and
pancreatic β-islet cells.
• Insulin activates Glucokinase in case of high sugar
Glucose transport intake
• Glucokinase is inhibited by fructose-6-phosphate,
which prevents glucose from being phosphorylated
faster than it is metabolized

phosphofructokinase- 1 (PFK-1)

• Glucose entry into most cells and regulated by

four glucose transporters (GLUT) with different
physiological roles
• GLUT 4 is in adipose tissue and muscle and
• The rate-limiting step of glycolysis is the
responds to the glucose concentration in peripheral
phosphorylation of fructose-6-phosphate by
blood.
phosphofructokinase-1 (PFK-1) using ATP
• Insulin binds to insulin receptors in skeletal
• PFK-1 is inhibited by ATP and citrate and
muscles, adipose tissue and cardiac muscles
activated by AMP and fructose 2,6-bisphosphate.
• Muscle stores excess glucose as glycogen
• During fasting or starvation, there is a decrease in
• Adipose tissue requires glucose to form fructose 2,6-bisphosphate, leading to a decrease in
dihydroxyacetone phosphate (DHAP), which is the rate of glycolysis.
converted to glycerol phosphate used to store
• After a carbohydrate diet, insulin levels increase
incoming fatty acids as triglyceride (TGL, three
and glucagon levels decrease; this causes an
fatty acids attached increase in fructose 2,6-bisphosphate, activating
to glycerol).
PFK-1 and increasing the rate of glycolysis when
• Glucose induces genetic expression of the insulin glucose is plentiful.
gene. Pyruvate kinase
• Insulin stimulates the movement of additional • The last enzyme in aerobic glycolysis, it catalyzes
GLUT 4 transporters to the membrane a substrate-level phosphorylation of ADP using
• The transport rate increases in adipose tissue and phosphoenolpyruvate (PEP).
muscle when insulin levels rise. • Pyruvate kinase is activated by fructose 1,6-
Glycolysis: bisphosphate from the PFK-1 reaction (feed-
Enzymes used in glycolysis: forward activation).
• Three enzymes in the pathway catalyze reactions
that are irreversible. When the liver produces
glucose, these enzymes must be used

46
 • Once in the matrix, Pyruvate is converted to
oxaloacetate or acetyl-CoA for entry into the
citric acid cycle if ATP is needed, or for fatty acid
synthesis if sufficient ATP is present
• The pyruvate dehydrogenase (PDH) is irreversible
and cannot be used to convert acetyl- CoA to
pyruvate or to glucose
• Pyruvate dehydrogenase in the liver is activated
by insulin

Pyruvate metabolism
• Cofactors and coenzymes used by pyruvate
dehydrogenase include (Tender Loving Care For
Nancy-TLCFN):

1. Thiamine pyrophosphate (TPP) from the

vitamin B1
2. Lipoic acid
3. Coenzyme A (CoA) from pantothenate
B5
4. FAD(H2) from riboflavin B2

NAD(H) from niacin B3

Glycolysis summary: • Alanine aminotransferase (ALT): Catalyzes the

• Net production is 2 ATP transfer of an amino group from alanine to alpha-
• Anaerobic glycolysis yields 2 ATP/glucose by ketoglutarate in the alanine cycle to form pyruvate
substrate-level phosphorylation. and glutamate.
• Aerobic glycolysis yields these 2 ATP/glucoses • Pyruvate carboxylase (Biotin): catalyzes the
plus 2 NADH/glucose that can be utilized for ATP physiologically irreversible carboxylation of
production in the mitochondria pyruvate to form oxaloacetate.
Pyruvate dehydrogenase: contributes to
Pyruvate metabolism transforming pyruvate into acetyl-CoA by a
Overview: process called pyruvate decarboxylation (B1, B2,
• pyruvate is critical for mitochondrial ATP B3, B5, lipoic acid)
generation Lactate dehydrogenase:
• Pyruvate is generated from several sources, • Used only in anaerobic glycolysis.
including the oxidation of lactate, the • Anaerobic glycolysis is common in RBCs, WBCs,
transamination of alanine, or as the terminal kidney medulla, lens, testes, and cornea
product of glycolysis. • It reoxidizes NADH to NAD

47
 • Without mitochondria and oxygen, glycolysis 2. Increased NAD/ NADH ratio
would stop when all the available NAD had been 3. Increased ADP levels and calcium
reduced to NADH.
• By reducing pyruvate to lactate and oxidizing Thiamin deficiency
NADH to NAD, lactate dehydrogenase prevents • Thiamine deficiency is commonly seen in
this potential problem from developing. alcoholics, who may develop a Wernicke
peripheral neuropathy and Korsakoff psychosis
Dynamic regulation of pyruvate dehydrogenase complex • Thiamine deficiency impairs glucose oxidation
affecting brain and cardiac muscle
• Besides pyruvate dehydrogenase, two enzymes
also using thiamine as cofactor enzymes (α-
Ketoglutarate dehydrogenase, ketoacid
dehydrogenase)
• Alcohol interferes with thiamine absorption from
the intestine.
• Symptoms include:
1. Ataxia
2. Ophthalmoplegia, nystagmus
3. Memory loss and confabulation
Deficiency of Pyruvate dehydrogenase complex
4. Cerebral hemorrhage
• Linked to genetic mutation in X chromosome (E1
• In case of alcoholics, and if thiamine deficiency is
alpha, the PDHA1 gene)
suspected, patients should be given IV thiamine in
• buildup of lactic acid in the body and a variety of the emergency department to prevent lactic
neurological problems acidosis before glucose (dextrose) is administered.
• Signs and symptoms appear shortly after birth such
as Krebs cycle (TCA)
1. lactic acidosis which can cause nausea, Overview:
vomiting, severe breathing problems,
• The citric acid cycle, also called the Krebs cycle or
and an abnormal heartbeat. the tricarboxylic acid (TCA) cycle
2. Infants with lethargy
• Occur in the mitochondria due to the need of
• Neurological problems include: oxygen (aerobic respiration)
1. intellectual disability, seizures, weak muscle tone
• Glycolysis occurs in the cytosol. The TCA cycle
(hypotonia), poor coordination, and difficulty
occurs in the mitochondria.
walking.
• The ultimate goal of TCA cycle is oxidation of
acetyl-CoA to carbon dioxide. The energy released
Treatment:
from this oxidation is saved as NADH, FADH2,
• Treated with proteins and amino acids to form
and guanosine triphosphate (GTP)
ketones for energy production
• Lycin and leucine amino acid diet

Arsenic toxicity:
Acetyl COA 2 CO2

• Excess arsenic binds to lipoic acid in the pyruvate NAD+ FAD+GDP +Pi
dehydrogenase complex leading to accumulation 3NADH+FADH2+GTP
of lactate
• Arsenic inhibits enzymes that require lipoic acid as TCA cycle:
cofactor such as pyruvate dehydrogenase, α- • The Krebs cycle begins when oxaloacetate
ketoglutarate dehydrogenase combine with Acetyl CoA using citrate synthase to
• Associated with lactic acidosis due to lipoic acid form citrate
deficiency • The pyruvate produced from glycolysis becomes
Signs and Symptoms: acetyl coenzyme A (acetyl CoA) through the
• vomiting, rice water stool enzyme pyruvate dehydrogenase.
• Garlic breath • Pyruvate dehydrogenase requires B1, B2, B3, B5
• QT prolongation and lipoic acid
Activators of PDH • Isocitrate converted to α- ketoglutarate by
1. Exercise isocitrate dehydrogenase (irreversible step)

48
 • Isocitrate dehydrogenase inhibited by NADH and
ATP
• Isocitrate dehydrogenase activated by ADP
• α- ketoglutarate is converted into succinyl COA
using α- ketoglutarate dehydrogenase
• α- ketoglutarate dehydrogenase requires 5
cofactors: B1, B2, B3, B5 and lipoic acid and
Inhibited by succinyl COA, NADH and ATP
• Succinate dehydrogenase require Vitamin B2
• Succinate dehydrogenase is on the inner
mitochondrial membrane, where it also functions
as complex II of the electron transport chain
• Citrate may leave the mitochondria (citrate shuttle)
to deliver acetyl-CoA into the cytoplasm for fatty
• NADH is produced inside the mitochondria
acid synthesis.
through citric acid cycle by pyruvate
• Succinyl-CoA is a high-energy intermediate that dehydrogenase
can be used for heme synthesis.
• Then NADH is oxidized in the electron transport
chain directing electrons for ATP production
• Once NADH has been oxidized, NAD can be
again utilized
• FADH2 is produced by succinate dehydrogenase
in the citric acid cycle and by the α-glycerol
phosphate shuttle which are located in the inner
membrane
• FADH2 is oxidized by transferring electrons into
the electron transport chain
• Once FADH2 has been oxidized, the FAD can be
made available once again for use by the enzyme.
• The main source of oxygen delivered by
hemoglobin
• Its function is to accept electrons at the end of the
chain, and the water formed is added to the cellular
water.
Composition of electron transport chain:
Summary of ATP production from Krebs cycle • Complex I- NADH coenzyme Q reductase
• Complex II- Succinate-Coenzyme Q reductase
• Complex III- Cytochrome C reductase
• Complex IV- Cytochrome C oxidase

Chemical energy and proton gradient

Electron transport chain

Overview

NADH + O2 NAD + H2O • The mitochondrial electron transport chain works

FADH2 + O2 FAD + H2O like a chemical battery.

49
 • In one side, an oxidation reaction is poised to
release electrons at very high energy;
• In another location, a potential electron acceptor
waits to be reduced
• Electricity is used to generate proton pumps which
drive protons from the matrix space across the
inner membrane into the intermembrane space,
creating a small proton (or pH) gradient
• Hydrogen ions passing through ATP synthase
down their concentration gradient drive the
formation of ATP through ATP synthase
• Energy is not released at once, but in incremental
amounts at each step
• The end result is that a proton gradient is normally •
maintained across the mitochondrial inner Binds irreversibly to cytochrome a/a3, preventing
membrane electron transfer to oxygen, and producing many
Electron transport inhibitors of the same changes seen in tissue hypoxia
• Inhibitors of electron transport chain share the Antidote for cyanide toxicity
following, • Nitrites may be used as an antidote for cyanide
1. Decreased oxygen consumption poisoning if given rapidly
2. Increased intracellular NADH/NAD and • It converts hemoglobin to methemoglobin, which
FADH2/FAD ratios binds cyanide in the blood before reaching the
3. Decreased ATP tissues.
• Sodium thiosulfate: administered IV, bind with
cyanide and become thiocynate, releasing the
hemoglobin and thiocyanate excreted by the
kidneys.
Carbon monoxide:
• Carbon monoxide binds to cytochrome a/a3 but
less tightly than cyanide.
• It also binds to hemoglobin, displacing oxygen.
• Antidote: High dose of oxygen
Uncouplers:
• Uncouplers are chemicals that decrease the proton
gradient, causing:
Barbiturate: 1. Decreased ATP synthesis
• Inhibits the transfer of electrons from complex I to 2. Increased oxygen consumption
Coenzyme Q 3. Increased oxidation of NADH
Rotenone: • Examples: 2,4-dinitrophenol (2,4-DNP) and
• Rotenone works by interfering with the electron aspirin (and other salicylates).
transport chain in mitochondria. • Brown adipose tissue contains a natural
• It inhibits the transfer of electrons from iron-sulfur uncoupling protein (UCP, formerly called
centers in complex I to ubiquinone. thermogenin), which allows energy loss as heat to
• Finally, it generates free radicals which damage maintain a basal temperature around the kidneys,
DNA and other components of the mitochondria neck, breastplate, and scapulae in newborns.
Cyanide • N.B Although Aspirin is used for treatment of
rheumatoid arthritis, but its overdose may lead to
uncoupling of oxidative phosphorylation,
increased oxygen consumption, depletion of
hepatic glycogen, and the pyretic effect of toxic
doses of salicylate

50
ATP synthase inhibitors Gluconeogenesis Pathway
Oligomycin:
• Antibiotic that inhibits ATP synthase by blocking
its proton channel (F0 subunit), which is necessary
for oxidative phosphorylation of ADP to ATP
(energy production).
• The inhibition of ATP synthesis would also
stop electron transport chain.
• No ATP is produced because electron transport
stops.
Antimycin A:
• Antimycin A is an inhibitor of cellular respiration,
specifically oxidative phosphorylation.
• It also will cause the disruption of the entire
electron transport chain. • Most steps represent a reversal of glycolysis
• Due to this, there can be no production of ATP. • The irreversible reactions of glycolysis are
bypassed by four alternate unique reactions of
Gluconeogenesis gluconeogenesis.
Overview: • The four unique reactions of gluconeogenesis are
• The liver maintains glucose levels in blood during 1. Pyruvate carboxylase, located in the
fasting through either glycogenolysis or mitochondrial matrix,
gluconeogenesis 2. Phosphoenol pyruate (PEP)
• The synthesis of glucose from non- carbohydrate carboxykinase located in mitochondrial
compounds is known as gluconeogenesis. matrix and cytosol
• Gluconeogenesis activated by glucagon and 3. Fructose-1, 6-bisphosphatase located in
epinephrine and inhibited by insulin the cytosol
• The major substrates/precursors for 4. Glucose-6-phosphatase located in the
gluconeogenesis: Lactate (anaerobic glycolysis), endoplasmic reticulum (ER).
pyruvate, glucogenic amino acids (proteins from Pyruvate Carboxylase
muscle), propianate and glycerol. • Mitochondrial enzyme requiring biotin.
• Gluconeogenesis occurs mainly in the liver and • It is activated by acetyl-CoA (from β-oxidation)
kidney Converts pyruvate to oxaloacetate in presence of ATP &
• The process occurs during periods of fasting, CO2
starvation, low-carbohydrate diets, Phosphoenol pyruate (PEP) carboxykinase
or intense exercise. • In the cytoplasm is induced by glucagon and
• The gluconeogenesis pathway consumes ATP, cortisol
which is derived primarily from the oxidation of • It converts OAA to phosphoenolpyruvate (PEP)
fatty acids. which requires GTP
• Hepatic gluconeogenesis is always dependent on • Phosphoenolpyruvate undergoes the reversal of
β-oxidation of fatty acids in the liver. glycolysis until Fructose 1,6-bisphosphate is
• During hypoglycemia, adipose tissue releases produced.
these fatty acids by breaking down triglyceride.
Fructose-1,6-bisphosphatase
• Regulatory enzymes that hydrolyzes phosphate
from fructose 1,6-bisphosphate rather than using it
to generate ATP from ADP.
• Fructose- 1,6-bisphosphatase is activated by ATP
and inhibited by AMP and fructose 2,6-
bisphosphate.
• Fructose 2,6-biphosphatse a molecule that
activates PFK-1 in glycolysis. This ensures that
both pathways are not active at the same time.

51
Glucose-6-phosphatase • In the presence of ROS, hemoglobin may
• Glucose-6-phosphate is converted to glucose by precipitate (Heinz bodies) and membrane lipids
glucose-6-phosphatase. may undergo peroxidation, weakening the
• Glucose-6- phosphatase is only in the liver membrane and causing hemolysis
• Deficiency of glucose-6-phosphatase leads to type • Several conditions that might exacerbate the
1a glycogen storage disease (Von Gierke disease) hemolysis:
characterized by hypoglycemia where patients are 1. Drugs: Sulfonamides, Nitrofurantoin, Primaquine,
unable to produce glucose by glycogenolysis or chloroquine, antituberculosis drugs
gluconeogenesis. 2. Acute viral or bacterial infections
3. Diabetic ketoacidosis
Substrates for gluconeogenesis 4. Inflammation promotes oxidation stress
• The carbon skeleton of glucogenic amino acids
results in the formation of pyruvate which leads to Clinical presentations
glucose production • Many individuals with G6PD deficiency are
• Oxidation of odd chain fatty acids yields 3 carbon asymptomatic.
propionyl COA • Neonatal hyperbilirubinemia (jaundice usually
• Succinyl COA formed from propionyl CoA enters appears within 24 hours after birth)
gluconeogenesis • G6PD resembles chronic granulomatous disease
G6PD which caused by genetic deficiency in NADPH
Overview: oxidase
• Function of G6PD is to protect red cells from • Fava beans may cause severe hemolysis in
oxidative damage G6PDH patients
• G6PDH is a metabolic enzyme involved in the Diagnosis
pentose pathway, especially important in red blood • Coombs test- negative
cell metabolism. • Heinz bodies/ bite cells on peripheral blood smear
• Because red blood cells contain a large amount of • Decreased Hb and Hct, normal MCV
oxygen, they are prone to spontaneously generate • Increased LAD
ROS that damage protein and lipid in the cell • Increased indirect bilirubin
• Glucose-6-phosphate dehydrogenase deficiency is • Beutler fluorescent spot test
an X- linked recessive hereditary disease Treatment
characterized by abnormally low levels of glucose- • Prevention by vaccination
6-phosphate dehydrogenase. • Vitamin E/ selenium
• More common among black, Middle Eastern, and • Blood transfusion
Mediterranean populations • Patients with chronic hemolysis or non-spherocytic
• Male cases are overrepresented than female cases anemia should be placed on daily folic acid
supplements.
Pathophysiology • The accumulation of the radicals in erythrocytes in
G6PDH deficiency gives protection against
malaria
Fructose metabolism

•
G6PD deficiency impairs the ability of an
erythrocyte to form NADPH resulting in
hemolysis
• NADPH helps restore glutathione stores so that
glutathione can then reduce reactive oxygen
species (ROS) (H2O2) to less harmful compounds
H2 O

52
Overview: • Dietary lactose present in milk
• Fructose is found in honey and fruit and as part of • Lactose is hydrolyzed to galactose and glucose by
the disaccharide sucrose lactase associated with the brush border membrane
• Absorption is not dependent on insulin of the small intestine
• Fructose is metabolized in liver and muscle • Galactose reaches the liver through the portal
• Fructose bypass PFK1 not like glucose and blood.
galactose Galactose metabolism pathway
• The 2 important enzymes in fructose metabolism • Galactose is phosphorylated by galactokinase
are: • Galactose 1-phosphate is converted to glucose 1-
phosphate by galactose 1-P uridyltransferase and
1. Fructokinase an epimerase
2. Fructose 1-P aldolase (aldolase B) • Genetic deficiency of Galactokinase and
uridyltransferase produce galactosemia
Essential fructosuria Hereditary deficiency of galactokinase
• Defect in fructokinase leads to accumulation of • Autosomal recessive disease
fructose in the blood stream • Due to accumulation of Galactitol (from
• Hexokinase becomes 1° pathway for converting conversion of the excess galactose in peripheral
fructose to fructose-6-phosphate. blood to galactitol)
• Genetic deficiency of fructokinase is benign • Cataracts, a characteristic clinical presentation in
• Detected in blood and urine patients with galactosemia
• Often asymptomatic • Accumulation of galactitol in the lens causes
osmotic damage and cataracts.
Hereditary Fructose Intolerance • High levels of galactose in the blood and urine
• Defect in aldolase B leads to accumulation of • May present as failure to track objects or to
fructose 1-phosphate in the liver and renal develop a social smile
proximal tubules. Classic galactosemia
• Deficiency in aldolase B also inhibits • Autosomal recessive disease
glycogenolysis and gluconeogenesis • Due to absence of galactose-1-phosphate
• Autosomal recessive uridyltransferase leads to accumulation of
• Characterized by: galactitol in the lens of the eye
• Signs and symptoms appear early in development
o Hypoglycemia when infants begin feeding
o Liver cirrhosis that include:
o Jaundice o Failure to thrive
o Vomiting o Jaundice/ hepatomegaly
• Symptoms are reversed after removing fructose o Hypoglycemia
and sucrose from the diet. o Mental retardation
o Infantile cataract
Galactose metabolism • Treatment: exclude galactose and lactose
Overview: (galactose + glucose) from diet.
Sources of Galactose:
Sorbitol
Overview:
• Cells use glucose for energy; however, unused
glucose could trap inside organs when aldose
reductase reduces it to sorbitol

53
Sorbitol and diabetes Treatment:
• Hyperglycemic state, the affinity of aldose • Avoiding lactose containing food or add lactase
reductase for glucose rises causing much sorbitol bills to the meal
to accumulate, and using much more NADPH Amino acid metabolism
• High blood levels of galactose also result in Overview
conversion to the osmotically active galactitol via • Amino acid metabolism involves deamination by
aldose Reductase moving its amino group to alpha-ketoglutarate,
• Some tissue lack sorbitol dehydrogenase such as forming glutamate.
retina, lens, kidney, and nerve cells, hence, sorbitol • Degradation of an amino acid, occurring in the
can accumulate under conditions of hyperglycemia liver and kidneys
• Liver, Ovaries, and Seminal vesicles have both • Amino acid catabolized into both ketogenic and
enzymes glucogenic products
• Amino acids can be classified according to the
Signa and symptoms properties of their main products as either of the
Due to intracellular sorbitol accumulation following:
• Retinopathy 1. Glucogenic (Ability to form glucose by
• Cataract gluconeogenesis)
• Peripheral neuropathy • Glucogenic amino acid help production of
pyruvate or TCA intermediates such as
Lactase deficiency (oxaloacetate, α-ketoglutarate, succinyl CoA, or
fumarate) when they are degraded
• Besides gluconeogenesis, glucogenic amino acids
produce lipids and energy
2. Ketogenic (In ability to form glucose, still be
used for ketogenesis or lipid synthesis)
Overview: • Ketogenic amino acid help production of
• Lactose is a disaccharide of galactose and glucose acetoacetate or one of its precursors, such as acetyl
• Digested by lactase to form glucose and galactose CoA or acetoacetyl CoA, providing lipids and
in the brush border of the intestine energy.
• Examples: Leucine and lysine, the two exclusively
Lactose containing food ketogenic amino acids,
• Diary product
• Processed food Note: isoleucine, phenylalanine, tryptophan, and tyrosine
are considered both glucogenic and ketogenic amino acid
Lactose deficiency
• Also called lactose intolerance or hypolactasia Metabolism of Phenylaniline:
• Defined as inability to digest and metabolized • Converted to Tyrosine
lactose • Considered both glucogenic and ketogenic amino
• Might developed due to loss of intestinal brush acid
border • Phenylaniline is hydroxylated by phenylalanine
• Most common among African American and Asian hydroxylase and produce tyrosine
• Congenital lactase deficiency is a genetic disorder • This step requires Tetrahydrobiopterin, which is
that prevent lactase expression from the first feed oxidized to dihydrobiopterin, meanwhile NADPH
is converted to NADP+
Signs and symptoms
• bloating Metabolism of Tyrosine
• cramp • Tyrosine first undergoes transamination to Para-
• osmotic diarrhea hydroxyphenylpyruvate

Diagnosis
• when the patient complained of abdominal pain,
flatulence
• Stool acidity test
• Hydrogen breath test

54
 2. Conversion of methionine to cysteine &
cystine
3. Degradation of cysteine & its conversion to
specialized products.

• Methionine has to be activated to S-

adenosylmethionine (SAM) or active methionine
to donate the methyl group.
• SAM is the main source of methyl groups in body
• ATP is consumed in the formation of SAM
• • SAM transfers the methyl group to an acceptor &
Para-hydroxyphenylpyruvate hydroxylase help gets itself converted to S-adenosylhomocysteine
produce homogentisate (Homogentisic acid) • The Methyl groups are used for biosynthesis of
• Homogentisate oxidase cleaves the benzene ring of Epinephrine and also function as N-methylguanine
homogentisate to form Maleylacetoacetate cap on mRNA
• Eventually Maleylacetoacetate is converted to • S-adenosylhomocysteine is hydrolyzed to
Fumarate homocysteine
• Fumarate is an intermediate in citric acid cycle and • Homocysteine can be remethylated to methionine
serve as a precursor for gluconeogenesis by homocysteine methyl transferase with the help
of Vitamin B12
Products of tyrosine • Homocysteine condenses with serine to form
Melanin: Cystathionine in the presence of cystathionine B-
• Tyrosine is precursor for melanin and tyrosinase is synthase
involved in its formation
Catecholamines:
• Tyrosine is hydroxylated to 3,4 dihydroxy
phenylalanine (DOPA) by tyrosine hydroxylase
• This step requires B6 as a coenzyme
• DOPA undergoes decarboxylation using dopamine
decarboxylase (require vit B6)
• Dopamine is further hydroxylated to
norepinephrine
• Norepinephrine is methylated to epinephrine or
adrenaline by N-methyl transferase
• S-adenosyl methionine (SAM) is the methyl donor
Metabolism of branched chain fatty acids
• Valine, Leucine & isoleucine are the branched
chain & essential amino acids.
• Valine is glucogenic amino acid
• Leucine is ketogenic amino acid
• Isoleucine is both ketogenic & glucogenic amino
acid.
• Leucine produces acetyl CoA & acetoacetate, the
substrates for fatty acid synthesis
• Valine and isoleucine are converted to propionyl
CoA, a precursor for glucose
Methionine metabolism Urea Cycle
• The sulfur – containing amino acids are Overview
methionine, cysteine & cystine. • Body protein is catabolized primarily in muscle
• Methionine is glucogenic & essential amino acid. and in liver.
• Methionine (or sulfur amino acids) metabolism • The carbon skeletons can be converted in the liver
may be divided into three parts. to glucose (glucogenic amino acids), acetyl CoA,
1. Utilization of methionine for and ketone bodies (ketogenic), or in a few cases
transmethylation reactions. both may be produced (glucogenic and ketogenic).

55
 • Excess nitrogen is eliminated from the body in the • Hydrolytic cleavage of the guanidino group of
urine. arginine, catalyzed by liver arginase (ARG1)
releases urea, the other product, Ornithine,
Urea Cycle reenters liver mitochondria for additional rounds
A. Formation of Carbamoyl phosphate of urea synthesis

Genetic deficiency of Urea cycle

Ornithine trans Carbamoylase deficiency
• Most common urea cycle disorders
• Ornithine Transcarbamoylase deficiency causes
enhanced excretion of Uracil.
• Excessive excretion of Uracil or its precursor
Orotic acid, results from an accumulation of
Carbamoyl phosphate in the mitochondria.
• Excess carbamoyl phosphate is converted to
orotic acid (part of the pyrimidine synthesis
pathway)
• Could occur with neonatal onset during the first
24-72 hours
• Characterized by:
A. Hyperammonia
B. Elevated blood glutamine
C. Decrease blood Urea nitrogen
D. Increase orotic acid in blood and urine
• N.B in case of carbamoyl phosphate synthetase
deficiency there NO Increase in orotic aciduria
• Difference between Carbamoyl phosphate
synthetase and Orithine Transcarbamoylase

Carbamoyl phosphate Synthetase Ornithine Transcarbamoylase

Hyperammonemia Hyperammonemia
• Increased Blood glutamine Increased Blood glutamine
Urea, which contains two nitrogens, is synthesized Decreased BUN Decreased BUN
in the liver from aspartate and carbamoyl NO orotic aciduria Orotic aciduria
phosphate, which in turn is produced from
ammonium ion and carbon dioxide by Clinical Presentations:
mitochondrial carbamoyl phosphate synthetase. • Lethargy
• carbamoyl phosphate synthetase is a rate- • Vomiting
limiting enzyme of the urea cycle, activated only • Hyperventilation begin and, if not treated, progress
in the presence of N-acetyl glutamate to coma, respiratory failure, and death
• All the following steps take care in the cytosol: Hyperammonia
B. Formation of Citrulline • Hereditary or acquired disorder
• The Carbamoyl group of Carbamoyl phosphate is • Excess of ammonia accumulate in the brain
transferred to ornithine, forming Citrulline and leading to glutamate depletion and inhibition of
ortho Phosphate TCA cycle
• The reaction is catalyzed by Ornithine trans • These conditions can be treated with a low protein
Carbamoylase diet and administration of sodium benzoate or
C. Formation of Argino succinate phenylpyruvate to provide an alternative route for
• Argininosuccinate synthase (ASS) links L- capturing and excreting excess nitrogen
Aspartate and Citrulline via the amino group of • Lactulose may be given to acidify the GIT and trap
aspartates and provides the second nitrogen of urea ammonia for excretion
D. Cleavage of Argino succinate Catecholamine synthesis/tyrosine catabolism
• Cleavage of arginosuccinate catalyzed by Catecholamines Synthesis
arginosuccinate lyase (ASL), proceeds with • Tyrosine is hydroxylated to 3,4 dihydroxy
retention of nitrogen in arginine and release of the phenylalanine (DOPA) by tyrosine hydroxylase
aspartate skeleton as fumarate • This step requires B6 as a coenzyme

56
 • DOPA undergoes decarboxylation using dopamine • Most common inborn error of amino acid
decarboxylase (require vit B6) metabolism
• Dopamine is further hydroxylated to Pathophysiology
norepinephrine • Due to deficiency of the enzyme phenylalanine
• Norepinephrine is methylated to epinephrine or hydroxylase (PAH) that impairs the body’s ability
adrenaline by N-methyl transferase to metabolize the essential amino acid
• S-adenosyl methionine (SAM) is the methyl donor phenylalanine. This leads to accumulation of
phenylalanine in body fluids
Diseases associated with catecholamines synthesis • PAH catalyzes the conversion of L-phenylalanine
Pheochromocytoma to L-tyrosine, the rate-limiting step in the oxidative
• Most common tumor of the adrenal medulla in degradation of phenylalanine
adults • Also, tetrahydrobiopterin deficiency results in
• A pheochromocytoma is a rare, catecholamine- elevated phenylalanine levels, known as malignant
secreting tumor derived from chromaffin cells phenylketonuria
(arise from neural crest) • The BH4 cofactor is also required for
• pheochromocytoma has classically been associated hydroxylation of tyrosine (a precursor of
with 3 syndromes—von Hippel-Lindau (VHL) dopamine) and tryptophan (a precursor of
syndrome, multiple endocrine neoplasia type 2 serotonin)
(MEN 2), and neurofibromatosis type 1 (NF1) Clinical Presentations
Pathophysiology • Fair skin and hair: Resulting from impairment of
• Pheochromocytoma result from excessive melanin synthesis
catecholamine (norepinephrine and epinephrine) • Eczema (including atopic dermatitis)
secretion by the tumor
• Stimulation of alpha-adrenergic receptors results
in elevated blood pressure, increased cardiac
contractility, glycogenolysis, gluconeogenesis, and
intestinal relaxation.
• Stimulation of beta-adrenergic receptors results
in an increase in heart rate and contractility
Clinical presentations
• Headaches
• Palpitations • Light sensitivity
• Diaphoresis • Hair loss
• Severe hypertension • Intellectual disability (the most common finding
• Pallor overall)
Diagnosis • Musty or mousy odor due to elevated levels of
• Pheochromocytoma is diagnosed by measuring phenylalanine metabolites such as phenylacetate,
elevated levels of vanillylmandelic acid (VMA) phenylacetate, and phenylpyruvate
(catecholamine metabolites) in blood or urine • Infants with classic phenylketonuria (PKU) are
• CT scanning or MRI is the preferred technique for normal at birth (due to maternal transfer) but if
localizing pheochromocytomas untreated show slow development, severe mental
Neuroblastoma retardation, autistic symptoms, and loss of motor
• Neuroblastoma is a poorly differentiated neoplasm control
derived from neural crest cells that typically Maternal PKU
affects infants and children younger than 5 years • Women with PKU who become pregnant must be
of age. especially careful about the phenylalanine level in
• Results from dopamine breakdown their blood so as not to adversely affect neurologic
• Associated with enhanced HVA and VMA development in the fetus
(catecholamine metabolites) in urine and • Infants whose phenylketonuria mothers have not
overexpression of maintained adequate metabolic control during
N-myc oncogene. pregnancy have a high risk for mental retardation,
Phenylketonuria microcephaly, seizures, tremors and failure to
Overview thrive.
• Autosomal recessive disease 1:10,000 Treatment

57
 • Life-long semisynthetic diet restricted in Pathophysiology
phenylalanine (small quantities are necessary • Due to deficiency of the hepatic enzyme
because it is an essential amino acid) homogentisate 1,2-dioxygenase (HGO) forces
• Increase tyrosine levels (Essential amino acids in the accumulation of homogentisic acid, which is
children) and tetrahydrobiopterin supplementation rapidly cleared in the kidney and excreted
• Aspartame (Artificial sweetener) should be • HGO is very important for tyrosine degradation
avoided in patients with Phenylketonuria • When urine contacts with air, homogentisic acid is
oxidized to form a pigmentlike polymeric material
Maple Syrup Urine disease responsible for the black color of standing urine.
Pathophysiology
• Autosomal recessive disorder Clinical presentations
• known as branched-chain ketoaciduria, is an • Slate blue or gray discoloration may be found in
aminoacidopathy due to an enzyme defect in the the sclerae or ear cartilage.
catabolic pathway of the branched-chain amino • Diminished joint mobility
acids leucine, isoleucine, and valine • Dark black urine
• Branched-chain alpha-keto acid dehydrogenase • Debilitating arthralgias
(BCKD) enzyme complex, catalyzes the • Progressive deposition of pigmentlike polymer
decarboxylation of the alpha-keto acids of leucine, material into collagenous tissues occurs.
isoleucine, and valine to their respective branched- • Black pigmented patches in the sclera developing
chain acyl-CoAs in patients aged 30-39 years (ochronosis)
• These are further metabolized to yield acetyl-CoA, Treatment
acetoacetate, and succinyl-CoA • Treatment includes diets low in phenylalanine and
• Absence of Branched-chain ketoacid tyrosine.
dehydrogenase lead to accumulation of these 3 Homocystinuria
amino acids Pathophysiology
• Note: BCKD require 5 cofactors: • Autosomal recessive disorders due to impaired
1. Thiamine B1 homocysteine metabolism
2. Lipoic acid • Homocystinuria might develop due to:
3. COA (Pantothenic acid)- Vitamin B5 1. Cystathionine synthase deficiency that lead to
4. FAD accumulation of homocysteine and methionine
5. Niacin B3 in blood and urine
Clinical presentations Treatment:
• Accumulation of branched-chain α-keto acids in o Increase cysteine in diet and decrease
the urine, causing a sweet odor methionine levels
• Accumulation of α-keto acids in the blood, lead to o Increase Vitamin B12 supplementation in
CNS defects, intellectual disability, and death order to shift conversion homocysteine to
• Severe metabolic acidosis methionine (using homocysteine
• Infants are normal for the first few days of life, methyltransferase) which require B12
after which they become:
o Progressively lethargic 2. Decrease affinity of cystathionine synthase for
o Lose weight pyridoxal phosphate
o Episodes of hypertonia and hypotonia Treatment:
o Urine develops a characteristic odor of o Increase Vitamin B6 and cysteine in diet
maple syrup
Treatment 3. Methionine synthase (homocysteine
• Treatment requires restricting dietary valine, methyltransferase) deficiency
leucine, and isoleucine. Especially in patients with Vitamin B12 deficiency
• Thiamine supplementations
Alkaptonuria
Overview
• Autosomal recessive disease
• Benign disease

58
 • Muscle glycogen is stored as an energy reserve for
muscle contraction

• Glycogen Synthesis
• Once Glucose is absorbed and enter the cell, it
converted to glucose-6 phosphate by glucokinase
enzyme
• Glucose-6- phosphate is converted to glucose 1-
phosphate and activated to UDP-glucose for
addition
to the glycogen chain by glycogen synthase
• Glycogen synthase is the rate limiting enzyme of
glycogen synthesis.
Clinical presentations • Glycogen synthase makes 1,4 linked polyglucose
chain
• High level of homocysteine in the urine
• Branching enzyme forms 1,6 bond to create a
• Mental retardation
branch
• Osteoporosis
• Tall stature Note: Branching enzyme is responsible for introducing
• Kyphosis α1,6-linked branches into the granule as it grows
• Lens subluxation (downward/ inward) • Glycogenolysis
• Accumulation of homocysteine in blood is • Glycogenolysis is the breakdown of glycogen and
associated with cardiovascular disease; deep vein also occurs in the cytosol
thrombosis, thromboembolism, and stroke • Glycogen phosphorylase is the rate limiting step in
• Dislocation of the lens (ectopic lens) glycogenolysis
• Vitamin deficiency associated with • Glycogen phosphorylase activated by
homocystinuria: Epinephrine and Glucagon and inhibited by
o Folate deficiency insulin
o Vitamin B12
• The glucose 1-phosphate formed is converted to
o Vitamin B6 glucose 6-phosphate by mutase enzyme
Glycogen synthesis& storage diseases
• Glycogen phosphorylase releases glucose 1-P from
• Overview the periphery of the granule until it encounters the
• Glycogen, a branched polymer of glucose, first branch points.
represents a storage form of glucose.
• Next, glucose-1-phosphate is converted to glucose-
• Glycogen synthesis and degradation occur in liver 6-phosphate by phosphoglucomutase.
and skeletal muscle, cardiac muscle and the kidney
• Glucose-6-phosphatase can then convert the
• Glycogenesis occurs in the cytosol glucose-6-phosphate into glucose.
• Debranching enzyme hydrolyzes both 1,4 and 1,6
bonds releasing glucose
Glycogen storage diseases:
• McArdle Disease
• Autosomal recessive disorder
• Deficiency of enzyme Myophosphorylase (the
muscle isoform of glycogen phosphorylase) is the
rate limiting step
• Type V glycogen storage disease

• Pathophysiology
Glycogenesis is stimulated by insulin and inhibited • Inability to break down glycogen to glucose-6-
by glucagon and epinephrine. phosphate in muscles leading to accumulation of
• During hypoglycemia, glycogen become the glycogen in muscles
source of glucose in the liver • Muscles lysis due to osmotic influx
• Glycogen stored in the liver is a source of glucose
mobilized during hypoglycemia

59
• Following muscle death, it releases myoglobin • Splenomegaly
develop myoglobinuria which is toxic to kidney • Growth retardation
leading to acute renal failure Diagnosis
Clinical presentations • Hypoglycemia
• Muscle cramps and muscle weakness • Myoglobinuria
• Fatigue • Increased serum lactate
• Burgundy colour urine, • Hyperlipidemia
• Rhabdomyolysis
• Exercise intolerance during the initial phase of Treatment
high-intensity exercise • High concentration of diet and corn starch
Diagnosis
• Increased creatinine levels • Pompe disease
• Elevated creatinine kinase • Autosomal recessive disorder
• Myoglobinuria • Type III glycogen storage disease
Treatment
• Restricted strenuous activity Pathophysiology
• Drinking the sucrose-containing drink, which • Due to deficiency in lysosomal α1,4 glucosidase
provides dietary glucose for the muscles to use enzyme
Von Gierke disease • The deficient enzyme normally resides in the
• Autosomal recessive disease lysosome and is responsible for digesting
Pathophysiology glycogen-like material accumulating in
• Glucose-6-phosphatase deficiency endosomes.
• Glycogen deposits in the liver (glucose 6-P • Enzyme deficiency leads to accumulation of
stimulates glycogen synthesis, and glycogenolysis glycogen in lysosomes
is inhibited) • Affects heart, muscles and liver
• Organs affected Hepatocytes, kidney, small
intestine Clinical presentations
• Shortness of breath
Clinical presentations • Breathing difficulty
• Severe hypoglycemia • Muscle weakness
• Seizures • Fatigue
• Hepatomegaly • Macroglossia
• Hypertension • Hepatomegaly
• Xanthomas • Decrease reflexes
Diagnosis • Aneurysms
• Increased serum lactate • Cardiomegaly
• Hyperlipidemia • Vacuolar myopathy
• Gout Treatment
• Nephropathy • Enzyme replacement therapy (lysosomal
Treatment glycogen-specific enzyme alglucosidase alfa) or
• Diet with high concentration of protein the treatment of infantile-onset Pompe disease,
(cornstarch) including in patients younger than age 8.
• Frequent oral glucose • High protein diet
• Avoidance of fructose and galactose • Respiratory toilet is important in noninfantile
Cori disease cases.
• Autosomal recessive disorder
• Type III glycogen storage disease
Pathophysiology
• Debranching enzyme deficiency
• Inability to break 1,6 links glycogens
Clinical Presentations
• Hepatomegaly
• Seizures
Lysosomal storage disease

60
Ceramide pathway Types of Sphingolipidoses diseases

Fabry disease
• X-linked recessive disorder
• Caused by a mutation in the gene that encodes the
lysosomal enzyme alpha-galactosidase which leads
to accumulation of Ceramide trihexoside in the
lysosomes.
Clinical Presentations
• Small, raised reddish-purple blemishes on the skin
(angiokeratomas)
• Peripheral neuropathy of hand and feet
• Eye manifestations, especially cloudiness of the
• Ceramide waxy lipids composed of fatty acids and cornea
sphingosine • Impaired arterial circulation and increased risk of
• Concentrated within the cell membrane of heart attack or stroke
eukaryotic cells • Cardiovascular disease
• Plays an important role in Cellular signaling, • Kidney disease
proliferation, differentiation and apoptosis Gaucher disease
• Autosomal recessive disorder
• Caused by deficiency in β-Glucosidase enzyme
that lead to accumulation of Glucocerebroside
Lysosomal storage Clinical Presentations
diseases • Splenomegaly
• Hepatomegaly
• Septic necrosis of femur bone
• Fractures Pancytopenia or thrombocytopenia
• Characteristic macrophages (crumpled paper
inclusions)

Sphingolipids Mucopolysaccharidoses

1-Sphingolipids
• Located in plasma membrane
• Sphingolipids released when membrane is
degraded are digested in endosomes after fusion
with lysosomes
• Genetic deficiencies of many of these enzymes
are known, and the diseases share some of the
characteristics of I-cell disease Gaucher Cell "crumpled tissue paper" like
• Sphingolipidoses or disorders of sphingolipid cytoplasm Found in lymphoid tissue and BM of
metabolism affect neural tissue patients with
Gaucher's Disease
Sphingolipid functions Note: Enzyme replacement therapy is available for Gaucher
• Cell recognition patients.
• Cell signaling Niemann-Pick
• Function as cell surface antigens that can define • Autosomal recessive disorder
various blood types • Caused by deficiency in Sphingomyelinase
• Act as second messenger enzyme that lead to accumulation of
• Sphingolipidoses in case of deficiency of the Sphingomyelin
enzymes needed to break down sphingolipids Clinical Presentations:
• Cherry red spot in macula

61
 • Hepatosplenomegaly • X-linked recessive disorder
• Microcephaly • Caused by deficiency in alpha-L iduronidase
• Progressive neurodegenerative diseases enzyme that lead to accumulation of Heparan
• Foamy macrophages with zebra bodies sulfate and dermatan sulfate in lysosomes
Clinical presentations
Tay-Sachs • NO Corneal cloudiness
• Autosomal recessive disorder • Aggressive behavior
• Caused by deficiency in Hexosaminidase A Fatty acid synthesis
enzyme that lead to accumulation of Ganglioside Overview:
GM2 Sources of fatty acid
Clinical presentations 1. Diet
• Cherry red spots in macula 2. De novo synthesis from carbohydrates or protein
• Blindness 3. Adipolysis
• Death usually <2 years Fatty acid cycle principles:
• Startle reflex • Excess glucose converted to fatty acids in the liver
• Progressive neurodegeneration and eventually converted to adipose tissue for
storage
• Developmental delays
• Acetyl COA, ATP, NADPH and CO2 are essential
• lysosomes look like anion skin
for fatty acid cycle
Krabbe disease • Acetyl-CoA is the intermediate step and free
palmitate is the end product
• Autosomal recessive disorder
Fatty acid cycle
• Caused by deficiency in Galactocerebrosidase
enzyme that lead to accumulation of
Galactocerebroside
Clinical presentations
• Peripheral neuropathy
• Developmental delay
• Optic atrophy
• Globoid cells

Metachromatic leukodystrophy
• Autosomal recessive disorder
• Caused by deficiency in Arylsulfatase A enzyme
that lead to accumulation of Cerebroside sulfate • The cycle starts with high carbohydrate meal
Clinical presentations which is broken down to glucose
• Central and peripheral demyelination • Glucose either follow glycolysis or join HMP
• Ataxia and dementia (memory loss) shunt in order to produce NADPH
• Yellow vision • In glycolysis, glucose is converted into pyruvate
2-Mucopolysaccharidoses (cross to inner membrane of the mitochondria)
Hurler syndrome • In mitochondria, pyruvate is converted to acetyl-
• Autosomal recessive disorder CoA using pyruvate dehydrogenase enzyme
• Caused by deficiency in alpha-L iduronidase • The citrate shuttle transports acetyl CoA groups
enzyme that lead to accumulation of Heparan from the mitochondria to the cytoplasm for fatty
sulfate and dermatan sulfate in lysosomes acid synthesis.
Clinical presentations • Acetyl CoA combines with oxaloacetate in the
• Gargoylism mitochondria to form citrate.
• Dwarfism, hunched back • Citrate is transported into the cytoplasm.
• Claw hands • In the cytoplasm, citrate is broken down into
• Corneal cloudiness acetyl CoA and oxaloacetate.
• Airway obstruction • Oxaloacetate is converted to malate. This reaction
represents an additional source of NADPH
• Die in adolescence
• At this step, Acetyl-CoA is activated by acetyl
• Develop heart diseases
COA carboxylase in order to be converted to fatty
Hunter syndrome
acid

62
 • Acetyl COA carboxylase is the rate limiting step in Fatty acid oxidation cycle
fatty acid biosynthesis • During fasting, Fatty acid in adipose broke down
• Acetyl CoA carboxylase requires biotin, ATP, and and sent to the cytoplasm.
CO2. • Long chain fatty acid is activated before
• Acetyl CoA carboxylase activated by insulin transported to the mitochondria through Fatty acyl-
(dephosphorylation) and citrate CoA synthetase (addition of COA)
• Malonyl COA is produced by addition of CO2 • Fatty acid-COA is then transferred to the outer
• Malonyl COA is moved to the liver by fatty acid mitochondria membrane and converted to fatty
synthase (NADPH is required) acylcarnitine using carnitine shuttle (Carnitine
• Fatty acid synthase is rapidly induced in the liver acyltransferase-1)
after a meal by high carbohydrate and • Fatty acylcarnitine is transferred to the inner
concomitantly rising insulin levels membrane through carnitine transporter
• Triglycerides, the storage form of fatty acids occur Note: Carnitine ship back using transferase
in the liver and adipose tissue enzyme
• Liver sends triglycerides to adipose tissue • Acyl-carnitine move from inner mitochondria to
packaged as very low-density lipoproteins mitochondria matrix
• Carnitine acyltransferase-2 transfers the fatty acyl
Clinical correlate: group back to a CoA (mitochondrial matrix)
• Accumulation triglyceride consider a risk factor • Malonyl-COA act as feedback inhibition to
for several chronic diseases including prevent new synthesized fatty acids from entering
hypertension, cardiovascular diseases the mitochondria through inhibition of carnitine
• Chronic alcohol consumption destroys hepatocytes acyltransferase-1
and impair lipid metabolism leading to steatosis, or • Fatty acid oxidation release Acetyl-CoA and in
fatty degeneration of the liver parenchyma. return reduces NAD-NADH and FAD into
FADH2
Fatty acid oxidation • This step is initiated by fatty-acyl CoA
Overview: dehydrogenase (LCAD, MCAD)
• Fatty acid oxidation occurs in mitochondria • The FADH2 and NADH are oxidized in the
matrix, 2 C units are releases as acetyl COA per electron transport chain, providing ATP
cycle • In muscle and adipose tissue, the acetyl-CoA
• Fatty acids are activated on the outer enters the citric acid cycle
mitochondrial membrane, where they are oxidized • In a fasting state, Fatty acid oxidation (liver)
in the mitochondrial matrix produce more acetyl-CoA than used in citric acid
• Fatty acid oxidation occurs in liver, muscle and cycle. These units of acetyl-CoA are shifted to
adipose tissue produce ketone bodies
• Short-chain fatty acids (2–4 carbons) and medium- • Summary During starving, burning fatty acid
chain fatty acids (6–12 carbons) transported easily releasing more ATP
to the mitochondria to be oxidized, while, Long-
chain fatty acids (14–20 carbons) are transported Note: Insulin activate both acetyl-CoA carboxylase and
into the mitochondrion by a carnitine shuttle to be malonyl-CoA which indirectly inhibit fatty acid synthesis
oxidized
Genetic deficiency in fatty acid oxidation

Myopathic Carnitine Acyltransferase-2 CAT-2/CPT-2

deficiency
Pathophysiology
• Autosomal recessive disorder
• Either due to myopathic correlate or CAT 2
deficiency lead to decrease ATP production
Clinical presentation
• Muscle weakness
• Muscle cramping
• Episode provoked by prolonged exercise
especially after fasting or cold

63
 • Muscle biopsy shows elevated muscle triglyceride
detected as lipid droplets in cytoplasm
• Myoglobinuria
Treatment
• Decrease muscle activity and IV glucose
Medium Chain Acyl-CoA Dehydrogenase (MCAD)
Deficiency
Pathophysiology
• Deficiency in MCAD leads to lack of breakdown
fatty acids into acetyl CoA that lead to
accumulation of fatty acyl carnitines in the blood

Clinical presentations
• Profound fasting hypoglycemia
• Absent ketones
• Dicarboxylic aciduria Ketogenesis
• vomiting • Occurs in mitochondria of hepatocytes when
• lethargy excess acetyl-CoA accumulates in the fasting state
• Seizures • Acetyl-CoA is converted into acetoacetate using
HMG-CoA synthase which eventually reduced to
• Coma
3-hydroxybutyrate.
• Liver dysfunction
• 3-hydroxybutyrate is being used by the muscles
• Hyperammonemia
and brain
Treatment
Ketoacidosis
• Avoid fasting
• Alcoholics, diabetic patients and prolonged
• IV glucose
starvation usually develop ketoacidosis
• Frequent feeding, high-carbohydrate, low-fat diet
• In case of diabetic patients, fatty acid release from
Ketone bodies
adipose tissue and ketone synthesis in the liver
Overview:
exceed the ability of other tissues to metabolize
• Ketone bodies are water soluble molecules them leading ketoacidosis
includes (Acetoacetate, Beta-hydroxybutyrate and
• Alcoholics can also develop ketoacidosis. Excess
acetone)
NADH force production of excess malate which
• Acetone results from breakdown of acetoacetate eventually lead to accumulation of Acetyl-CoA.
• Ketone bodies produced in the liver • Excess Acetyl-CoA shunts glucose, amino acids,
(Mitochondria) and FFAs toward the production of ketone bodies
• Ketone bodies produced from beta-oxidation fatty • Excess of ketone bodies cannot used by RBS,
acid during prolonged starvation, alcoholism and instead lead to ketonemia and ketonuria
diabetes
• The liver cannot ketine bodies for energy because
• Ketone bodies are converted into Acetyl-CoA it lacks the enzyme thiophorase (β-ketoacyl-CoA
which enters citric acid cycle for energy transferase).
production Clinical presentations
• During fasting, muscle metabolizes ketones, • Breath with a sweet or fruity odor, acetone
preventing their accumulation in blood.
• Polyuria, dehydration, and thirst
• In case of increase ketone concentration in the
blood lead to ketoacidosis Note: The urinary nitroprusside test (Ketone test) detects
only acetoacetate and can dramatically underestimate the
extent of ketoacidosis and its resolution during treatment

Ketone bodies
Overview:
• The liver is central to the regulation of cholesterol
levels in the body
• the liver synthesizes the various lipoproteins
involved in transporting cholesterol and other
lipids throughout the body.
64
 • Lipoproteins are particles that contain • The fatty acids released enter the tissue for storage
triacylglycerol (TAG), cholesterol, phospholipids in adipose tissue, and the glycerol is retrieved by
and proteins called apolipoproteins. the liver
• Lipoproteins divided into 4 major types: • The chylomicron remnant is picked up by
hepatocytes through the apoE receptor
1. Chylomicrons • Following this hydrolysis, Chylomicrons remnant
2. Very low-density lipoprotein (VLDL) is formed (enriched in cholesterol ester and apoB-
3. Low-density lipoprotein (LDL) 48 and apo-E).
4. High-density lipoprotein (HDL)

• Triglycerides and cholesterol are transported in the

blood as lipoproteins.
• They classified according to the percentage of
protein in the particle from least dense to most
dense:
• Chylomicrons < VLDL < IDL (intermediate-
density lipoproteins) < LDL (low-density
lipoproteins) < HDL (high-density lipoproteins).
• The chylomicrons and VLDL are rich in
triglyceride but also have small amount of
cholesterol Easters

Very low-density lipoprotein (VLDL)

• VLDL and chylomicrons metabolism is similar
taken into consideration VLDL is being assembled
in the hepatocytes
• Sources of VLDL
1. Excess fatty acid on diet
2. Increased hepatic synthesis of fatty acid
3. Hepatocytes uptake of chylomicrons
• VLDL composed of triglyceride and cholesterol
ester, phospholipids and apoproteins (ApoB-100)
• ApoB-100 is added in the hepatocytes to mediate
release into the blood
Chylomicrons • VLDL acquire apoC-II and apoE from HDL in the
• Chylomicrons are synthesized by enterocytes from blood and are metabolized by lipoprotein lipase in
lipids absorbed in the small intestine. adipose tissue and muscle.
• Chylomicrons transport dietary triglyceride from VLDL remnants (IDL, intermediate-density lipoprotein)
the gut to liver or adipose tissue • VLDL removed from the capillaries by lipoprotein
• The enzyme lipoprotein lipase required for the lipase and the remaining portions will be either
metabolism of both chylomicrons and VLDL VLDL remnant or IlDL (intermediate-density
allowing the delivery of free fatty acid to muscle lipoprotein)
and adipose tissue • IlDL is losses its triglyceride content and keep its
• lipoprotein lipase is found in the surface of cholesterol ester portion
endothelial cell which is indirect contact with • A portion of the IDLs is picked up by hepatocytes
blood through their apoE receptor, but some of the IDLs
• While in the blood, chylomicrons acquire apoC-II remain in the blood, where they are further
and apoE from HDL particles metabolized to LDL
• lipoprotein lipase (in adipose tissue) is activated by Low density lipoprotein (LDL)
apoC-II • Once triglyceride reaches the liver it transformed
• apoB-48 is required for release from the epithelial into LDL
cells into the lymphatics. • The function of LDL is to deliver cholesterol to the
cells and tissue for biosynthesis

65
 • The uptake of cholesterol by cells is done by • Eventually cholesterol ester converted bile acids
receptor-mediated endocytosis • Workout and exercise might increase HDL levels
• ApoB-100 is the only apoprotein on LDL, and HDL plays an important role in atherosclerosis, by
endocytosis of LDL is mediated by apoB-100 picking up accumulating cholesterol before the
receptors (LDL receptors) advanced lesion forms
LDL and atherosclerosis • ApoA-1 activates LCAT, which in turn adds a
• When patient present high levels of LDL- LDL fatty acid to cholesterol to produce a cholesterol
could be oxidized by free radicals leading to ester that dissolves in the core of the HDL.
deposit on the endothelial basemen membrane
• The macrophages will engulf the oxidized LDL Hyperlipidemia
and degrade it forming foam cells Type I-Hyperchylomicronemia
• As the fatty streak enlarges over time, necrotic • Autosomal recessive genetic mutation
tissue and free lipid accumulates, surrounded by • Due to deficiency in lipoprotein lipase or
epithelioid cells and eventually smooth muscle apolipoprotein C II mutation
cells, an advanced plaque with a fibrous cap. • Associated with increase triglycerides levels in the
• The plaque eventually begins to occlude the blood blood
vessel, causing ischemia and infarction in the • Associated with elevated lipoprotein
heart, brain, or extremities. Chylomicrons in the blood
• By time the plaque becomes unstable leading to Clinical presentations
rupture and thrombosis causes: • Red-orange eruptive xanthomas
o Myocardial infarction • Fatty liver
o Acute ischemic stroke • Acute pancreatitis
o Mesenteric ischemia • Abdominal pain after fatty meal
o Claudication • Hepatomegaly
• Pancreatitis
• Characteristic creamy supernatant layer of
chylomicrons.
• NO risk of atherosclerosis
Type IIa-Familial hypercholesterolemia
• Autosomal dominant
• Due to absence of LDL receptors or defective
ApoB-100 that lead to elevated levels of LDL and
cholesterol
Clinical presentations
• High risk of atherosclerosis and coronary artery
High density lipoproteins (HDL) disease
• HDL is produced in the liver and released into the • Corneal arcus
blood stream • Homozygous condition, usually death <20 years
• They contain apoA-1 used for cholesterol recovery due to myocardial infarction
from fatty streaks in the blood vessels • Xanthomas of the Achilles tendon
• The main function of HDL to engulf cholesterol • Tuberous xanthomas on elbows
from the blood stream and send back to liver and Type IV-Hypertriglyceridemia
adipose tissue • Autosomal dominant
• This step is achieved by Lecithin–cholesterol • Due to hepatic overproduction of VLDL lead to
acyltransferase (LCAT) increase blood levels of VLDL and Triglycerides
• LCAT is an enzyme in the blood that is activated • Linked to insulin resistance
by apoA-1 on HDL Clinical presentations
• LCAT emulsifications producing cholesterol • Acute pancreatitis
esters, which dissolve in the core of the HDL, Type III-Dysbetalipoproteinemia
allowing HDL to transport cholesterol from the • Autosomal recessive disorder
periphery to the liver • Due to hepatic overproduction of VLDL that lead
• Cholesterol ester transfer protein (CETP) help to increase VLDL and Triglycerides
transfer HDL cholesterol esters to either LDL, or Clinical presentations
IlDL • Premature atherosclerosis

66
 • Tuberoeruptive xanthomas
• palmar xanthomas
Abetalipoproteinemia
• Autosomal recessive disorder
• Known as hypobetalipoproteinemia
• Due to low or absence of ApoB-48 and APoB-100
• Low level of serum triglycerides and cholesterol
• Absence of chylomicrons, VLDL, LDL
• Due to deficiency in Chylomicrons, lipid
accumulates in the enterocytes
• Abnormal absorption of vitamin A and E Ouabin: cardiac glycoside that inhibits ATP-dependent
sodium-potassium exchange across cell membranes. The
Clinical presentations binding of ouabain to the sodium-potassium pump (also
• Steatorrhea called Na+/K+ ATPase) prevents the conformational
• Cerebellar ataxia changes necessary for its proper function.
• Pigmentary degeneration in the retina Digoxin and digitoxin are potent inhibitors of cellular
Na+/K+-ATPase which cause intracellular sodium
• Acanthocytes (thorny appearing erythrocytes)
concentration to increase leads to indirect inhib ition of
• Possible loss of night vision
Na+/Ca2+ exchange leads to increase cardiac contractility
• Failure to thrive
• Greasy stool Pharyngeal arches and their derivatives
Treatment Abnormalities of Arch1
• Restriction of long-chain fatty acids, • Cleft lip
• Large doses of oral vitamin E. • Cleft palate
The Sodium-Potassium Pump
Overview
• The process of Sodium-Potassium exchange across
the cell membrane is mediated through active
transport
• This process requires ATP to provide the
necessary energy
• This process is responsible for maintaining the
large excess of Na+ outside the cell and the large
excess of K+ ions on the inside.
• It accomplishes the transport of three Na+ to the
outside of the cell and the transport of two K+ ions
to the inside
• Na+ / K+ pump is required to maintain action
potential in nerve cells.

67
 Chapter 2:

Microbiology

68
Bacterial cell wall • The major component of the outer layer of gram
Gram positive VS gram negative cell wall negative bacteria such as Neisseria and
Haemophilus species
• Composed of O antigen, oligosaccharide and Lipid
A
• Lipid A responsible for the toxic effects of the
bacteria
• In cases of bacterial infection, bacterial cells are
lysed by host immune system leading to release of
lipid A into the circulation causing fever, diarrhea
and eventually fatal endotoxic shock (septic shock)
Structure Gram positive Gram negative • LPS binds to several immune cells especially
Lipoteichoic acid Present Absent monocytes, dendritic cells and macrophages which
Peptidoglycan layer Thick multilayer Thin (single layer)
Periplasmic membrane Absent (rarely Obvious
promote the release of inflammatory mediators
seen) such as cytokines, Il4
Outer membrane Absent Present
Porins Absent Present Bacterial capsule
Lipopolysaccharide Absent Abundant
• Polysaccharide layer outside cell envelope
Flagella Present Present
Toxins Exotoxin Endotoxin and • When it’s neatly arranged called Glycocalyx,
Exotoxins however when it loses its integrity called Slim
Capsule Present Present layer
• Quellung reaction used to visualize capsule under
Peptidoglycan the microscope (anti-capsular serum)
• Composed of amino acids and glucose • Considered one of the virulence factors of the
• Involved in binary fission during bacterial cell bacteria, it prevents phagocytosis and inhibit
reproduction bacterial engulfment by macrophages
• Transpeptidase enzyme that cross-links the
peptidoglycan chains to form rigid cell walls
• Protects again osmotic pressure damage
Lipoteichoic acid
• Found in gram positive bacteria
• Help maintain cell wall rigidity Examples:
• Has antigenic properties being able to stimulate • Even- E. coli
specific immune response. • Some- Strep Pneumonia
• Produce IL1 and tumor necrosis factor (TNF) • Pretty- Pseudomonas aeruginosa,
• IL1 causes release of endogenous pyrogen • Nasty- Neisseria meningitis
• Increase functional chemokine secretion • Killers- Klebsiella pneumonia
• Inhibits lipopolysaccharide-induced adhesion • Have- Haemophilus influenza
molecule expression • Shiny- Salmonella typhi
• Bodies- Group B Strep
Periplasm
• The space between the inner and outer membrane
in Gram-negative bacteria
• Extremely small in gram positive bacteria in
comparison of gram negative
• Play several roles regarding transport, degradation
and motility
• β-lactamases are located in the periplasmic space Pilus and fimbriae
Note: β-lactamases cleave the amide bond in the β- • Required for bacterial conjugation
lactam ring, rendering β-lactam antibiotics • Bacteria attach to the pili to start the reproduction
harmless to bacteria cycles
Lipopolysaccharide (LPS) • Fimbriae is required by the bacterial to produce
biofilm

69
 Coccobacilli:

Flagellum
• Protein structure used for bacterial motility
Plasmid
• Circular DNA found in bacterial cytoplasm
• Carry genes which are essential for bacterial
resistance against antibiotics
Bacterial Morphology • A type of bacterium with a shape intermediate
Bacilli: between cocci (spherical bacteria) and bacilli (rod-
Gram Positive Gram Negative shaped bacteria).
Clostridium E. Coli
• Examples: Haemophilus influenzae, Gardnerella
Bacillus Enterobacter vaginalis, and Chlamydia trachomatis
Listeria Proteus
Spirilla:
Mycobacterium Salmonella
• large, elongate, spiral shaped, rigid cells
Pseudomonas
• Gram-negative, curved and spiral-
Yersinia shaped bacteria found in stagnant, freshwater
Legionella environments
Shigella • Some species cause rat bite fever
Klebsiella • Examples: Borrelia, Treponema, Leptospira,
Spirillum
Helicobacter
•
Vibrio
Pseudomonas

Cocci:
• Diplococci (e.g. Streptococcus
pneumoniae and Neisseria gonorrhoeae)

• Streptococci (e.g. Streptococcus pyogenes).

• Staphylococci irregular (grape-like) clusters of cocci

(e.g. Staphylococcus aureus).

Branching filaments:
• Called filament form the appearance
of branching when two filaments attach to one
another.

70
 • Actinomycetes, Norcardia
Endospore producing bacteria:
• Examples: Bacillus anthrax and clostridium
perfringes

Poor staining bacteria:

• Treponema (thin to be detected)
• Mycobacteria (high lipid cell wall content)
• Mycoplasma (without cell wall)
• Legionella, Rickettsia, Bartonella, Anaplasma and
Ehrlichia (intracellular bacteria)
• Chlamydia atypical cell wall due to decrease
muramic acid (intracellular)
Giemsa stain
• Method used to detect phosphor group on the
DNA
• Help to identify intracellular parasites
plasmodium,trapanosoma, histoplasma, chlamydia
• Periodic acid Schiff stain (PAS):
• Method used to detect polysaccharide (sugar) such
as glycogen, glycoprotein and Proteoglycan
(signaling molecules at surface)
• Used to stain macrophages in whipple’s disease
• Whipples’s disease: Bacterial infection caused by
Tropheryma whipplei
Ziehl nelson staining (carbol fuchsin)
Stains and special culture requirements • Known as acid fast stain
Principle of bacterial staining: • Used to differentiate between acid fast
• Basic stain: stain -ve charged molecules in the (Mycobacterium) and non-acid fast (Norcardia)
bacterial cell surface • Acid-fast bacteria retain carbol fuchsin, so they
• Acidic stain: stain +ve charged molecules in the appear red.
bacterial Capsule India ink
Gram stain • Used for negative staining and encapsulated
organisms
• Method used to differentiate between gram
positive and gram-negative bacteria • Visualize in dark background
• Depends on the composition of the cell wall • Used for identification of Cryptococcus
Principle: neoformans (Large polysaccharide capsule)
• By addition of crystal violet, all bacteria appear Silver ink (Gomori’s Methenamine silver stain GMS)
violet • Method used to stain fungi and bacteria.
• Addition of iodine form crystal violet iodine • The fungi and bacteria are turned black, while
complex (crystals) everything else is stained green with Light green
SF solution.
• Addition of acetone/alcohol: Bacteria with thick
peptidoglycan cell wall become dehydrated and • Chromic acid oxidation forms aldehydes from
retain the crystal violet iodine complex (violet), fungal cell wall mucopolysaccharide components
however, bacteria with thin peptidoglycan layer • Fungi ( Coccidioides E , Pneumocystis jirovecii)
unable to retain these crystals (appear pink) • Bacteria ( Legionella, Helicobacter pylori)
• Safranin (counterstain) stain gram negative
bacteria (red)

71
Bacterial growth curves • contain red blood cells which have been lysed at
Bacterial growth phases: 80 C
Lag phase: • Contain also factor V NAD and factor X hemin
• The number of bacterial cells remain constant but • Used to isolate Haemophilus influenza and
start preparing for cell division Neisseria meningitis
• Phase of metabolic activity Thayer Martin Media (VPN):
• Last from 0-5 hours • Entails 3 different antibiotics
Exponential (log) phase: • Vancomycin: to cover gram positive bacteria
• The number of bacterial cells increased • Polymyxin: to cover gram negative bacteria
significantly • Nystatin: to kill fungi
• From 5-10 hours • Used to isolate Neisseria gonorrhea and meningitis
Stationary phase Bordet-Gengou agar:
• Bacterial growth reaches steady state, the number • Contain blood, potato extract, and glycerol, with
of new cells produced balances the number of cells an antibiotic such as cephalexin or penicillin
that die • Used to isolate Bordetella Pertussis
• Most of culture nutrients are consumed resulting in Tellurite plate, Loffler’s media:
accumulation of metabolites • Used to isolate Diphtheria and Clostridium
• Lasts more than 10 hours Lowenstein Jensen Agar:
Death phase • Used to isolate mycobacterium Tuberculosis
• Occur when incubation period exceeds stationary Eaton’s Agar:
phase • Used to isolate Mycoplasma Pneumonia
• The culture medium lacks nutrients hence bacteria Charcoal yeast agar:
die • Used to isolate Legionella
• Viable count: the number of actively Sabouraud agar:
growing/dividing cells in a sample • Used to isolate Fungi
Special culture requirements: MacConkey agar
Chocolate blood agar: • Used to isolate gram negative and enteric bacilli
based on lactose fermentation
• Used to isolate detection of E. coli 157:H7.
Type of culture Uses • Charcoal yeast • Legionella
agar
• Chocolate blood • Haemophilus
agar influenza and
• Sabouraud agar • Fungi
Neisseria
meningitis
• MacConkey • E. coli 157:H7
agar
• Thayer Martin • Neisseria
Media gonorrhea and
meningitis
Obligate Aerobes and Anaerobes
Overview:
• Bordet-Gengou • Bordetella
• Bacterial metabolism of oxygen yields superoxide
agar Pertussis
radicals which are toxic to the cells, only bacteria
containing enzymes (catalase, peroxidase,
• Tellurite plate, • Diphtheria and superoxide dismutase) can survive in the presence
Loffler’s media Clostridium of oxygen

• Lowenstein • Mycobacterium
Jensen Agar Tuberculosis

• Eaton’s Agar • Mycoplasma

Pneumonia

72
 • Lack catalase and superoxide dismutase
• Clostridium, Actinomyces and Treponema

2.2. Facultative anaerobes

• Versatile bacteria which could grow under
both aerobic and anaerobic conditions.
• Energy production through aerobic respiration
or fermentation process
• Staph, E.coli, Listeria vibrio, Salmonella,
Shigella, Klabsella
• Based on bacterial oxygen requirements, bacteria
could be divided into: 3. Microaerophiles:
1. Aerobes: • Could grow under reduced oxygen concentration,
• Could survive in ambient air and can’t grow in its prefer fermentation for energy production
absence • Jars or bags might be a possible environment for these
1.1. Obligate aerobes: bacteria.
• Absolute dependent on oxygen for survival (ATP • Streptococcus pyogenes, H. Pylori, Borrelia and
production) Campylobacter.
• Lack of fermentation process
• Nocardia - pulmonary infection in 4. Aerotolerance bacteria:
immunosuppressed patients • Anaerobic bacteria that could survive in presence of
• Pseudomonas- common in burns, diabetic wounds, oxygen but can’t use oxygen for energy production
pneumonia (cystic fibrosis)
• Mycobacterium tuberculosis causes fever, weight
loss, cough
• Bacillus

2. Anaerobes
2.1. Obligate anaerobes:
• Can’t survive in the presence of oxygen (oxygen is
toxic for them)
Classification Characteristics Examples

Obligate aerobes • Require oxygen • Nocardia

• Produce superoxide dismutase
• Pseudomonas
• M.Tuberculosis
• Bacillus

Obligate anaerobes • Cannot survive in oxygen • Clostridium

• Lack catalase and superoxide dismutase
• Actinomyces
• Treponema

73
 Facultative • Could grow under both aerobic and • Staph
anaerobes anaerobic conditions.
• E.coli
• Listeria vibrio
• Salmonella
• Shigella
• Klebsiella

Microaerophilic • Could grow under reduced oxygen • Streptococcus pyogenes

concentration
• H. Pylori, Borrelia
• Campylobacter

Aerotolerance • Anaerobic bacteria survive but can’t use

oxygen

Bacterial Endotoxin

LPS

Tissue
Macrophages Complements
Factors

Nitric
IL 1 TNF C3a C5a
oxide

Effects of Endotoxins:
• Produce by gram negative bacteria • Endotoxin initiate liver released Il4 which causes
• Endotoxin upregulates TNF-α, IL-1 and IL-6, fever
complement and coagulation pathways • TNF is one of the main cytokines responsible for
• Lipopolysaccharide (LPS): The major component septic shock
of the outer layer of gram negative bacteria such as • TNF induces vasodilation and loss of vascular
Neisseria and Haemophilus species permeability and eventually leads to hypotension
• Composed of O antigen, oligosaccharide and Lipid • Nitric oxide a potent vasodilator -hypotension
A
• Lipid A responsible for the toxic effects of the
bacteria
• In cases of bacterial infection, bacterial cells are
lysed by host immune system leading to release of
lipid A into the circulation causing fever, diarrhea
and eventually fatal endotoxic shock (septic shock)
• LPS binds to several immune cells especially
monocytes, dendritic cells and macrophages which
promote the release of inflammatory mediators • Hypotension is usually associated with reflex
such as cytokines, Il4 tachycardia

74
 • Reflex tachycardia ↓Co= ↑HR X SV↓ • Superantigens bind first to the MHC Class II on
antigen presenting cells then T cell receptors
• These cascades of inflammation eventually lead to
severe toxic shock
Overprod
uce
inflamma
tory
mediator
s
Cytokine EX IL-
Superanti s 1,IL-6
gens EX IFN and TNFα

T cell Activates
activatio macroph
ns ages

• Note: During septic shock the heart attempts to

compensate by working harder, increasing the Bacteria produces Superantigen
heart rate and the amount of blood pumped. Staphylococcus aureus:
Eventually, the bacterial toxins and the increased • Produce Superantigen that causes toxic-shock-like
work of pumping weaken the heart. As a result, the syndrome (TSLS)
heart pumps less blood, and vital organs receive • The most common toxin is TSS toxin type-1
even less blood. (TSST-1)
• Endotoxins activates the complement system • Signs and symptoms:
(Anaphylatoxins C3a,5a) which lead to increase • Fever
vascular permeability, swelling and neutrophil • Rash
chemotaxis.
• Hypotension
• LPS acts on platelets and causes disseminated
• Skin peeling
intravascular coagulation (DIC) leading to
• Desquamation, typically of the palms and soles
ischemic damage to various organs e.g brain
Mechanism of shock:
(encephalopathy), Kidney (renal failure), Heart
(cardiac arrest). • The patient first subjected to Staph infection
• Untreated infection progresses to systemic
E-Endotoxin infection especially in patients lacks protective
N-Nitric oxide antitoxin antibody
D-DIC/death • Once the infection reached the blood circulation,
O-Outer membrane the toxin will trigger cytokines release (IL-1) and
T-TNF-alpha TNFα
O-O antigen Streptococcus pyogenes (Erythrogenic toxin):
E-Extremely heat stable • Named as streptococcal pyrogenic exotoxin SPE
I-Il-1 • When injected intradermal into susceptible
N-Neutrophil chemotaxis individuals produced erythematous reaction (Dick
Bacterial Exotoxin part 1 test)
Overview • Three types of SPE (A, B, C)
• Exotoxins are produced inside most of gram- Symptoms include:
positive bacteria • Fever
• Exotoxins are secreted and causing severe damage • Shock
to the tissues • Desquamation
• The genes of most of exotoxins are carried inside • Rash
plasmids • Hypotension
• Highly immunogenic Different toxins produced by Staphylococcus aureus:
Categories of Exotoxins: Alpha toxin
Superantigen • Pore-forming toxin
• Group of antigens which induce continuous T-cell • Has cytotoxic effect
activation leading to massive cytokine release

75
 • Create unregulated pores in the membrane of
targeted cells Activate Loss of
Beta toxin Guanyla electroly
↑cGMP
• Produce an enzyme called sphingomyelinase C te tes and
which is toxic to many cell types including cyclase water
macrophages, leukocytes, fibroblasts and
erythrocytes • Heat labile toxin (AB toxin) similar to cholera
Gamma toxin toxin
• Comprises two non-associated protein • The toxin activates adenylate cyclase-↑ cAMP-
• Damage leukocytes Increased chloride secretion (Secretory or watery
Panton-Valentine leucocidin diarrhea)
• Cytotoxin • LT composed of A and B components
• Associated with increased virulence of certain • The A component is enzymatically active, and
strains the B component is the cell binding component.
• Associated with community-associated
Methicillin-resistant staphylococcus aureus (CA- Heat labile Enterotoxin
MRSA) Secretio
• Causes necrotic hemorrhagic pneumonia n
Enterotoxin of chlori
ADP- de ions
• Heat stable toxin ribosylatio and
• Associated with food poisoning and traveler’s n of the Activate
water
diarrhea alpha- adenylcyc ↑cGMP
subunit of lase from
Exfoliative toxins (Disambiguation) a Gs the ente
• Associated with staphylococcus skin scalded protein rocyte in
syndrome (SSSS) to
Different toxins produced by Streptococcus pyogenes the gut l
umen.
Streptolysin O
• Immunogenic
• Oxygen labile
• Hemolytic (hemolysis of red blood cells)
• Anti-streptolysin O titer used to measure
streptolysin O antibodies levels for the diagnosis
of scarlet fever and rheumatic fever
Streptolysin S
• NOT Immunogenic
• Cardiotoxic Bacillus Anthracis (Anthrax)
Pyogenic exotoxin A, B, C • Causes Anthrax (Cutaneous anthrax)
• Causative agent of scarlet fever and toxic shock • Cutaneous anthrax characterized by
syndrome necrotic, black eschar
Bacterial Exotoxin part II • Produce Edema Toxin which increase fluid
Toxins increase fluid secretion in the gut: secretion and lead to neutrophils dysfunction
• Edema toxin is a lethal toxin leads to cell death
Diarrhea Vibrio Cholerae:
• Produce Cholera Toxin that causes ↑cAMP
(Increase NaCl secretion and H2O efflux)
Bacillus Vibro
E.coli • Characterized by watery diarrhea named as rice-
anthrasis cholerae water stool
E coli: • Hypersecretion of electrolytes and water
• Enterotoxigenic E. coli causes Traveler’s diarrhea Yersinia Enterocolitica
• Enterotoxins produced by ETEC include heat- • Causes diarrhea, enterocolitis
labile enterotoxin (LT) and heat-stable • Acute terminal ileitis (Pseudo corhn disese)
enterotoxin (ST). • Right quadrant pain RLQ (pseudo appendicitis)
Heat stable enterotoxin • Yersinia stable toxin -↑ CAMP that lead to
diarrhea
76
 • Invade mucosal wall causing bloody diarrhea 1. Toxin A: which is responsible for toxin
Protein synthesis inhibition toxins: activity
Shigella species: 2. Toxin B: Receptor binding domain which
binds to Epidermal growth factor (EF-2)
leading to cardiac and cranial nerve
deficits
• Mechanism of action depend on releasing an
exotoxin (Toxin A) which inhibit adenosine
diphosphate (ADP) ribosylation of EF-2 which
eventually inhibit protein synthesis
Pseudomonas aeruginosa
• Exotoxin A is responsible of tissue necrosis.
Inhibit protein synthesis by inhibition of
• Penetrate through mucosal surface of colon and elongation factor-2 through ADP-ribosylation of
invade intestinal epithelium releasing shiga toxin EF2.
• Shiga toxin inhibits protein synthesis (inactivate • Exotoxin A composed of A and B components
60S ribosome) which lead to GI mucosal damage-
• The A component is enzymatically active, and
dysentery
the B component is the cell binding component.
• Shiga toxin enhances cytokine release causing Neurotransmitter release inhibitors:
hemolytic uremic syndrome (HUS)
Clostridium Tetani:
• Associated with diarrhea and severe dehydration
Enterohemorrhagic E. coli 0157:H7:
• Produce shiga like toxin
• Causes hemorrhagic colitis
• Bloody diarrhea
• Bind to epithelial cells and produce shiga like
toxin that block protein synthesis causing cell
death
• Considered as foodborne infection (undercooked
or contaminated food commonly associated with •
Clostridium tetani infect the patient at the wound
Burger)
site and release tetanus toxin
• Associated with Hemolytic uremic syndrome HUS
• Tetanus toxin induce tetanic paralysis
characterized by progressive renal failure,
hypotension, hemolytic anemia, ↑ LDH and • MOA: Inhibits the release of Inhibitory
uremia neurotransmitters such as GABA and glycine from
interneurons leading to lack of inhibition
(continuous activation or muscle contraction)
• The patient suffers from sustained muscle
contraction in the jaw (trismus) and facial muscles
(risus sardonicus)
• Opisthotonus or arching of the back
Clostridium Botulinum:
• Heat labile toxin which prevent release of acetyl
choline release at neuromuscular junctions that
leads to termination of paralysis causing rapid
flaccid paralysis
• In adult associated with spore ingestion though
canned or jarred food
• In babies associated with floppy baby syndrome
Corynebacterium Diphtheria:
through jarred honey
• Causes Pseudomembranous pharyngitis (grayish
• Symptoms are urinary retention and constipation,
white membrane)
dyspnea, dysarthria, dysphagia
• Produce Shigella toxin
• Shigella toxin composed of 2 fragments:

77
 Coagulase test:
• Used to differentiate staph. Aureus from another
coagulase negative staph such as staph. Epidermis
and staph. Saprophyticus
• Coagulase is an enzyme like protein which causes
plasma to clot by converting fibrinogen to fibrin.
Novobiocin sensitivity test:
• Novobiocin resistance is intrinsic to staph.
Saprophyticus ONLY
• Used to differentiate between coagulase negative
Clostridium Perfringes: Staphylococci
• Attack soft tissues and wound, associated with Gas Hemolysis test:
gangrene by producing enterotoxins (α toxin) • Differentiated test for hemolytic reaction
• α-toxin hydrolyses and cleaves phospholipid C and • Blood agar is used for this test
diacylglycerol leads to myonecrosis • Alpha α hemolysis means partially breakdown of
• Could survive in undercooked food leads to food hemoglobin (Greenish color)
poisoning • Beta is complete lysis of red blood cells
• Diagnosis through blood culture (double zone of • Gamma means NO hemolysis
hemolysis) Optochin sensitivity test:
Bordetella Pertussis: • Used to differentiate between Strep. Pneumonia
• Primary cause of whooping cough from other alpha hemolytic streptococci
• Pertussis toxin inhibit G protein coupled receptor • Strepto. Pneumoniae is the only streptococcus
• Has one A subunit (toxic part) ↑cAMP and B susceptible to small concentration of the antibiotic
subunit (involved in binding) Bacitracin susceptibility test:
Increased cAMP associated with: • Bacitracin is a polypeptide antibiotic derived from
• ↑ insulin release leading to hypoglycemia B. subtilis that functions to block cell wall
• ↑ histamine sensitization, cough and vascular formation by interfering with the
permeability dephosphorylation of the lipid compound that
• Interfere with phagocytosis of neutrophils which carries peptidoglycans to the growing microbial
increase the survival of the microbe and prolong cell wall.
the disease. • Used for identification of Group A staphylococci
(S. Pyogenes).
Clinical bacteriology Salt tolerance test for enterococcus species:
• The ability of the bacteria to grow in high salty
medium
• This test is used to identify enterococcal group D
Gram positive staphylococcus
• Staphylococcus aureus
• Staphylococcus epidermis

Catalase test: • Staphylococcus saprophyticus

• Used to test the presence of catalase enzyme in the Staphylococcus aureus:
bacteria • Frequently found in the skin, nose and respiratory
• It’s an essential test to differentiate between system
streptococcus and staphylococcus • Catalase and Coagulase positive

78
 • Virulence factor (Protein A) binds to FC complex Common to appear in female genital tract (UTI)
of the antibody hence prevent bacterial engulfment Gram positive Streptococcus:
by macrophages (Inhibit phagocytosis) • S. Pneumoniae
Diseases caused by S. aureus: • S. Virdans
• Skin infections:
• S.Pyogenes (Group A streptococci)
• Folliculitis (carbuncle)
• Impetigo (baby honey crusted vesicles) • S.agalactiae (Group B streptococci)
• Wound infection-abscesses • Group D streptococci
• Pneumonia: initially started by flu, fever, coughing, S. Pneumoniae:
shortness of breath (after influenza infection) • Catalase negative
• Kidney: Urinary tract infection in the bladder • Optochin sensitive organism
• Heart: Endocarditis • Encapsulated cocci (quelling test)
• Brain: meningitis • Alpha hemolytic
• Bones: osteomyelitis, septic arthritis • Secrete IGA protease
• GIT: S. aureus food poisoning diarrhea and emesis Diseases caused by S. Pneumoniae:
(short incubation period 2-6 hours) • Meningitis (fever, headache)
• Eye: Blepharitis • Otitis media
• Pneumonia
MRSA: Methicillin resistant S. aureus which is responsible • Sinusitis
for nosocomial infection • Septic arthritis
Acquired resistance through Penicillin binding protein 2A • Endocarditis
(PBP2A) (new form created by MRSA capable of cell wall
• Patients without a spleen, HIV and
synthesis immunocompromised patients are susceptible for
Note: Linezolid, Daptomycin and vancomycin are overwhelming sepsis with Streptococcus
commonly used antibiotic for more resistant strains pneumoniae. Prophylaxis by (Prevnar vaccine)
S. aureus toxic mediated diseases such as S. Virdans:
• Toxic shock syndrome TSST-1 (Fever, shock, • Found in the oral flora and saliva
hypotension, ↑ALT, AST)
• Alpha hemolytic positive and catalase negative
• Associated with prolonged used of vaginal
• Optochin sensitivity used to differentiate between
tampons or nasal packing
S. Pneumoniae and S.Virdans (resistant to
• Rapid onset food poisoning (Enterotoxins) optochin)
• Exfoliative Toxin A or B scalded skin syndrome in • Negative quelling test
babies (Impetigo) honey crusted vesicles
• strep mutans and mitis cause dental cares
• MRSA is usually associated with Panton-Valentine
• Strep Sanguinis could cause subacute endocarditis
leucocidin (cytotoxin)
following a dental procedure especially for
• Panton-Valentine leucocidin is an aggressive toxin damaged prosthetic heart valve
which increase bacteria’s ability to infect skin
• Staphyloxanthin considered as a new virulence NOTE: Quelling reaction (test the presence of
factor created by S. aureus to develop resistance polysaccharide capsule) and optochin sensitivity test are
against the immune system used to differentiate between S. Pneumonia and S. Virdans
Staphylococcus Epidermis:
S.Pyogenes (Group A streptococci)
• Found in the skin also contaminate blood cultures
• β hemolytic positive and catalase negative
• Coagulase negative and catalase positive Diseases caused by S. Pyogenes:
• Infect prosthetic devices such as hip plant, IV
• Skin infection like Staph. Aureus (Folliculitis,
catheter and foley catheter through biofilm
cellulitis, impetigo)
adherence
• Pharyngitis (sore throat)
• Intravascular devices such as prosthetic heart
• Necrotizing fascitis causes gas gangrene
valves and shunts
• Toxic shock syndrome
• Treatment with Vancomycin with or without
Rifampin, Gentamycin
Staphylococcus Saprophyticus: • Auto immune disorders:
Rheumatic fever:
• Coagulase negative and catalase positive
• Common to occur in developing countries

79
 • Cross reactivity (heart failure-Edema-myocarditis- S. Pyogenes (Group B streptococci):
chest pain) common children 5-15 years old Streptococcus agalactiae
• Occurs 2-3 weeks after the patient experienced • Common to live in female’s vagina
pharyngitis • Associated with infection of newborn (neonatal
• Fever meningitis, pneumonia and sepsis)
• Valvular damage • Catalase negative- β hemolytic
• Elevated ESR or C-reactive protein • pregnant woman with (35-37 gestation) are tested
• Red rash for infection, and if positive Penicillin is given for
• Subcutaneous nodules aschoff bodies prophylaxis
• Sydenham chorea Key words: Strep. Agalactiae – inside the vagina- babes
• Type II hypersensitivity reaction infection
Acute glomerulonephritis (Acute post streptococcal Group D streptococci:
nephritis) • Catalase negative- hemolytic
• Appear after a week of infection • 4 types
• Tea colored urine • 2 are Enterococci (Enterococcus faecalis and
• Treatment by Penicillin Enterococcus faecium)
• Type III hypersensitivity reaction • 2 of which are not (Streptococcus bovis and
• Hematuria (tea colored) Streptococcus equinus)
• Hypertension • Streptococcus bovis is associated with colon
• Edema cancer, bacteremia and subacute endocarditis
• Antibody–antigen complexes deposit in the • Enterococci:
glomerular basement membrane. • More resilient than streptococci, can grow in bile,
NaCl 6.5%
✓ usually grow inside colon flora
✓ These species are resistant to many antibiotics
✓ Associated with nosocomial infection VRE
Vancomycin resistant enterococci
✓ Associated with UTI, endocarditis and bacteremia

Keywords: Strept.bovis Colon cancer- Enterococci

(nosocomial infection VRE-colon flora)
Bacillus Anthracis

Overview:
• Rod shape
• Gram positive encapsulated bacteria
• Only organism which has a protein capsule D-
glutamate
Virulence factors:
• Streptolysin O
• M protein (anti phagocytic)
• Anti C5a peptidase
• Streptolysin S
• Hyaluronidase
• Exotoxin
• DNase B
• Pyogenic exotoxin

• Streptolysin S & O: could rupture RBCs and WBCs

• Antibodies for streptolysin O (ASO) or anti-DNase B
indicate a recent infection Cutaneous anthrax:
Key words: Strep. Pyogenes- rheumatic fever (Type II • Anthrax is considered a disease of herbivores such
sensitivity)-acute glomerulonephritis (Type III sensitivity)- as sheep, goat, horses
Virulence factors • Lives dormant in soil with the spores
80
 • Human become infected when in contact with • Inhibits the release of Inhibitory neurotransmitters
infected animals such as GABA and glycine from interneurons
• Mechanism of infection usually acquired by the leading to lack of inhibition (continuous activation
entry of the spores through injured skin (cutaneous or muscle contraction)
anthrax) • The patient suffers from sustained muscle
• Named as woolsorter’s disease contraction in the jaw (trismus) and facial muscles
• Associated with painless necrotic ulcer with black (risus sardonicus)
eschar • Opisthotonus or arching of the back
• Mechanism of pathogenesis: through delivery of • Prophylaxis through tetanus vaccine
Exotoxin called edema toxin which increase fluid • Treatment by administration of tetanus toxin
secretion and lead to neutrophils dysfunction immunoglobulin (tetanus vaccine booster),
• Edema toxin is a lethal toxin leads to cell death antibiotics, muscle relaxant (Diazepam) and
Inhalation Anthrax: wound debridement
• Inhalation of the spores lead to fever, flu like Clostridium botulinum
symptoms, myalgias, pulmonary hemorrhage, • Heat labile toxin which prevent release of acetyl
mediastinitis choline release at neuromuscular junctions that
• Widening mediastinum in chest x- ray leads to termination of paralysis causing rapid
• chest pain flaccid paralysis
• septic shock • In adult associated with spore ingestion though
• lung crackles due to hemorrhage canned or jarred food
• Positive exudates • In babies associated with floppy baby syndrome
Diagnosis: through jarred honey
• Blood culture • Symptoms are urinary retention and constipation,
• hemorrhagic CSF dyspnea, dysarthria, dysphagia
• widening mediastinum in chest x- ray • Treatment by injection of human botulinum
• lung crackles immunoglobulin
Clostridium perfringens
• Positive exudates
Treatment • Attack soft tissues and wound, associated with gas
gangrene by producing enterotoxins (α toxin)
• Antibiotics
• α-toxin hydrolyses and cleaves phospholipid C and
• Monoclonal antibody called raxibacumab
diacylglycerol leads to myonecrosis
Bacillus Cereus • Could survive in undercooked food leads to food
Overview: poisoning
• Causes food poisoning • Diagnosis through blood culture (double zone of
• The spore survives high temperature in cooking hemolysis)
rice known as Reheated type syndrome Clostridium difficile
• The Spore survive the cooking process and • Causes pseudomembranous enterocolitis
germinate enterotoxin • Occurs as a result of prolonged antibiotic
• Treatment with antibiotic isn’t recommended since administration such as Clindamycin and
the causal agent is toxins ampicillin, also proton pump inhibitors
• Infection with Bacillus Cereus divided into 2 • Associated with diarrhea
types: • Produces 2 toxins:
1. Nausea and Vomiting which usually 1. Toxin A (enterotoxin) which alter fluid
occur within 1-5 hours caused by secretions
cereulide (performed toxin) 2. Toxin B (Cytotoxin) which disrupt
2. Diarrhea type characterized by non- cytoskeleton
bloody diarrhea within 8-15 hours • Treatment by Metronidazole and Vancomycin
Clostridium species • For recurrent cases, use fidaxomicin and fecal
Clostridium tetani microbiota transplant
• Often found in rusty places • Diagnosed by colon spectroscopy, stool analysis
• Clostridium tetani infect the patient at the wound and PCR
site and release tetanus toxin Corynebacterium Diphtheria:
• Tetanus toxin is tetanic paralysis Overview:
• Gram positive bacilli
81
 • Slender rods with clubbing at both ends Diagnosis
• Grow on tellurite agar • Culture on potassium tellurite (forms gray-black
• Rare in US due to availability of vaccines cultures)
(DTAP/DPT) • Diagnosed by culture metachromatic granules
Pathogenesis (blue and red) with aniline dye
• Throat swab
• Elek test diphtheria toxin
• Leukocytosis (proteinuria)
• Loeffler coagulated blood serum
Treatment:
• Antibiotics: Erythromycin or Penicillin
• Vaccines: Antitoxin immunoglobulin, TDaP
(tetanus, diphtheria and pertussis)
Listeria Monocytogenes:
• The only gram-positive bacteria that produces
endotoxin
• Listeria monocytogenes could be found in dairy
products, vegetables, fish and meat products
• In healthy patients could cause mild gastroenteritis
• Listeria develops rocket tail structure which allow
free motility
• Causes Diphtheria • Grows at 4 degrees inside macrophages especially
• Affect the pharynx of young children less than 12 in immunocompromised patients
years old via respiratory droplets • In healthy individual CD4T cells kills the bacteria
• Composed of 2 fragments: inside the macrophages
3. Toxin A: which is responsible for toxin Who are at risk with listeriosis:
activity Immunocompromised patients such as
4. Toxin B: Receptor binding domain which 1. Infants
binds to Epidermal growth factor leading 2. Elderly patients
to cardiac and cranial nerve deficits 3. Patient receive chemotherapy
• Mechanism of action depend on releasing an 4. HIV/AIDS
exotoxin (Toxin A) which inhibit adenosine 5. Patients can develop brain abscesses
diphosphate (ADP) ribosylation of elongation Pregnant women are subjected to bacteremia which results
factor-2 (EF-2) which eventually inhibit protein in
synthesis 1. Neonatal death
Clinical presentations: 2. Premature labor
• Causes fever, sore throat 3. Amnionitis
4. Continuous abortion (granulomatosis
• Pseudomembranous pharyngitis (grayish white
membrane) infantiseptica)
5. Still birth (dead baby)
• Swelling
Newborn could acquire listeriosis during vaginal infection:
• Cervical lymphadenopathy 1. Neonatal meningitis
• Dysphagia and cough 2. Flu like symptoms
• lymphadenopathy, myocarditis 3. Headache
• arrhythmias 4. Diarrhea
5. Fever
6. Cyanosis (Neonatal Listeriosis)
Diagnosis:
• Tumbling motility in broth.
• CSF collection by lumbar puncture
• Colonies are surrounded by zone of β-hemolysis
Treatment:
• Ampicillin
• Trimethoprim-sulfamethoxazole (TMP-SMX).
82
Actinomyces 2. Reticulonodular or diffuse alveolar pulmonary
Overview: infiltrates,
• Actinomyces are gram positive anaerobe, beaded 3. Lung abscess formation
filamentous bacilli (Not acid fast) 4. Pleural effusion
• Lives in oral bacterial flora Treatment
Pathogenesis: • Surgical removal of the abscess
• Occurred usually post-surgical operation • TMP-SMX
• prevalent in periodontal pockets, dental plaques, Mycobacterium Tuberculosis
and on carious teeth Overview:
Clinical presentations: • Infectious contagious disease
• Cervicofacial actinomycosis characterized by • Gram positive acid-fast bacteria
abscess formation, draining sinus tracts, fistulae, • Heating is needed to melt the outer cell wall in
and tissue fibrosis order to allow penetration and staining with
• Oral facial nodules carbolfuchsin (resist depolarization by acid)
• Sulfur granules (small yellow bodies found in the • Hydrophobic aerobic bacilli (obligate aerobic)
pus of actinomycotic abscesses and consisting of require high level of oxygen for survival
clumps of the causative actinomycete. • Grow slowly
• Lock Jaw • Mycobacterium Tuberculosis cell wall
Diagnosis characterized waxy lipid content such as mycolic
• Microscopic examination of the pus, which usually acid
contain yellow sulfur granules • This thick lipid cell wall allows to survive within
• Increased inflammatory markers (↑ESR, ↑CRP, the macrophages for years
↑WBC) • Mycobacterium entail 2 virulence factors:
Treatment
• Abscess drainage through surgical therapy and • 1-Cord factor allow mycobacterium to form long
excision of sinus tracts and recalcitrant fibrotic and slender formation
lesions, decompression of closed-space infections
• Penicillin is considered the drug of choice for ▪ The cord factor inhibits neutrophils migration and
treatment of actinomycosis damage mitochondria
Nocardia ▪ Cord factor causes elevation in the levels of TNF
Overview: interfere with lipid metabolism, causing a severe
• Nocardia are gram positive aerobe (Weak acid weight loss.
fast) ▪ Intracellular growth of M. tuberculosis causes
• Lives in the soil increased activation of macrophages, and
• Differentiated from actinomyces by acid-fast subsequent production of multiple cytokines.
staining, as Nocardia typically exhibit varying
degrees of acid fastness due to the mycolic acid 2- Sulfatides- inhibit the phagosome lysosome
content of the cell wall fusion which is important for intercellular survival
Pathogenesis: Pathogenesis:
• Causes Nocardiosis (opportunistic infection) • Mycobacterium spread from person to person
• Associated with immunocompromised patients through the air
causing pulmonary and cutaneous infection • Common in older adults and immunocompromised
• Nocardia infection characterized by its ability to patients (e.g., AIDS patients, who lack the cellular
disseminate to any organ, particularly CNS, and its immunity necessary to combat this bug).
tendency to relapse • Lower immunity leads to secondary TB
Clinical presentations: • Primary TB starts with idiopathic symptoms
• lung abscesses and cavitations • Probability of TB transmission depend on:
• Fever ➢ The immune system status of the exposed person
• Productive cough ➢ Length of exposure
Diagnosis ➢ Virulence or strength of TB
• Microscopic examination of the pus,
• Blood culture- Gram positive and weak acid fast
• Radiographic findings such as:
1. Irregular nodules (which may cavitate),

83
 1-
Primary exposure of bacteria from active host
2-
Neutrophils and macrophages release name as
facultative intracellular growth
3- Bacteria starts to multiply inside the
macrophages
4- Then diffuse from macrophages to lymphatics
(facultative intracellular growth)
5- Initiation of cell mediated immunity
6- Macrophages migrate to lymph node for
protection
7- More macrophages are being activated by
Gamma interferons and IL-12
8- Lung necrosis associated with formation of
granuloma around dead macrophages
Pathogenesis life cycle: (calcified structure from fibroblast and
Mostly Primary TB collagen) caseous necrosis
Comparison between Primary and Secondary tuberculosis
Primary TB Secondary TB

Incidence Affect 5-10% of patients which develop Reactivation during immunocompromised state
active TB

Infection site Affect upper lobe (most oxygenated part)

Symptoms Asymptomatic BUT can lead to exudative • Miliary TB (hazy glass appearance)
plural effusion
• Fever

• Night sweat

• Weight loss

• Malaise

• Dry cough progressed to purulent sputum

• Hemolysis

• Apical rales (lung exam)

Clinical Diagnosis of TB:

Extrapulmonary TB: 1. Chest X-ray upper lobe infiltrate with cavitation
Usually occur in case of reactivated TB or Secondary TB characterized by:
• Lymph node infection (lymphadenopathy): called • Pleural diffusion
scrofula and manifests as large, matted lymph • Ghon complex calcified primary focus
nodes. • Ranke’s complex- calcified primary focus plus
• Pleural and pericardial infection presents (pleural calcified lymph node
effusion) 2. Sputum sampling, the definitive diagnosis is
• Kidney infection (WBS without bacteria) sterile identified TB with acid staining
Pyuria • 3 morning samples and cultures takes 4-8 weeks
• Brain infection: Subacute meningitis 3. PCR DNA of TB
• Pott’s disease 4. Tuberculin skin test (PPD) purified protein
• Choroidal tubercles derivative used to test latent TB

84
 • Purified protein derivative (PPD): used to test • Highly contagious
whether the patient has already developed • Leonine like face (lion-like face)
immunity towards TB • Lethal
• It is positive for active, latent, and past infections, • Nasal cartilage (saddlenose deformity), testes
demonstrating only the presence of a type IV (infertility), and eyes (blindness).
hypersensitivity (cell-mediated response) to TB Lepromatous Tuberculoid:
antigens • Occurs in response high immune response humoral
• A subdermal injection of proteins is read 48 to 72 Th1-type immune response
hours later • Non-contagious
• acid-fast bacteria in sputum is the only test to • Low bacterial load
diagnose active infections Treatment:
• In healthy patients PPD >15 mm
Lepromatous Leprosy Lepromatous
• Homeless and high prevalence exposure, prisoners,
Tuberculoid
health care workers are vulnerable to TB
• If PDD with 10mm means that the patient Treatment Dapsone+ Rifampin+ Dapsone+
develops reactivated TB Clofazimine Rifampin
• For HIV patients who under close with TB
patients, chest x-ray showed positive Ghon
complex with > 5mm. Signs and symptoms:
❖ Occurs slowly through the year
Treatment of Tuberculosis: • First symptoms: Numbness and loss of
2 months regimens by the following drugs then switch for 4 temperature sensation
months (INH +Rifampin) • With disease progression: Loss of pain, touch
Isoniazid (INH): sensation
Side effect: ❖ Reddish skin patch
• Peripheral neuropathy –overcome by giving Clinical diagnosis:
(Vitamin B6-Pyrodoxin • Can’t grow in culture (grow in mouse footpad)
• Hepatotoxicity monitor AST, ALT levels • Skin biopsy, PCR
Rifampin • Lepromin skin test
Side effects: Neisseria
• Red orange urine Overview:
• induced CYT P-450 (double the dose) Neisseria
Pyrazinamide
Ethambutol
Side effects: Optic neuritis
N. Gonorrhea N. Meningitis
Leprosy
Overview: • Both N. Gonorrhea and N. Meningitis are Gram-
• Chronic mycobacterium disease negative, diplococci
• Caused by Mycobacterium Leprae (acid fast Neisseria Gonorrhea
bacillus) • NO poly saccharide capsule
• Bacteria prefer to grow in cooler conditions such • The second-most common sexually transmitted
as skin, nose, eyes disease (STD) after chlamydia.
• Affects peripheral nerves causing glove and • Catalase and Oxidase positive
stocking “loss of sensation” • Glucose fermenter
• Like TB, Mycobacterium Leprae develops Pathogenesis
resistance against macrophages • The term gonorrhea refers to urethritis
• The protection mechanism depends on innate and/or cervicitis in a sexually active person.
immune system • N. Gonorrhea spread during sexual contact, also
Types: could be transmitted from the mother to the
Lepromatous Leprosy: newborn during birth
• Affects the entire body • Gonorrhea can also spread throughout the body to
• Depend on the immune system of the host (low cause localized and disseminated disease
cell mediated immunity)

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Clinical presentations: • Affects neonates causing neonatal conjunctivitis
Males Females (ophthalmia neonatorum) from the birth canal
• Urethritis • Vaginal discharge treated by silver nitrate eye drops
(yellowish white • Vaginitis • Symptoms include eye pain, redness and purulent
discharge) Inflammation of discharge
• Acute vaginal wall) • Treatment by application of silver nitrate or
epididymitis • Dysuria erythromycin eye drops to prevent ophthalmic
• Renal infection • Dyspareunia infection
• Burning upon (painful Diagnosis:
urination intercourse) • Culture from female or male discharge exudate on
• Urethral exudate • Endometritis Thayer- martin medium (chocolate agar)
• Prostatitis (infection of the • Thayer-martin medium entails mixture of different
uterus) antibiotic called VCN inhibitors such as
• Mild lower 1. Vancomycin to kill Gram positive
abdominal pain organisms
2. Colistin or Polymyxin to kill Gram
negative organisms
• Vaginal discharge: The most common presenting 3. Nystatin as antifungal
symptom of gonorrhea, vaginal discharge from • A positive culture will indicate infection with N.
endocervicitis is usually described as thin, purulent, Gonorrhea
and mildly odorous; however, many patients have
minimal or no symptoms from gonococcal cervicitis NOTE very important:
• 80% of infected women are asymptomatic ❖ A negative culture on Thayer-Martin in a patient
(endometritis) exhibiting symptoms of pelvic inflammatory
disease most likely indicates an infection
• Most of the cases of endometritis progress to
with Chlamydia trachomatis.
salpingitis (inflammation of the fallopian tubes) or
oophoritis (inflammation of the ovaries) called pelvic
inflammatory disease (PID) which characterized by • Gram stain (kidney shaped diplococci)
▪ Abdominal pain Treatment
▪ Fever • Ceftriaxone is the antibiotic of choice for
▪ Discharge Gonorrhea
▪ Irregular bleeding • In case of sexually transmitted gonorrhea
▪ Fibroid tissue deposition which might cause (Ceftriaxone+ azithromycin) or doxycycline to
sterility cover Chlamydia (common coinfection)
▪ Progress to abscesses, Peritonitis • Administration of condoms to decrease sexual
▪ Scarring of the fallopian tube lead to fallopian transmitted disease
ectopic pregnancy • No vaccine available BUT a recent vaccine
▪ Infection and inflammation may spread to the liver produced in 2018 called MeNZB vaccine is shown
capsule causing acute gonococcal perihepatitis to have efficacy, albeit relatively low, against N.
(Fitz-Hugh-Curtis syndrome) gonorrhoeae
Virulence factors:
Fitz-Hugh-Curtis syndrome associated with Violin- • Pili help in attachment of gonococci to mucosal
string (adhesions of parietal peritoneum to liver) surfaces and contribute to resistance by preventing
• N. Gonorrhea BUT NOT Chlamydia can cause ingestion and destruction by neutrophils.
oropharyngeal infection through oral sex • Neisseria LPS is referred to
• N. Gonorrhea could develop septicemia or as lipooligosaccharide (LOS) to protect against
disseminated gonococcal infection manifested by phagocytosis
arthritis-dermatitis syndrome then progress to • Porin channels (porA, porB) form pores in the
septic arthritis outer membrane help invading epithelial cells
Characterized by fever, joint pain • Opacity-associated (Opa) proteins increase
NOTE: Examination of synovial fluid reveal gram- adherence between gonococci and phagocyte
negative diplococci within white blood cells Neisseria Meningitis
(WBCs) • Gram negative diplococcus
• Catalase and oxidase positive

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 • Thick polysaccharide capsule • Culture on Thayer-Martin VCN media
• Glucose positive maltose fermentation • Quellung reaction
Pathogenesis Virulence factors:
• Meningococcal meningitis primarily affects • Thick polysaccharide capsule protects against
infants, children, and young adults phagocytosis
• Meningococcal meningitis can occur as an • Lipo-oligosaccharide endotoxin (LOS)
epidemic in subgroups in closed quarters such as • Immunoglobulin A1 (IgA1)
people in the military services or students in Treatment:
dormitories • Ceftriaxone and Penicillin are drugs of choice for
• Transmitted by Inhaled droplets/ oral secretions treatment
• There are at least 13 serogroups of the bacterium, • Ciprofloxacin and rifampin for prophylaxis
with the most important being serogroups A, B, C, • Serogroup A, B, C, Y and W-135 meningococcal
and W-135 infections can be prevented by vaccines.
Clinical presentations:
Haemophilus Influenzae
• Meningococcemia (meningitis or sepsis) affect
central nervous system but usually proceeded by Overview:
sore throat or respiratory infection • Small, pleomorphic, gram negative coccobacillus
• The neurologic damage associated with meningitis • Some strains possess polysaccharide capsule and
is a consequence of the following 3 main subdivide into 6 different types (a-f), the most
processes: virulent strain is H influenzae type b (Hib)
1. Direct bacterial toxicity Types of Haemophilus Influenzae
2. Indirect inflammatory processes, such as cytokine Typeable Non typeable
release, ischemia, vasculitis, and edema Haemophilus type Nontypeable H
3. Systemic effects, including shock, seizures, and B (Hib) influenzae (NTHi)
cerebral hypoperfusion
• Initially the symptoms started by fever, headache, Capsule Encapsulated Nonencapsulated
a stiff neck, nausea, vomiting and altered mental
state such as confusion or coma
• The bacteria release endotoxin (LPS), causing
vascular hemorrhage (seen as a petechial rash) and Causativ • Epiglottiti • Mucosal
an acute inflammatory response (seen as spiking e agent s Infection
fever, chills, arthralgia, and muscle pain) of Common in ❖ Otitis media
• Meningococcal infection may spread through the children from 6 ❖ Pneumonia
bloodstream and localize in other parts of the body months to 3 years ❖ Conjunctiviti
causing Septic arthritis, purulent pericarditis • Infantile s
• Systemic meningococcal infection causes adrenal meningiti ❖ Bronchitis
hemorrhage and insufficiency Known as fulminant s
meningococcemia or Waterhouse-Friderichsen • Neonatal
syndrome infection
Waterhouse-Friderichsen syndrome: such as
• Defined as adrenal gland failure due to bleeding bacteremi
into the adrenal gland. Characterized by a in kids
hypotension, vasomotor collapse, septic shock, Vaccine Available Not available
disseminated intravascular coagulation (DIC),
adrenal insufficiency followed by cardiovascular • Infants are more susceptible to Hib due to lack of
dysfunction and multiple organ failure immune globulin to Hib
• Skin rash is one its characteristic features with Epiglottitis
pink macules or papules progress to large purpuric • Upper airway obstruction with acute onset of
plaques inflammatory edema
• Treatment: Antibiotic and glucocorticoids to • Swelling significantly reduces the airway aperture
increase blood pressure levels • Associated with dysphagia, respiratory distress
Diagnosis • The thickening of the epiglottis results in the
• Retrieval of meningococci from Blood, CSF, joint "thumb sign".
fluid • Most commonly in children with 1-5years old

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 • Availability of Hib vaccine significantly reduced Pathogenesis:
its incidence • Causes whooping cough
• Pertussis is a toxin-mediated disease.
• Pertussis is a very contagious disease, spreads
from person to person by coughing or sneezing
• The bacteria attach to the cilia of the respiratory
epithelial cells, produce toxins that paralyze the
cilia, and cause inflammation of the respiratory
tract, which interferes with the clearing of
pulmonary secretions
• whooping cough affects mostly unimmunized
infants and young adults
Clinical stages of Pertussis:
• Pertussis is a 6-week disease divided into
incubation, catarrhal, paroxysmal, and
convalescent stages
Incubation Period:
Diagnosis
• Patient gets inoculated
• Lumbar puncture for CSF analysis (gram negative
• Last for 7-10 days with mild respiratory symptoms
rods)
Catarrhal Period:
• Culture through chocolate agar
• It includes nasal congestion, rhinorrhea, and
• Growth requirement, Factor X (hematin), factor V
sneezing, low-grade fever, tearing.
(NAD)
• Pertussis is most infectious when patients are in
• Satellite phenomena, Hib grows around colonies of
the catarrhal phase
Staph. Aureus on unheated blood agar
• Last for 1-2 weeks
• Staph. Aureus lysis blood cells releasing Factors X
• At this point, culture analysis could be done.
and V, hence, Hib feed on them
Paroxysmal Period:
• Quelling reaction for detection of polysaccharide
• Patients present with paroxysms of intense
capsule
coughing lasting up to several minutes.
Virulence factors:
• This stage lasts cough 2-4 weeks
• Thick polysaccharide capsule (polyribosylribitol
phosphate) protects against phagocytosis • Initially dry, intermittent evolved into inexorable
paroxysms
• Lipo-oligosaccharide endotoxin (LOS)
• These episodes of violent coughing followed by an
• Immunoglobulin A1 (IgA1) allow to stick to upper
inspiratory “whoop” (gasp
airways
of air through a narrowed epiglottis).
• Β-lactamase
• people with Pertussis cough up (expectorate) large
Vaccines
amounts of thick mucus, which may cause
• A conjugate vaccine such as (DPT vaccine)
vomiting (post-pertussis emesis)
• This vaccine contains type b capsular
• Lymphocytosis
polysaccharide (polyribosylribitol phosphate)
Convalescent stage:
conjugated to diphtheria toxoid or other protein.
• Begins 4 weeks after onset of the disease.
• Given at 2 months, 4 months and six months
• Coughing become less frequent and not intense
Treatment: • Gradual recovery during this phase
• Ceftriaxone is the drug of choice for treatment of Complications associated with pertussis:
meningitis • Aspiration of mucous into the lungs may cause
• Glucocorticoids to decrease inflammation and bacterial pneumonia
swelling associated with Epiglottitis • Increase in the blood pressure at the nose
• Amoxicillin / Clavulanic Acid for treatment of (epistaxis) and eyes (scleral hemorrhage)
mucosal infection • Seizures
• Rifampin for prophylaxis • Inguinal hernia
Bordetella Pertussis Diagnosis:
Overview: • Culture isolation on Bordet-Gengou medium or
• Pleomorphic gram-negative aerobic coccobacillus PCR

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 • The culture specimen should be obtained during
the first 2 weeks of cough by using deep
nasopharyngeal aspiration
• For PCR testing, nasopharyngeal specimens
should be taken at 0-3 weeks following cough
onset
Virulence factors:
Pertussis toxin:
• Has one A subunit (toxic part) ↑cAMP and B
subunit (involved in binding)
Increased cAMP associated with:
1. ↑ insulin release leading to hypoglycemia
2. ↑ histamine sensitization, cough and vascular
permeability
3. Interfere with phagocytosis of neutrophils Clinical Presentations
4. Prevent chemotaxis • Main cause of Legionnaire’s disease (sever
5. Lymphocytosis pneumonia) with high fever, cough, headache and
6. ↑ IL4 production muscle aches
Adenylate cyclase/hemolysin toxin • The Bacteria enters through the alveoli, multiply
• Impair alveolar macrophage inhibition inside the macrophages and neutrophils
Treatment: • Causes Pontiac fever- self limiting
• Supportive treatment (hospitalization especially to Risk factors:
infants). • Smocking
• Azithromycin or erythromycin, recommended at • Compromised immune system
catarrhal stage so it could decrease the coughing • Chronic lung disease
exacerbation at the paroxysmal stage Diagnosis
• DTaP vaccine: Recommended at the ages of 2, 4, 6, • Urine antigen test: detection of Legionella
and 15-18 months pneumophila in the urine and if the patient has
• Tdap vaccine (booster shot): Recommended at pneumonia so he considered to have Legionnaire’s
preschool age (7-10 years) disease
Legionella Pneumophila • Transtracheal aspiration of bronchioalveolar
Overview: lavage
• Gram negative aerobic waterborne bacilli • Cultured on charcoal yeast extract with iron and
cysteine
• The Legionella bacterium was first identified in
Virulence Factors
the summer of 1976 during the 58th annual
convention of the American Legion in • Legionella Pneumophila could multiply inside the
Philadelphia phagocytes
Pathogenesis • Inhibit phagosome-lysosome fusion which allow
• Legionella is an obligate or facultative intracellular intracellular growth
parasite. • Catalase positive (peroxide) hence, inhibit
• Water is the major environmental reservoir generation of bactericidal substances in phagocytic
for Legionella cells
• Contaminate water systems, air conditioning units • Dot/icm type IV secretion system (defective
and transmitted through aerosolized droplets organelle trafficking)
• Could replicate and grow inside lung’s • Coiling phagocytosis
macrophages and neutrophils • Unique lipid cell wall which allow
thermoresistance
• Degrades FC portion of antibodies and
compliments
• Beta lactamase resistant
• Metalloprotease dampens the cytokine secretion
from infected macrophages and limits the levels of
cytokine transcripts in infected macrophages.

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Bacteria causes atypical pneumonia: • Exotoxin A is responsible of tissue necrosis.
• Legionella Pneumophila Inhibit protein synthesis by inhibition of
• Mycoplasma elongation factor-2 through ADP-ribosylation of
• Chlamydia EF2
Treatment: • Exotoxin S: Inhibit protein synthesis
• Macrolides (Erythromycin, Azithromycin) • Elastase: Destruction of elastin containing tissue
• Drug of choice for atypical pneumonia (blood vessels, skin, cornea)
Pseudomonas aeruginosa • Phospholipase C is a thermolabile haemolysin.
• P. aeruginosa produces at least four proteases
Overview: causing bleeding and tissue necrosis
• Gram negative rode, strict aerobe Treatment:
• Oxidase positive and lactose nonfermenters. • Aminoglycosides plus extended spectrum
• Characteristic sweet grape like odour Penicillin (Piperacillin, Ticarcillin)
• This pathogen is widespread in nature soil, water • Steroids are used in conjunction with these
and plants antibiotic
Pathogenesis: • Proper hygiene regarding medical devices like
• Pseudomonas aeruginosa is an opportunistic catheters is important to prevent opportunistic
pathogen common with immunocompromised infection in a patient
patients • Severe burn victims should be put into strict
• common in immunocompromised patients with isolation to prevent unnecessary contact with
diabetes. potential pathogens.
• It’s a frequent cause of nosocomial infection such Salmonella
as pneumonia, bacteremia
Overview:
• Gram-negative, rod-shaped bacilli that can cause
Clinical Presentations salmonellosis
• Pseudomonas aeruginosa could affect several • It has flagella
organs such as: • Only about 3.4% of Salmonella infections in
• Urinary tract- UTI the United States are laboratory-confirmed (self-
• Respiratory tract-Pneumonia, Cystic fibrosis limiting)
• Heart-Endocarditis • Salmonella might be life threating when it didn’t
• Ear-Otitis Externa (swimmer’s ear) handle properly
• Blood stream-Bacteremia/Sepsis Pathogenesis
• Eye-Conjunctivitis, Keratitis (contact lens) • It is the most common cause of foodborne illness.
• Hair- Hot tub folliculitis Salmonella occurs in raw poultry, eggs, beef,
• A common type of folliculitis, a condition which vegetables, dairy products and shellfish
causes inflammation of hair follicles with • Salmonella typhi induce typhoid fever
papulopustular lesions • Salmonella osteomyelitis is predominantly seen in
• Bones and joints (osteomyelitis) patients with haemoglobinopathies such as sickle
• Skin Ecthyma gangrenosum cell anemia
Ecthyma gangrenosum: are hemorrhagic (bloody) pustules
that evolve into necrotic (black) ulcers. Clinical presentations of typhoid fever:
Diagnosis • Bloody diarrhea
• Urine culture, blood cultures (oxidase, Catalase • Fever
positive, β-hemolytic) • Abdominal cramps
• Sputum in case of patient with cystic fibrosis • Headache
• Surface swab from burned patient • Dehydration
• The blue-green pigment due to pyocyanin • Myalgia
• Isolation of thick sputum from patient lungs due to • Rose spot on chest and abdomen (critical sign in
alginate production typhoid fever)
Virulence factors: • Symptoms usually last 4 - 7 days
• Pyocyanin impair ciliary function, and produce • Typhoid carrier state
toxic free radicals • Salmonella typhi lives only in human. Persons
• The pili allow adherence to the epithelium. with typhoid fever can carry the bacterial in their
blood stream and intestine for long period
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 • Persons who recovered from typhoid fever called Treatment
Carriers since they continue to carry the bacteria • Beta-Lactamase Ampicillin
• Both ill and carrier persons have salmonella in • Trimethoprim TMP-SMX
their stools • Because shigellosis is self-limiting, its recommend
Diagnosis withholding antibiotic therapy since antibiotic
• Bone marrow aspiration prolong bacterial excretion
• Stool culture • Anti-diarrheal compounds shouldn’t have given. It
• Blood analysis, associated with leucopenia, might worsen the situation
anemia, neutropenia • Fluid and electrolytes replacement
• Urine culture • Zinc supplements especially for infants.
Treatment: Yersinia enterocolitica
• Supportive care (oral rehydration) Overview:
Shigella • Gram negative coccobacillus-shaped
Overview • Facultative anaerobe that is motile at temperatures
• Enterobacteriaceae ranging from 22 to 30°C
• Gram negative bacilli Pathogenesis:
• Transmitted through eating contaminated food,
• Non-motile, non-sporing and non-capsulate
especially raw or undercooked pork, or infected
• Lactose negative
pet faeces.
• Four subgroups: S. dysenteriae, flexneri, sonnei
and boydii
Pathogenesis
• Spread by fecal-oral transmission or ingestion of
contaminated food or drinks
• Commonly in developing countries where poor
sanitation and water supplies are polluted
• Leading cause of infant diarrhea in developing
countries
• Mechanism of pathogenesis: penetrate through
mucosal surface of colon and invade intestinal
epithelium releasing shiga toxin (Similar to
Enterohemorrhagic E. Coli) Clinical Presentations
• Shiga toxin inhibits protein synthesis (inactivate • Starts with diarrhea, fever, abdominal pain
60S ribosome) which lead to GI mucosal damage- • The patient may also develop erythema nodosum
dysentery • Enterocolitis
NOTE: Shiga toxin enhances cytokine release causing • Acute terminal ileitis (Pseudo corhn disese)
hemolytic uremic syndrome (HUS) • Acute mesenteric lymphadenitis (pseudo
• Like Salmonella, invades the GI tract via M cells appendicitis) in children 5-15 years
of Peyer patches. • Acute diarrhea in children < 5 years
• Very low infectious dose ID50 • Adult diarrhea
Clinical Presentations • Might progress to spondyloarthropathies
• Causes bacillary dysentery or shigellosis (inflammatory arthritis of the spine and joints)
• Shigellosis starts with acute gastroenteritis • HLA-B27 is a positive for spondyloarthropathies
associated with abdominal pain and diarrhea or reactive arthritis
• Progress to mucus with pus and blood Acute mesenteric lymphadenitis:
• Severe dehydration • Inflammation of the mesenteric lymph node
• Bloody diarrhea • Difficult to differentiate from acute appendicitis
• Causes reactive arthritis • Yersinia enterocolitica spread through the
Diagnosis intestinal lymphatics to reach the lymph node
• Stool specimen with fecal blood Diagnosis
• Appearance of neutrophils in fecal smear • Culture of faeces and joint fluid (↑HLA-B27)
• Culture in selective medium to isolate shigella • Culture on broth medium at 28 degrees.
from faeces e.g. XLD agar: shigella produce red
pink colonies

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Virulence Factors 2. Enterohemorrhagic E. coli (EHEC):
• Yersinia adherence proteins (Ail, YadA and • Causes hemorrhagic colitis
invasion) • Bloody diarrhea
• M cells: Antigen-sampling intestinal epithelial • Bind to epithelial cells and produce shiga like
cells toxin that block protein synthesis causing cell
• Enterotoxin -↑ CAMP that lead to diarrhea death
Escherichia Coli • Considered as foodborne infection (undercooked
or contaminated food)
Overview:
• 0157:H7 strain of EHEC causing hemolytic uremic
• Gram negative rod
syndrome
• Normally live in the intestines of people and
Hemolytic uremic syndrome:
animals. Progressive renal failure associated with:
• E. coli can be transmitted through contaminated
• Thrombocytopenia and hemolytic anemia
water or food, or through contact with animals or
• Damage to the lining of blood vessel walls
persons.
• Destruction of red blood cells (hemolysis)
• Leading cause of urinary tract infection which can
lead to acute cystitis and polynephritis • Schistocytes (Fragment part of red blood cells)
common in hemolytic anemia
• Causes gastroenteritis, neonatal menegitis and
nosocomial pneumonia • Elevated lactate dehydrogenase (LDH)
E. coli strains: • Destruction of blood platelets (involved in
1. Enteropathogenic E coli (EPEC): clotting)
• Main cause of childhood diarrhea. • Disseminated intravascular coagulopathy (DIC)
• Pathogenic • Septic shock
Pathophysiology:
• Characterized by loose stool, tenesmus, GIT
symptoms • Glomeruli become clogged with platelets and
damaged red blood cells, hence, the kidney's
• Adhere to apical surface
ability to filter and eliminate waste products.
• Blocks absorption by attaching to the apical
Diagnosis:
surfaces causing the villi to flatten
• Large pink colonies on Mac Conkey agar
• No Toxin is produced
• Lactose fermenters
• Frequent in summer months
Virulence factors (E coli antigenic structure):
• Treatment by administration of oral rehydration
solution
2. Enterotoxigenic E. coli (ETEC):
• Causes traveler’s diarrhea
• Heat labile toxin (AB toxin) similar to cholera
toxin
• The toxin activates adenylate cyclase-↑ cAMP-
Increased chloride secretion (Secretory or watery
diarrhea)
• Toxigenic
Note:
• There are 2 types of enterotoxins LT (labile toxin)
and ST (stable toxin):
• LT, heat labile bind to Gm1 gangliosides in the
small intestine, hence increase cAMP production • K antigen (Capsular K): Protect against
(Increase fluid transport into the bowel) phagocytosis
• LT composed of A and B components • H antigen (Flagella): Help in motility and
• A active and B for binding chemotaxis
1. Enteroinvasive E. coli (EIEC): • O antigen: Lipopolysaccharide (LPS)
• Causes dysentery (diarrhea with mucus) • Fimbriae promote virulence (especially in UTI)
• Invade intestinal epithelia and release Shiga like Klebsiella Pneumoniae
toxin, resulting in an inflammation and necrosis Overview:
• Invasive • Gram-negative bacteria with polysaccharide
• No toxin is produced capsule

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 • The organisms are named after Edwin Krebs, a Clinical presentations:
19th century German microbiologist 1. Gastroenteritis and characterized by:
Pathogenesis • Bloody diarrhea
• Infection with Klebsiella pneumonia occurs in the • Dysentery
lungs, where they cause destructive changes • Abdominal pain
• Major cause of nosocomial pneumonia • Crypt abscesses
• Affects alcoholics, diabetics and malnutrition, • Gastric ulceration
intubated and debilitated patients 2. Guillain Barre syndrome: Acute inflammatory
• Also associated with Foley catheter-associated polyradiculoneuropathy with resultant weakness
UTIs and diminished reflexes.
• Pneumonia occurred because of aspiration of 3. Reactive arthritis
stomach contents Diagnosis:
Clinical presentations: • Stool specimen
• Pneumonia • Culture: Campy agar grows at 42 C
• Focal lung infection Virulence factors
• Productive cough • Antigenic diversity
• Necrosis • Flagellum – Used for bacterial motility and
• Inflammation chemotaxis
• Hemorrhage occur within lung tissue, sometimes • Adhesion and invasion through lipopolysaccharide
producing a thick, bloody, mucoid sputum described as and flagella
currant jelly sputum • Produce enterotoxin which  cAMP. Destroyed
• Wound infection upon boiling (heat labile toxin)
• Nosocomial sepsis • Cytotoxins which stop cell growth
Virulence factors: • Superoxide dismutase
• Poly saccharide capsule Vibrio
1. protect against phagocytosis and antibiotics
Vibrio Cholera:
2. Makes the colonies moist and mucoid
• Vibrio has two important species Vibrio Cholera
• Β-lactamase and Vibrio parahaemolyticus
Diagnosis Overview
• Mucoid colonies due to polysaccharide capsule
• Halophilic (salt loving)
• Grows on MacConkey and blood agar media • Grow in alkaline medium
Treatment:
• Gram negative halophilic bacteria
• Third generation cephalosporins (eg, cefotaxime,
• Non-lactose fermenting
ceftriaxone)
• Facultative anaerobe
• Broad spectrum antibiotics
• Oxidase positive
Campylobacter Jejuni • Cholera is common in developing country
Overview: (endemic) due to poor sanitation
• Microaerophilic curved negative rods • Mechanism of pathogenesis: The bacteria binds to
• Comma S or gull-wing shaped spiral rods the epithelium which release cholera toxin that
• Thermophilic growing well at 42 C causes ↑cAMP (Increase NaCl secretion and H2O
• Oxidase, Catalase and Nitrate reduction positive efflux)
• Part of the normal intestine flora of domestic
animals
Pathogenesis:
• Source of infection: food of animal origin,
especially raw milk, poultry and meat
• Transmission through fecal-oral route
• The most common cause of community-acquired
inflammatory enteritis.
• Campylobacter Jejuni may cause bacteremia in
individuals with AIDS.
• Multiply in the small intestine, penetrate the gut
epithelium and disrupt fluid absorption

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Clinical Presentations • Considered risk factor for:
• Profuse watery diarrhea known as rice-water stool • Gastric adenocarcinoma, lymphoma
• Occasional vomiting and abdominal cramps • Mucosa-associated lymphoid tissue lymphomas
• Diarrhea dehydration which leads to hypotension, (MALTomas)
tachycardia, oliguria and finally renal failure • Gastroesophageal reflux disease (GERD)
• Decrease intravascular volume Gastriti
• Massive fluid loss s
• Decrease renal perfusion
• Less renal output Chroni
Acute
Virulence factors: c
• Enterotoxin (Cholera toxin): Hypersecretion of Type A-Autoimmune disease
electrolytes and water (pernicious anemia)
• Pili: Adhesion to mucosal cells
• Mucinase (protease): induce intestinal Type B -Occur in the pylorus-
Caused by H.Pylori
inflammation
• Serotype 01 is the most common Type AB combination of both
Treatment: types
• Rehydration
Diagnosis
• Glucose IV fluids
Vibrio parahaemolyticus: • Carbon-13 urea breath test (urease breath test):
Concentration of the labeled carbon is high in
• Gram negative bacteria
breath only when urease is present in the stomach,
• Found in salt water
a positive reaction indicates H pylori infection
• Halophilic
• H pylori fecal antigen test
Pathogenesis:
• Catalase, urease and oxidase positive
• Transmitted by Fecal-oral route or ingestion of
Virulence Factors:
undercooked sea food specially shellfish and sushi
• Flagella: Used for bacterial motility to invade
• Causes gastroenteritis, self-limiting diarrhea,
gastric mucosa
abdominal pain
• The body's natural defenses cannot reach the
• Causes skin infection when the wound exposed to
bacterium in the mucus lining of the stomach
warm seawater
• Once H. pylori is safely landed in the mucus, it is
Diagnosis
able to fight the stomach acid that does reach it
• Β- hemolysis in high salt blood agar known as
with an enzyme it possesses called urease.
kanagawa phenomena
• Urease converts urea from saliva and gastric juices
Virulence factors:
into bicarbonate and ammonia, which are strong
• Has two hemolysins virulence factors,
bases (neutralize gastric acid)
thermostable direct hemolysin (tdh) contributes to
• Mucinase to break mucous layer
the invasiveness of the bacterium in humans,
• Catalase enzyme, helps survive within the
• TDH-related hemolysin (trh)
neutrophils
Type III secretion systems (T3SS1 and T3SS2) codes for
adhesion • Lipopolysaccharide for host cell adherence
Helicobacter Pylori • Type IV secretion system
Treatment
Overview:
• Triple antibiotic therapy (Clarithromycin+
• Gram negative rod Amoxicillin+ Metronidazole)
• Catalase, urease and oxidase positive
• Proton Pump inhibitors (Omeprazole)
• Wavy shaped
• Bismuth Salicylate (coating stomach lining)
• Highly motile microorganism Spirochetes
Pathogenesis:
Overview:
• Common route of H. pylori infection is either oral-
to-oral or fecal-to-oral contact • Elongated motile spiral shaped bacteria with axial
filaments
• Infect human stomach
• Spin to achieve propulsion
• Associated with inflammatory responses
Clinical Presentations: • Contains endoflagella
• Causes gastritis and peptic ulcer disease (90% • Extremely small detected only by dark field
microscope

94
 • Systemic signs include fever, malaise and
lymphadenopathy
• Widespread mucocutaneous rash (global red
macular rash) all over the body involve palms and
soles
• condylomata lata and patchy alopecia
• All such lesions and aggregations contain
treponemes.
Pathogenesis: • Patients at this stage develops moth-eaten
• Spirochetes associated human diseases appearance
Species Disease • Latent syphilis is one of the characteristics of this
Treponema Pallidum Syphilis phase, where the features of secondary syphilis
Borrelia burgdorferi Lyme disease have resolved but the patient considered
Leptospira interrogans Leptospirosis (Weil’s seroreactive positive
disease) • Diagnosis: Dark field microscope, (VDRL test,
RPR) nonspecific then FTA-ABS
Treponema Pallidum:
Condylomata lata: painless, highly infectious gray-white
• Primary cause of Syphilis (STD)
aggregations that develop in warm, moist sites such as
• Could be detected in fresh primary or secondary
genital areas
lesions by dark filed microscope or fluorescent
antibody technique
Patchy alopecia: hair loss of the scalp and facial hair,
• Can’t cultivated in culture media
including the eyebrows
• Transmission through:
1. sexual contact of an infected person
2. Mother to fetus in utero (Treponema Pallidum
crosses the placenta)

Clinical presentations of Syphilis:

Syphilis progresses in three stages:
Primary stage:
Tertiary Syphilis
• painless chancre with incubation period (3 to 6
• Composed of three categories:
weeks)
1. Gummatous syphilis:
• Chancre:
• Localized granulomatous dermal lesions
• A lesion has a punched-out base and rolled edges
called Gummas
• Highly infectious
• Characterized by necrotic center on the
• Appear on the cervix, vaginal wall and anal canal skin (painless) yet painful for bones
• Characterized by mononuclear leukocytic • Associated with release of macrophages
infiltration, macrophages, and lymphocytes
and fibroblast which reflect the
• The spirochetes could be isolated from the exudate immunogenic response of the host to the
of the chancre infection
• Diagnosis: Dark field microscope, VDRL test, • Appear 3-10 years after primary
FTA-ABS, RPR infection
2. Cardiovascular syphilis:
• Venereal Disease Research Laboratory (VDRL • Caused by chronic inflammation
test) destruction of the vasa vasorum leading
• Rapid Plasma Reagin (RPR) to aneurysm formation in the ascending
• Fluorescent Treponemal Antibody Absorption Test aorta (Aortitis)
(FTA-ABS) • As a result, aortic valve insufficiency
Secondary stage: may also occur
• Develops about 4-10 weeks after primary syphilis • Appear 10 years after primary infection
• The spirochetes spread throughout the body
causing dissemination N.B: Vasa vasorum: the penetrating vessels that
nourish the walls of large arteries.

95
 3. Neurosyphilis: • Hutchinson’s teeth (the upper incisors are widely
• Could be developed in several forms; spaced and notched)
A. Syphilis meningitis: • Mulberry molars (the molars have too many cusps)
• when spirochetes invade CNS • CN VIII deafness, optic nerve atrophy and corneal
• Usually occur 6 months post inflammation might lead to blindness
primary infection Diagnosis:
• Characterized by fever, stiff • Dark light microscope: detection of spirochetes in
neck, headache and CSF active lesions (chancre, condyloma lata, macules)
showed high protein, high • VDRL and RPR are nonspecific tests depend on
lymphocytes and low glucose. the presence of antibodies against cardiolipin and
• Positive syphilis test lecithin (present in the blood stream after
infection)
B. Meningovascular syphilis: • FTA-ABS is a confirmatory, accurate and specific
• Occur because of damage to test for Treponema Pallidum
blood vessels of meninges, Cases of false positive VDRL test:
brain and spinal cord • Pregnancy
• Cause sever neurological • Viral infection (eg, EBV, hepatitis)
damage • Drugs
• Rheumatic fever
C. Parenchymal Syphilis • Lupus and leprosy
• Causes tabes dorsalis and Treatment:
general paresis • Benzathine penicillin G
• Both conditions characterized • Jarisch-Herxheimer reaction; Flu-like symptoms
by Argyll-Robertson pupil (The (headache, fever, myalgia) after Penicillin
pupil accommodates but not treatment due to release of pyogenic toxins
react) called also prostitute’s
pupil Borrelia burgdorferi:
• Tabes dorsalis is also associated • Primary cause of Lyme’s disease
with Positive Romberg’s test
• Transmitted to humans via tick bites from infected
and Charcot joint
Ixodes tick
Diagnosis: VDRL test RPR then FTA-ABS
• Mouth is the natural reservoir of lyme’s disease
Tabes dorsalis: is severe damage at the posterior
column and dorsal root ganglia leading to ataxia, • Common in the northeast cost of USA
loss of reflexes and impaired proprioceptive • Could be detected by light microscopy with
sensation, leading to a wide-based gait Giemsa, Aniline or Wright stains.
Romberg’s test: A test used evaluate neurological
function for balance sensation (proprioception), Pathogenesis:
vestibular function and vision • Borrelia burgdorferi infection involves 3 stages:
Charcot joint: progressive degeneration of weight 1. Early stage:
bearing joint and eventually lead to bone deformity • Flu‑like symptoms.
due to loss of sensation. • Erythema chromicum migrans – Rash at the site of
Congenital syphilis: infection
• Treponema Pallidum crosses the placenta • Lymphadenopathy
• Congenital syphilis can be prevented if the mother • Bulls-eye lesion that develops around the site of a
is treated in the first trimester lone star tick bite
• Early congenital syphilis mimics secondary • These signs start 10 days after tick bite
syphilis (rash, condyloma lata)
• Late congenital syphilis mimics tertiary syphilis 2. Second stage:
and characterized by: • Early disseminated disease
• Saddle nose (changes in the cartilage of the nasal • Characterized by high immune response
septum) manifested by ECM with multiple skin lesions
• Saber shins (inflammation and bowing of the tibia) • Nervous system (facial nerve (bell) palsy,
• Clutton’s joints (inflammation of knee joints) peripheral neuropathy)

96
 • Heart (AV node block, require peace maker Gardnerella Vaginalis
replacement) Overview:
• Joints (Migratory arthritis) • Pleomorphic
• Facultative anaerobic gram rod
3. Late stage: • Associated with sexual activity
• Encephalopathy • Causes bacterial vaginosis due to bacterial
• Chronic arthritis overgrowth (disruption of normal bacterial flora)
• Knee pain NOT STD infection
• Migratory polyarthritis Signs and Symptoms:
• Polyneuropathy • Fishy smell
Diagnosis: • Itching
• Depend on the appearance of ECM rash • Burning of the labia
• Could be detected by light microscopy with • Gray/off-white vaginal discharge
Giemsa, Aniline or Wright stains. Diagnosis:
• ELISA or western blot • Detection of Clue cells in vaginal smear
Treatment:
Treatment: • Metronidazole
• Doxycycline
• Ceftriaxone
Leptospira interrogans:
• Primary cause of Leptospirosis
• Found in water contaminated with animal urine
• Most common among surfers in Hawaii
Clinical presentations:
• Symptoms start when bacteria invade blood and
CSF causing flu-like symptoms
• Hepatocellular dysfunction (Jaundice) Chlamydia
• Conjunctivitis (photophobia) Overview:
• vasculitis of capillaries • Obligate intracellular bacteria
• Advanced stage of Leptospirosis manifests icteric • Lacks peptidoglycan cell wall due to reduced
leptospirosis (Weil disease): muramic acid
• Jaundice • Lack ATP, require ATP from the host cell
• Renal failure with oliguria, azotemia • Multiply in the cytoplasm of host cell
(↑Bilirubin/creatinine ratio) • Extremely small
• Hemorrhage • The chlamydial growth cycle involves
• Systemic inflammatory syndrome or shock transformation between distinct forms: the
• Anemia elementary body (EB) and the reticulate body (RB)
Diagnosis:
• Culture of blood or CSF Elementary body Reticulate body
• PCR of urine, blood or CSF • Extremely • Intracytoplasm
• ELISA small ic form
• Liver function tests • Enter via • Replicate and
• CSF analysis endocytos grow inside the
• Coagulation studies is cell by fission
• Renal function studies • Released
Treatment: from
• Doxycycline ruptured
• Ampicillin or amoxicillin infected
• Azithromycin or clarithromycin cell
• Fluoroquinolone such as ciprofloxacin or
levofloxacin

97
 • Caused atypical pneumonia
Diagnosis:
• Identification of cytoplasmic inclusions (RB) on
Giemsa or Fluorescent antibody
• In case of neonatal conjunctivitis diagnosis is
made by observing inclusion bodies in cells
scraped from the eyelids.
• In case of urethritis PCR or urine sample is
required
Treatment:
Life cycle of Chlamydia • Azithromycin
Pathogenesis: • Doxycycline
• Chlamydia targets mucous membranes such as Rickettsia infection
(Eyes, GIT and Lungs) Overview:
Chlamydia subtypes • Obligate intracellular parasite (rely on ATP)
1. Chlamydia Trachomatis: • Gram negative pleomorphic rod
• Divided into different serological strains • Require tick vector
• Serotype (A-C)/more common in • Mammals and arthropods are natural hosts for
developing countries causes Trachoma Rickettsia species
characterized by sever conjunctivitis and • Doxycycline is the drug of choice for tick bites
might lead to blindness. Pathogenesis:
• Serotype (L1-L3) causes • Rickettsia infection is transmitted through a bite f
Lymphogranuloma venerum infected tick
STD/painless • Infection starts by invading the endothelial lining
• Serotype (D-K) causes of blood vessels
1. Urethritis characterized by dysuria and • Adhesins protein help the rickettsia to be
white discharge phagocytosed into the host cells
2. Epididymitis in men Classification of Rickettsia infection
3. Pelvic inflammatory disease (PID)
characterized by lower abdominal pain, Rickettsia
cervical discharge, fever and dyspareunia
4. Ectopic pregnancy
5. Neonatal pneumonia from birth canal
Rash No Rash
infection (staccato cough)
6. Neonatal conjunctivitis or inclusion
conjunctivitis from birth canal infection Rocky
Anaplasmosi
characterized by yellow discharge and mountain Ehrilchiosis
s
swelling of eyelids spotted fever

N.B Chlamydia trachomatis infection Typhus fever Q fever

might progress to reactive arthritis known
as Reiter syndrome (inflammatory Rash group:
arthritis, urethritis, and conjunctivitis) Rocky mountain fever:
• Causes by Rickettsia Rickettsii
2. Chlamydia Pneumonia:
• Symptoms start after a week of tick bite
• Cause atypical pneumonia with
• Patient suffers from vasculitis (fever, headache and
characterized staccato cough. Spread
ascending rash) (starts from wrists-palms and soles
from human to human
-ankles then spread to the trunk)
3. Chlamydia Psittaci: • Mechanism of pathogenies: Invasion of
endothelium wall of blood vessels which causes
• Transmitted through exposure of bird
wide spread rash, conjunctival redness, edema and
faeces
hypotension
• Common among bird breeders and pet
shop workers

98
 The patient's
rash is a
major
diagnostic
sign of
Rocky
Mountain
spotted
fever
(RMSF).
Image
courtesy of
the Centers Anaplasmosis:
for Disease • Caused by Anaplasma
Control and • Granulocytes with morulae in cytoplasm
Prevention
(CDC).

Typhus fever:

Typhus

Q fever:
• Caused by Coxiella burnetiid
Epidemic typhus Endemic Typhus • Does NOT require a vector
Human body louse Fleas • Transmitted by transmission by aerosolized
tic/cow feces
Rickettsia Prowazekii Rickettsia Typhi • Form endospores that provide it the ability to
surivive outside host cell
• Rash starts with small pink macules appear on the • Causes Pneumonia, granulomatous hepatitis and
trunk then spread-out culture-negative endocarditis
Mycoplasma Pneumoniae
Overview:
• Pleomorphic bacteria which lacks cell wall
• Penicillin are not effective due to absence of cell
wall
• More common in closed environments such as
prisons and Military
Pathogenesis:
• Transmission through inhalation of respiratory
NO rash Group: infected droplets
• Mechanism of Pathogenesis: Target respiratory
Ehrlichiosis:
epithelial cells with the advantage of H2O2 release
• Caused by Ehrlichia chaffeensis that responsible for ciliary movement inhibition
• Transmitted by dog tick Clinical Presentations:
• Monocytes with morulae in cytoplasm (mulberry- • Cause Atypical Pneumonia (walking pneumonia)-
like inclusions) nonproductive Cough, fever-malaise
• Diffuse Interstitial infiltrate
Diagnosis:
• X-ray showed diffuse interstitial infiltrate

99
 • Positive cold agglutinin test: blood clumping on • Inhalation of bat/bird stools associated with
ice (due to formation of anti-RBC antibodies) invasion of lung alveoli and macrophages
• PCR • The macrophages in lymph node engulf the spores
• Culture on Eaton agar (Fried egg shaped) and form granuloma
Treatment: • Severe Histoplasmosis might lead:
• Macrolides (Azithromycin, Clarithromycin and • Acute respiratory distress syndrome
Erythromycin • Pericarditis
• Fibrosing mediastinitis
• Pruritic chest pain
Atypical
Pneumonia Diagnosis:
• Appearance of yeast forms in macrophages and
giant cells
• Usually the macrophages are filled with
Mycoplasma Chylamydia Legionella Histoplasma
Pneumonia Pneumonia Pneumonia • Urine or skin antigen test
• Chest x-ray
• Pancytopenia
Types of Systemic Mycoses: • Elevated alkaline phosphatase
• Fungi that switch between the yeast and mold • Blood culture
forms are termed dimorphic Treatment
• Dimorphic fungi are the main source of systemic • Fluconazole or itraconazole for local infection
infection • Amphotericin B for systemic infection
• Mold usually grow at 20 C, while yeast grow at 37 • Amphotericin B could cause renal insufficiency
C. and ototoxicity
• Coccidioides, which is a spherule (not yeast) in Note: Amphotericin B might lead to ototoxicity and
tissue. nephrotoxicity
• Inhalation of mold spores from the soil is the
primary route of infection Blastomycosis
• Whenever these spores reach the lung (high • Caused by Blastomyces dermatitidis
temperature), the dimorphic fungi transform into • More common in eastern (Mississippi) and central
yeast USA
• Four types of systemic mycoses: • Blastomyces dermatitidis lives in soil or rotten
1. Blastomycosis roads near lakes and rivers
2. Histoplasmosis
Clinical presentations:
3. Coccidiomycosis
• The patient develops primary pneumonia with
4. Paracoccidiomycosis
symptoms of high fever, chills, a productive
• Considered endemic infections in the United States
cough, and pleuritic chest pain.
• All types could predispose patient to Pneumonia
• Skin infection is considered the primary
and disseminate into the body leading to systemic
pathogenesis (skin lesions)
infection (Immunocompromised patients)
• Skin infection might progress to verrucous (wart-
• Systemic mycoses can form granulomas (like TB)
like) or granuloma
Histoplasmosis: • Blastomycosis usually disseminate and invade
• Caused by Histoplasma capsulatum many organs in case of immunocompromised
• More common in Mississippi and Ohio states patients
• Histoplasma commonly found in soil (bird or bat • Blastomycosis causes bone infection and joint pain
droppings) Diagnosis:
• Named as caves disease or spelunker’s lung • Detection of Blastomyces yeast forms with broad-
disease based buds in in sputum, skin scrapings, or pus.
Clinical presentations: • Elevated leukocytosis
• Usually the patient is asymptomatic but might • Hypoxemia due to inflammation and decrease
develop pneumonia with flu-like symptoms oxygen in blood stream
(cough, fever, malaise, body ache) • Positive KoH test

100
 • Positive blood culture Para-coccidioidomycosis:
Treatment: • Caused by Paracoccidiodies brasiliensis
• Fluconazole or itraconazole for skin infection • More common in latin America
• Amphotericin B for systemic infection • Men are more predisposed than females
Coccidioidomycosis: Clinical presentations:
• Caused by Coccidioides immitis • Usually patients are asymptomatic, but the
• More common in the southwestern United States symptoms might develop to pneumonia and
(southern California, Arizona, Nevada, New pulmonary fibrosis.
Mexico).
• Known as Valley fever or California fever
• In the air appear as spores while in the lung appear
as spheres

Clinical presentations:
• Usually patients are asymptomatic, but the
symptoms might develop to pneumonia. In chronic • Dissemination- lungs- dry productive cough,
causes develops into disseminate infection malaise, fever, shortness of breath, oral lesions
(meningitis). • Cervical lymphadenopathy
• The patient might also develop pulmonary fibrosis Diagnosis:
• Coccidioidomycosis characterized by triad of • Captain’s wheel formation
“desert rheumatism” include fever, arthralgia, and Types of cutaneous Mycoses:
erythema nodosum and may occur in acute Tinea
infection
• Caused by dermatophytes (cutaneous fungal
• Erythema nodosum: palpable painful nodules on infection)
anterior tibia.
• Types of dermatophytes Trichophyton,
• In case of disseminate infection (meningitis) the Microsporum, Epidermophyton
patient develops headache, blurry vision,
• These fungi feed on keratin of hair, nails and skin
photophobia, decline in cognition, hearing
• Usually associated with Purities
changes, and focal neurologic deficit
• Diagnosis: Skin scraping with KOH prep shows
Diagnosis: branched hyphae.
• A lumbar puncture with analysis of cerebrospinal
fluid (CSF) Tinea capitis (barber’s itch/folliculitis):
• Chest x-ray • Infection of head and scalp
• Serologic analysis detecting fungal antigen or • Characterized by alopecia and scaling and
host IgM or IgG antibody produced against the associated with lymphadenopathy
fungus
• Microscopic detection of spherules Tinea Corporis:
• Positive fungal culture • Infection of body /torso
• Known as ringworm because its erythematous
scaling ring and central clearing
Tinea Cruris (Jock itch):
• Infection of inguinal area
• Characterized by scaly patches of skin
Tinea Pedis (Athlete’s foot)
3 subtypes:
• Interdigital
• Moccasin distribution
A Coccidioides immitis spherule
containing endospores. • Vesicular type

Tinea unguium (onychomycosis)

Treatment:
• Infection of nails
• Amphotericin B for systemic infection
• Characterized by brittle, thickened, yellowish nails

101
Tinea versicolor and tinea nigra
• Considered as superficial infection
• Caused by Malassezia species
• Produces acids which have bleaching effect,
degradation of lipids and discoloration of the skin
• Characterized by hyperpigmentation and pink
patches
• Associated with hot and humid weather
• Diagnosed microscopically as spaghetti and meat
balls
• Treatment by antifungal and selenium sulfide
Opportunistic Fungal infection Aspergillus fumigatus:
Overview: • Monomorphic septate hyphae which branch at 45
• Opportunistic fungal infection is more common in angle
immunocompromised patients such as AIDS with • Transmitted through inhalation of spores
CD4< 200. • Aspergillus produce aflatoxin (Associated with
• Also, neonates and diabetic patients are more hepatocellular carcinoma)
prone to these infection
Candida albicans
• Dimorphic yeast
• Pseudo hyphae with budding yeast
Clinical presentations:
• Can cause systemic or superficial infection
• Local infection such as oral and esophageal thrush
especially in immunocompromised patients such
as (AIDS, diabetes, steroids and neonates)

Note: Oral candidiasis could overlap with oral hairy

leukoplakia. The difference is leukoplak ia cannot be
scraped off easily and tends to occur on the sides of the Septate hyphae that branch at 45 angle
tongue, while mucosal or esophageal candidiasis could be
scraped off Clinical presentations:
• Causes invasive aspergilloses in
• Diaper rash in newborns (satellite lesions) immunocompromised patients (Patients with
• Vulvovaginitis chronic granulomatous disease)
• Diabetic patients are more prone to fungal • Invasive aspergilloses start with invasive fungal
infection due to the high glucose level sinusitis and rapidly begin to disseminate and
(opportunistic medium for fungi) spread to the brain
• Systemic disseminated infection (Fungemias or • Associated with post-TB infection. Aspergillus
Candidemia) such as endocarditis (IV drug might invade lung cavities and reside for years
abusers) leaving lesions and granulomas
Treatment: • Cause allergic bronchopulmonary aspergillosis
• Oral fluconazole or topical azole for vaginal (ABPA)
infection ABPA:
• Fluconazole or echinocandins for oral thrush • Hypersensitivity reaction due to inhaled
• Amphotericin B or caspofungin for systemic Aspergillus causing release of peripheral
infection eosinophilia and bronchospasm
• Consider prophylactic fluconazole in HIV patients • Usually associated with asthma and cystic fibrosis
with recurrent candidiasis Treatment:
• Systemic aspergillosis treated by voriconazole,
caspofungin, or amphotericin B
Cryptococcus Neoformans:
• 5–20 μm yeast with white capsule halos

102
 • Unequal body- NOT dimorphic • Symptoms include cavernous sinus thrombosis,
• Could be found in Soil and transmitted through headache, facial pain, black necrotic eschar in the
inhalation of yeast from (pigeons and bird face, facial cellulitis, diplopia and vision loss
droppings) • Diabetic patients (Ketoacidotic patients) are prone
Clinical presentations: to these infections due to increase blood glucose
• Associated with meningitis manifested by fever, levels
headache and confusion • Associated with high mortality 60-70% while
• Also associated with lung and skin infection disseminated infection with 100% mortality.
• Pruritic chest pain, lymphadenopathy
• Systemic disseminated infection includes
cryptococcosis, cryptococcal encephalitis (“soap
bubble” lesions in brain), primarily in
immunocompromised.

Rhinocerebral mucormycosis

Diagnosis:
• Right angle hyphae on plate culture
• Tissue biopsy of necrotic tissue
Treatment:
• Amphotericin B
Soap bubble lesions in the brain consistent • Posaconazole
with Cryptococcus neoformans infection • Surgical debridement of necrotic tissue
Pneumocystis jirovecii
Diagnosis: Transmitted through inhalation
• CSF lumbar analysis and stain for encapsulated Clinical presentations:
yeast (Indian Ink stain) • Causes Pneumocystis pneumonia (diffuse
• Measurement of cryptococcal antigen level interstitial pneumonia) especially among AIDS
• Latex agglutination test detects polysaccharide patients CD4 count< 200
capsular antigen • Pneumocystis pneumonia linked to AIDS patients
• Culture on Sabouraud agar especially when CD4 count< 100
• Detection of soap bubble in the brain Diagnosis:
Treatment: • Chest x-ray and hypoxemia in an
• Oral fluconazole for mild infection immunocompromised patient
• Amphotericin B + flucytosine followed by • Diffuse, bilateral ground-glass opacities on
fluconazole for cryptococcal meningitis. CXR/CT, with pneumatoceles B
Mucor and Rhizopus spp: • lung biopsy or bronchoalveolar lavage.
• Irregular non-septate hyphae branching at wide • Disc-shaped yeast seen on methenamine silver
angles (>90°). stain of lung tissue
Clinical presentations: Treatment:
• Rhinocerebral mucormycosis commonly affects • TMP-SMX is the drug of choice. Pentamidine and
individuals with diabetes and those in dapsone for prophylaxis only
immunocompromised states • Prophylaxis should begin with a CD4 count <200
• Fungi start grow in the blood vessels then spread in all AIDS patients
into the brain frontal lobe and start forming Sporothrix schenckii
abscesses rhinocerebral mucormycosis • Dimorphic with cigar shaped budding yeast

103
 • Transmitted through a cut or puncture wound in Diagnosis:
the skin • Entero-test: detection of Trophozoites / cysteine in
stool
• IgA deficiency in an individual with recurrent
giardiasis.
• Multinucleated trophozoites
Treatment:
• Metronidazole
Entamoeba histolytica
• Transmitted through ingestion of contaminated
Photomicrograph that shows the water with Entamoeba cyst
conidiophores and conidia of the fungus • Causes amebiasis- Amebic dysentery
Sporothrix schenckii
• Could disseminate to other organs, leading to
Source: Medscape
abscess formation in the lung, liver, colon, and
brain (rarely)
Clinical Presentations:
Clinical presentations: • Abdominal pain, bloody diarrhea
• The causative agent of sporotrichosis, commonly • (Dysentery) liver abscess characterized Anchovy
known as "rose gardener’s disease" paste exudate, RUQ pain and ulceration of
• Cutaneous sporotrichosis is a small skin lesion intestinal epithelium
characterized by ulceration and/or erythema Diagnosis:
• Infection spreads through the lymph node and • Blood test, detection of trophozoite with RBC in
causes lymphocutaneous sporotrichosis. cytoplasm
• Detection of cyst with multiple nuclei
• Colon biopsy- flask shaped ulcers
• Antigen testing against Entamoeba histolytica
Treatment:
• Metronidazole for invasive disease
• Iodoquinol/paromomycin colonization
Cryptosporidium parvum:
• Can be found in unfiltered water
• Characterized by sever watery diarrhea in AIDS
patients
• Mild diarrhea/ self-limiting diarrhea in
Source: Medscape immunocompetent individuals
Diagnosis:
Treatment: • Detection of oocysts on acid fast stain (like TB)
• Antifungal such as Itraconazole Treatment:
• Potassium Iodide • Supportive treatment: filtering drinking water
GIT protozoa infection • Nitazoxanide in immunocompetent patients
Giardia Lamblia Giardia Entamoeba Cryptospori
• Transmitted through oral -fecal route by ingestion Lamblia histolytica dium
of contaminated water with Giardia cyst parvum
Clinical Foul-smelling, Bloody Severe
• Common among hikers and campers (drinking
from untreated river/spring water) presentati fatty diarrhea diarrhea watery
ons diarrhea
• Infection starts when Giardia trophozoites attack
(AIDS)
intestinal enterocytes causing injury and atrophy
Giardiasis amebiasis-
followed by alteration in fat absorption (Foul-
smelling, fatty diarrhea) Amebic
dysentery
• Causes Giardiasis
Treatmen Metronid Metronidaz Nitazoxanid
Clinical Presentations:
t azole ole- e
• Associated with flatulence, bloating, abdominal
Iodoquinol
pain and foul smell odour

104
 Diagnosi Multinucl detection Detection of • Diagnose by antibodies against T. gondii or biopsy
s eated of oocysts on of brain lesions
trophozoi trophozoite acid fast Treatment
tes with RBC stain • In case of immunocompromised /AIDS patients
in (CD4 count<100) recommended for prophylaxis
cytoplasm TMP-SMX or sulfadiazine
• For systemic or congenital toxoplasmosis
sulfadiazine and pyrimethamine
CNS protozoa infection Naegleria fowleri:
Toxoplasma gondii • Ameba in fresh water
• Protozoa found in most animals. Common in cat • Transmitted through ingestion of Trophozoite via
faeces (oocysts) the olfactory mucosa and cribriform plate of the
• Transmitted through ingestion of cysts in infected swimmer
undercooked meat (e.g., pork or lamb) Clinical presentations:
• The infection starts when the cyst reached GIT • Get access to the brain rapid onset of acute
where it decyst and eventually the sporozoites mengioencephalites (1-14d later)
released attacking macrophages • Very low survival rate
• The infected macrophages burst allowing the Diagnosis
sporozoites to circulate in the blood where it • lumper puncture of CSF
invades other host cells including nerve cells Treatment:
Clinical presentations: • Amphotericin B
• Flu like illness (Runny nose, cough and fever) Trypanosoma brucei and cruzi:
• Immunocompromised HIV or AIDS present with Trypanosoma brucei
altered mental status or encephalitis – brain • Named as African trypanosomiasis caused by
abscess Trypanosoma brucei Gambiens (East Africa) and
• Systemic infection is usually associated with ring- Trypanosoma brucei rhodesiense
enhancing lesions on CT or magnetic resonance • Transmitted by tsetse fly
imaging Clinical presentations:
• Infection started when Trypomastigotes are
disseminated through the body and replicate in the
blood, lymphatics, and spinal fluid. Symptoms are:
• Large painful chancre (Tsetse fly bites leaves an
itchy chancre)
• Recurrent fever, lymph node swelling
• CNS changes manifested by headache, changes in
behavior, focal neurological deficits
• Eventually excessive somnolence leading to
eventual coma and death.
Brain MRI with contrast showing
Diagnosis:
multiple ring-enhancing lesions
• Detection of Trypomastigote in blood smear
Treatment:
Congenital toxoplasmosis:
• Suramin for bloodborne disease or melarsoprol for
• Transmitted to pregnant woman when become in CNS penetration
close contact to oocyst in cat faeces Trypanosoma cruzi
• Congenital toxoplasmosis is associated with: • More common in south America
• Intrauterine infection (still birth) • Causes Chagas disease and caused by reduviid bug
• Chorioretinitis or kissing bug
• Hydrocephalus • Enter the blood through the bite wound or through
• Intracranial calcifications mucous membranes
• Pregnant woman should avoid cats to avoid • Associated with dilated cardiomyopathy, apical
congenital problems atrophy, megacolon and megaesophagus
Diagnosis: Diagnosis:
• CT/MRI showing ring enhancing lesions (caused • Detection of trypanosomes in the blood during
also by CNS lymphoma) acute infection.

105
Treatment:
• Benznidazole or nifurtimox.
Acanthamoeba:
• Free-living amoebae
• Transmitted through skin inhalation or the blood
• Causes Keratitis in contact lens users
• Causes chronic meningoencephalitis in
immunocompromised patients
Leishmania
Localized cutaneous
Babesia microti:
leishmaniasis
• Transmitted by the bite of the infected Ixodes tick
(also cause Lyme disease) • Diffuse Leishmaniasis: Disseminated
• Also, could be transmitted through blood subcutaneous infections which may last longer in
transfusion immunocompromised patients
• Causes babesiosis and associated with fever,
fatigue, myalgia and hemolytic anemia • Mucocutaneous Leishmaniasis: Caused by L. L.
Diagnosis: braziliensis, L. Mexicana and associated with ulcer
• Visualization of Babesia trophozoites (ring forms) in the skin and mucous membrane.
and merozoites (Maltese crosses
• Visceral Leishmaniasis (L. donovani): Known as
Kala-azar and characterized by hyperpigmented
skin lesions disseminated to liver, spleen and
lymph nodes causing spleno and hepatomegaly.
Pancytopenia, fever, weight loss
Diagnosis:
• Visualization of amastigotes within macrophages
and tissues

Babesia microti in a thin blood smear stained with

Giemsa. Note the intra-erythrocytic vacuolated forms
indicated by the black arrows.

Treatment:
• Quinine and clindamycin.
Leishmania donovani and Leishmania species
(leishmaniasis)
• Most common in tropical regions (Mexico, South
America, southern Europe, Asia, Middle East, and specimen from a patient with visceral
North and East Africa) leishmaniasis—showing a macrophage (a
• Transmitted through bite of infected sandfly. special type of white blood cell) containing
Types of Leishmania infection: multiple Leishmania amastigotes
• Cutaneous Leishmaniasis caused by L. Tropica
characterized by skin ulcer at site of sandfly bite Treatment:
• Sodium Stibogluconate
Chagas disease drugs
Chagas disease
• Known as known as American trypanosomiasis. It
is caused by the parasite Trypanosoma cruzi,
which is transmitted to animals and people by
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 insect vectors (Reduviid bugs) and is found only in • Leishmania donovani responsible for visceral
the Americas (mainly, in rural areas of Latin leishmaniasis known as kala-azar disease
America where poverty is widespread). • Characterized by:
• Reduviid bug known as kissing bug or Triatomine 1. Spiking fevers,
• The infection starts when the bug deposited feces 2. hepatosplenomegaly
in a painless bite 3. pancytopenia
Clinical presentations • Diagnosed by amastigotes in macrophages in bone
• Acute infection characterized by ever or swelling marrow, liver, spleen
around the site of inoculation • Treatment: sodium stibogluconate
• Romaña's sign, which includes swelling of the
eyelids on the side of the face near the bite wound Cutaneous leishmaniasis
is one of the recognized signs of acute infection • Characterized by amastigotes in macrophages in
• Complications of chronic infection (10-20 years cutaneous lesions
after infection) includes: • Treatment: sodium stibogluconate
Heart
• Dilated cardiomyopathy leads to congestive heart Trichomonas Vaginalis:
failure • Causes trichomoniasis
• Heart rhythm abnormalities that can cause sudden • Acquired by sexual transmission ONLY since
death; cannot form cysts
Esophagus • Causes vaginitis characterized by foul-smelling,
• Dilation of the esophagus greenish discharge; itching and burning
• Weight loss • In women cause inflammation of the cervix
• Swallowing difficulties (Cervicitis)
• Achalasia lead to malnutrition • In men causes urethritis
Diagnosis
• Microscopic detection of motile trophozoites on
wet mount
• Strawberry cervix

Colon
• Megacolon leading to difficulty with passing stool
Diagnosis
• Microscopic examination of Peripheral smear Trichomonas Endoscopic image
(During the acute phase of infection, parasites may vaginalis infected pap smear showing frothy
be seen circulating in the blood) test. discharge and vaginitis
Treatment associated with
• Nifurtimox drug of choice Trichomonas vaginalis
African sleeping sickness
• Known as African trypanosomiasis Treatment:
• Caused by Trypanosoma brucei/ gambiense • Metronidazole for both partners
• Treatment: Pentamidine, Suramin, melarsoprol
Anti-Leishmaniasis
Leishmaniasis
• Leishmania is responsible for the disease
Leishmaniasis
• Transmitted by sandflies
Visceral leishmaniasis

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Type of vaginal discharge:

Strongyloides stercoralis (threadworm)

• Strongyloides found in the soil where it penetrates
the skin reaching lung and intestine
• White/thick discharge usually at the end of • It invades intestinal mucosal wall and spread into
menstrual cycle (Yeast or candida infection) blood stream and stay forever
• Gray/fishy smell (bacterial infection)
Diagnosis:
• Greenish/itchy/burning (trichomoniasis)
• Detection of rhabditiform larvae in faeces
Nematodes (roundworms) Treatment:
Nematodes infect intestine • Bendazoles
Pinworm (Enterobius vermicularis)
• Transmitted through infected food with pinworm
eggs
• Mature pinworms hatch and live in the large
intestine.
• Pinworms are more active at night around anus
where it lays their eggs
• Cause anal pruritis
Diagnosis:
• Scotch tape test, detection of the eggs on adhesive
tape when applied to preanal area
Hookworms (Ancylostoma duodenale, Necator americanus)
Treatment:
• Warm climate and poor sanitation are risk factors
• Bendazoles
for hookworm’s infection
Ascaris lumbricoides (giant roundworm):
• Hookworm eggs found in the soil where it
• Found on soil penetrates the soles of bare feet.
• Transmitted through ingestion of Ascaris eggs • It migrates to the lung through blood stream then
• The infection starts when it migrates to the reaches the intestine during coughing.
intestine and penetrate intestinal mucosa reaching • The symptoms start by allergic reaction from skin
blood stream penetration includes pruritic rash and itching.
• Symptoms include malnutrition or bowel • The symptom might progress to pneumonitis, iron
obstruction, biliary obstruction, intestinal deficiency anemia since hookworm is sucking
perforation. blood from intestinal wall.
• The patient might progress into pneumonitis
Treatment:
Diagnosis: • Bendazoles or pyrantel pamoate
• Microscopic detection of oval eggs in faeces
Treatment:
• Bendazoles or pyrantel pamoate

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Trichinella spiralis:
• Transmitted to human through eating undercooked
meat (especially pork)
• Initially larvae excyst in the stomach then migrate
to the muscle (inflammation) through blood
circulation
• The symptoms include muscle pain and weakness
and periorbital edema
Onchocerca volvulus:
Diagnosis: • Transmitted by female black fly
• Detection of Trichinella cyst on muscle biopsy • Skin is considered the main site of infection
Treatment: • The symptoms include initial pruritis followed by
• Bendazoles subcutaneous nodules, hyperpigmented skin
lesions in chronic conditions
• Severely affect retina causing river blindness
Treatment:
• Ivermectin

Whipworm (Trichuris trichiura):

• Transmitted through oral-fecal route
• The infection starts in the intestine then spread to
large intestine
• The symptoms include bloody diarrhea and rectal
prolapse
Treatment: Loa loa:
• Bendazoles • Transmitted by biting flies such as Deer fly, horse
fly, mango fly
• Characterized by calabar swellings and appear in
the conjunctivae of the eye
Treatment:
• Diethylcarbamazine.
Nematodes infect tissue:
Wuchereria bancrofti:
Toxocara canis:
• Transmitted by female mosquito
• Usually found in dogs
• More common in tropical and subtropical regions
• Transmitted through fecal-oral route
• Causes lymphedema and elephantiasis
• Causes visceral larva migrans
• Initially the infection starts when the larvae Treatment:
penetrate the intestinal mucosa then find its way to • Diethylcarbamazine.
blood stream
• The symptoms include: Cestodes (Tapeworms)
• Hepatitis Taenia Solium
• Myocarditis • Transmitted by Ingestion of larvae encysted in
• Seizures, coma undercooked pork
• Retinal lesions of the eye. • Ingestion of contaminated food with Taenia eggs
Treatment: • The patient initially suffers from abdominal pain
and if the larvae migrate to the brain it might cause
• Bendazoles
aacysticercosis or neurocysticercosis
• Neurocysticercosis characterized by cystic CNS
lesions and seizures
Diagnosis:
• MRI brain scan shows Cerebral cysticercosis
showing a cyst containing developing larva.

109
 • First snails are infected with nematodes then fish
or shellfish transmit the infection to human

Schistosomiasis (blood flukes)

• S mansoni with lateral spine shape
• Migrate to the liver causing portal hypertension-
Liver and spleen enlargement -Liver fibrosis

• S. haematobium with terminal shape

• Migrate to the lung causing pulmonary
hypertension

Computed tomographic (CT) scan of the

brain in a patient who presented with an
episode of generalized tonic-clonic seizure.
Note the calcified lesion in the left parieto-
occipital region. Source: Medscape

Treatment:
• First line of treatment (intestinal symptoms)
Praziquantel, while progressive cysticercosis • Can cause
should be treated with Albendazole squamous cell carcinoma of the bladder (painless
Diphyllobothrium latum (fish tapeworm): hematuria)
• Transmitted through consumption of raw fish Clonorchis sinensis (Chinese liver fluke)
or seafood
• More common in Asia
• Fish tapeworm live on intestinal B12 • Transmitted through undercooked fish
• Causes Vitamin B12 deficiency features: • Associated with cholangiocarcinoma
• Megaloblastic anemia • Cause Portal hypertension and hepatic cancer
• Increased MCV • Infect gall bladder causing pigmented gallstones
• Hyper segmented neutrophils
• Increased homocysteine
• Increase methylmalonic acid levels
Treatment:
• Praziquantel
Echinococcus granulosus (dog tapeworm)
• Transmitted through dog faeces and sheep
(intermediate host)
• The infection starts in the intestine then migrate to
the liver showing cystic cavity (hydatid cyst). Treatment for all trematodes is praziquantel
• Rupture of the cyst might cause anaphylaxis and
treated by injection of ethanol before surgical Ectoparasites
removal Sarcoptes scabiei
Diagnosis: • Ectoparasites means outside hence it usually
• Liver CT scan shows eggshell calcification infects the outer layer of the skin (startum
corneum)
Treatment:
• Causes scabies
• Albendazole
• Characterized by severe itching (pruritis) and
burrows in hands and feet
Trematodes
• Mites burrow under the skin and lay eggs
Overview:
• Very common among children and overcrowded
• Infection of trematodes are carried out through two population such as prisons, nursing homes
intermediate host • Transmitted through skin to skin contact

110
Treatment
• Permethrin
• Wash clothes and bedding
Pediculus humanus (lice)
Phthirus pubis (pubic louse)
• Scalp and neck (head lice) or waistband and axilla
(body lice).
• Feed on human blood
• Can transmit Rickettsia prowazekii (epidemic
typhus), Borrelia recurrentis (relapsing fever), Note: All viruses are single stranded (Haploid) except HIV
Bartonella quintana (trench fever). is DS
• Treatment: • Interaction between viruses
• Permethrin Recombination:
• Ivermectin lotion • Produced by recombining pieces of DNA from
different virus strains resulting in new progeny not
• Malathion
present in the original infecting viruses
• Occurs by homologs crossing over
Nit combing
Reassortment:
• When two viruses infect the same cell and during
Viral structure and genetics
this process genetic material is being exchange
• Viral structure
• Reassortment occur among influenza virus
Envelope Virus Non-Envelope Virus (segmented genome)
(Naked)

Sensitive to heat Heat resistant

Enclosed within a lipid Lacks bilayer lipid

membrane membrane

Transmitted by direct Oral-fecal transmission

contact (blood – Sexual-
respiratory)

Complementation:
• Interaction at a functional level NOT at the nucleic
acid level.
• This process allows defective viruses to replicate
Icosahedral Helical and spread
• If the cell is coinfected with 2 viruses and one of
Capsid and nucleic The capsid shaped into a them is not functional (defective) so both viruses
acid just like naked filamentous, or rod-shaped help each other’s to complement the missing part.
Icosehedral structure However, the defect virus will die in the next cell
due to absence of the complement protein
The genetic material is Central cavity that encloses its Phenotypic mixing:
fully enclosed inside nucleic acid • The cell is being attacked by two viruses each of
of the capsid which holds its own unique genetic material.
poliovirus, rhinovirus, The plant tobacco mosaic virus • Both viruses share capsid or coat protein
and adenovirus. • Viral genome of one virus may be encapsulated in
the capsids or the other virus Pseudovirion

111
 • The infectious power will be determined based on
the parental genome is packed

DNA Viruses
Herpes Simplex Viruses:

Herpes simplex type-1:

The blotches become itchy The rash can form a band

blisters that ooze fluid. A that only appears on one
few days later, the blisters side of your body. The
dry out and scab skin remains painful until
after the rash has gone

• Associated with orofacial infection Epstein Barr Virus (HHV4)

Mechanism of transmission: Mechanism of transmission: Oral saliva (from kissing) and
• Saliva and respiratory system genital secretions – Common in teens
Clinical Presentations:
Clinical Presentations:
• Blister in the lips
• Causes active Mononucleosis
• Gingivostomatitis
• Lymph node and spleen enlargement, flu-like
• Keratoconjunctivitis
symptoms and painful pharyngitis
• Temporal lobe encephalitis
• Patients with active mononucleosis should avoid
Treatment: sport due to high risk of splenic rupture.
• Acyclovir Swollen lymph nodes in the neck of
Herpes simples type-2: a person with infectious
• Associated with genital infection mononucleosis
• Affects Sacral nerve root ganglia (S2-S5)
Mechanism of transmission:
• Sexual contact and perinatal
Mechanism of infection:
Clinical Presentations: transf
• Genital herpes EBV
ormed Lymp
B h
• Viral meningitis (neurovirulence) infect B
cells
Viral Lysis
node
B cells replic into
• Newborn infection (birth defects, neonatal cells transf
that
ation blood
and
contai splee
encephalitis, intrauterine death) if the mother throug ormati
n
inside strea
n
h on B cell m
displayed HSV II infection (through Herpes CD21
latent enlarg
Labialis) viral ment
DNA,
Varicella Zoster Virus (HHV3):
• Dormant in dorsal ganglia and reactivation during
stress or immunocompromise patients Diagnosis:
• Monospot test for heterophile antibody (not
Mechanism of transmission: specific)
• Respiratory transmission and skin contact • Confirmation is done by anti-EBV
• Two weeks incubation period followed fever, immunoglobulin M
malaise and pharyngitis then by vesicular rash in • Atypical lymphocytes on peripheral blood smear
face and trunk.
• After a week of lesion rupture, the patient is no Cancer associated with EBV:
longer contagious
• Hodgkin’s Lymphoma
Clinical Presentations: • Burkitt’s Lymphoma
• Causes Chicken box and Shingles (Reactivated • Diffuse Large Cell Lymphoma
infection) • Nasopharyngeal carcinoma in Asian adults
• Immunocompromised patients might develop • Oral Hairy Leukoplakia
severe conditions of pneumonia and encephalitis.
112
The transformed B cells are not controlled by the immune Human Herpes Virus 8 (HHV8):
system that result in massive proliferation eventually • Transmitted sexually and transplant patients
leading to cancer • Causes Kaposi sarcoma in AIDS patients
Cytomegalovirus (HHV-5): Kaposi sarcoma: nodules or blotches that may be red,
purple, brown, or black
Mechanism of transmission: Human Papillomavirus:
• Transmitted though close contact such as sexual • Most common sexually transmitted infection in
intercourse, transplacental, organ transplant United states
Clinical Presentations: • Composed of several serotypes but most
• Typically occurred in immunocompromised importantly (1&2&6&11)
patients • Associated with genital warts usually appear as a
• AIDS patients with immunocompromised small bump or group of bumps in the genital area
immunity develop CMV retinitis, colitis, and • Infection could progress to cancer such as cervical
viremia. cancer (serotype 16,18) or cancer of the vulva,
CMV retinitis: Cotton wood exudate, hemorrhage and vision vagina, penis, or anus.
loss • Vaccination is recommended for prophylaxis.
• Patients undergo bone marrow transplant develop
CMV pneumonitis
• CMV cross the placenta leading congenital CMV
such as microcephaly, birth defects, hepatomegaly
and blueberry muffin baby
• Causes false positive Monospot test
(Mononucleosis-like disease)

Reprinted with permission from Schiffman M,

Wentzensen N. From human papillomavirus to cervical
Right eye-Multiple Left eye - broad cancer. Obstetrics and Gynecology 2010;116(1):177–
cotton wool spots retinal whitening and 185.
adjacent to the nerve intraretinally
and throughout the hemorrhages along Adenovirus:
macula, consistent the superior arcades,
with HIV retinopathy with cotton wool Mechanism of transmission
spots adjacent to the 1. close contacts touching or shaking hands
nerve consistent with 2. Coughing or sneezing
CMV retinitis and 3. Oral fecal
HIV retinopathy • Most common cause of febrile illness in children.
Clinical Presentations:
• Conjunctivitis- Pink eye
Diagnosis:
• Respiratory tract infection: Pneumonia, Febrile
• Intranuclear inclusion bodies “Owl’s eye”
pharyngitis and rhinitis
Human Herpes Virus 6 (HHV6):
• Gastroenteritis
• Causes roseola, or exanthem subitem
• Myocarditis
• Known as sixth disease and occur mostly in infants
• Acute hemorrhagic cystitis
• consisting of several days with high fever followed
• Diarrhea
by macular rash on the trunk
• High fever might develop to seizures
Human Herpes Virus 7 (HHV7):
• Causes roseola, but less common
• Reactivate later in life

113
 Herpes Viruses
Cytomegalovirus (HHV-5):
• Transmitted though close contact such as sexual
intercourse, transplacental, organ transplant
• Typically occurred in immunocompromised
patients
• AIDS patients with immunocompromised
immunity develop CMV retinitis, colitis, and
Tonsillopharyngitis viremia.
• Causes false positive Monospot test
(Mononucleosis-like disease)
Pox viruses
• Diagnosed by Intranuclear inclusion bodies “Owl’s
• Envelope DNA virus from pox viridae family
eye”
• Smallpox variola virus
Herpes Simplex Virus:
• Cowpox caused by vaccinia milk made blisters
Herpes simplex type-1:
• Molluscum contagiosum (water warts),
characterized by flash colored domed lesion with a • Associated with orofacial infection
dimple in the center • Transmitted through Saliva and respiratory system
Polyomavirus: • Characterized by Blister in the lips,
• The JC virus or John Cunningham virus is a type Gingivostomatitis, Keratoconjunctivitis and
of human polyomavirus Temporal lobe encephalitis
• Associated with immunocompromised patients Herpes simples type-2:
• Associated with progressive multifocal leuko- • Associated with genital infection
encephalopathy • Sacral nerve root ganglia (S2-S5)
Hepadnavirus: • Transmitted through Sexual contact and perinatal
• Known as Hepatitis E virus (Enteric) • Characterized by genital herpes
• Spread by fecal-oral route • Diagnosed by PCR, tzanck smear test, detection of
• Associated with hepatitis, hepatocellular intranuclear Cowdray A inclusion
carcinoma and hepatic cirrhosis Tzanck smear: Used to determine whether skin lesions are
• Symptoms similar to Hepatitis A virus caused by a herpes virus, a blister is scraped, and its
Parvovirus B19: contents are smeared on a slide for detection of
• Small, nonenvelope ,Single strand DNA virus multinucleated giant cells
• Causes childhood rash named fifth disease or Varicella Zoster Virus (HHV3):
erythema infectiosum or slapped cheek syndrome • Dormant in dorsal ganglia and reactivation during
• Causes transit aplastic anema crisis in patients with stress or immunocompromise patients
hemolytic anemia ( sickle cell anemia, thalathemia • Causes Chicken box and Shingles (Reactivated
) infection)
• Can cause hydrops fetalis in pregnant women • Immunocompromised patients might develop
severe conditions of pneumonia and encephalitis.
• Characterized by vestibular rash which is painful
and itchy

Erythema infectiosum

The blotches become itchy The rash can form a band

blisters that ooze fluid. A that only appears on one

114
 few days later, the blisters side of your body. The
dry out and scab skin remains painful until
after the rash has gone

Epstein Barr Virus (HHV4):

• Causes active Mononucleosis
• Infect B cells Reoviridae
• Common among teenagers (15-20 years old) • Naked-ds RNA
kissing disease Rotavirus
• Spleen and hepatomegaly, flu-like symptoms and • Most common in daycare kinder garden
painful pharyngitis • Associated with fecal-oral gastroenteritis (infantile
• Diagnosed by diarrhea)
1. Monospot test for heterophile antibody Signs and symptoms
(not specific) • Anorexia
2. Confirmation is done by anti-EBV • Low-grade fever
immunoglobulin M • Watery, bloodless diarrhea
3. Atypical lymphocytes on peripheral blood • Vomiting
smear • Abdominal cramps
Cancer associated with EBV: Coltivirus
• Hodgkin’s Lymphoma • Colorado fever tick
• Burkitt’s Lymphoma • Transmitted by wood tick
• Diffuse Large Cell Lymphoma
• Nasopharyngeal carcinoma in Asian adults Picornaviridae
• Oral Hairy Leukoplakia • Naked
The transformed B cells are not controlled by the immune • + sense SSRNA
system that result in massive proliferation eventually • Usually common in summertime
leading to cancer
Swollen lymph nodes in the neck of
a person with infectious
mononucleosis
Picornaviridae

RNA viruses
Overview Enterovirus Rhinovirus Heparnavirus
• All RNA viruses are single-stranded (ss) except
Reovirus
• ss (−) RNA viruses require RNA polymerases
contained in the complete virion. • Enteroviruses (acid-stable): Include polio virus;
• It should be transcribed first from negative to coxsackie virus A; coxsackie virus B; D68;
positive strand which include Arenaviruses, echoviruses
Bunyaviruses, Paramyxoviruses, • Rhinoviruses (acid labile)
Orthomyxoviruses, Filoviruses, and • Heparnaviruses: HAV
Rhabdoviruses. Heparnaviruses (Hepatitis A virus-HAV)
• Most RNA are enveloped; the only naked ones are • Associated with acute virus hepatitis
Picornavirus, Calicivirus and Hepevirus, and • Fecal-oral transmission
Reovirus.
• Self -limiting infection
• Segmented viruses: different genes on different • Not required a carrier
pieces of RNA such as:
1. Reovirus
• Symptoms usually last less than 2 months:
2. Orthomyxovirus
1. Fatigue
3. Bunyavirus
2. Fever
4. Arenavirus
3. Appetite loss

115
 4. Jaundice
5. Nausea
6. Abdominal discomfort

Coxsackie virus
• Transmitted though fecal-oral
• Associated with aseptic meningitis, myocarditis,
Echovirus pericarditis
• Associated with aseptic meningitis, myocarditis • Herpangina known as Mouth blisters (painful
and URT infection mouth infection)
• Transmitted by fecal-oral • Hand, foot and mouth disease (Vesicular and
• Diagnosed by CSF analysis revealed: Papular rash)
1. High lymphatic count • Acute lymphoglandular pharyngitis
2. Normal glucose level
3. Low number of WBC

Calicviridae
• Naked, +ssRNA

Norwalk Virus
Poliovirus • Transmitted though Fecal-oral route
• Transmitted by fecal-oral • Common among school aged child to adult
• Fecal-oral Virus targets anterior horn motor • Cause acute gastroenteritis especially related to
neurons cruise ships
• Initial symptoms include • Characterized by nausea, vomiting, diarrhea, pus
1. headache, fatigue, fever in stools
2. Neck pain or stiffness • Self-limiting
3. Pain or stiffness in the arms or legs Flaviviridae
4. Muscle weakness or tenderness • Envelope virus, +ssRNA
• Advanced stage includes paralytic polio (flaccid • Arthropod-borne virus
asymmetric paralysis, no sensory loss) Yellow fever virus
• Prophylaxis through polio vaccine: Live vaccine • Transmitted through Ades mosquitoes and the
(Sabin); killed vaccine (Salk) reservoir might be human or monkeys
• Characterized by high fever, black vomit (GIT
Rhinovirus hemorrhage)
• Most common virus that cause common cold • Jaundice
• Congested and runny nose • Liver inflammation (inclusion bodies)
• High mortality rate more than 50%
• Most common in south Africa

116
 2. In advanced situation the patient might experience
neck stiffness, disorientation, coma, tremors,
occasional convulsions
• Diagnosed by Lumbar puncture and detection of
SLEV

Dengue virus
• Most common mosquito born infection due to poor
sanitation and stagnant water
• Characterized by Severe headache (retroorbital), Togaviridae
Myalgias, Arthralgias • Envelope virus, +ssRNA
• Hemorrhagic fever
• Thrombocytopenia Rubella
• Backbone fever (rash, muscle and joint pain) • German measles or 3-days measles
• Rubella is one TORCH infection: toxoplasmosis,
West Nile encephalitis virus rubella, cytomegaly virus and herpes or HIV
• Characterized by:
• Erythematous rash begins on face, progresses to
torso)
• Fever
• Posterior auricular/ occipital lymphadenopathy
• Fine truncal rash
Congenital rubella syndrome
• Infection during the first 16 weeks of pregnancy
presents major risks for the unborn baby.

• Usually spread by infected mosquitoes.

Mosquitoes become infected when they feed on
infected birds
• The virus is hard to transmitted by human contact
• Signs and Symptoms:
• Fever
• Malaise
• Backpain
• Anorexia • patent ductus arteriosis
• In rare care develop paralysis, muscle weakness • Pulmonary stenosis
and encephalitis • Cataracts
• Diagnosis: • Microcephaly
1. Lymphocytic pleocytosis • Sensorineural deafness (VIII)
2. Increased protein, lactic acid • Blue berry muffin baby
3. Detection of virus-specific antibody IgM and • Mental retardation
neutralizing antibodies (detection of IgG is not Treatment
specific) • MMR vaccine to mother before pregnancy
• Treatment: • Child given vaccine 12 to 15 months
• Supportive care (antipyretics, fluids) Orthomyxoviridae
• Envelope virus, (-) ssRNA
St. Louis encephalitis virus Influenza virus
• Related to Japanese encephalitis virus • Transmitted through direct contact
• Signs and symptoms include • The reservoir for influenza A is (birds, pigs and
1. Flu like symptoms (Fever, headache, malaise) humans)

117
 • The reservoir of influenza B are human only • Pathophysiology:
• H5N1 strain from birds to humans • Narrowing of the larynx and trachea below the
• H1N1 strain— swine flu level of the glottis causing the characteristic
• Envelope contains two glycoproteins, audible inspiratory stridor
Hemagglutinin and Neuraminidase • The steeple or pencil sign of trachea
• Viral neuraminidase enables the virus to be
released from the host cell.
• Neuraminidases are enzymes that cleave sialic
acid groups from glycoproteins and are required
for influenza virus replication.
• Influenza virus bind through hemagglutinin into
sialic acid sugars on the surfaces of epithelial cells
in nose, throat, lungs and mammals • Treatment in mild cases:
Signs and symptoms • Cool mist
• Headache and malaise • Coughing can be treated with warm, clear fluids to
• Fever, chills, myalgias, anorexia loosen mucus in the oropharynx
• Bronchiolitis, croup, otitis media, vomiting • Frozen juice popsicles also can be given to ease
(younger children) throat soreness
• Super infection by staph aureus • Treatment in severe cases:
• Pneumonia/secondary bacterial infections • Corticosteroids
• Can lead to Reye syndrome or Guillain-Barré • Nebulized epinephrine
syndrome • Steroids
• Other infectious causes for croup-like illnesses
Genetic shift Genetic drift include the following:
Responsible for pandemics Causes epidemics 1. Adenovirus
Rare genetic reassortment Due to virus 2. Respiratory syncytial virus (RSV)
Coinfection of cells with two mutation 3. Influenza virus
different strains of influenza A
(H5N1 and H3N2) Respiratory Syncytial Virus (RSV)
Influenza A only Influenza A and B • Most common during winter
Deadly and sudden slow • F protein cause formation of synctitium
• Signs and symptoms
Prevention: 1. In adults: colds
2. infants/preemies: bronchiolitis, and necrosis of
bronchioles, atypical pneumonia (low fever,
tachypnea, tachycardia, expiratory wheeze)
Treatment:
• supportive treatment
• Bronchodilators (Albuterol)
• Chest physiotherapy
• Epinephrine
• Killed vaccine • Excessive nasal suction of secretion
• Zanamivir- Neuraminidase inhibitor (inhalation) • Nebulized hypertonic saline
for H1N1 • Systemic or inhaled corticosteroids
• Oseltamivir- Neuraminidase inhibitors (orally) for
H5N1

Paramyxoviridae
• Envelope virus, (-) ssRNA
Human parainfluenza virus type 1-
• Cause croup infection ((laryngotracheobronchitis):
hoarseness, seal-like barking cough, stridor,
subglottal swelling)

118
 • palivizumab (monoclonal antibody) • Pathophysiology:
1. After contact, virus binds to peripheral nerves by
Rubeola (Measles) binding to nicotinic acetylcholine receptor or
• Characterized by 3Cs: indirectly into the muscle at site of inoculation
1. Cough 2. virus travels by retrograde axoplasmic transport to
2. Coryza dorsal root ganglia and spinal cord
3. Conjunctivitis 3. once virus gains access to spinal cord, brain
4. Photophobia becomes rapidly infected
5. Koplik spots → maculopapular rash from ears
down (red spots with a bluish white center)
6. Giant cell pneumonia (Warthin-Finkeldey cells) in
immunocompromised patients
7. Maculopapular rash
• Chronic symptoms include:
• Subacute sclerosing panencephalitis (SSPE):
progressive brain inflammation caused by measles
virus characterized by:
1. Behavior change
2. Intellectual problems
3. Myoclonic seizures
4. Blindness
5. Ataxia
• Diagnosis:
• Detection of oligoclonal bands of antibodies in
CSF
Mumps virus • Signs and symptoms:
• The symptoms start with flu like symptoms
followed by neurological symptoms include:
1. Hydrophobia
2. Seizures
3. Disorientation
4. Hallucination
5. Pharyngeal spasm
6. Hypersalivation
• Diagnosis
• Negri bodies
• Transmitted through respiratory droplets • Intracytoplasmic inclusion bodies (brain biopsy)
• Lytic infection of epithelial cells of upper • DFA (impression smears of corneal epithelial
respiratory tract and parotid glands → spread cells)
throughout body • Treatment:
• Signs and symptoms: • Long incubation period allows immunization
• The symptoms start with headache and malaise opportunity
and might progress to • vaccine for high-risk individuals
• Parotitis Bunyonviridae
• Orchitis (lead to sterility in males) Hantavirus
• Meningoencephalitis • Infection caused by aerosolized mouse urine- deer
• Treatment and prevention: mouse with high incidence in summer and spring
• live, attenuated vaccine, MMR • Hantavirus pulmonary syndrome/ hemorrhagic
Rhabdoviridae fever (cough, myalgia, dyspnea, tachycardia,
Rabies virus pulmonary edema and effusion, and hypotension
• The reservoir are bats, raccoons, foxes, shunks and Retroviridae
dogs • dsRNA
• Transmitted through an animal bite that carry • HIV
rabies virus • Human T cell leukemia virus

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 • In most viruses, DNA is transcribed into RNA, and • Lacks endonuclease enzyme hence no
then RNA is translated into protein proofreading ability
• In retrovirus, RNA is reverse-transcribed into Hepatitis D:
DNA, which is integrated into the host cell's • Caused by RNA delta virus
genome (when it becomes a provirus), and then • Transmitted sexually, perinatal and parentally
undergoes the usual transcription and translational • Defective virus, virus that requires the presence of
processes to express the genes carried by the virus HBV to replicate
• Hepatitis D can occur simultaneously with HBV
(coinfection) or displayed later after chronic
Hepatitis B infection (Superinfection)
• The HBsAg coat provided to HDV by HBV enable
the defective virus to invade the hepatocytes
Hepatitis B

Structure:
• Hepatitis B is a member of Hepadnavirus family
• The virus particle called virion composed of outer lipid
envelope and an icosahedral nucleocapsid core
composed of protein

Components:
• HBsAg mushroom looking structure
• Chain of HBsAg (core antigen)
• HBeAg (early antigen)
Hepatitis A, C, E and D • Hepatitis B virus DNA polymerase
Hepatitis A&E Mechanism of transmission:
• Transmitted though oral/fecal route • Transmitted by bloody/body fluid
• Acute infection with short incubation period • Blood transfusion
• No carrier states • Needles IV drug abuse
• Caused by picornavirus • Sex
• Asymptomatic Pathogenesis:
• Self-limited acute hepatitis with hepatocyte • The virus gains entry into the cell by binding to
swelling receptors on the surface of the cell (Unknown) and
• Hepatitis E caused by RNA Hepevirus entering it by endocytosis.
• Causing fulminant hepatic failure in pregnant • Following endocytosis, the virus membrane fuses with
women the host cell's membrane, releasing the nucleocapsid
• With Bad prognosis especially pregnant women into the cytoplasm
• Diagnosed with patchy necrosis • Note: HBV is a noncytopathic virus. This means that
Hepatitis C: the virus itself does not cause direct damage to liver
• Caused by RNA flavivirus cells. Instead, it is the immune system’s aggressive
• Transmitted through blood and post-transfusion response (recruitment of cytokines and lymphatic T
• Chronic disease, may progress to hepatic cirrhosis cells) to the virus that usually leads to inflammation
and carcinoma and damage to the liver (hepatitis).
• Require long incubation period • HBV can cause acute hepatitis, until the immune
• Require carrier state system is able to clear the virus from the body,
• Diagnosed by lymphoid aggregates with asteatosis usually within six months of becoming infected
with the virus.

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 • HBV can become a chronic infection. This means surface antigen (HBsAg) from serum and the
that the immune system is not able to get rid of the appearance of HBsAb (anti-HBs)
virus within six months after infection • During this period, IgM anti-HBc is the only
• In response to acute hepatic infection, ALT and detectable antibody
AST enzymes concentration significant increased. • After 6 months (IgG anti-HBs +) means the patient
Serology course: become a chronic carrier
• 70% asymptomatic “silent disease)
• 20% Sever symptoms “Icteric hepatitis)
• 5% chronic hepatitis B carriers
Signs and symptoms
• The first symptoms are flu like symptoms such as
fever, chills, myalgia, joint pain
• Loss of appetite, headache
• Nausea
• Icteric RUQ pain,
• Yellowing of the skin, whites of the eyes and
under the fingernails (jaundice)
Acute hepatitis B virus infection: Lab serology:
• An acute hepatitis B infection follows a relatively • Initial blood tests to diagnose HBV infection look
long incubation period - from 60 to 150 days with for one antigen, HBsAg (the hepatitis B surface
an average of 90 days. antigen), and two antibodies, anti-HBs (antibodies
• HBsAg (hepatitis B surface antigen) is the first to the HBV surface antigen) and anti-HBc
serologic marker to appear in a new acute (antibodies to the HBV core antigen).
infection/ chronic, which can be detected during • There are two types of anti-HBc antibodies
the first two weeks of infection. produced: IgM antibodies and IgG antibodies.
• The presence of HBsAg indicates that the person is • IgM antibodies are produced early during
infectious. infection. IgG antibodies are produced later while
• The body normally produces antibodies to HBsAg infection and replace IgM antibodies.
as part of the normal immune response to • HBsAg+, HBeAg+ and IgG anti-HBs (negative)
infection. REFER to acute hepatitis B infection
• HBsAg is the antigen used to make hepatitis B • HBsAg (negative), IgG anti-HBs (Positive)
vaccine REFER to patient receive vaccine
• In response to infection, the body starts to produce • IgG anti-HBc (Positive), HBsAg (negative), IgG
IgM antibody to hepatitis B core antigen (IgM anti-HBs (Positive) REFER to past infection of
anti-HBc) Hepatitis B and recovered
• HBsAg will start to drop then IgM anti-HBc will • IgG anti-HBc (Positive), HBsAg (negative), IgG
decline also anti-HBs (negative) the patient in window period
• IgG anti-HBc – this blood test remains positive • If the patient has positive IgM anti-HBc, HBsAg
indefinitely as a marker of past HBV infection. (negative), IgG anti-HBs (negative) REFER to
window period
Note: Patient who recovered from acute infection will Chronic hepatitis B virus infection:
be negative for HBsAg
• HBeAg (hepatitis B e-antigen) is detectable in
patients with a new acute infection; the presence of
HBeAg is associated with higher HBV DNA
levels, thus, increased infectiousness.
• In response to increase HBe Ag, the body will start
produce IgG anti-HBe
• Once HBeAg started to be cleared out of the body,
the system is going to produce IgG anti-HBs to
acquire immunity •
The window period of HBV: During chronic infection, the system will
continually produce HBsAg
• The short period when the body system gets cleared
from the virus i.e. between the disappearance of

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 • In response to chronic infection, IgG anti-HBe and • After this attachment, gp120 attaches to CCR5 or
IgG anti-HBe will be produced. CXC).
• Although IgM anti-HBc is produced during the • The attached gp120 and co-receptor undergo a
first weeks of exposure but its effect will be conformational change.
diminished throughout chronic infection • After the conformational change of gp120, gp41
• Complications of chronic HBV infection include has the ability to make a structural change.
primary hepatocellular carcinoma and cirrhosis. • CCR5 receptors are subjected to mutations,
Treatment: patients with homozygous mutations are resistant
• Alpha interferon to HIV infection while heterozygous mutations are
• A defovir associated with lower pre-AIDS viral loads and
• Lamivudine delayed progression to AIDS
• Entercavir • Inside the CD4 cells, HIV uses reverse
• Tenofovir/Telbivudine transcriptase enzyme to convert RNA to DNA
• Post- exposure prophylaxis HIV, this conversion help HIV to enter the nucleus
• Hepatitis B vaccine and combine with cell genetic material
• Hepatitis B Immunoglobulin (HBIG) • Inside CD4 nucleus, HIV release integrase enzyme
HBeAg, which is a marker for active disease to allow insertion its viral DNA into DNA of CD4
(anti-HBsAg) confer immunity to the virus cells.
HIV/AIDS • Once HIV integrated into CD4 cell DNA, HIV
uses CD4 machinery to replicate and produce more
Outline:
HIV protein.
• Virus structure • HIV RNA moves to the surface getting out from
• HIV life cycle the host CD4 cells and releasing protease enzyme
• Stages of HIV infection (cut out the large protein chains into smaller ones)
Virus structure:

• Composed
of nucleic acid (DNA or RNA) and Capsid
(protein coat)
• Entails diploid genome (2 RNA copies)
• Envelope glycoprotein (Glycoprotein 120 &
Glycoprotein 41) Stages of HIV infection:
• Glycoprotein 120 attach to host CD4 T cells
• Glycoprotein 41 responsible for fusion and entry
• Matrix protein P17
• Capsid protein 24
HIV life cycle:
• HIV targets the immune system through CD4 cells
• HIV uses CD4 cells to multiply and replicate
The HIV cycle involves several stages:
• Binding: HIC virus attach CD4, the virus binds
itself to the surface of the CD4 receptor either
CCR5 (late infection) or CXR4 (Early infection)
CCR5 are expressed on macrophages, dendritic cells,
eosinophils and microglia

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Acute HIV infection: Opportunistic infection in AIDs:
• Starts with flu-like symptoms (fever, fatigue, • CD4+ cell count< 400
pharyngitis and headache) • Reactivation of past infection like syphilis,
• During this phase HIV virus multiply rapidly and shingles
destroys CD4 cells • Dissemination of bacterial infection
• The virus load is extremely high and that increases • Fungal infection such as coccidioidomycosis and
the risk of HIV transmission non-Hodgkin lymphomas
• During this time the immune systems fight back Systemic infection:
and decrease the viral load but the virus itself • Involved in Histoplasma capsulatum
continue replicating inside the lymph node • Target macrophages
Latency period (clinical latency): • CD4 T cell < 100
• Last for 7 years • Fever, weight loss, fatigue, cough, dyspnea,
• Asymptomatic nausea, tongue ulcer, diarrhea
• The virus continues to replicate and CD4 count Skin:
decreases
• When the CD4 counts reached <400 the patients
will be susceptible to several infections including
skin (athlete’s foot, oral thrush and shingles)
bacterial (Mycobacterium tuberculosis)
AIDS:

• Yeast infection such as Candida Albicans

characterized by fluffy white cottage Cheese
Lesions on the skin (Oral thrush)
• Involved in Esophagitis and vaginal yeast infection

• AIDS will develop when the CD4 counts reached

< 200
• The patient is subjected to opportunistic infections
• In cases of lack of treatment, the patient dies
within 2 years
• NOTE: CD4 count refers to the risk status of the
patient, while Viral load refers to how quickly the
patient progressing to death
Diagnosis of HIV: • CD cells <400
• Elisa screening test to detect HIV antibodies Bacillary angiomatosis:
• Western blot analysis for confirmation (No longer • Caused by Bartonella henselae
used by CDC) • Characterized by lesions on and under the skin
• Viral load tests determine the amount of viral (non-neoplastic vascular lesions)
RNA in the plasma. For newborn babies GIT tract
• High viral load associated with poor prognosis. • Cryptosporidium it’s a parasite disease
• Affect distal small intestine
• Viral load is used to monitor the progress of drug
administration • Characterized by chronic watery diarrhea when
Diagnosis of AIDS: CD4 < than 200
• CD cell count < 200 cells/microliter. Normal cell • Diagnosed by Acid-fast oocysts in stool
count (500-1500 cells/mm3) Neurological manifestations:
• CD4 percentage in T lymphocytes < 14 %. Normal • Encephalopathy
40% • Caused by JC virus reactivation
• Progression of opportunistic infection. Constant • Progressive multifocal leukoencephalopathy DMC
candida infection and PCP pneumonia • Demyelination of the brain

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 • Brain abscess Neonatal Infection
• Caused by Toxoplasma Gondie -Multiple ring Congenital Toxoplasmosis
enhancing lesions • Caused by transplacental acquisition
• CD4 <100 of Toxoplasma gondii.
• Meningitis • Source of infection: Ingestion of inadequately
• Caused by Cryptococcus Neoformens cooked meat containing cysts or food, or water
• lumbar puncture for CSF analysis or stain with contaminated with cat feces.
India ink Clinical presentations
• CD4 count <50 • Usually infected pregnant women are
• Dementia asymptomatic, but the neonates may suffer from:
1. Jaundice
Eyes
2. Myocarditis
• Retinitis: Caused by cytomegalovirus 3. Intracranial calcifications
• Diagnosed by Cotton cool spots on funduscopic 4. Hydrocephalus
exams 5. Chorioretinitis
• CD4 <50 6. Seizures
• CMV also causes Esophagitis 7. Hepatosplenomegaly
Oncological manifistations: 8. Prematurity
• Kaposi sarcoma: Diagnosis
• Caused HHV-8 • PCR
• Neoplastic vascular lesions Treatment
• Purple cutaneous lesions in internal organs or skin • pyrimethamine, sulfadiazine, and leucovorin.
Oral hairy leukoplakia: Congenital Rubella
• Caused by Epstein-Barr virus EBV • Congenital rubella typically results from a primary
• Characterized by Unscrapable white plaque on maternal infection
lateral tongue Clinical presentations
Note: In case of Candida albicans, scraping the tongue yield • Usually infected pregnant women are
white materials with bleeding asymptomatic, but it may suffer from upper
Non-Hodgkin’s lymphoma: respiratory infection including fever,
• Caused by Epstein-Barr virus EBV conjunctivitis, maculopapular and joint symptoms
• Appear in the back of the Pharynx • The fetus might develop the following symptoms:
Squamous cell carcinoma 1. Microcephaly
• Due to HPV infection 2. Cataracts
3. Hearing loss
• Cervical or anal
primary CNS lymphoma 4. Patent duct arteriosus
5. thrombocytopenia with purpura
• Caused by Epstein-Barr virus EBV
6. Dermal erythropoiesis resulting in bluish red skin
Lung
lesions
• Interstitial pneumonia
• Caused by CMV Cytomegalovirus
• Diagnosed by Intranuclear inclusion bodies “Owl’s • Acquired by exposure to infected cervical
eye” secretions, breast milk, or blood products.
• Aspergillosis: • Neonates known to protective against CMV
• Caused by Aspergillos Fumugatous infection through maternal antibody, however,
• Characterized by pleuritic pain and hemoptysis preterm infants who lacks these antibodies are
• Pneumocystis pneumonia subjected to serious infection
• Caused by Pneumocystis jirovecii Clinical presentations at birth:
• CD4 count < 200 • Sensorineural hearing loss
• Tuberculosis like disease • Jaundice
• Caused by Mycobacterium avium intracellular • Periventricular calcifications
• CD4 <50 • Sepsis-like syndrome
• Microcephaly
• Hepatitis

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Diagnosis • Failure to gain weight or failure to thrive
• Culture detection or PCR
Treatment Late signs:
• Parenteral antiviral Ganciclovir or oral • Abnormal notched and peg-shaped teeth, called
Valganciclovir Hutchinson teeth
HIV • Blindness
• Neonates are exposed to HIV infection in utero, • Clouding of the cornea (the covering of the
during labor or after delivery eyeball)
• Decreased hearing or deafness
• Deformity of the nose with flattened nasal bridge
(saddle nose)
• Gray, mucus-like patches around the anus and
vagina
• Joint swelling
• Saber shins (bone problem of the lower leg)
• Scarring of the skin around the mouth, genitals,
and anus
Diagnosis
• Darkfield microscopy of lesions, placenta, or
umbilical cord
• Serologic testing of mother and neonate; possibly
CSF analysis
• According to WHO, giving antiretroviral drugs Treatment
(ARVs) to either the HIV-infected mother or HIV- • Penicillin
exposed infant can significantly reduce the risk of Red rash in childhood
transmitting HIV through breastfeeding Coxsackievirus
Neonatal herpes simplex infection
• Transmission during delivery through an infected
maternal genital tract
Clinical presentations
• Skin vesicles •
Involved in hand, foot, mouth disease
• Encephalitis
• Signs and Symptoms:
• Might progress to disseminated disease that
include hepatitis, disseminated intravascular • Causes painful red blisters in the throat and on the
tongue, gums, hard palate, inside of the cheeks,
coagulation
and the palms of hands and soles of the feet.
Diagnosis
Roseola
• HSV culture or PCR
• Due to exposure to virus infection HHV6
• Immunofluorescent testing of lesions or electron
microscopy
Treatment
• High-dose parenteral acyclovir
Congenital Syphilis
• Acquired through exposure of Treponema
pallidum and transmitted to fetus via placenta
• Untreated syphilis in pregnancy is also associated
with a significant risk of stillbirth and neonatal
death

Clinical presentations
Early signs:
• Copper-colored rash on the palms and soles • Named as roseola infantum" or "sixth disease".
• Papular lesions around the nose and mouth and in • Signs and Symptoms:
the diaper area, as well as petechial lesions
• Blood-stained nasal discharge causing snuffles

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 • The presentation in roseola classically is that a
child with a high fever develops a rash after the
fever abates
• The rash can be characterized by:
1. Pinkish-red spots, patches or bumps start on the
chest before spreading to the face, neck and arms
2. isn't usually itchy or uncomfortable
3. normally fades and disappears within two days

Measles
Slapped cheek syndrome
• Signs and Symptoms
1. Fever
2. Runny nose
3. Sore throat
4. Headache
5. GIT upset
• After a few days, a distinctive bright red rash on
both cheeks (the so-called “slapped cheeks”)
• The rash usually begins on the face and then • After another few days, a light pink rash may also
moves down the neck and the rest of the body over appear on the chest, stomach, arms and thighs.
the course of a few days (Head down and This often has a raised, lace-like appearance and
confluent). may be itchy.
• Signs and Symptoms:
1. Cough Chicken box
2. Conjunctivitis
3. Coryza
4. Koplic spots (gray-white papules)
5. The measles rash is red-brown blotches.

• It causes a rash of red, itchy spots that turn

into fluid-filled blisters.
• They then crust over to form scabs, which
eventually drop off.
• The spots normally appear in clusters and tend to
be:
1. behind the ears
2. on the face
Rubella
3. over the scalp
• A fine, pink rash that begins on the face and
quickly spreads to the trunk and then the arms and 4. on the chest and belly
legs, before disappearing in the same sequence 5. on the arms and legs
• Signs and Symptoms:
• Fever Nosocomial Infection
• Headache Overview
• Stuffy or runny nose • Infection developing in patients after admission to
• Inflamed, red eyes the hospital. The infection can originate from the
outside environment, another infected patient, staff
• Enlarged, tender lymph nodes at the base of the
that may be infected
skull, the back of the neck and behind the ears
• Signs and symptoms might appear during patient
• Aching joints
stay or after their discharge

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 • Microorganisms involved in these infections are Antibiotic
able to survive in hospital environment and • Suspected organism: Clostridium Difficile
develop resistance to antibiotics and disinfectants • Signs and Symptoms:
Sources of nosocomial microbes 1. Fever
• Cross infection from patient to patient 2. Diarrhea
• Transmitted through medical personnel 3. Leukocytosis
• Patient´s own flora Needle sticks
• Hospital environment such as:
Aspiration Hepatitis B, C
• In Unconscious patients and pulmonary ventilation
may lead to pulmonary infection caused by gram Introduction to Antimicrobials
negative bacteria especially anaerobes Overview:
• Signs and Symptoms: • Bacteria are eukaryotic organisms
1. Right lower lobe infiltrate • They have DNA, mRNA, protein machinery, and a
2. purulent malodorous sputum cell wall for protection
3. Might progress to alter mental status in elderly • These are the targets of antibiotics
patients • Antibiotics are
Surgical wound infection N.B Bacterial proteins composed of 30S and 50S
• S aureus (including MRSA), gram negative subunits
anaerobes
Mechanism of Action of Antibiotics (possible targets):
• Signs and Symptoms:
Cell-wall synthesis:
1. Erythema
2. Tenderness • β-Lactam Antibiotics inhibiting the synthesis of
3. Induration the peptidoglycan layer of bacterial cell walls
4. Purulent discharge around wounds (Penicillin)
IV catheters • Vancomycin
• Suspected organism: S aureus (including MRSA), Cell-membrane integrity:
S epidermidis (long term), Enterobacter • Daptomycin
• Signs and Symptoms: DNA gyrase:
1. Erythema • Fluoroquinolones (ciprofloxacin and levofloxacin)
2. Induration • Nalidixic acids
3. Tenderness mRNA synthesis (RNA polymerase):
4. Drainage from access sites • Rifampin
Mechanical ventilation, endotracheal intubation Protein Synthesis (30S and 50S subunits)
• Suspected organism: P aeruginosa, Klebsiella, • Inhibitors of 30S are Aminoglycosides and
Acinetobacter, S aureus Tetracyclins
• Usually associated with patients in intensive care • Inhibitors of 50S are Chloramphenicol and
units Macrolides
• Signs and Symptoms: Folic acid synthesis
1. New infiltrate on chest X ray • Sulfonamides
2. Increase sputum production; • Trimethoprim
3. Sweet odor (Pseudomonas) Sulfa antibiotics inhibit the pathway that bacteria use to
Urinary catheterization synthesize folic acid, which is considered a major
• Suspected organism Proteus spp, E coli, Klebsiella metabolite used to produce DNA, RNA or most proteins
• Signs and Symptoms: inside the cell
1. Dysuria, Antibiotic selection criteria:
2. leukocytosis • Organism identification
3. Costovertebral angle tenderness • Understand drug safety profile
Water aerosols • Recognition of the site of infection.
• Suspected organism: Legionella • Example: Drugs that could pass the blood brain
• Signs and Symptoms: barrier are ideal to treat meningitis
1. CNS abnormalities • Understand the patient antibiotic history (in terms
2. GIT symptoms (Diarrhea, nausea, Vomiting) of immune system, renal or hepatic function)
3. Signs of pneumonia

127
 • Development of Anaphylaxis shock due to Definitions:
penicillin administration Bacteriostatic VS Bactericidal:
• Patient with Renal insufficiency could accumulate Bacteriostatic: Inhibit bacterial growth and replication to
toxins of the drug used allow the immune system to recover and attach the bacteria
• Caution should be taken in case of pregnant or Bactericidal: Kill bacteria immediately
lactating women to avoid drug crossing into the
placenta or the milk respectively.
Bacteriostatic Bactericidal

Macrolides Aminoglycosides
Clindamycin Vancomycin
Sulfonamides Penicillins
Trimethoprim Cephalosporins
Tetracyclines Carbapenems
Chloramphenicol Monobactams
Spectinomycin Fluoroquinolones
Metronidazole

N.B: in some case both bacteriostatic and bactericidal drugs might use in combination to broaden its efficacy
Drug Resistance:
The ability of bacteria to survive and grow in the presence of a drug that normally kills or inhibits the microbe’s growth.
That could be achieved through either making changes in the cell wall, RNA, DNA or by insertion of certain mutations
Empiric therapy (early intervention):
Applied before the confirmation of the causing pathogen. Fighting the infection sooner decreases the risk of
complications. Usually, empiric antibiotics are broad-spectrum to enhance the magnitude of treatment towards either
Gram-Positive or Gram-negative bacteria.
Once the diagnosis is confirmed for example (Blood culture test), treatment might change to more specific antibiotic
(narrow-spectrum antibiotic)
Antimicrobial prophylaxis:
Prevention the spread of microbial infection before it begins, especially if the infected patient is in close contact with
others.
Penicillin (β-Lactams)
Overview:
• Bacterial cells are surrounded by a cell wall made of peptidoglycan.
• Peptidoglycan is linked together to provide protection for the cell
• Bacterial cells entail penicillin binding protein inside the cell which is involved in cell wall synthesis.
• Transpeptidase: bacterial enzyme that cross-links the peptidoglycan chains to form rigid cell walls
• β-Lactam Antibiotics inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls (Penicillin)
Classification of Penicillin antibiotics:
• Natural penicillin
• Anti-staphylococcus penicillin
• Anti-pseudomonal penicillin
• Extended spectrum
Natural Penicillin:
Examples:
• Penicillin G, V Penicillin G (IV and IM form)
• penicillin V (oral).
• Penicillin G benzathine (I/M) For syphilis

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Mechanism of Action (MOA):
• Bind penicillin-binding proteins (transpeptidases) therefore inhibit secretion of peptidoglycan.
• Without peptidoglycan, the cell wall will be vulnerable for invasion and disruption
• Penicillin is considered Bacteriocidal due its powerful disruption of Bacterial cell wall
Clinical Use of Penicillin:
1. Streptococcal pneumonia,
2. Streptococcal pyogenes which causes Pharyngitis
3. Actinomyces,
4. Neisseria meningitis,
5. Treponema pallidum,
6. Syphilis,
7. Listeria monocytogenes.
8. Gram positive.
Adverse Effects:
• Hypersensitivity reaction such as anaphylaxis reaction characterized by urticaria, swollen and skin itching,
hypotension, bronchospasm, fever, purities.
• Diarrhea
• Hemolytic anemia (lysis of red blood cells)
Resistance:
• Bacteria which have β-lactamase will be resistance to Penicillin
• β-lactamase cleaves the β-lactam ring therefore the antibiotic won’t be effective anymore.
Anti-staphylococcal penicillin (penicillin resistant drugs):
• Staphylococcal bacteria developedβ-lactamase by time
• New group of Penicillin’s which are resistant to β-lactamase (Penicillinase-resistant Penicillins).
• Coverage for methicillin-sensitive Staphylococcus aureus (MSSA).
Examples:
• Methicillin.
• Naficillin.
• Oxacillin.
• Dicloxacillin.

Mechanism of action:
• The same mechanism of penicillin (prevents the peptidoglycan synthesis and cross linking of the peptidoglycan)
Clinical use:
• Staphylococcus aureus except Methicillin-resistant Staphylococcus aureus ( MRSA)
• Skin infection such as folliculitis

Adverse Effects:
• Hypersensitivity reaction such as anaphylaxis reaction leads to urticaria, swollen and skin itching, hypotension,
bronchospasm, fever, purities.
• Methicillin causes Interstitial nephritis (inflammation of the kidney) diagnosed by increased levels of eosinophils
Aminopenicillin:
• Extended coverage (wide spectrum)
• (Penicillinase-sensitive Penicillins).

Examples:
• Amoxicillin. (Greater Oral bioavailability than ampicillin)
• Ampicillin.
Clinical use:
• Gram- positive and Gram-negative
• Gram-negative rods including such as
1. Hemophilus influenza.
2. E.coli/enterococci. Involved in UTI and food infection.

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 3. Listeria monocytogenes. Common in pregnant women when they eat cheese products
4. Proteus mirabilis.
5. Salmonella. Associated with Diary product and raw milk

Adverse Effects:
• Hypersensitivity reaction.
• Rash (Jerisch Herxheimer reaction). Diagnosed as Runny nose, flu, coughing, pharyngitis.
• Pseudomembranous colitis (clostridium difficile). Patient suffers from persistent diarrhea.
Anti-pseudomonal penicillin:
Examples:
• Ticarcillin.
• Carbenicillin.
• Pipracillin

Note: β-Lactamase inhibitors (clavulanic acid, sulbactam, tazobactam) are used in combination with β-lactam
antibiotics to extend their coverage by inhibiting β-lactamases. Combinations include (Trade names)

• amoxicillin + clavulanic acid = Augmentin

• ticarcillin + clavulanic acid = Timentin
• ampicillin + sulbactam = Unasyn
• piperacillin + tazobactam = Zosyn

Mechanism of action:
• same as that of penicillin but with beta lactamase inhibitors so considered as broad-spectrum antibiotics

Clinical use:
• Pseudomonas.
• Gram negative rods.

Cephalosporins:

1St Generation 2nd Generation 3rd Generation 4th Generation

Examples cefazolin, cefaclor, cefoxitin, ceftriaxone, cefotaxime, cefepime
cephalexin cefuroxime, cefpodoxime, ceftazidime
cefotetan
Organisms Gram positive Gram positive Broad gram-
H influenzae Ceftriaxone for meningitis, positive and
Proteus mirabilis Enterobacter gonorrhea, gram-negative
aerogenes coverage
E coli Neisseria spp Ceftazidime for Pseudomonas. Pseudomonas
Serratia aeruginosa
Klebsiella Cefotaxime for spontaneous
pneumoniae Marcescens bacterial peritonitis (cirrhotic
patients due to excessive
Proteus mirabilis alcohol usage)

E coli

Klebsiella
pneumoniae.

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Mechanism of action: Clinical Use of Aztreonam:
• Cephalosporin inhibits the bacterial cell wall • Aerobic Bacteria
synthesis. • Gram negative rodes
• Cephalosporins are considered Bacteriocidal • NO ctivity aneorobic bacteria
antibiotics • Used for penicillin allergic patients
• Cephalosporins are β-Lactam ring modified to be Adverse Effects:
resistant to penicillinases • GIT distress
Adverse Effects:
Vancomycin
• Hypersensitivity.
Mechanism of Action (MOA):
• Vitamin K deficiency
• Inhibit Call wall synthesis through binding to D-
• Disulfiram like reaction (nausea, vomiting due to alanyl-D alanine the precursor of the cell wall
excessive alcohol consumption
• Prevent polymerization of peptidoglycan causing
• Increases nephrotoxicity of aminoglycosides lysis of Cell wall
• Low cross reactivity with penicillins.
• Considered as a Bacteriocidal antibiotic.
Route of Administration:
Carbapenem 1. Intravenous Injection (IV): Most common route of
Drug names: administration since it is NOT absorbed from the
• Doripenem intestine.
• Imipenem 2. Oral: The only approved indication for oral
• Meropenem vancomycin therapy is in the treatment of
• Ertapenem pseudomembranous colitis, where it must be given
Mechanism of Action (MOA): orally to reach the site of infection in the colon.
• Inhibit Cell wall like penicillin Clinical Use of Vancomycin:
• Highly resistance to B-lactamase 1. Serious Gram-negative infection such as MRSA
• Imipenem rapidly inhibited by Dehydropeptidase I (Methicillin resistance Staphylococcus aureus)
2. Pseudomonas colitis (Clostridium difficile)
• Imipenem should be given with Cilastatin
characterized foul-smelling, and watery stools
• Cilastatin is a peptidase inhibitor that block renal 3. Prophylaxis before surgery
degradation of Imipenem (decrease renal toxicity
Adverse Effects:
of Imipenem)
Although Vancomycin is considered a well-
Clinical Use of Carbapenems:
tolerated antibiotic, but it might have sever toxicity
• Life threating conditions such as:
• Gram positice cocci, gram negative rodes and • Nephrotoxicity due to IV administration
anaerobic bacteria N.B: Vancomycin excreted through the Kidney
Adverse Effects:
• Ototoxicity
• GIT distress
• Thrombophlebitis at infusion site (vein
• CNC toxicity seizures at high plasma levels Inflammation)
(Meropenam less seizures)
• Red man syndrome: Due to high infusion rate that
• Skin rash leads to massive release of histamine
• Imipenem rapidly inhibited by Dehydropeptidase I (vasodilation) and transit hearing loss
(increased renal toxicity) N.B Red man syndrome could be overcome by
Aztreonam (Monobactams) pre-treatment with antihistaminic
Outline: (Diphenhydramine) and by slow injections.
• Mechanism of Action • Dress Syndrome: Vancomycin is involved in
• Clinical use vancomycin in drug rash with eosinophilia and
• Adverse effects systemic symptoms
Mechanism of Action (MOA): Mechanism of resistance:
• Inhibit peptidoglycan cross linking by binding to • vancomycin-resistant enterococci (VRE)
penicillin binding protein 3 Protein synthesis inhibitors
• Highly resistance to B-lactamase Overview
• Bactericidal • Eukaryotic ribosomes are larger. They consist of a
• Synergistic with aminoglycosides 60S large subunit and a 40S small subunit, which
come together to form an 80S

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 • Antibiotic that target bacteria usually attack 70S • Misreading of mRNA
(prokaryotes) leaving 80S unaffected • Prevent tRNA translocation and consequently
• Bacterial ribosomes are composed of 3 active sites there is No protein synthesis
• A site: The point of entry for the aminoacyl tRNA • Require oxygen for uptake into bacterial cell wall
• P site: where the peptidyl tRNA is formed in the (oxygen dependent mechanism) therefore efficient
ribosome for aerobic bacteria NOT anaerobic
• E site: the exit site of an empty tRNA after it gives • Aminoglycosides penetrate body fluid Except CSF
its amino acid to the growing peptide chain.
Mechanism of action: Different forms of Aminoglycosides:
1. Protein synthesis inhibitor are ALL Bacteriostatic 1. Neomycin
except Aminoglycosides are Bactericidal 2. Tobramycin
2. Divided according to which ribosomal subunit is 3. Amikacin
being targeted 4. Gentamycin
Examples: 5. Streptomycin
Protein 30 S inhibitors 50 S inhibitors Clinical Use of Aminoglycosides:
Synthesis • Target aerobic bacteria such as gram-negative
inhibitors Bacteria which are oxygen dependent: E. Coli,
Aminoglycosides Linezolid Pseudomonas, klebsiella, Enterobacter
Tetracyclines Macrolides • Used in combination with B-lactams inhibitor for
Clindamycin synergistic effect
Chloramphenicol Adverse Effects:
• Nephrotoxicity (manifested by elevated creatinine
Aminoglycosides and albumin levels)
Overview • Ototoxicity might lead to deafness
• Aminoglycosides are protein synthesis inhibitors • Neuromuscular blockade
which bind to 30 S subunit Tetracyclines
Examples:
▪ Tetracycline
▪ Doxycycline
▪ Minocycline
▪ Demeclocycline
Mechanism of Action (MOA):
• Protein synthesis inhibitors
• Bind to 30S subunit and inhibit aminoacyl-tRNA
binding to the ribosome–RNA complex
• Actively transported (concentrated) into bacterial
cells.
Clinical Use of Tetracyclines:
• Broad spectrum bacteriostatic
• Limited use due to its toxicity
• Minocycline for Acne
• Eukaryotic ribosomes are larger. They consist of a
• Doxycycline is widely used to treat:
60S large subunit and a 40S small subunit, which
➢ Borrelia burgdorferi (Lyme disease)
come together to form an 80S
➢ Atypical Mycoplasma pneumonia
Mechanism of protein synthesis in Bacteria:
➢ Chlamydia infection (STD)
Protein synthesis composed of 3 major steps:
➢ Rickettsia
3. Initiation: Aassembly of ribosome on mRNA
molecule • Doxycycline excreted fecally so could be used for renal
4. Elongation Repeated cycles of amino acid edition failure patients
5. Termination Release of protein chain • Demeclocycline is used as ADH antagonist
Mechanism of Action (MOA): ➢ Demeclocycline inhibit the renal antidiuretic
hormone
• Protein synthesis inhibitors
• Irreversibly bind to 30S subunit and inhibit
formation of initiation complex

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 ➢ Used to treat hyponatremia due to the Gray baby syndrome in premature infants due to lack of
syndrome of inappropriate antidiuretic liver UDP-glucuronyl transferase. Characterized by ashen
hormone (SIADH) gray skin discoloration, cyanosis, vomiting, vasomotor
Adverse Effects: collapse
• Staining of teeth (yellow teeth)
• Photosensitivity (increased risk of sunburn) N.B: UDP-glucuronyl transferase play a major role in
• Retardation of fatal bone growth in children transferring Bilirubin to soluble forum which get easily
metabolized.
• Contraindicated in pregnancy
• Contraindicated to use with:
N.B: Chloramphenicol is Metabolized and completely
➢ Calcium (milk or dairy products)
inactivated by glucuronidation in liver
➢ Antacids
Tetracyclines form chelates with these Mechanism of resistance:
products and interfere with their • Through enzymatic inactivation by
absorption acetyltransferases which metabolize
Mechanism of resistance: chloramphenicol to inactive form.
• Through inhibition of drug accumulation inside
bacterial cell Clindamycin
• Decrease bacterial uptake of antibiotic Mechanism of Action (MOA):
• Increased influx out through plasmid encoded • 50S subunit inhibitors-Inhibit protein synthesis by
pump blocking polypeptide transfer eventually block
Chloramphenicol peptide chain prolongation
Clinical Use of Clindamycin:
Mechanism of Action (MOA):
• Anaerobic infections (Bacteroides fragilis,
• Bind to 50S ribosomal unit and inhibit clostridium perfringens
peptidyltransferase activity.
• Clindamycin to kill anaerobic bacteria Above the
• Prevent the formation of peptide bond and block diaphragm such as aspiration pneumonia,
protein synthesis. lung/dental/skin abscesses
• Considered as a Bacteriostatic antibiotic. • Metronidazole to kill anaerobic bacteria Below the
• Not used anymore in developed countries due its diaphragm such as pseudomembranous colitis,
toxicity bacterial vaginosis, abdominal penetrating
• Cheap antibiotic so it’s used in developing wounds).
countries Adverse Effects:
Clinical Use of Chloramphenicol: • Pseudomembranous colitis (clostridium difficile)
4. Drug of choice for treatment of Meningitis • Clindamycin associated with overgrowth
(Developing countries) while Ceftriaxone is • Fever
commonly used in Developed countries
• Diarrhea
N.B: Lipid soluble, with excellent tissue
penetration including the CNS Macrolides
N.B: Sources of Meningitis are: Examples:
➢ Streptococcus pneumoniae 6. Azithromycin
➢ Neisseria meningitidis 7. Erythromycin
➢ Haemophilus influenzae type b 8. Clarithromycin
5. Rickettsial diseases: In children and pregnant Mechanism of Action (MOA):
women, where tetracyclines should be avoided • Protein synthesis inhibitors by blocking peptide
6. Brain abscesses chain elongation
Adverse Effects: • Binds to the 23s rRNA (50s) ribosome and
• Anemia (dose dependent) and Pancytopenia prevents the translocation of the tRNA on the
N.B: Pancytopenia: deficiency of blood mRNA
components (red cells, white cells, and platelets). • Bacteriostatic
• Aplastic anemia ((dose independent) • Potent inhibitors of CYP450 system, leading to
• Gray baby syndrome: Occurred in premature many drug–drug interactions.
infants Clinical Use of Macrolides:
• Chlamydia (STDs)

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 • Atypical Pneumonia such as (Mycoplasma, • Trimethoprim—inhibits dihydrofolate reductase
Chlamydia, legionella) (DHFR) to block conversion of DHF to
• Gram positive cocci specially for patient allergic to tetrahydrofolate (THF)
penicillin Clinical Use of Sulfonamides:
• Upper respiratory infection such as sore throat, 1. Gram-negative and positive bacteria such as S.
pharyngitis, tonsillitis pneumoniae, H. influenzae, Shigella, Salmonella,
• Otitis media specially for patient who are allergic Neisseria gonorrhoeae, Chlamydia, Nocardia
to penicillin 2. E.Coli
Adverse Effects: ➢ Main source of Urinary tract infection
• Mortality (UTI)
• Arrhythmia (QT interval prolongation) ➢ Bactrim is a combination of
• Acute cholestatic hepatitis sulfamethaxazol (sulfanomides) SMX
• Skin rashes and eosinophilia and Trimethoprime TMP for treatment of
mild UTI
• Drug-Drug interaction due to its CYP450
inhibition (increases serum (Theophyllines, 3. Toxoplasma gondii main source of Toxoplasmosis
Toxoplasmosis:
warfarin, clopidogrel)
➢ Appeared as flu like symptoms
Mechanism of Resistance:
➢ spread by eating poorly cooked food that
• Methylation of 23 RNA (50S ribosome) which
contains cysts or exposure to infected cat
alter drug affinity
feces
Sulfonamides
➢ If infected during pregnancy, a condition
Common sulfonamide drugs: known as congenital toxoplasmosis may
• Sulfamethoxazole affect the child
• Sulfadiazines ➢ Cutaneous toxoplasmosis appeared in
• Sulfisoxazole. immunodeficient patients such as
Bacterial synthesis of DNA and RNA: HIV/AIDS who are subjected to
• Bacteria make its own Folic acid from a Toxoplasmosis
constitutive production of P-aminobenzoic acid ➢ Might damage Eye causing Toxoplasma
• Dihydropteroate is an important enzyme which chorioretinitis
transfer PABA to Dihydrofolic acid (DHF) ➢ Effected treatment is a combination of
• Dihydrofolate reductase (DHFR) next convert Pyrimethamine, sulfadiazine
Dihydrofolic acid (DHF) to Tetrahydrofolic acid Adverse Effects:
(THF) which eventually used to produce DNA, • Hypersensitivity reactions
protein. • Hemolytic anemia especially in patient with
Glucose-6-phosphate dehydrogenase deficiency
(G6PD)
➢ Absence of this enzyme causes red blood
cells to break down prematurely. This
destruction of red blood cells is called
hemolysis.
➢ G6PD protects red blood cells from the
effects of potentially harmful molecules
called reactive oxygen species (Free
radical scavenger)
• Tubulointerstitial nephritis
• Photosensitivity
• kernicterus/hyperbilirubinemia in infants due to
Mechanism of Action (MOA): increased bilirubin production
• Sulfonamides are structural analogues to PAPA ➢ Usually appeared in newborn infants with
the main precursor for bacterial folic acid. Jaundice (yellow pale skin)
(Antimetabolite) • Interfere with drug metabolism such as Warfarin,
• Sulfonamides inhibit folate synthetase through phenytoin and methotrexate due to bilirubin drug
inhibiting Dihydropteroate enzyme displacement
• skin rash including severe reactions (Stevens-
Johnson syndrome

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Mechanism of resistance: • Contraindicated to pregnant women and children
• Through induction of certain mutations which below 18 years old due to possible damage to the
overproduce PABA or adopt alternative ways for cartilage
folate synthesis. • CYP450 inhibition (Ciprofloxacin)
Trimethoprim Mechanism of Resistance:
Mechanism of Action (MOA): • Chromosome encoded mutation in DNA Gyrase
• Drug efflux pump
• Trimethoprim—inhibits dihydrofolate reductase
(DHFR) to block conversion of DHF to Plasmid mediated resistanceAnti-Tuberculosis drugs
tetrahydrofolate (THF) Rifamycins:
• Bacteriostatic Mechanism of Action:
Clinical Use of Trimethoprim: • Inhibits DNA-dependent RNA polymerase
• Trimethoprim used as synergistic drug with Clinical uses:
sulfonamides to treat UTI infection (trimethoprim- • M. Tuberculosis
sulfamethoxazole (SMX+TMP) • Prophylaxis against meningitis
• Shigella, Salmonella, Pneumocystis jirovecii • Chemoprophylaxis against Influenza Type B
pneumonia • Serious staph infection, used in combination
• Prophylaxis therapy with B-lactam antibiotics to decrease the
Adverse Effects: probability of resistance such as MRSA infection
• Megaloblastic anemia due to deficiency in folic Side effects:
acids affect red blood cell production (MCV • Orange red color of body fluids (urine, tears and
greater than 100 Macrocytic anemia) sweat)
• Bone marrow suppression (Leukopenia, • Hepatotoxicity
granulocytopenia) ➢ Rifamycin is excreted through the liver with high
• Folinic acid (leucovorin) is commonly used to incidence of induction of P-450 isozymes (increase
minimize bone marrow suppression metabolism of itself or the combined drug)
Fluoroquinolones ➢ Decrease half-life of several drugs such as
Examples: warfarin, corticosteroids, oral contraceptives, oral
9. Ciprofloxacin hypoglycemic, digoxin, methadone
10. Norfloxacin ➢ Rifabutin is the drug of choice for HIV patients
11. Levofloxacin since its avoid induction of P-450 isozymes
12. Moxifloxacin Mechanism of resistance
13. Gatifloxacin • Structural changes to RNA polymerase
14. Nalidixic acid • Rifamycin treatment alone are vulnerable for
Mechanism of Action (MOA): resistance, used in combination therapy
• Inhibit DNA gyrase (bacterial topoisomerase Isoniazid:
II) & topoisomerase IV (the enzymes that cause Mechanism of Action:
DNA to rewind after copying) • Inhibits mycolic acid synthesis which is crucial for
• Bactericidal mycobacterial cell wall
Clinical Use of Fluoroquinolones: • Requires bacterial catalase-peroxidase (KatG) to
• Gram negative rods convert INH to active metabolite.
• UTI (E. Coli) Clinical uses:
• GI infection (Pseudomonas) • M. Tuberculosis
• Neisseria • Drug of choice for treatment for all Tuberculosis
• Otitis externa cases
Adverse Effects: Side effects:
• Tender rupture in elderly (65 years) +prednisone • Isoniazid (INH) induces Injures, Neurons&
• Arrhythmia QT interval prolongation) Hepatocytes
• Tendonitis • Hepatotoxicity
• GIT upset • Peripheral neuropathy overcome by administration
• Headache of Vit B6 (pyridoxine)
• Dizziness • Causes drug-induced lupus
• Skin rash erythematosus (diagnosed by Anti histone
antibodies)

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 • Sideroblastic anemia •Anaerobic bacteria (BELOW diaphragm) such as:
• Anion gap metabolic acidosis leads to ➢ Clostidium difficile
neurotoxicity and seizures ➢ Bacteroides fragilis
Mechanism of resistance ➢ Helicobacter pylori (Gastric ulcer)
• Alteration in bacterial catalase-peroxidase Triple therapy: Metronidazole+ Clarithromycin
Pyrazinamide: (Macrolide)+PPI (Omeprazole)
Mechanism of Action: Adverse Effects:
• The exact mechanism of action isn’t known yet • Disulfiram reaction (Alcohol with metronidazole
• Prodrug need to be activated first by develops nausea and vomiting)
pyrazinamidase to inhibit fatty acid synthase I • Metallic taste
(involved in mycolic acid biosynthesis) • Hemolytic anemia if they have G6PD deficiency
• Metabolite active only in acid pH (inside Antifungal
phagolysosomes) Classification of antifungal drugs
Clinical uses:
• M. Tuberculosis
Anti fungal
Side effects:
• Uricemia (gout) B 3-Glucan

• Hepatic toxicity
Polyenes Azoles Allylamines synthase Other
inhibitors

Mechanism of resistance
• Mutations in gene coding pyrazinamides Amphoteracin B Fluconazole Terbinafine Caspofungin Griseofluvin

Ethambutol:
Nystatin Itraconazole
Mechanism of Action:
• Inhibit synthesis arabinosyl transferase
required for mycobacterial cell wall. Ketoconazole

Clinical uses:
• M. Tuberculosis Clotrimazole

Side effects:
• Optic neuropathy
Streptomycin
Mechanism of Action:
• Inhibit protein synthesis (interfere with 30s
component)
Clinical uses:
• Considered as a second line of treatment of M.
Tuberculosis •
Fungal infection is either systemic or superficial
Side effects: mycoses
• Ataxia, Tinnitus, vertigo, nephrotoxicity

Metronidazole
Mechanism of Action (MOA):
• Generation of toxic metabolites (Nitro reductase)
that disrupt bacterial DNA
• Free radical generations that damage DNA
• Bactericidal
Clinical Use of Metronidazole:
• Protozoa such as:
➢ Giardia lamblia (Giardiasis) smelling
diarrhea
➢ Entamoeba histolytica (Amebiasis)
diarrhea
➢ Trichomonas Vaginalis (STD)

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Amphotericin B Clinical applications
Mechanism of action • Nystatin (too toxic for systemic use)—used as
• Interact with ergosterol in fungal membranes to “Swish and swallow” for oral candidiasis (thrush);
form artificial “pores,” which disrupt membrane topical for diaper rash or vaginal candidiasis
permeability Azoles
• The pores disrupt membrane function allowing • Interfere with the synthesis of ergosterol by
electrolytes (Particularly) and small molecules to inhibiting 14-a-demethylase, a fungal P450
leak from the cell, resulting in cell death enzyme, which converts lanosterol to ergosterol
Clinical applications Clinical applications
• Drug of choice for sever systemic mycoses • Used in cases local and less serious systemic
infection mycoses
• Treatment of cryptococcus infection, preferably in • Fluconazole: Prophylaxis and suppression of
combination with flucytosine (synergistic effect) cryptococcal meningitis in AIDS patients and
• Blastomyces candidal infections of all types- Penetrates CSF
• Coccidioides hence can be used in meningeal infection
• Histoplasma • Ketoconazole: Paracoccidioides and backup for
• Candida Blastomyces and Histoplasma
• Mucor • Clotrimazole and miconazole: Used topically for
• In case of fungal meningitis applied intrathecally candidal and dermatophytic infections
Side effects • Itraconazole and Voriconazole: Blastomycoses,
• Nephrotoxicity that include decrease GFR, Sporotrichoses, Aspergillosis
Elevated BUN, Decrease K and Mg • Isavuconazole: For serious Aspergillus and Mucor
• Fever infections
• Chills Side effects:
• Muscle rigor • Decrease synthesis of steroids leads to decrease
• Hypotension due to histamine release libido, gynecomastia and menstrual irregularities
• Anemia • Hepatotoxicity
• Arrhythmia • Ketoconazole and itraconazole are metabolized by
liver enzymes (Inhibition of hepatic P450s)
• IV phlebitis
• Note: Patient should be supplied with K and Mg to
avoid hypokalemia and hypomagnesemia
• Amphotericin B toxicity can be avoided by using
liposomal amphotericin B, or by drug
• combinations (e.g., + flucytosine), permitting ↓ in
amphotericin B dose
• Resistant fungal strains appear to have low
ergosterol content in their cell membranes
Nystatin
Mechanism of action
• Interact with ergosterol in fungal membranes to
form artificial “pores,” which disrupt membrane
permeability

Flucytosine
Mechanism of action
• Flucytosine enters fungal cells a cytosine-specific
permease enzyme
• Activated by fungal cytosine deaminase to 5-
fluorouracil (5-FU), which after triphosphorylation
is incorporated into fungal RNA
• It inhibits thymidylate synthase that decreases
• The pores disrupt membrane function allowing dTMP production and inhibit DNA synthesis and
electrolytes (Particularly) and small molecules to cell division
leak from the cell, resulting in cell death Clinical applications

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 • Use in combination with amphotericin B in severe Plasmodium life cycle:
candidal and cryptococcal infections—enters CSF
• Note: Fungal resistance might increase in case of Plasmodium life
using Flucytosine alone cycle
Side effects
• Bone marrow suppression
Caspofungin/Fungins/ Anidulafungin Sexual phase Asexual phase
(Mosquito) (Human)
• Inhibit the synthesis of beta-1,2 glucan, a critical
component of fungal cell walls
Clinical applications Exoerythrocytic
schizogony (pre-
• Invasive aspergillosis/ candida infection erythrocytic)
Side effects
• GIT upset
Erythrocytic
• Flushing due to histamine release schizogony

Terbinafine
• Active only against dermatophytes by inhibiting
squalene epoxidase →↓ Ergosterol
Clinical applications
• Onychomycosis—fungal infection of finger or toe
nails
Side effects
• GI distress
• Rash
• Headache
• Taste disturbance
• ↑ liver function tests
• Sporozoite found in salivary glands of female
Griseofulvin mosquitoes
• Active only against dermatophytes (orally, not • Infected mosquito bites the skin releasing
topically) by depositing in newly formed keratin sporozoites into blood stream infecting liver cells
and disrupting microtubule structure • Once it reaches hepatocytes in turn into merozoites
Clinical applications which quickly invade red blood cells
• Oral treatment of superficial infections; inhibits • Within red blood cells, merozoites release
growth of dermatophytes (tinea, ringworm). enzymes that trigger red cell lysis
Side effects • Some parasites develop into Gametocytes and
• Disulfiram-like reaction released into blood stream
• Teratogenic
• Carcinogenic Signs and Symptoms of Malaria
• Increase Cytochrome P-450 and warfarin • Headache (noted in virtually all patients with
metabolism malaria)
• Cough
Introduction to antiprotozoal drugs • Fatigue
Overview • Malaise
• Malaria is a mosquito-borne infectious disease • Shaking chills
caused by plasmodium • Arthralgia
• Transmitted by infective bite of female Anopheles • Myalgia
mosquitos • Paroxysm of fever, shaking chills, and sweats
• Malaria Is unicelular (every 48 or 72 hours, depending on species)
• Anemia in severe cases

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 Malaria species Signs Lindane
Plasmodium 48 hours after spikes • Block GABA channels lead to neurotoxicity
Vivax/ovale • Available as 1% lotion or shampoo
Plasmodium Malaria 72 hours after spikes Clinical uses:
Plasmodium Irregular fever spikes causes • used to treat head lice, tiny insects that infest and
falciparum cerebral malaria irritate your scalp
• Scabies (Sarcoptes scabiei)
Diagnosis
• Thick and thin blood smear

immature-ring An erythrocyte A mature

form, of the filled with schizont within Chloroquine
malarial merozoites an erythrocyte Mechanism of action:
parasite within
peripheral
erythrocytes

Anti-malarial drugs
Chloroquine
• For sensitive species •
• MOA: Block plasmodium heme polymerase Block plasmodium heme polymerase leading to
Mefloquine atovaquone/proguanil are used in case of accumulation of toxic hemoglobin to the parasite
resistance • Prevent heme polymerization into hemozoin
Quinine might be used in serious condition, but with caution causing heme accumulation
especially in case of G6PD patients (Hemolytic anemia) • Chloroquine increase pH inside parasite vacuole
• Note: In G6PDH deficiency, the ability of • Heme damage plasmodium membrane
erythrocytes to detoxify oxygen radicals is • Interfere with DNA synthesis
impaired. Ironically, the accumulation of the • Effective against all plasmodium species EXCEPT
radicals in erythrocytes in G6PDH deficiency Falciparum
gives protection against malaria
• Female heterozygous for G6PDH deficiency have Chloroquine resistance
increased resistance to malaria • Due to enhanced efflux of parasite vesicle
(increased expression of human multi drug
Anti-mite/ louse resistance transporter P-glycoprotein) leads to
Permethrin decrease intracellular concentration in the blood
• Consider as neurotoxin Inhibit Na channel which
lead to neuronal membrane depolarization Drugs used to overcome Chloroquine resistance
• Available as 5% cream or 1% liquid • Artemether+ Lumefantrine
• Artesunate+ Mefloquine
Malathion: • Atovaquone+ Proguanil
• Acetylcholinesterase inhibitors • Recommended to take these drugs as prophylaxis
• Available as 5% lotion before visiting endemic africans countries where
Malaria exist

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Chloroquine Toxicity • Inhibit viral • Zidovudine,
Retinopathy transcriptase didanosine,
Antiviral drug zalcitabine,
Overview lamivudine,
• Obligate intracellular parasite stavudine,
• Viruses have no cell wall and made of nucleic acid nevirapine,
components efavirenz
• Depend on host cell • Inhibit viral aspartate • Indinavir,
• It then uses the host cell’s energy to synthesize protease ritonavir,
protein, DNA, and RNA saquinavir
• A virus cannot replicate on its own • Inhibit viral • Zanamivir,
• Viruses are hard to target because they live inside neuraminidase oseltamivir
the cells
• Antiviral drugs usually have several side effects
since any drug that kills a virus may also kill cells
• Many antiviral drugs are purine or pyrimidine
analogs
• Some Antiviral drugs entail the characteristics of
prodrugs (need to be activated to become active)

Zanamivir/Oseltamivir
Signs and Symptoms of influenza:
1. Fever* or feeling feverish/chills
2. Cough
3. Sore throat
4. Runny or stuffy nose
Steps of viral replication 5. Muscle or body aches
1. Cell entry 6. Headaches
2. Penetration 7. Fatigue (tiredness)
3. Uncoating
4. Transcription of viral genome Adapted from center for disease control and prevention
5. Translation (CDC)
6. Assembly
7. Release

Characteristics of Antiviral drugs

• Interfere with viral nucleic acid synthesis or
regulation
• Interfere with the ability of virus to bind to cells
• Stimulate body`s immune system

Mechanism of actions of antiviral drugs

Mechanism of Actions Major drugs

• Block viral • Amantadine,
penetration/uncoating enfuvirtide,
maraviroc
• Inhibit viral DNA • Acyclovir,
polymerase Foscarnet,
ganciclovir
• Inhibit viral RNA • Foscarnet,
polymerase ribavirin

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Mechanism of action: • Most of Herpes simplex virus strains are resistance
• Inhibit neuraminidases of influenza A and B to acyclovir due to lack of thymidine kinase
• Oseltamivir reduces shedding of both influenza A Clinical uses
and B virus by inhibiting the release of infectious • Activity includes herpes simplex virus (HSV) and
virus from infected cells varicella-zoster virus (VZV)
• Viral neuraminidase enzyme activity is important • Actively using against both forms of HSV I &II
both for: and advanced HSV induced encephalitis
• viral entry into uninfected cells and for the release • Used as prophylaxis in immunocompromised
of recently formed virus particles from infected patients
cells • Acyclovir Reduces viral shedding in genital
• and for the further spread of the infectious virus in herpes; ↓ acute neuritis in shingles but has no
the body effect on postherpetic neuralgia
• Acyclovir available as topical, oral and IV form
• NO effect against CMV
• Valacyclovir, a prodrug of acyclovir, has better
oral bioavailability, can be used in acyclovir
resistant strains
Side effects
• Crystalluria (maintain full hydration) and
neurotoxicity (agitation, headache, confusion—
seizures in OD)
Herpes Simplex Virus subtypes
Herpes simplex type-1:
• Associated with orofacial infection
• Transmitted through Saliva and respiratory system
• Characterized by Blister in the lips,
Gingivostomatitis, Keratoconjunctivitis and
Clinical uses: Temporal lobe encephalitis
• Treatment and prevention of influenza A and B Herpes simples type-2:
• When started early: decrease duration of flu • Associated with genital infection
symptoms by 2-3 days • Sacral nerve root ganglia (S2-S5)
Acyclovir • Transmitted through Sexual contact and perinatal
• Characterized by genital herpes

Ganciclovir
Mechanism of action:
• Similar to that of acyclovir
• Guanosine analog
• First its monophosphorylated by thymidine kinase
then triphosphate form inhibits viral DNA
polymerase and causes chain termination
Clinical uses:
• Used to treat CMV, especially in
immunocompromised patients.
• Also used for HSV, VZV
Mechanism of action • Valganciclovir, a prodrug of ganciclovir, has better
oral bioavailability
• Guanosine analogs
• prophylaxis and treatment of CMV infections,
• Monophosphorylated by viral thymidine kinase
including retinitis, in AIDS and transplant
(TK), then further bioactivated by host-cell kinases
patients— relapses and retinal detachment occur
to the triphosphate that terminate DNA polymerase
Side effects:
chain replication
• Bone marrow suppression (leukopenia,
• Resistance possibly due to changes in DNA
neutropenia, thrombocytopenia)
polymerase or to decreased activity of TK
• Renal toxicity.

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 • More toxic to host enzymes than acyclovir • Different from Ganciclovir since it doesn´t require
• Crystalluria (maintain hydration) any kinase activation
Sources of CMV transmission: Clinical uses:
• Congenital • Drug of choice for Ganciclovir resistance
1. Premature birth. • Entail high activity versus acyclovir-resistant
2. Low birth weight. strains of HSV
3. Yellow skin and eyes (jaundice) • CMV retinitis in immunocompromised patients
4. Enlarged and poorly functioning liver. Side effects:
5. Purple skin splotches or a rash or both. • Dose-limiting nephrotoxicity with acute tubular
6. Abnormally small head (microencephaly) necrosis, electrolyte imbalance with hypocalcemia
7. Enlarged spleen. (tremors and seizures)
8. Pneumonia Mechanism of resistance:
• Blood transfusion, organ transplantation • Mutation of DNA polymerase
• Adult cytomegalovirus infection in the
immunocompetent host Cidofovir
Mechanism of action:
Signs and symptoms in adult: • Selective inhibition of viral DNA synthesis
• Viral pneumonia Clinical uses:
• Hepatitis • Treatment of cytomegalovirus (CMV) retinitis in
• Encephalitis patients diagnosed with AIDS
• Retinitis Side effects:
• Diagnosis: Characterized by Owl's eye appearance • Nephrotoxicity (Co-administration with
of inclusion bodies probenecid and IV saline to decrease toxicity).

Drug of choice for treatment of CMV infection

• Gancyclovir Foscarnet Cidofovir

Owl's eye

HIV/AIDS Drugs
Overview
• HIV is a retrovirus
• HIV targets the immune system through CD+4
cells
• HIV uses CD+4 cells to multiply and replicate
• Inside the CD+4 cells, HIV uses reverse
transcriptase enzyme to convert RNA to DNA
HIV, this conversion help HIV to enter the nucleus
and combine with cell genetic material
• Inside CD+4 nucleus, HIV release integrase
enzyme to allow insertion its viral DNA into
• DNA of CD+4 cells.
Foscarnet • Once HIV integrated into CD+4 cell DNA, HIV
Mechanism of action: uses CD+4 machinery to replicate and produce
• Pyrophosphate analogue more HIV protein
• Inhibits DNA polymerase AIDS

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 • AIDS will develop when the CD+4 counts • Highly active antiretroviral therapy (HAART) has
reached  400 often resulted in ↓ viral RNA, reversal of the
• The patient is subjected to opportunistic infections decline in CD4 cells, and ↓ opportunistic
• In cases of lack of treatment, the patient dies infections
within 2 years • ZDV can be used for general prophylaxis and
• NOTE: CD+4 count refers to the risk status of the during pregnancy to decrease risk of fetal
patient, while Viral load refers to how quickly the transmission
patient progressing to death • NRTIs are used together with a protease inhibitor
(PI)
Diagnosis of AIDS: Examples
• CD cell count  400 cells/microliter. Normal cell • Abacavir (ABC)
count (500-1500 cells/mm3) • Didanosine (ddI)
• CD+4 percentage in T lymphocytes  14 %. • Emtricitabine (FTC)
Normal 40% • Lamivudine (3TC)
• Progression of opportunistic infection. Constant • Stavudine (d4T)
candida infection and PCP pneumonia • Tenofovir (TDF)
• Zidovudine (ZDV, formerly AZT)
Side effects:
• Bone marrow suppression: Can be reversed by
Granulocyte colony stimulating factors or
erythropoietin which stimulate new red blood cells
• Peripheral neuropathy
• Lactic acidosis
• Anemia (ZDV)
• Pancreatitis (Didanosine)
• Neutropenia
• Headache
• Fatigue
Treatment of HIV
• Myalgia
• An initial antiretroviral regimen generally consists
of two nucleoside/nucleotide reverse transcriptase Non-Nucleoside reverse transcriptase inhibitors (NRTIs):
inhibitors (NRTIs) in combination with a third
• Inhibit reverse transcriptase at a site different from
active drug from one of the following classes:
the one NRTIs bind to
1. nonnucleoside reverse transcriptase inhibitor
(NNRTI) • NNRTIs do not require phosphorylation to be
active
2. protease inhibitor
3. integrase strand transfer inhibitor (INSTI). • Are not myelosuppression
• Additive or synergistic if used in combination
Reverse Transcriptase Inhibitors (RTIs) with NRTIs and/or PIs
Nucleoside reverse transcriptase inhibitors (NRTIs): Examples:
• They are nucleoside Antimetabolites such as • Delavirdine contradicted during pregnancy
Zidovudine • Efavirenz contradicted during pregnancy
• Converted to active forms via phosphorylation • Nevirapine
reactions Side effects:
• They inhibit the HIV reverse transcriptase enzyme • Delavirdine- Rash
competitively and act as a chain terminator of • Efavirenz- Vivid dreams, drowsiness, insomnia,
DNA synthesis rash, hyperlipidemia
• Incorporate into the growing HIV viral DNA • Nevirapine Rash, hepatotoxicity
strand by reverse transcriptase, then viral DNA
synthesis will be terminated
• Tenofovir is the only NtRTI (need to
phosphorylate), has a single phosphate on its sugar
residue and must be further phosphorylated to the
triphosphate form

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 Protease and Fusion inhibitors

Protease inhibitors
• Bind reversibly to the active sites of HIV
Aspartate protease enzyme and interfere with its Protease inhibitors
cleaving function Mechanism of action:
• Aspartate protease (pol gene encoded) is a viral • Bind reversibly to the active sites of HIV
enzyme that cleaves precursor polypeptides in HIV Aspartate protease enzyme and interfere with its
buds to form the proteins of the mature virus core. cleaving function
• The advantage of protease inhibitors, since its • Aspartate protease (pol gene encoded) is a viral
working in the last step of viral cycle, its effective enzyme that cleaves precursor polypeptides in HIV
against new and chronically infected cells buds to form the proteins of the mature virus core.
• Resistance occurs via specific point mutations in • The advantage of protease inhibitors, since its
the pol gene working in the last step of viral cycle, its effective
• Ritonavir is the most commonly used protease against new and chronically infected cells
inhibitor • Resistance occurs via specific point mutations in
Examples: the pol gene
• Atazanavir • Ritonavir is the most commonly used protease
• Darunavir inhibitor
• Fosamprenavir
• Indinavir
• Lopinavir
• Ritonavir
• Saquinavir
Side effects
• Nephrotoxicity (Crystalluria)
• Hematuria
• Hyperglycemia

Integrase inhibitors
Raltegravir
• Raltegravir inhibits HIV integrase to prevent the
viral genome being incorporated into the human Side effects:
genome • General side effects:
• Hyperglycemia, GI intolerance (nausea, diarrhea),
lipodystrophy (Cushing-like syndrome).
Indinavir
• Nephropathy
• Hematuria
• Thrombocytopenia

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Ritonavir for viral RNA replication and assembly of HCV
• Major drug interactions induce CYP 1A2 and virions
inhibits the major P450 isoforms (3A4 and 2D6) • prevent hyperphosphorylation of NS5A which is
required for viral protein production
Rifampin
• Rifampin (potent CYP/UGT inducer) reduces Ribavirin
protease inhibitor concentrations; use rifabutin • It’s a guanosine analog used to stop viral RNA
instead. synthesis
• It’s a prodrug when metabolized resembles purine
RNA nucleotides
• Inhibits synthesis of guanine nucleotides by
competitively inhibiting inosine monophosphate
dehydrogenase.
• Depletes intracellular GTP pools
• Ribavirin induces mutations in the virus that lead
to viral death or production of virus with
diminished infectivity
• Ribavirin alters T-cell profiles in favor of T-helper
1 cells that are more antiviral

Side effects:
• Hemolytic anemia-increase uric acid levels
• Causes birth defects, and pregnant women or
women hoping to become pregnant should not take
Fusion inhibitors ribavirin
• Bind to GP41, GP 120 and prevent HIV entry into • Hair loss
the cell (Inhibits fusion HiV1 to CD4+) • Pancytopenia
• Enfuvirtide: binds to pg41 and inhibits the fusion
HIV-1 to CD4+ cells Simeprevir
• Maraviroc: blocks the binding of the gp120 HIV • Hepatitis C virus (HCV) NS3/4A protease
protein to CCR5 on macrophage surface to prevent inhibitor
viral entry • viral protease NS3/4A complex is essential for
• Enfuvirtide and maraviroc block the entry of HIV cleaving the HCV encoded polyprotein into
into cells. Side effects: Skin reaction at injection individual viral proteins facilitating replication, the
sites. drug blocks the viral replication process.
Hepatitis C therapy Side effects:
• Photosensitivity reactions, rash.
Sofosbuvir
• Sofosbuvir is an inhibitor of the HCV NS5B RNA-
dependent RNA polymerase, which is essential for
viral replication.
• Sofosbuvir is a nucleotide prodrug that undergoes
intracellular metabolism to form the
pharmacologically active uridine analog
triphosphate (GS-461203), which can be
incorporated into HCV RNA by the NS5B
polymerase and acts as a chain terminator
Side effects:
• Fatigue
• Headache
Ledipasvir • Nausea
• Inhibitor of the Hepatitis C Virus (HCV) Non- Sterilization and Disinfection
Structural Protein 5A (NS5A), which is required • Sterilization: complete removal or killing of all
viable organisms (vegetative and sporing states).

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 • Spore: reproductive structure that can adapted
surviving for extended periods in unfavorable
conditions
• Disinfection: the removal or killing of disease-
causing organisms. Compounds for use on skin:
antiseptics.
Sporicidal:
• Autoclaving (steam under pressure): → (130°C for
3 mins or 120 °C for 15 mins) (sterilizing)
• May not reliably inactivate prions.

•
Dry heat might be used 180°C for 2hr
• Chlorine/bleach Oxidizes and denatures proteins
(oxidizing agent inactivating sulfhydryl-containing
enzymes)
• Hydrogen peroxide Oxidizes and denatures
proteins through free radical generation

Not Sporicidal:
• Denature proteins and disrupt cell membranes.
• Alcohol
• Chlorhexidine
• Quaternary amine

May be Sporicidal:
• Halogenation of DNA, RNA, and proteins
• Iodine
• Iodophors

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Chapter 3:

Immunology

147
Lymphoid structures breathing and shortness of breath. Following
trauma, fat is released directly from the bone
marrow into the circulation.
• This is because after trauma, an elevated pressure
in the medullary cavity of the bone causes the
release of fat globules into venous system
supplying the bone.
• This explains the obstruction of the fat emboli in
the lung capillaries.
Thymus

What’s lymphoid tissue?

• Lymph means clear fluid
• This fluid flows in in lymphatic vessels, lymphatic
tissue and red bone marrow.
• The main function is to filter out of capillaries and
drains into lymphatic vessels to become lymph.
• Lymph eventually drains into venous blood.
• Lymph drains interstitial fluid, transports dietary
•
lipids and facilitates immune responses. Encapsulated, bilobed organ, located in the
Primary& Secondary lymphoid organs: anterior mediastinum
• Derived from the third pharyngeal pouch
Lymphoid • Morphologically thymus changes during
organs development, during early childhood, the thymus
is large and is easily seen on a chest radiograph.
However, during adulthood it becomes invisible on
a chest film.
• Provide an adequate condition for T cell
Primary Secondary differentiation and maturation
• They are called T cells because they mature in
the thymus from thymocytes

Spleen CT scan of the chest

Bone Marrow revealing a
Lymph nodes large necrotic mass
Thymus glands in the left anterior
Tonsil mediastinum (indica
• Provide the right environment for immature ted by the red
progenitor cells to generate, mature line). Histology late
• Function as the house for stem cells to divide and r established the
mature into B- and T- cells diagnosis of a
• Both T-cell and B-cells are 'born' in the bone thymoma.
marrow.
Bone marrow: • Thymoma is considered the most common tumor
• Red marrow is the bone marrow parenchyma and associated with the thymus
contains the hematopoietic stem cells, which • Thymoma is usually associated with myasthenia
function in the formation of all blood cell lines, gravis
including B and T cells. • Removal of thymus glands in myasthenia gravis
• Yellow marrow is the bone marrow stroma associated with better prognosis
(supportive tissue) and contains mostly fat.
• Note: Orthopedic injuries especially fractures of
the long bones are the most common cause of fat
embolism syndrome, characterized by rapid

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Thalamus composed of 2 areas:
Cortex

Medulla:
• low cellular density with mature T cells having
already gone through positive and negative
selection.
• This area also contains Hassall corpuscles, which
are remnants of apoptosed T cells seen on
• High cellular density with packed immature T cells histology.
awaiting positive (functional) selection. Lymphatic drainage
• The immature T cells undergo positive selection Overview:
where it binds (reversibly/Not strong binding) to
the cell surface proteins major histocompatibility
complex class I (MHC I) or II.
• T cells which bind strongly to MCH I/II will
undergo apoptosis.
• The majority of developing thymocytes will die
during this process.
• Thymocytes that interact well with MHC I mature
into CD8+ cells.
• Thymocytes that interact well with MHC II mature
into CD4+ cells.
• Thymocytes that survive positive selection
migrate towards the boundary of the cortex and • The overall drainage system of the body is
medulla in the thymus. asymmetrical
• Don’t bind to human body antigens • The right lymphatic duct receives lymph from
• Some immature T cells mange to pass through the only the upper right side of the body (right arm,
periphery chest, half of head)
• If the peripheral system didn’t recognize the • The lymph from the rest of the body enters the
escaped T cells, the patient is going to progress to bloodstream through the thoracic duct via all the
autoimmune disease remaining lymphatic trunks.
• The autoimmune cells are removed by the process • The thoracic duct drains a much larger portion of
of negative selection, which occurs in the the body than does the right lymphatic duct
corticomedullary junction
• Negative selection destroys cells that see the Lymph node Area of body drained
body's own normal antigens as foreign invaders. Upper limb and lateral Axillary
breast

Stomach Celiac
superior mesentery Duodenum

Inferior mesenteric Sigmoid colon

Internal iliac Lower rectum to anal canal (above

pectinate line), bladder, vagina
(middle third), cervix, prostate
Superficial inguinal Anal canal (below pectinate line),
skin below umbilicus (except
This figure depicts the process This figure depicts the process popliteal area), scrotum, vulva
of positive selection for T of negative selection for T Popliteal Dorsolateral foot, posterior calf
cells. cells. Para-aortic Testes, ovaries, kidneys, uterus

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Lymphatic drainage and associations • Sarcoidosis
Axillary
• Lymph nodes located in the armpits.
• Drain lymph vessels from the lateral quadrants of
the breast
Associated pathology:
• A local infection of the arm or breast, including
skin and wound infections and cellulitis. The
bacteria are carried in the lymph to the axillary
lymph nodes, causing a reaction there.
• An infection that is affecting your whole
body, such as strep throat, measles,
mononucleosis, herpes or AIDS.
• Cancers, including lymphomas, leukemias, and
breast cancer.
Cervical lymph node: • Immune disorders such as lupus or rheumatoid
• Located in the neck region and divided into two arthritis.
groups: Celiac
• Anterior superficial and deep nodes include • The celiac lymph nodes are grouped into three
submental and submaxillary (tonsillar) nodes sets: the gastric, hepatic and splenic lymph nodes.
located under the chin and jawline. Associated pathology:
• Posterior lymph nodes are located along the back • Mesenteric lymphadenitis
of the neck. • Typhoid fever
Associated pathology: • Ulcerative colitis
• Bronchitis • Celiac disease
• Tonsillitis Paraaortic lymph nodes
• Sore throat • Group of lymph nodes that lie in front of
• Infectious mononucleosis the lumbar vertebrae near the aorta. These lymph
• Kawasaki disease nodes receive drainage from the gastrointestinal
Mediastinal lymph nodes: tract and the abdominal organs
• Glands that are located in the part of the chest that Associated pathology:
lies between the sternum and the spinal column • Metastasis especially colorectal cancer
• Mediastinal lymphadenopathy generally suggests a Internal iliac and Superficial inguinal:
problem related to lungs, whether benign or • Inguinal lymph nodes are the lymph nodes in the
malignant. inguinal region
Associated pathology: Associated pathology:
• Anthracosis (Miner`s lung) • Sexually transmitted infections
• Cystic fibrosis • The presence of swollen inguinal lymph nodes is
• Lung cancer an important clinical sign
• Tuberculosis because lymphadenopathy (swelling) may indicate
• Chronic obstructive pulmonary disease an infection, or spread as
• Acute Lymphoblastic Leukemia a metastasis from cancers, such as anal
cancer and vulvar cancer.
• Granulomatous disease
Popliteal:
Hilar lymph nodes:
• Dorsolateral foot/ posterior calf Foot
• located in the retrotracheal region or the area
Associated pathology:
posterior to the trachea.
Associated pathology: • leg cellulitis
• Enlargement of the hilum may occur due to: • Popliteal artery entrapment syndrome
• Tumors (such as lung cancer)
Secondary lymphoid structures
• pulmonary hypertension
Overview:
• Enlarged hilar lymph nodes due to conditions such
• Sites where lymphocytes undergo differentiation
as infections (especially tuberculosis and fungal
(increase specificity) and clonal expansion
infections)
(increase number) in antigen- dependent manner.
• Cancer (either local or metastatic)
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 • Examples of secondary lymphoid organs
• lymph nodes, spleen, tonsils, adenoids, and
mucosa-associated lymphoid tissue (MALT).
Lymph nodes:
• T cells undergo maturation in the thalamus then
through the circulation to lymph nodes and other
organs
• Lymph nodes are spread throughout the body and
present in group where lymphatic vessels come
together to form larger vessels such as in the
groins, neck and axilla.
• Lymph nodes are also part of the lymphatic Cortex:
system that includes the lymphatic vessels, • The cortex is composed of the cortical sinuses
lymphoid tissue and lymphoid organs. surrounded by dense accumulations of
• Lymph nodes filter and purify the lymph before it lymphocytes.
flows into the venous system. • Arranged into spherical follicles, lymphoid
• Encapsulated and trabeculated secondary follicles.
lymphoid organs with many afferent vessels • Where that B lymphocytes are activated and
(Many ways in and one way out) undergo proliferation.
Functions of lymph nodes:

•
• Filtration of debris and microorganisms via
phagocytosis
• facilitate the interaction between antigen Paracortex
presenting cells and circulating lymphocytes to • Contains high endothelial venules
initiate an immune response • T cells are concentrated within the paracortex
• Activation and proliferation of B lymphocytes • Paracortex enlarges in an extreme cellular immune
• Activation of T lymphocytes to become T helper response (eg, viral infection).
and T cytotoxic cells
Medulla Thymic hypoplasia (DiGeorge syndrome):
• The medulla of a lymph node is composed
of medullary cords (densely packed • Lymphoid follicles are usually present, but lymph
lymphocytes) interspersed between medullary node paracortical areas and thymus-dependent
sinuses. The medullary sinuses are composed regions of the spleen show variable degrees of
primarily of reticular fibers, reticular cells depletion.
and macrophages.

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Flow Through a Lymph Node:
Afferent
Lymphatic
vessel

Subcapsular
sinus

Trabecular
sinus

Medullary
sinus

Efferent
lymphatic
vessel

Spleen:
• Located between the stomach, left kidney and
diaphragm, the spleen is the largest lymphoid
organ in the body

The spleen is divided into two pulps:

• Red pulps: Filtration of red blood cells. Enlarged spleen
• Composed of macrophages and the rest of the red
pulp is occupied by numerous venous sinuses • The spleen contains macrophage
(VS). • These macrophages are activated when bacteria
• RBCs undergo phagocytosis by splenic bound by IgG antibodies or the complement
macrophages component C3b.
• Also encapsulated bacteria are removed by splenic Note: IgM is produced by plasma cells in the
macrophages spleen and lymph nodes
• White pulps: Reservoir for T cells • These types of antibodies and complement are
• Contains the periarterial lymphatic sheath (PALS), immune substances called opsonizes, molecules
which contains T cells and follicles that contain B that bind to the surface of bacteria to
cells. facilitate phagocytosis
• B cells are found in the marginal zone between red • In cases of splenic dysfunction, IgG and C3b are
pulp and white pulp still bound to bacteria, but they cannot be removed
from the blood circulation due to the loss of the
Cases of splenic dysfunction: splenic macrophages. Hence the bacteria are free
• Splenic macrophages remove Heinz bodies from to cause infection (encapsulated bacteria) such as:
RBC leading to characteristic bite cells
• In case of patients with G6PD deficiency, large ▪ Streptococcus pneumonia
number of Heinz bodies are produced ▪ Haemophilus influenza type B
• Patients with infectious mononucleosis (EBV ▪ Neisseria meningitidis
▪ Salmonella
infection) develops splenomegaly increase risk of
splenic rupture ▪ Klebsiella pneumonia
▪ Group B streptococcus

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 Splenic
Myeloid linage:
dysfunction • Monocytes:
o Circulate in the blood, differentiate to
↓ IgM
macrophages in the tissues

↓ complement
activation C3b

↓ opsonization

Bacterial o Phagocytose pathogens

infection
o Produce cytokines that initiate inflammation (Il-1,
Cells of the immune system IL8, IL-12, IL-6 and TNF α)
Overview: o Play an important role in tissue repair
o Large, kidney-shaped nucleus with frosted glass
cytoplasm

• Dendritic cells:

• Hematopoietic stem cells located in the bone o Cells with long

marrow and capable of differentiating into all cytoplasmic arms, found in all tissues
different mature blood cells types and tissues o Express MHC II and Fc receptors on the surface
which considered the immune cells o Three major functions:
• Multipotent and self-renewal
1. Efficient antigen presentation to lymphocytes
(professional antigen- presenting cell (APC)
2. Stimulate adaptive immune response
3. Initiate inflammatory response

• Neutrophils:

Haematopiotic
stem cells
o Mature cells with
multilobed nucleus
o Contains toxic cytoplasmic granules
o Number increases in bacterial infection
Myeloid Lymphatic o Main function: Circulating phagocytes

• Eosinophils:
o Mature cells with a bilobed nucleus

153
 o Contain the major basic proteins C. Natural killer cells

o Packed with large

eosinophilic granules of uniform size o Named
o Main function: Protect against parasitic and like this because they don’t require activation to
helminthic infections kill cells that lack MHC
o CD56+ lymphocyte that contains cytoplasmic
• Basophils: toxic granules (such as granzymes)
o Mature cells with large blue granules o Activity enhanced by Il-2, Il-12, IFN-β, IFN-α
o Able to recognize stressed cells in the absence of
• Mast cells: antibodies and MHC allowing for faster immune
o These cells release histamine in response to response
antigen exposure o Able to kill malignant cells, virus-infected cells, or
o Concentrated within the respiratory and antibody-coated (opsonized) cells
gastrointestinal tracts

o Like Basophil
(contain large cytoplasmic granules) with small
nucleus Innate and adaptive immunity
o Cromolyn sulphate is used as mast cells stabilizer Overview:
(used for asthma prophylaxis) • The innate and adaptive immune response work
together to stop an infection.
Lymphoid linage: • Initially, once a pathogen has broken through the
• Lymphocytes: anatomic and physiologic barriers, the innate
Divided into 3 classes: immune response is immediately activated,
A. B cells oftentimes it is able to contain and eliminate the
o Belongs to adaptive immune system (Humoral infection.
immune response) • BUT, when the innate immune response is unable
o Differentiate into either memory B cells or plasma to handle an infection, the adaptive immune
cells (circulating antibodies) response is engaged and activated by the innate
B. T cells immune response in an antigen-specific manner.
o Belongs to white blood cells and plays a role in • Typically, it takes 1-2 weeks after the primary
cell mediated immunity infection for the adaptive immune response to
o T cells differentiate into either CD4+, helper T begin clearance of the infection through the action
cells, CD8+ cytotoxic T cells, regulatory T cells or of effector cells and antibodies.
memory T cells • Once an infection has been cleared, both the innate
and adaptive immune responses cease.
• Antibodies and residual effector cells continue to
provide protective immunity, while memory cells
provide long-term immunologic protection from
subsequent infection.

154
 • Phagocytic cells (monocytes/macrophages,
neutrophils and dendritic cells) are considered the
first line of defense mechanism against infection
• They recognize pathogens via shared molecules
that are not expressed on host cells.
• Receptors of the innate immune system are
referred to as pattern recognition receptors (PRRs).
• PRRs recognize pathogen-associated molecular
patterns (PAMPs), such as LPS, flagellin
(bacteria), nucleic acids (viruses).
• PPRs could also recognize damage-associated
molecular patterns (DAMPs) released from dying
or damaged cells.
• Receptors of innate immune system examples:
Innate immunity: Toll like receptors (TLR), Nod like receptors
• Innate immunity provides the body’s first line of (NLR), Rig like receptors (RLR)
defense against infectious agents. • These receptors are present intrinsically, encoded
Characterized by: in the germline genes, and are not generated
• Fast (Minutes to hours) through somatic recombination as the lymphocyte
receptors are generated.
• nonspecific response to infection
• Lack of immune memory.
Adaptive immunity:
• Does not improve after exposure to antigen Characterized by:
• Always present • Increased with each repeat exposure—
• Available on short notice to protect immunologic memory
• It allows for an individual to have basic immunity • Capable of distinguishing self from non-self
Functions: • Self-limiting
• Fight against microbes
• Activation of adaptive immunity Functions:
• Protect against persistent or recurrent challenge
Components: (immunologic memory-specificity)
1. Anatomical barrier: • Protect against several pathogens
Physical barrier (skin, cilia, mucosal tissue and
• Protect against auto immune reaction. Ability to
normal flora), chemical barrier (enzymes,
distinguish between self (host cells) and non-self
antimicrobial peptides)
(pathogens)
2. Cell response
Recognize pathogen by receptors
Components:
3. Soluble proteins
• T cells, B cells and circulating antibody
• Such as Natural killer cells (in case of
viral infection and malignancy)
Specificity:
• Phagocytic cells (Macrophages,
• Different microbes could be recognized by
Neutrophil)
different antibody molecules
• Dendritic cell activates adaptive immune
response Receptors:
Specificity:
• Encoded by genes produced by somatic
• Has limited specificity. Different microbes could recombination of gene segments; greater diversity
be recognized by the identical mannose receptor
Receptors: Receptor distribution:
• Included in germline with limited diversity • Variation through V(D)J recombination during
Receptor distribution: lymphocyte development
• Non- clonal: Identical receptors are found at cells
of the same lineage such as Neutrophils Crosslink between innate and adaptive immune response
Mechanisms of pathogen recognition:

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 Innate Immunity Adaptive Immunity
2. Cell mediated immunity is mediated by T cells,
Antigen independent Antigen dependent with dendritic cells playing important roles
No time lag A lag period in antigen presentation.
Not antigen specific Antigen specific T cells can function by various methods:
No immunologic memory Development of memory
Present at birth Developed after birth
A. Activating macrophages to kill phagocytosed
microbes
B. Directly destroy infected cells
C. Releasing cytokines and alter the milieu around
them.
Innate versus Adaptive immunity:

• The responses of both innate and adaptive are

overlapped in a positive feedback mechanism
• Phagocytic cells recognize pathogens by binding
PAMPs leading to phagocytosis.
• Phagocytic cells present antigen to facilitate
stimulation of specific T lymphocytes with
subsequent release of cytokines that trigger
initiation of specific immune responses.
• T lymphocytes produce cytokines that enhance
phagocytosis
• Cytokines will drive differentiation of B
lymphocytes into plasma cells and isotype
switching.
• Antibodies will aid in the destruction of pathogen
through opsonization, complement activation and
antibody-dependent cellular cytotoxicity. MHC class I and II
Overview:
Types of adaptive immunity: • T lymphocyte development (origin of MHC):
1. Humoral immunity is mediated by antibodies that
are produced by B lymphocytes. • Immature lymphocytes leave the bone marrow
and proceed to the thymus, the second primary
lymphoid organ dedicated to the maturation of T
cells (double negative T lymphocytes since they do
not express CD4 or CD8 on their surface
• Within the thalamus, cortex packed with immature
T cells, while the inner medulla receives ONLY
mature T cells.
• As the developing thymocytes begin to express
their T cells receptors (TCRs), they are subjected
to a rigorous 2-step selection process (positive and
• It is the principal defense mechanism against negative selection)
extracellular microbes and their toxins, with • TCRs designed to bind to antigen presenting cells
secreted antibodies binding to microbes and toxins (APCs)
to assist in their elimination. • Major histocompatibility complex (MHC)
antigens is necessary to remove those cells that

156
 would bind to normal self-antigens and cause • Functionally, antigen is loaded into the MHC I in
autoimmunity. the endoplasmic reticulum before the MHC I is
• MHC is a cell surface protein which is essential for inserted into the cell membrane.
acquired immune system • Normally the antigen that is loaded onto MHC I is
• Binds to antigens derived from pathogens and self-antigen, and cytotoxic T cells (CD8+ T cells)
display them on the cell surface to be recognized will not react to it.
by T cells • In case of viral infection, viral proteins will also be
• Able to differentiate between self and non-self- loaded onto MHC I. This is how cytotoxic T cells
antigens confer immunity to viral infection.
• Detects when the body’s own cells are either • They recognize MHC I with loaded viral antigen
infected or subjected to malignancy and targets it for cytotoxic destruction.
• There are 2 major classes of cell-bound MHC gene MHC II
products: I and II. • Class II MHC molecules are expressed on the
• Both class I and class II molecules are structurally professional antigen-presenting cells of the body
and functionally distinct from one another (primarily the macrophages, B lymphocytes, and
• MHC gene products are also called human dendritic cells).
leukocyte antigens (HLA). • After APCs phagocytose microbes, they process
and load these antigens onto MHC II. Then the
Class I and Class II gene products: MHC II is inserted into the cell membrane for
Class I gene products Class II gene products binding and recognition by helper T cells (CD4+ T
HLA-A HLA-B HLA-C HLA- HLA- HLA- HLA-
cells).
DM DP DQ DR • Helper T cells can then activate B cells and/or
trigger local inflammation.

MHC I

Previously discussed:
• TCRs capable of binding with low affinity will
receive a positive selection signal to divide and
migrate into medulla
• TCRs that bind too strongly to self MHC
molecules will be induced to undergo apoptosis
(negative selection) because these cells would
have the potential to cause autoimmune disease.
• Double positive thymocytes co-express CD4 and
CD8
• If TCR binds MHC class I named as CD8 positive
• If TCR binds MHC class II named as CD4 positive
• Class I molecules are expressed on all nucleated • CD4+ cells that recognize class II MHC are
cells in the body, as well as platelets EXCEPT destined to become “helper T cells (Th)
RBCs • CD8+ cells that recognize class I MHC are
Note: Pathogens within red blood cells can go destined to become cytotoxic T lymphocytes
undetected by cytotoxic T cells, e.g., malaria. (CTLs).

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 • Is adrenocortical insufficiency due to the
HLA and disease associations destruction or dysfunction of the entire adrenal
Overview (previously discussed): cortex.
• There are 2 major classes of cell-bound MHC gene • It affects glucocorticoid and mineralocorticoid
products: I and II. function
• Both class I and class II molecules are structurally • Highest genetic risk is associated with the Major
and functionally distinct from one another Histocompatibility region (MHC), specifically
• MHC gene products are also called human human leukocyte antigen (HLA)-DR3 haplotypes
leukocyte antigens (HLA). (containing HLA-B8)
HLA and disease associations • Addison disease is also associated with HLA-
HLA subtypes Disease DR3&4
A3 Hemochromatosis
B8 Addison disease, myasthenia gravis, Graves’s
Myasthenia Gravis:
disease
B27 Psoriatic arthritis, Ankylosing spondylitis, IBD-
associated arthritis, Reactive arthritis
DQ2, DQ8 Celiac disease
DR2 Multiple sclerosis, hay fever, SLE,
Goodpasture syndrome
DR3 Diabetes mellitus type 1, SLE, Graves’ disease,
Hashimoto thyroiditis, Addison disease
DR4 Rheumatoid arthritis, diabetes mellitus type 1,
Addison disease
DR5 Hashimoto thyroiditis

• Myasthenia gravis (MG) is a relatively rare

Hemochromatosis:
acquired, autoimmune disorder caused by an
antibody-mediated blockade of neuromuscular
transmission resulting in skeletal muscle
weakness.
• The autoimmune attack occurs when
autoantibodies form against the nicotinic
acetylcholine postsynaptic receptors at the
neuromuscular junction of skeletal muscle
• People with certain human leukocyte antigen
(HLA) types have a genetic predisposition to
• autoimmune diseases.
Hemochromatosis is the abnormal accumulation of • The histocompatibility complex profile includes
iron in parenchymal organs, leading to organ HLA-B8.
toxicity.
• It is the most common autosomal recessive
genetic disorder and the most common cause of
severe iron overload
• Mutations in human leukocyte antigen A3 (HLA-
A3) and human leukocyte antigen B7 (HLA-B7)
were linked to Hemochromatosis
Graves’s disease:
Addison disease: • Graves' disease is an immune system disorder that
results in the overproduction of thyroid hormones
(hyperthyroidism).
• Although a number of disorders may result in
hyperthyroidism, Graves' disease (GD) is a
common cause.
• HLA-B8 was reported to be associated with GD in
many studies

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Psoriatic Arthritis:

• Psoriatic arthritis is most commonly a seronegative • Is an autoimmune disease in which the

oligoarthritic found in patients with psoriasis, body's immune system mistakenly attacks healthy
• Characterized by differentiating features of distal tissue in many parts of the body.
joint involvement and arthritis mutilans • Symptoms vary between people and may be mild
• Human leukocyte antigen (HLA)-B27 associated, to severe.
psoriatic arthritis has also been classified among • Common symptoms include painful and swollen
the seronegative spondyloarthropathies. joints, fever, chest pain, hair loss, mouth
Celiac disease: ulcers, swollen lymph nodes, feeling tired, and a
• Celiac disease is a chronic disorder of the digestive red rash which is most commonly on the face
tract that results in an inability to tolerate gliadin Goodpasture syndrome (GPS):
• When patients with celiac disease ingest gliadin,
an immunologically mediated inflammatory
response occurs that damages the mucosa of their
intestines, resulting in maldigestion and
malabsorption of food nutrients.
• A strong association exists between celiac disease
and two human leukocyte antigen (HLA)
haplotypes (DQ2 and DQ8).
• Damage to the small intestinal mucosa occurs with • Known
the presentation of gluten-derived peptide gliadin, as anti-glomerular basement membrane disease, is
consisting of 33 amino acids, by the HLA a rare autoimmune disease in which antibodies
molecules to helper T cells that mediates the attack the basement membrane in lungs and
inflammatory response. kidneys, leading to bleeding from the lungs
Multiple sclerosis: and kidney failure.
• Multiple sclerosis (MS) is a potentially disabling • It is thought to attack the alpha-3 subunit of type
disease of the brain and spinal cord (central IV collagen, which has therefore been referred to
nervous system) as Goodpasture's antigen.
• The immune system attacks the protective sheath
(myelin) that covers nerve fibers and causes
communication problems between your brain and
the rest of your body.
• Characterized by Numbness, Slurred speech,
Fatigue and Dizziness
• It has been shown that, T cells infiltrating the
central nervous system and of myelin basic
protein-reactive T cells found in HLA-DR2 MS Hashimotos Thyroiditis
patients.
• Hashimotos Thyroiditis is an autoimmune disorder
Hay fever:
whereby the body produces antibodies against
• Hay fever, also known as allergic rhinitis, is a type itself that leads to the destruction of the thyroid
of inflammation in the nose which occurs when gland thereby causing a Thyroid Disease known
the immune system overreacts to allergens in the as Thyrotoxicosis in the early phase of Hashimotos
air. Thyroiditis or Hypothyroidism in the late phase.
• Signs and symptoms include a runny or stuffy
nose, sneezing, red, itchy, and watery eyes, and
swelling around the eye.
Systemic lupus erythematosus (SLE)

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 Characteristics T cells B cells

Origin of Red bone marrow Red bone marrow

undifferentiated cells

Site of differentiation Thymus Red bone marrow

Primary Locations Lymphatic tissues Lymphatic tissues

70-80% of the circulating lymphocytes 20-30% of the circulating lymphocytes in
in blood blood
Primary functions • Provide cellular immune • Provide humoral immune
response in which T cells response in which B cells interact
interact with the antigens to indirectly, producing antibodies
destroy them that destroy the antigens
• CD4+ T cells help B cells • Maintain immunologic memory
make antibodies and produce
cytokines to recruit phagocytes
and activate other leukocytes.
• CD8+ T cells directly kill
virus-infected cells.

T cells activation and immunity

• T-cell precursors move from the bone marrow

(born) to the thymus (maturate) where they are
selected for self-tolerance by exposure to major
histocompatibility complex (MHC)
• Most T-cell precursors entering the thymus are
destined to die there (apoptosis)

• Only those with TCRs appropriate to protect the

host from foreign invaders will be permitted to exit
to the periphery.
• CD4+ cells that recognize class II MHC are
destined to become “helper” T cells (Th).
• CD8+ cells that recognize class I MHC are
destined to become cytotoxic T lymphocytes CD4+ T cells known as Helper T cells
(CTLs). • Helper T cells release cytokines into bloodstream
to warn the immune system of the presence of a
dangerous cell or virus
• when an antigen-presenting (APC) cells expresses
an antigen on MHC class II, a CD4+ cell will aid
those cells through a combination of cell to cell
• Stimulation of helper T cells by interleukins
become either Th1 or Th2 cells with specific
functions to help regulate both the humoral and
cell-mediated immune system
Note:
• In the advanced stages of HIV infection, loss of
functional CD4+ T cells leads to the symptomatic
stage of infection known as the acquired
immunodeficiency syndrome AIDS.

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Subtypes recognize their antigen on the surface of
• Th1 helper cells lead to an increased cell-mediated antigen presenting cells (APCs).
response, typically against intracellular bacteria 2. The T cell receptor (TCR) on both CD4+
and protozoa. helper T cells and CD8+ cytotoxic T
• They are triggered by IL-12 and their effector cells binds to the antigen as it is held in a
cytokines are IFN-γ and IL-2. structure called the MHC complex, on
• They also secrete IL-2, which activates CD8+ the surface of the APC. This trigger
(cytotoxic T cells) to kill virally infected cells. initial activation of the T cells
• Main partner cell types: include Macrophage, 3. Besides T cells, both CD4 and CD8
CD8+ T cell molecules then bind to the MHC
• Th2 helper cells lead to a humoral immune molecule too
response, typically against extracellular parasites 4. This normally takes place in the
including helminths. secondary lymphoid organs.
• They are triggered by IL-4 and IL-2, and their 5. In addition to TCR binding to antigen-
effector cytokines are IL-4, IL-5, IL-9, IL-10, IL- loaded MHC, both helper T cells and
13 and IL-25. cytotoxic T cells require several
secondary signals to become activated
• Main partner cell types: include eosinophils, mast
and respond to the threat.
and B cells
6. The costimulatory molecules B7-1
(CD80) and B7-2 (CD86) on APCs bind
CD8+ T cells
to CD28 on the mature, naïve T cells,
• A type of cells that kills cancer cells, cells that are
providing the second signal necessary for
infected (particularly with viruses), or cells that are
successful activation.
damaged in other ways.
7. The activated CD4+ (helper) T
• Cytotoxic T cells have CD8, which binds to MHC lymphocytes will begin to produce and
I on virus-infected cells. secrete cytokines and increase surface
• Destruction mechanism either by forcing the cell expression of cytokine receptors.
to commit suicide, or
• The CD4+ T cell will also release IL-2 which lead
• Secret enzymes that kill the cells (perforin, to:
granzyme B)
A. activation and proliferation of CD8+ cytotoxic T
cells to kill virally infected host cells
B. Cause CD4+ T cell proliferation and
differentiation in an autocrine manner

Activations of T cells
• Several surface molecules are involved in the
activation of mature, naive T lymphocytes:
• First (primary) signal: recognition of the MHC:
peptide complex by the T cell receptor and
coreceptors (CD4 and CD8)
• Second (costimulatory) signal: recognition of B7
by CD28

1. Once T cells leave the thymus, they

circulate throughout the body until they

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 proliferation, hypermutation, and isotype
switching.
• Once a B cell becomes a plasma cell, it is no
longer able to proliferate because it is designed for
maximal immunoglobulin secretion.
• Two signals to make a Th2 cell secrete B cell
activating cytokines:
A. The TCR–MHC II antigen interaction
B. CD40–CD40 ligand interaction.

B cells, antibodies and Humoral immunity

Overview:
• Antibody formation is accomplished by mature
plasma B cells, which synthesize and release
antibodies
• Antibody is a large protein, constitutes γ-globulin
produced by plasma cells.
• It is used by the immune system to identify and
neutralize pathogens such as bacteria and viruses
• Antibodies are also called Immunoglobulins
Humoral immunity antibodies synthesis
(immunoglobulins)
Antibody structure and function:
• What is the structure of antibody molecule?

• Each antibody consists of four polypeptides; two

B cell activation and class switching heavy chains and two light chains joined to form a
"Y" shaped molecule.
• A helper T cell subtype 2 (Th2 cell) can then
recognize the antigen on the MHC II with its T cell • Both heavy and light chains bonded via interchain
receptor (TCR). of di-Sulphide linkages
• Each heavy chain composed of one constant and
one variable region
• The trunk of the “Y” is the constant fragment (Fc)
and the two branches are antigen-binding
fragments (Fab)
• The Fc region is the constant region:
• Include the carboxy terminal and various
carbohydrate side chains and play an important
role in both complement factor binding and
determining the isotype of the immunoglobulin
(IgM, IgA, IgE or IgD).
The Th2 cell will then secrete specific cytokines • Fab region:
(IL-4, IL-5, and IL-6) to stimulate B cell • Determine the idiotype of the immunoglobulin

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Generation of antibody diversity:
Antigen dependent Antigen Independent
Somatic hypermutation Random recombination of VJ (light-chain) or
and affinity V(D)J (heavy-chain) genes
maturation (variable
region)

Isotype switching Random addition of nucleotides to DNA during

(constant region) recombination by terminal deoxynucleotidyl
transferase (TdT)
Random combination of heavy chains with light
chains

Isotype switching:
• Biological mechanism that changes a B cell's
production of immunoglobulin from one type to
another.
• During this process, the constant-region portion of
the antibody heavy chain is changed, but the
variable region of the heavy chain stays the same
• The antibody retains affinity for the same antigens, Types of Antibodies
but can interact with different effector molecules. • Antibodies of primary humoral response (IgM)
• Antibodies of secondary immune response
• All isotypes can exist as monomers.
• Mature, naive B cells prior to activation express
IgM and IgD on their surfaces.
• They may differentiate in germinal centers of
lymph nodes by isotype switching into plasma
cells that secrete IgA, IgE, or IgG.

Mechanism of Isotype switching:

• Isotype switching occurs after mature B cell
activation
• Generation of different classes of antibodies (with
constant variable domains but include changes at
the antibody heavy chain)
• mature B cells produce both IgM and IgD, which
are the first two heavy chain segments in the
immunoglobulin locus
• After activation by antigen, these B cells
proliferate.
• If these activated B cells encounter specific
signaling molecules via their CD40 and cytokine
receptors (both modulated by T helper cells), they B cell differentiation
undergo antibody class switching to produce IgG,
IgA or IgE antibodies IgD (Immunoglobulin D class)
• Expressed on the surface of mature B cells
• Unknown function BUT, IgD works with IgM in
B cell development.
• IgD is found in very low levels in serum and does
not activate the complement pathway
IgM (immunoglobulin M):
• The first isotype of immunoglobulin that can be
produced by a B cell with or without T-cell help.
• Therefore, considered the fast-antigenic response

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 • The IgM molecule on the surface of the B cell is a
monomer, but the secreted form of this molecule is
a pentamer.
• The design of the IgM pentamer maximizes its
effect critical to the body early during antigenic
challenge. Because of its multimeric structure (5 of
the Y shaped monomers joined into one unit),
plasma IgM has 5 times the capacity for binding
antigenic epitopes.
• The multimeric structure of IgM also makes it the
most effective antibody at activating
complement, a set of serum proteases important in
mediating inflammation and antigen removal. IgA
• However, the pentamer is very bulky and therefore • More commonly produced in the submucosa than
does not cross the placenta. in the lymph nodes and spleen
IgG • Prevents attachment of bacteria and viruses to
mucous membranes; does not fix complement.
• Occurs as a monomer in the bloodstream and as a
dimer when secreted
• Uses transepithelial transport for navigation
• IgA is secreted onto mucosal surfaces
(gastrointestinal, genitourinary, and respiratory) to
block attachment of pathogens to mucous
membranes.
• Most produced antibody overall but has lower
serum concentrations.
• Released into secretions (tears, saliva, mucus)
and breast milk. Picks up secretory component
from epithelial cells, which protects the Fc portion
• from luminal proteases.
The preponderant isotype of immunoglobulin that
begins to be produced after IgM during the
Functions of IgA
primary immune response.
• Serves as a major protective defense of the
• Most abundant isotype in serum
mucosal surfaces of the body Any pathogen that
• IgG has the following characteristics: infects the mucosa will induce
1. Activates complement
• Functions as a neutralizing antibody by inhibiting
2. Acts as an opsonin, enhancing phagocytosis
the binding of toxins or pathogens to the mucosa
3. Neutralizes pathogen and toxins
of the digestive, respiratory, and urogenital
4. Mediates antibody dependent cellular toxicity
systems
(ADCC)
• IgG is also actively transported across the
placenta and thus plays a crucial role in protection
of the fetus during gestation (passive immunity).

IgE

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 • Binds directly to Fc receptors present on mast seen to be expressed by white blood cells
cells, eosinophils and basophils (leukocytes).
• Involved in elicitation of protective immune • The function of the immune system depends in a
responses against parasites and allergens (Type I large part on interleukins.
hypersensitivity) • Deficiencies of several of them were linked to
• It does not activate complement or act as an autoimmune diseases or immune deficiency.
opsonin. • Most interleukins are synthesized by helper CD4
T lymphocytes, as well as through monocytes,
macrophages, and endothelial cells.
• They promote the development and differentiation
of T and B lymphocytes, and hematopoietic cells

Bilogical Functions of the antibody isotypes

Functions IgM IgM IgA IgD IgE Interleukin 1:
• Produced by activated macrophages- participate in
the regulation of immune responses and
Complement + + - - -
activation
inflammatory reactions
• Enhance corticosteroid release, leukocyte
recruitment
Neutralization +/- + + - -
• Induce fever and shivering
• Induces chemokine secretion to recruit WBCs.
Opsonization - + - - -
Interleukin 2:

Antibody-dependent - + _ _ +/-
mediated cytotoxicity

Placental transport - + - - -

•
Triger mast cells and _ _ _ _ + Stimulates growth of helper, cytotoxic, and
granule release
regulatory T cells, and NK cells.
• T Lymphocytes regulate the growth and
Naïve B cells antigen + _ _ + _ differentiation of T cells and certain B cells
receptor
through the release of secreted protein factors.
• IL2 is a lymphokine that induces the proliferation
Memory B cell _ + + - + of responsive T cells.
antigen receptor

Interleukin 3:
• Interleukin that stimulates bone marrow
Interleukins Overview • regulates blood-cell production by controlling the
Overview: production, differentiation and function of
• Interleukins are a group of cytokines (secreted granulocytes and macrophages
proteins and signaling molecules) that were first

165
Interleukin 4:
• produced by CD4 T cells specialized in providing
help to B cells to proliferate and to undergo class • IL-6 stimulates several types of Leukocytes, and
switch recombination (IgE and IgG) and somatic the production of acute Phase Proteins in the
hypermutation. Liver.
• IL-4 also promotes CD8+ Cell growth and • IL-6 is particularly important in inducing B- Cells
• promotes TH2 Cell differentiation to differentiate into antibody Forming Cells
(Plasma Cells).

Interleukin 8:
• Produced by most cells of the body, especially
Macrophages and Endothelia Cells.
• • IL-8 enhances Inflammation, by enabling
Immune Cells to migrate into tissue, & is a
powerful inducer of Chemotaxis for Neutrophil
Interleukin 5: Cells
• It regulates eosinophil growth and activation, and
thus plays an important role in diseases associated
with increased levels of eosinophils, including
asthma.
• Secreted by Th2 cells that enhances
immunoglobulin class type switching to IgE
Interleukin 6:
• Is produced by many cell types, including T- Cells,
Macrophages, B-Cells, Fibroblasts, and Endothelia
Cells.
Interleukin 10:
• Secreted by regulatory T cells to suppress cell-
mediated immunity and stimulate humoral
immunity.
• Decreases expression of MHC class II and Th1
cytokines.
• Inhibits activated macrophages and dendritic cells
• Attenuates inflammatory response.

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Interleukin 12: bound oxidase that generates oxygen metabolites,
which are toxic to ingested microorganisms.
• Oxygen uptake increase greatly, undergoes a series
of changes “Respiratory Burst”
Respiratory Burst
• Respiratory Burst” occurs during:
1. Activation of macrophages during phagocytosis
2. Abrupt rise in Oxygen consumption
3. Activation of NADPH oxidase/Phagocyte
oxidase

• Secreted
by macrophages with functions to enhance NK
cells and T cells.
• It is involved in the stimulation and maintenance
of Th1 cellular immune responses, including the
normal host defense against various intracellular
pathogens, such as Leishmania, Toxoplasma,
Measles virus, and Human immunodeficiency
virus 1 (HIV).
• IL-12 also has an important role in pathological • Respiratory burst Plays an important role in the
Th1 responses, such as in inflammatory bowel immune response that initiate the rapid release of
disease and multiple sclerosis reactive oxygen species (ROS).
• Two oxygen-dependent mechanisms of
Oxidative Burst intracellular digestion are activated because of this
Overview: process.

1. NADPH oxidase reduces oxygen to superoxide

anion, which generates hydroxyl radicals and
hydrogen peroxide, which are microbicidal.

2. Myeloperoxidase in the lysosomes acts on

hydrogen peroxide and chloride ions to produce
hypochlorite (the active ingredient in household
bleach), which is microbicidal.

•
When molecular oxygen (O2) is partially reduced,
unstable products called reactive oxygen species
(ROS) are formed.
• Reactive oxygen species include:
1. Superoxide (O2–)
2. Hydrogen peroxide (H2O2)
3. Hydroxyl radical (OH)
• The polymorphonuclear neutrophil produces these
substances to kill bacteria in the protective space
of the phagolysosome during the oxidative burst
accompanying phagocytosis.
• Phagocytosis is an Innate defense mechanism is
ingestion of extracellular particles
NADPH oxidase
• Performed by specialized cells such as Blood
• Present in membrane associated of phagocytic
Monocytes, Neutrophils and tissue Macrophages
cells
• During phagocytosis, a metabolic process known
as the respiratory burst activates a membrane-
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 • NADPH oxidase catalyzes the production of • Fever induced by prostaglandin Il-1, PGE1, TNF
a superoxide free radical by transferring one alpha
electron to oxygen from NADPH. • Diagnosis: Failures of phagocytic cells to generate
• During this process O2 is transported from the oxygen radicals are easily detected by the
extracellular space to the cell interior and the H+ is nitroblue tetrazolium (NBT) reduction test or
exported. neutrophil oxidative index
Superoxide dismutase
• Catalyzes the dismutation of
the superoxide(O2−) radical into either
molecular oxygen (O2) or hydrogen
peroxide (H2O2).
Myeloperoxidase
• Abundantly expressed in neutrophil granulocytes
• produces hypochlorous acid (HOCl)
from hydrogen peroxide(H2O2)
and chloride anion (Cl−) during the
neutrophil's respiratory burst.
Active and passive immunity
• Hypochlorous acid is cytotoxic to bacteria
• Myeloperoxidase contains a blue-green heme-
containing pigment that gives sputum its color.
Glutathione peroxidase
• Glutathione (GSH) is crucial for the detoxification
of H2O2 that has diffused into the cytosol
Glutathione reductase
• Catalyzes the reduction of glutathione disulfide
(GSSG) to the sulfhydryl form glutathione (GSH)
Chronic granulomatous disease
• Chronic granulomatous disease is most frequently
caused by genetic deficiency of NADPH oxidase
in the polymorphonuclear neutrophils (PMN).
• This defect eliminates the phagocyte’s ability to
produce many critical oxygen-dependent
intracellular metabolites (·O2 –, OH, 1O2, and
H2O2).
• The 2 other intracellular killing mechanisms
remain intact (myeloperoxidase + H2O2 → HOCl
and lysosomal contents).
Artificial Active Artificial Passive immunity
• If the patient is infected with a catalase-positive immunity
organism (e.g., Staphylococcus, Klebsiella, Duration Long lasting immunity Short lasting immunity half-life 3
Serratia, Aspergillus), the myeloperoxidase system of weeks
immunity
lacks its substrate (because these organisms Time Body needs time to Ready-made antibodies
destroy H2O2), taken to synthesis antibody after
• Thus, CGD patients suffer from chronic, recurrent achieve exposure to antigen
immunity
infections with catalase-positive organisms. Such Time of Before the person is At the time when the person is
as: injection infected infected or at high risk of getting
• Staphylococcus aureus, Klebsiella, Escherichia the disease
Type of Vaccines containing Serum containing specific
coli, Candida, and Aspergillus. injection dead or weakened antibody
• These species neutralizing their own H2O2, antibody
leaving phagocytes without ROS for fighting Necessity Required because the Not required
of booster first injection usually The first injection usually enough
infections dose induces a slow & low
• The patient is subjected to recurrent pulmonary level of antibody
infection • Natural • Antitoxin
infections • Immunoglobulin for
• Skin, lymphatic tissue Hepatic infection • Vaccines intravenous
• Toxoid (Kawasaki disease)

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 • Digitalis antibody
fragment
• Humanized
monoclonal antibody
• Maternal Ig crossing
the placenta

• After exposure to
Tetanus toxin,
Botulinum, toxin,
HBV, Varicella,
Rabies virus, or
diphtheria toxin
• unvaccinated Type I hypersensitivity:
patients are given • When someone is exposed to an allergen, it can
preformed
antibodies (passive) lead to a rapid immune response that occurs almost
immediately. Such a response is called
Types of vaccines: an allergy and is classified as a type I
Attenuated hypersensitivity.
• Comprised of live organisms which lose capacity • The first exposure activates a primary IgE
to cause disease but still replicate in the host antibody response that sensitizes an individual to
• Attenuated vaccines are comprised of live type I hypersensitivity reaction upon subsequent
organisms, there is slight potential to revert to a exposure.
virulent form Immune mechanism:
• Stimulating both a humoral and cell mediated • Allergen-specific IgE antibodies bind to mast cells
immune response, as they mimic the natural via their Fc receptor
infection and typically elicit lifelong immunity Mechanisms of tissue injury:
• Not safe-dangerous for immunocompromised Immediate reaction
patients/pregnancy because even attenuated • Degranulation and release of vasoactive amines
viruses can cause them significant disease. (ie. histamine) and proteases
Examples • Degranulation: a reaction in which the contents of
• Polio (sabin), Varicella (chickenpox), Smallpox, the granules in the mast cell are released into the
BCG, Yellow fever, Influenza (intranasal), MMR, extracellular environment.
Rotavirus Late phase reaction
Nonattenuated • Synthesis and secretion of prostaglandins and
• Used by U.S. military against adenovirus types 4 leukotrienes
and 7 • Cytokine-induced inflammation and leukocyte
Killed vaccines recruitment
• Utilize organisms that are killed so they can no
longer replicate in the host
• Inactivated by chemicals rather than heat, as heat
will often denature the immunogenic epitopes
• Typically require several doses to achieve desired
response
• Safer but weaker immune response
• Produce humoral immunity
Examples
• Rabies, Influenza, Polio (Salk) and Hepatitis A
Hypersensitivity response
Overview: Source of allergy:
• Hypersensitivity diseases are conditions in which • Food allergy milk, egg, fish and peanuts
tissue damage is caused by immune responses. • Dust, cats, dogs, pet dander, pollen
• They may result from uncontrolled or excessive • Bee stings
responses against foreign antigens or from a failure
of self-tolerance, in which case they are called Clinical presentations:
autoimmune diseases.

169
 • They can be involved in antibody-dependent cell-
mediated cytotoxicity (ADCC) with cytotoxic T
cells.

• These antibodies can cause tissue destruction by 3

main mechanisms:

1. Opsonization of cells leading to either

phagocytosis/activation of complement system/
NK cell killing
2. Activation of the complement system which
recruit neutrophils and macrophages that cause
tissue damage
3. Cellular dysfunction

• In some types of type II hypersensitivity,

complement is activated and/or ADCC is active
(hemolytic disease of the newborn).
• In other types, cell function is altered in the
absence of complement activation and ADCC
• Allergic rhinitis (hay fever): Histamine (myasthenia gravis).
stimulates mucus secretion in nasal passages and • During Type II antigen and antibody interaction
tear formation from lacrimal glands, promoting the may cause localized damage, but they do not
runny nose and watery eyes of allergies. circulate so the damage is localized to the specific
Interaction of histamine with nerve endings causes tissue.
itching and sneezing.
• The vasodilation caused by several of the
mediators can result in hives,
headaches, angioedema (swelling that often affects
the lips, throat, and tongue), and hypotension (low
blood pressure).
• Systemic anaphylaxis Bronchiole constriction
(Asthma) caused by some of the chemical
mediators leads to wheezing, dyspnea (difficulty
breathing), coughing, and, in more severe
cases, cyanosis (bluish color to the skin or mucous
membranes).
• Gastrointestinal problems: Vomiting can result
from stimulation of the vomiting center in the
cerebellum by histamine and serotonin. Histamine
can also cause relaxation of intestinal smooth
muscles and diarrhea Disorders associated with type II hypersensitivity
Diagnosis: Cytotoxic Mechanism Clinical
• The main test used by allergists is scratch testing manifestations
in which a positive test result in a wheal and flare Autoimmune Opsonization, Hemolysis, anemia
hemolytic anemia phagocytosis, and
reaction of the scratched skin site. complement-mediated
Type II hypersensitivity (cytotoxic hypersensitivity): destruction of RBCs
Acute rheumatic Inflammation, Myocarditis, arthritis
• Mediated by IgG and IgM antibodies fever macrophage activation
(autoantibodies) binding to cell-surface antigens Goodpasture Complement- and Fc Nephritis, lung
or matrix-associated antigens on basement syndrome receptor– mediated hemorrhage,
inflammation linear Ab deposits
membranes. Transfusion reaction opsonization + Hemolysis
• These antibodies can either activate complement, complement activation
resulting in an inflammatory response and lysis of Autoimmune opsonization and Bleeding
thrombocytopenic complement activation
the targeted cells, purpura
Non-cytotoxic

170
 Myasthenia gravis Ab inhibits acetylcholine Muscle weakness, extracellular destruction of the immune complex,
binding, downmodulates paralysis
receptors
damaging localized cells in the process.
Graves’ disease Ab-mediated stimulation Hyperthyroidism Clinical presentations:
of TSH receptors followed by • Fever, urticaria, arthralgia, proteinuria,
hypothyroidism
pemphigus vulgaris Autoimmune disease Oral blisters lymphadenopathy occur 1–2 weeks after antigen
Bullous pemphigoid Formation of anti- Skin lesions exposure
hemidesmosome Serum sickness
antibodies.
• Systemic type occurs when immune complexes
deposit in various body sites, resulting in a more
Other common Type II hypersensitivities:
generalized systemic inflammatory response
Hemolytic disease of the newborn (HDN)
(within 1-2 weeks)
• IgG from mother crosses the placenta, targeting
Examples:
the fetus’ RBCs for destruction
• These immune complexes involve non-self-
• Characterized by Anemia, edema, enlarged liver or
proteins such as antibodies produced in animals
spleen, hydrops (fluid in body cavity), leading to
for artificial passive immunity such as Tetanus
death of newborn in severe cases
vaccine
Hemolytic transfusion reaction
• Certain drugs such as haptens, penicillin
• IgG and IgM bind to antigens on transfused RBCs,
• Microbial antigens that are continuously released
targeting donor RBCs for destruction
over time during chronic infections:
• Characterized by Fever, jaundice, hypotension,
➢ Subacute bacterial endocarditis
disseminated intravascular coagulation, possibly
➢ chronic viral hepatitis
leading to kidney failure and death
Diagnosis:
Arthus reaction
• Direct and indirect coombs test of RBC for
• Localized type occurs within 3-10 hours after
hemolytic anemia.
intradermal injection of antigen into a pre-
• Direct immunofluorescence of the glomerular sanitized person (has circulating IgG) causing
basement membrane for Goodpasture syndrome necrosis, edema and local pain
Disorders associated with type III hypersensitivity
Type III hypersensitivity (Antigen-Antibody- Disease Clinical Manifestations
Complement): Systemic lupus Nephritis, arthritis, vasculitis, butterfly
• Antigen-antibody complexes are deposited in erythematosus facial rash
Poststreptococcal Nephritis, “lumpy-bumpy” deposits
tissues lead to: glomerulonephritis
Polyarteritis nodosa Systemic vasculitis

Diagnosis:
• immunofluorescent staining
Type IV hypersensitivity
• Known as delayed- type hypersensitivity or
antibody-independent cytotoxicity
• Can be organized into three subcategories based on
T-cell subtype, type of antigen, and the resulting
effector mechanism.
1. The antigen presenting cells activate helper T
1. cells, stimulating differentiation into memory TH1
Complement activation with production of pro- cells.
inflammatory C3a and C5a • These sensitized memory TH1 cells release
2. IgG binding to antibody receptors on localized cytokines that activate macrophages
mast cells, resulting in mast-cell degranulation • Activated macrophages are responsible for much
3. Increased blood-vessel permeability (vasculitis) of the tissue damage
with chemotactic recruitment of neutrophils and 2. Effector CD4+ T cells recognize antigen and
macrophages release inflammation-inducing cytokines
Note: neutrophil degranulation results in the 3. Directly killing target cells through CD8+
release of lysosomal enzymes that cause cytotoxic T cells

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 • T-cell-mediated tissue injury is common during Anaphylactic reactions
the protective immune response against persistent • Less common but sever reactions
intracellular microbes. • IgA-deficient recipient who is transfused with
IgA-containing blood products

Signs and symptoms:

• Type I hypersensitivity symptoms include:
o Generalized flushing
o laryngeal edema
o bronchospasm and dyspnea
o profound hypotension, shock and potential
cardiopulmonary arrest

Treatment:
• The transfusion should be stopped immediately
and adrenaline 1 in 1000 (0.3-0.5 mL) given
Disorders associated with type IV hypersensitivity immediately.
Disease Clinical manifestations • Supportive therapy for the circulation and
Tuberculin test PPD Indurated skin lesion (granuloma) respiratory system may be necessary
Diagnosis:
Contact dermatitis Vesicular skin lesions, pruritus, rash
• Diagnosis must be made by demonstrating
Multiple sclerosis Progressive demyelination, blurred vision, Paralysis deficiency of IgA and the detection of an anti-IgA.
Rheumatoid Rheumatoid factor (IgM against Fc region of IgG),
• Those patients should receive only IgA-deficient
arthritis alpha-cyclic citrullinated peptide (a-CCP) components which are collected from a special
antibodies, chronic arthritis, inflammation, panel of IgA-deficient donors.
destruction of articular cartilage and bone

Guillain-Barré Ascending paralysis, peripheral nerve Febrile non-hemolytic transfusion reactions (FNHR)
syndrome demyelination • Caused by cytokines from leukocytes in transfused
Contact dermatitis Nickel allergy, exposure to urushiol oil from poison red cell or platelet components, causing fever,
ivy/oak chills, or rigors.
graft-versus-host Abdominal swelling, yellow discoloration of the
• Host antibodies attack donor HLA antigens and
disease (GVHD) skin and/or eyes, leukocytes
Celiac disease Gluten-sensitive enteropathy
Signs and symptoms:
Corhn disease Chronic intestinal inflammation due to Th1 and • Type II hypersensitivity symptoms include:
Th17 cells, obstruction o Fever
o Chills
o Headache
Blood transfusion reactions
Allergic reactions
Acute hemolytic transfusion reactions (HTR)
• Type I hypersensitivity reaction against plasma
• Intravascular hemolysis due to ABO blood group
proteins in transfused blood
incompatibility
• The primary antigen exposure stimulates plasma
• Extravascular hemolysis host antibody reacts
cells to produce specific IgE.
against foreign antigens
• This IgE binds to mast cells via its Fc receptor and
sensitizes them.
Signs and symptoms:
• Causes crosslinking of surface IgE stimulating o Flank pain, hemoglobinuria
degranulation of mast cells. o Fever, hypotension
Signs and symptoms: B cells immunodeficiency disorders
• Itching, pruritis, fever, wheezing, urticaria Selective IgA deficiency
Molecular defects
Treatment: • Most common immunodeficiency
• Antihistaminic • Unknown cause but mostly multiple genetic causes
Clinical presentations

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 • Mostly asymptomatic • Normal level of B cells but with diminished levels
• ↓ IgA levels and normal IgM and IgG with ↑ of of IgG and IgA and with high levels of IgM
IgE. • Associated with higher risk for Pneumocystis
• Repeated sinopulmonary and gastrointestinal infection.
infections
• ↑ atopy T cells disorders
• Susceptibility to giardiasis Thymic aplasia (DiGeorge syndrome)
• Prone to autoimmune disease Molecular defect:
• Anaphylaxis to IgA-containing products. • Heterozygous deletion of chromosome 22q11.
• Failure of formation of 3rd and 4th pharyngeal
Example: Patient with bloody diarrhea and needed blood pouches
transfusion BUT few minutes later, the patient develops • Lack of thymus and parathyroid development
itching (anaphylaxis) to IgA containing blood products
Diagnosis: Clinical presentations
• Blood test analysis reveal that IgA <7 mg • Characteristic facies and a clinical triad of cardiac
• Heterophilic antibodies have been reported malformations, hypocalcemia and hypoplastic
in IgA-deficient individuals thymus
X-linked (Bruton) agammaglobulinemia • Tetany (Hypocalcemia is the primary cause of
Molecular defects tetany)
• Deficiency of the Bruton tyrosine kinase (btk) o Low ionized calcium levels in
which promotes pre-B cell expansion the extracellular fluid increase the
• Lack of B-cell development permeability of neuronal membranes to
• X linked recessive in boys sodium ion, causing a progressive
depolarization (contraction of peripheral
Clinical presentations skeletal muscles)
• Recurrent bacterial infection after 6 months o Tetany is characterized by contraction of
distal muscles of the hands (carpal spasm with
• Increased susceptibility to encapsulated bacteria
and bloodborne viruses extension of interphalangeal joints) and feet
(pedal spasm) and is associated with tingling
• ↓ circulating B-cells, ↓ immunoglobulins of all
around the mouth and distally in the limbs.
isotypes
o Recurrent fungal and viral infection
• ↓ Maternal IgG
• Congenital heart & great vessel defects (tetralogy
• B-cell maturation does not progress past the pre-B
of Fallot, truncus arteriosus)
cell stage while maintaining cell-mediated
• Thymic aplasia
immunity.
Diagnosis
Common variable immunodeficiency:
Molecular defects • ↓T cells, ↓ PTH, ↓Ca2+
• Thymic shadow absent on CXR.
• Several associated genetic defects
Clinical presentations
Il-2 receptor deficiency (severe combined
• Most common form of primary B cell deficiency
immunodeficiency):
• ↓measurable IgG and IgA (occasionally IgM) Molecular defect
resulting in immunodeficiency
• IL-2 Is the major cytokine that is produced during
• Onsets in late teens, early twenties the primary response of Th cells
• B cells present in peripheral blood • Upon differentiation into one of the two types of
• Associated with higher rates of lymphomas, gastric Th effector cells, Th1 and Th2, IL-2 production
cancer and↑ autoimmunity declines and is replaced by production of Th1-like
Hyper IgM syndrome: (IFN-γ) or Th2-like (IL-4) cytokines
Molecular defects • Therefore, deficiency in Il-2 receptor is associated
• Deficiency of CD40L on activated T cells with with ↓ Th1 response & ↓IFN-
inability for class switching Clinical presentations
Clinical presentations
• Characterized by disseminated mycobacterial and
• High serum titers of IgM with diminished levels of fungal infection
IgG and IgA
• Normal level of B cells Hyper IgE syndrome (Job syndrome):
Molecular defect
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 • Defects in JAK-STAT signaling pathway leading • low levels of circulating lymphocytes
to impaired Th17 function Treatment
• Decreased IFN-gamma production • Bone marrow transplant
• Unresponsive neutrophils and chemotaxis Ataxia telangiectasia
Clinical presentations Molecular defect:
• Characterized by: • Known as ataxia–telangiectasia
1. Coarse facies syndrome or Louis–Bar syndrome
2. Cold (noninflamed) staphylococcal abscesses • ATM gene defects (Defect in the ATM kinase
3. Increased IgE and eosinophils, eczematous rash involved in the detection of DNA damage and
4. Pathological bone fractures progression through the cell cycle
5. Retained primary teeth • Autosomal recessive disorder
Clinical presentations
Chronic mucocutaneous candidiasis • Ataxia (gait abnormalities)
Molecular defect • Telangiectasia (capillary distortions in the eye)
• A type of T-cell dysfunction. • Deficiency of IgA and IgE production
• Result from congenital genetic defects in IL-17 or
IL-17 receptors. Diagnosis
Clinical presentations • Increased AFP
• Candida albicans infections of skin and mucous • Decreased IgA, IgG, and IgE.
membranes
• Hyperkeratosis, skin
ulcer, dyspareunia, endocardium abnormality,
vision problems, hepatitis, seizures, hematuria
and meningitis.

T& B cells disorders •

Severe combined immunodeficiency (SCID) Lymphopenia, cerebellar atrophy
Molecular defect: • Increased risk of lymphoma and leukemia
• Known as bubble boy disease and bubble baby
disease Hyper IgM disorder
• Defects in common γ chain of IL-2 receptor Molecular defect
• Cause widespread defect in interleukin signaling • Defective CD40L on helper T-cell
with low or absent T cells and NK cells and non- • Normal level of B cells but with diminished levels
functional B cells. of IgG and IgA and with high levels of IgM
• X-linked recessive disorder • X-linked recessive
• Associated with adenosine deaminase deficiency • This condition usually results from an inability to
Clinical presentations: undergo isotype class switching secondary to
• Recurrent viral, bacterial, fungal, protozoal deficiency in CD40 ligand on Th2 cells.
infection Clinical presentations
• Chronic diarrhea; skin, mouth, and throat lesions; • Associated with higher risk for Pneumocystis
opportunistic (fungal) infections infection, CMV and cryptosporidium
Diagnosis Wiskott-Aldrich syndrome:
•  T cells recombinant excision circles
• Absence of thymic shadow (CXR), germinal Molecular defect
centers (lymph node biopsy), and T cells (flow • Defect in the WAS protein which plays a critical
cytometry). role in actin cytoskeleton rearrangement

174
 • T cells can NOT recognize actin cytoskeleton
Clinical Presentations

Thrombocytopenia

Eczema Immunodeficiency
Diagnosis
• IgA and IgE and  IgM
• Low platelets
• Increased risk of autoimmune disorders and
cancers Hyper acute Graft Rejection
Transplant rejections and grafts • Occurs immediately within minutes to hours
Overview • Type II cytotoxic hypersensitivity
• Transplantation is the process of taking cells, • Antibodies bind to the grafted tissue and activate
tissues, or organs (a graft) from one individual (the complement and the clotting cascade resulting in
donor) and implanting them into another thrombosis and ischemic necrosis
individual or another site in the same individual • Due to pre-formed antibodies
(the host or recipient). • Graft must be removed.
Types of grafts:
• Autologous grafts (or autografts) are those Acute Graft Rejection
where tissue is moved from one location to another
in the same individual (skin grafting in burns or
coronary artery replacement with saphenous
veins).
• Isografts (or syngeneic grafts) are those
transplanted between genetically identical
individuals (monozygotic twins).
• Allogeneic grafts are those transplanted between
genetically different members of the same species
(kidney transplant).
• Xenogeneic grafts are those transplanted between
members of different species (pig heart valves into •
human). Occurs within days to weeks
Mechanism of graft rejection: • Develop type IV hypersensitivity reaction
• As the graft becomes vascularized, CD4+ and • Both CD4 and CD8 T cells play a role as well as
CD8+ cells that migrate into the graft from the antibodies against donor MHCs
host become sensitized and proliferate in response • Reversible by Immunosuppressive therapy
to both major and minor histocompatibility (Interleukins inhibitors, D-cyclosporine)
differences • Characterized by Vasculitis of graft vessels with
• The cytokines play a critical role in stimulating dense interstitial lymphocytic infiltrate
macrophage, cytotoxic T cell. • Diagnosis by graft biopsy
• Interferons and TNF-α and -β all increase the Chronic Graft Rejection
expression of class I MHC molecules in the graft,
while IFN-γ increases the expression of class II
MHC as well
• These processes increase the susceptibility of cells
in the graft o MHC-restricted killing.

•
Occurs within months to years
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 • Predominantly T cell mediated (CD4+ T cells
respond to recipient)
• Type III and Type IV hypersensitivity directed
against the foreign MHC molecules which look
like self-MHC presenting a foreign antigen
• Difficult to treat and usually results in graft
rejection
• Chronic rejection appears as fibrosis and scarring
in all transplanted organs
• In heart transplants, chronic rejection manifests as
accelerated coronary artery atherosclerosis. In
transplanted lungs, it manifests as bronchiolitis
obliterans

Graft-versus-host disease •
• Timeline varies Activation of T cells in response to a foreign
• When the grafted tissue is bone marrow. antigen presented by an antigen-presenting cell
• Bone marrow transplantation applicable in cases of (which include dendritic cells, macrophages & B
cancer patients (leukemia), since the bone lymphocytes).
marrow is the source of pluripotent hematopoietic • This induces “adaptive immune responses”
stem cells, it can be used to reconstitute myeloid, involving multiple cell types that are involved in
erythroid, and lymphoid cells cell-mediated immunity involving activated
• Grafted immune-competent T cells proliferate in macrophages, natural killer T cells and
the irradiated immunocompromised disease host cytotoxic T cells, as well as stimulation of
and reject cells with foreign proteins and cause humoral immunity involving B cells & plasma
organ dysfunction cells that produce antibodies that bind to foreign
• It is necessary to remove these cells before antigens and enhance phagocytosis and cellular
transplantation to avoid the appearance of graft- toxicity of the foreign cells
versus-host disease in the recipient. • Interleukin 2 (IL-2) plays a critical role in the
• Type IV hypersensitivity reaction. initial activation of T cells
• Signs and symptoms include: Maculopapular • Many other cytokines (e.g. IFN- γ, TNF-β, IL-4 &
rash, jaundice, hepatomegaly, diarrhea, and IL-5) are involved in later steps in the pathways
gastrointestinal hemorrhage. resulting in activation of other cell types such as
General treatment in graft rejections: macrophages & B cells
• Daclizumab, basiliximab (anti-IL-2 receptor
antibody) Cyclosporine:
• Muromonab (anti-CD3)
• Belatacept (CTLA-4-Ig)
• Alemtuzumab (anti-CD52) CD52 is a marker
found on all lymphocytes
• Monoclonal antibodies are used in the treatment
and prevention of graft rejection along with the
classic therapies (corticiosteroids, cyclosporine A,
rapamycin, etc.).
Cyclosporine
Overview

Cyclosporine (CsA) binds to cyclophylin (CpN),

forming a complex that binds and blocks the
function of the enzyme calcineurin (CaN). As a
result, CaN fails to dephosphorylate the

176
 cytoplasmic component of the nuclear factor of Bind to FK-
activated T cells (NF-ATc), and the transport of binding
NF-ATc to the nucleus and the binding of NF-ATc protein
to the nuclear component of the nuclear factor of
activated T cells (NF-ATn). The NF-ATc–NF-
ATn complex binds to the promoter of the ↓ 𝑐𝑎𝑙𝑐𝑖𝑛𝑒𝑢𝑟𝑖𝑛
interleukin 2 (IL-2) gene and initiates IL-2
production.
↓ activation of
T-cell
Mechanism of action: transcription
factors

Bind to
cyclophilin ↓ 𝐼𝑙 − 2

Clinical use:
↓ 𝑐𝑎𝑙𝑐𝑖𝑛𝑒𝑢𝑟𝑖𝑛

• Tacrolimus used alternatively to cyclosporine in

↓ activation renal and liver transplants
of T-cell Toxicity:
transcription
factors
• Nephrotoxicity due to vasoconstriction
• Hyperglycemia: reduce in pancreatic cells
• Hypertension
↓ 𝐼𝑙 − 2
• Hyperlipidemia
• Neurotoxicity
Clinical use: • Gingival hyperplasia
• Cyclosporine is DOC for organ or tissue • Hirsutism
transplantation (+/– mycophenolate, +/– steroids, Sirolimus (Rapamycin)
+/– cytotoxic drugs) Mechanism of action:
• Other uses: Psoriasis, rheumatoid arthritis. • mTOR inhibitor: binds to FKBP- Blocks T-cell
Toxicity: activation and B-cell differentiation thereby
• Nephrotoxicity due to vasoconstriction preventing response to IL-2.
• Hyperglycemia: reduce in pancreatic cells
• Hypertension
• Hyperlipidemia
• Neurotoxicity
• Gingival hyperplasia
• Hirsutism
Tacrolimus
Mechanism of action:

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 Bind to FKBP • Allopurinol and azathioprine should not be co-
binding prescribed unless the combination cannot be
protein avoided.
• Allopurinol interferes with the metabolism of
Inhibit mTOR
azathioprine, increasing plasma levels of 6-
mercaptopurine which may result in potentially
fatal blood dyscrasias.
• The dose of azathioprine should be reduced to
Inhibit
translation 25% of the recommended dose and the patient’s
blood count should be monitored assiduously

↓ 𝐼𝑙 − 2Recombinant cytokines
Aldesleukin:
• Used for treatment of renal cell carcinoma,
metastatic melanoma
• MOA: Aldesleukin binds to the IL-2 receptor
Clinical use:
which leads to stimulate growth and differentiation
• Immunosuppressant post- kidney transplant in of T cells.
conjunction with cyclosporine and corticosteroids Epoetin alfa (EPO analog):
• Used with drugs eluting stents to prevent ischemia • Erythropoietin: used to treat anemias due to:
Toxicity: A. Chronic kidney disease
• Pancytopenia B. Zidovudine in patients with HIV-infection
• Insulin resistance C. The effects of concomitant myelosuppressive
• Hyperlipidemia chemotherapy
• NOT nephrotoxic • MOA: Erythropoietin or exogenous epoetin alfa
binds to the erythropoietin receptor (EPO-R) and
Azathioprine activates intracellular signal transduction pathways
Colony stimulating factors:
• Sargramostim (GM-CSF) granulocyte macrophage
colony-stimulating factor
• Filgrastim (G-CSF) granulocyte colony-
stimulating factor
Shared the following characteristics:
• Secreted by Macrophages and Th cells Bone
marrow
• Clinical uses: Induces proliferation; used to
counteract neutropenia following ablative
• Toxicity chemotherapy
• MOA: Sargramostim binds to the Granulocyte-
Mechanism of action:
macrophage colony stimulating factor receptor
• Purine antimetabolite: Azathioprine inhibits (GM-CSF-R-alpha or CSF2R). This leads to the
DNA and RNA synthesis by preventing production of hemopoietic cells and neutrophil
interconversion among the precursors of purine
• MOA. Filgrastim also stimulates the release of
synthesis and suppressing de novo purine synthesis
neutrophils from bone marrow storage pools and
• Azathioprine is a prodrug metabolized into 6- decreases their time to maturation. Filgrastim acts
mercaptopurine to increase the phagocytic activity of mature
neutrophils, thus allowing them to prevent
Clinical use: infection.
• Used in cardiac and kidney transplantations
• Rheumatoid arthritis, Crohn disease, Interferon:
glomerulonephritis, other autoimmune conditions • IFN-α Chronic hepatitis C (not preferred) and B,
renal cell carcinoma
Toxicity: • IFN-β Multiple sclerosis
• Leukopenia • IFN-γ Chronic granulomatous disease

178
Oprelvekin (Interleukin 11): which is a photo-oncogene and over-expressed in
• Oprelvekin binds to the interleukin 11 receptor breast tumor cells.
which leads to a cascade of signal transduction Clinical uses:
events. • Metastatic breast cancer
• IL-11 is a thrombopoietic growth factor that Cetuximab
directly stimulates the proliferation of • Cetuximab binds to the epidermal growth factor
hematopoietic stem cells receptor (EGFR) on both normal and tumor cells.
• Clinical uses: Autoimmune thrombocytopenia • EGFR is over-expressed in many colorectal
Thrombopoietin: cancers.
• Clinical uses: The procurement of platelets for
donation, and recovery of platelet counts after Clinical uses:
myelosuppressive chemotherapy. • Treatment of EGFR-expressing, metastatic
Summary colorectal carcinoma
• Metastatic squamous cell carcinoma of the head
Cytokine Clinical uses and neck
Aldesleukin (Interleukin-2) ↑ lymphocyte differentiation and ↑ NKs—
used in renal cell cancer and metastatic Bevacizumab
melanoma • Bevacizumab is an antineoplastic agent and
Oprelvekin (Interleukin 11) ↑ platelet formation—used in prevents or reduces the formation of blood vessels
thrombocytopenia
Filgrastim (G-CSF) ↑ granulocytes—used for marrow recovery (angiogenesis) thereby preventing or reducing
metastatic disease progressing.
Sargramostim (GM-CSF) ↑ granulocytes and macrophages—used for • Bevacizumab binds VEGF and prevents vascular
marrow recovery
Thrombopoietin Thrombocytopenia endothelial growth and endothelial cell
proliferation
Interferon-α Hepatitis B and C, renal cell carcinoma, Clinical uses:
melanoma
Interferon- β Multiple sclerosis • Glioblastoma
• Colorectal cancer
Interferon- γ Chronic granulomatous disease →↑ TNF
• Renal cell carcinoma
• Cervical cancer
Therapeutic antibodies • Lung cancer
Cancer therapy Autoimmune disease therapy
Alemtuzumab Eculizumab
• Binds to the CD52 antigen present on most B and • Treatment of patients with paroxysmal nocturnal
T lymphocytes. This binding leads to antibody- hemoglobinuria (PNH) to reduce hemolysis.
dependent lysis of leukemic cells. • Eculizumab is a monoclonal antibody directed
Clinical uses: against the complement protein C5.
• Chronic leukocytic leukemia • This antibody blocks the cleavage of C5
• Multiple sclerosis Clinical uses:
• Auto immune hemolytic anemia • Atypical hemolytic uremic syndrome
Rituximab • Paroxysmal nocturnal hemoglobinuria
• Monoclonal antibody that targets the CD20 Daclizumab
antigen, which is expressed on the surface of pre- • Inhibits (anti-CD25) IL-2-mediated activation of
B and mature B-lymphocytes. lymphocytes, a critical pathway in the cellular
• After binding to CD20, rituximab mediates B-cell immune response involved in allograft rejection.
lysis (or breakdown). Clinical uses:
Clinical uses: • Relapsing multiple sclerosis
• Non-Hodgkin’s Lymphoma Ustekinumab
• Rheumatoid arthritis • Blocks interleukin IL-12 and IL-23
• Multiple sclerosis Clinical uses:
• Chronic lymphocytic leukemia • Psoriasis, psoriatic arthritis
Natalizumab
• Pemphigus Vulgaris
Trastuzumab • Block α4-integrin which expressed by
inflammatory cells with VCAM-1 on vascular
• Trastuzumab is a recombinant humanized IgG1
endothelial cells, and with CS-1 and/or osteopontin
monoclonal antibody against the HER-2 receptor,
expressed by parenchymal cells in the brain.
a member of the epidermal growth factor receptors
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 • α4-integrin is required for white blood cells to
move into organs, therefore, natalizumab prevents
these immune cells from crossing blood vessel
walls to reach affected organs thereby decreasing
inflammation.
Clinical uses:
• Treatment of multiple sclerosis.
Other applications
Abciximab
• Binds to the intact platelet GPIIb/IIIa receptor,
which is a member of the integrin family of
adhesion receptors and the major platelet surface • Produced by activated macrophages, although it
receptor involved in platelet aggregation can be produced by many other cell types such as
Clinical uses: CD4+ lymphocytes, NK cells, neutrophils, mast
• The prevention of cardiac ischemic complications cells, eosinophils, and neurons.
Denosumab • The primary role of TNF is in the regulation
• Designed to target RANKL (RANK ligand), a of immune cells.
protein that acts as the primary signal to promote • TNF is able to induce fever, to
bone removal/resorption. induce apoptotic cell death, to induce sepsis
• In many bone loss conditions, RANKL (through IL1& IL6 production), to
overwhelms the body's natural defense against induce cachexia, induce inflammation, and to
bone destruction. inhibit tumorigenesis and viral replication.
Clinical uses: • Dysregulation of TNF production has been
• Treatment of postmenopausal women with implicated in a variety of human diseases,
osteoporosis at high risk for fracture including Alzheimer’s disease, cancer, major
Digoxin immune Fab depression, and inflammatory bowel
• Binds excess digoxin or digitoxin molecules disease (IBD).
circulating in the blood (making them unavailable • Anti- TNF-α agents have been successfully
for binding at their site of action on cells in the introduced into the treatment of inflammatory
body) diseases such as RA, juvenile idiopathic arthritis,
Clinical uses: psoriatic arthritis, psoriasis, Crohn’s disease,
• Digitoxin toxicity ulcerative colitis, ankylosing spondylitis, and
• Digitoxin overdose Behçet’s disease
Omalizumab Etanercept:
• Inhibits the binding of IgE to receptors on mast • Etanercept is made from the combination of two
cells and basophils, blocking the IgE-mediated naturally occurring soluble human 75-kilodalton
secretion of inflammatory mediators from these TNF receptors linked to an Fc portion of an IgG1
cells • The effect is an artificially engineered dimeric
Clinical uses: fusion protein (decoy receptor for TNF-α + IgG1
• Severe Asthma Fc)
• Chronic Urticaria • Clinical uses: Rheumatoid arthritis, psoriasis and
Palivizumab ankylosing spondylitis
• Binds to the fusion glycoprotein of RSV. This
prevents its binding and uptake by host cellular
receptors.
Clinical uses:
• Prophylaxis of respiratory diseases caused by
respiratory syncytial virus.

TNF alfa inhibitors

Overview:

180
Drug interaction: Toxicity:
• Drug-induced lupus • Cytokine release syndrome typically 45 min. after
Infliximab, adalimumab, certolizumab, golimumab injection
• They are monoclonal antibodies and have • Hypersensitivity reactions
identical structures and affinities to the target
• Infliximab, adalimumab and golimumab are
full IgG1 monoclonal antibodies against
human TNF-α.
• Infliximab is a chimeric mouse/human anti-
TNF-α. monoclonal antibody (mAb)
composed of a murine variable region and a
human IgG1 constant region.
• Adalimumab and golimumab are fully
humanized anti- TNF-α mAbs, which is
indistinguishable from the normal human
IgG1.
• Certolizumab is a Fab’ fragment of an anti- TNF-
α mAb and lacks the Fc portion. The hinge region
of certolizumab is covalently linked to 2 cross-
linked chains of a 20-kDa of poly- ethylene glycol,
which is named as certolizumab pegol
• MOA: Anti-TNF-α monoclonal antibody

Differences between Etanercept and other Anti-TNF-α

monoclonal antibody:

Muromonab
Mechanism of action:
• Blocks function of CD3 in T lymphocytes
(involved in Ag recognition & signal
transduction), resulting in a transient activation of
T cells, release of cytokines, and blocking of T-
cell proliferation and differentiation
Clinical use:
• Acute Allograft Rejection or Acute Graft-Vs-Host
Disease Treatment
• Cardiac or Hepatic Allograft Rejection, Steroid
Resistant

181
 Chapter 4:

Behavioral Sciences

182
Clinical Studies

Case Control Studies

• Study that compare 2 groups of people, those with a disease or condition under the study against a suitable
comparison group without the disease or condition
• Considered as retrospective study
• Very useful for studying conditions with very low incidence or prevalence
Examples
• Compares cases of treatment-resistant TB with those of nonresistant TB
• Patients with COPD had higher odds of a smoking history than those without COPD.
• A study trying to show that people who smoke (the attribute) are more likely to be diagnosed with lung cancer
(the outcome), the cases would be persons with lung cancer, the controls would be persons without lung cancer
(not necessarily healthy), and some of each group would be smokers. If a larger proportion of the cases smoke
than the controls, that suggests, but does not conclusively show, that the hypothesis is valid.

Cohort Studies

• Population group of those who have been exposed to risk factor is identified and followed over time and compared
with a group not exposed to the risk factor.
• Cohort studies can be retrospective (looking back in time, thus using existing data such as medical records or
claims database) and ask who develop the disease or prospective (requiring the collection of new data) and ask
who will develop the disease
• Can determine incidence and causal relationships and must follow population long enough for incidence to
appear.

Relative risk
• Comparative probability asking, “How much more likely?
• Done by calculating the IR of the exposed group divided by the IR of the unexposed group.
• How much greater chance does one group have of contracting the disease compared with the other group?
Cross sectional studies
• The presence or absence of disease (and other variables such as the frequency of the disease and frequency of
risk factors) are determined in each member of the study population or representative sample at a particular time
• Disease prevalence, not incidence, is recorded
• Can used to describe the absolute and relative risk
• The effect of hyperlipidemia (Risk factor) on coronary artery disease

183
Twin concordance study
• Compares the frequency with which both monozygotic twins vs both dizygotic twins develop the same disease.
• Study the importance of genetic and environmental factors on individuals Used to describes behavioral genetics
and psychology
• Measures heritability and influence of environmental factors (“nature vs nurture”).

Adoption Study
• Adoption studies are meant to evaluate genetic and environmental influences on phenotype.
• Typically used in combination with twin studies when making habitability estimates
• Compares siblings raised by biological vs adoptive parents.

Randomized controlled clinical trial

• Used to test the effectiveness of new treatment
• subjects are randomly allocated into “intervention” and “control” groups to receive or not receive an
an experimental/preventive/therapeutic procedure or intervention.
• The randomness in the assignment of subjects to groups reduces selection bias and allocation bias, balancing
both known and unknown prognostic factors, in the assignment of treatments

Cross over study

• A cross-over study is one in which, for ethical reasons, no group involved can remain untreated.
• Crossover designs are common for experiments in psychology, pharmaceutical science, and medicine.
• All subjects receive the intervention but at different times

Example:
• Group A receives X treatment for 3 months while group B is the control.
• For the second 3 months, group B receives X treatment and group A is the control.

Meta-analysis studies
• Meta-analysis is the statistical procedure for combining data from multiple studies.
• When the treatment effect (or effect size) is consistent from one study to the next, meta-analysis can be used to
identify this common effect.
• Compensate for poor research

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Clinical Trial
Definition
• Researchers design clinical trials to answer specific research questions related to a medical product including
drug safety and efficacy
• Clinical trials often conducted when bringing new drug into the market
• Clinical trials follow randomized controlled clinical trial (RCT) and it usually double blinded studies
• In this case the subjects are randomized into 2 groups “intervention or control group”
• Being double blinded to decrease any possible bias
• A control group (often the placebo group) will includes subjects who do not receive the drug under investigation
• The control group is used as a source of comparison to be certain the experiment group is being affected by the
intervention and not by other factors.
• For a medical product to receive approval by the Food and Drug Administration (FDA)

Phases of Clinical Trials

1. Preclinical trials
2. Request for new drug application to be tested in human
3. Phase 1 Studies
4. Phase 2 Studies
5. Phase 3 Studies
6. Submission of new drug application (Asking FDA to consider the drug for marketing approval
7. Phase 4 studies
Preclinical studies
• Studies are done on experimental animals or human cells to test for a prove of concept of a new target
• These studies tended to evaluate:
1. Drug pharmacodynamics in vivo and In vitro
2. Pharmacokinetics (Absorption, distribution and elimination)
3. Toxicity profile
4. Therapeutic index (Safety and efficacy evaluation)
• If the screening is successful, the agency will send a request for FDA asking for approval to start testing in
humans (Investigational New Drug Application IND)

Phase I
• The first trial to be conducted in human
• Used to test drug pharmacokinetics, dynamics and safety
• Performed in a small subject number (healthy volunteers)
• Used to test the maximum tolerated dose (MTD) of the new treatment
• Note: In some case Phase 0 might exit to perform micro dosing studies before starting phase I trial in healthy
subjects in order to get a preliminary data regarding pharmacokinetics

Phase II
• Named as Therapeutic exploratory trials
• Testing with a larger group of people (typically 100–300) to determine efficacy and to further evaluate its safety
• Usually performed against a placebo

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 • Aim to establish dose efficacy relationship, duration of therapy, frequency of administration and therapeutic
window
• Phase II clinical trials can de divided into

Phase IIa Phase IIb

• Early phase • Late phase
• 20-200 patients • 50-300 patients
• Comparison with standard drug • Comparison with a placebo or standard drug

Phase III
• Named as therapeutic confirmatory trial
• Performed on large groups of people 1000-3000 to confirm drug efficacy and monitor side effects
• To determine efficacy of the drug against already proved therapy
• Takes a long time up to 5 years
• If the drug shows efficacy in comparison of the already approved drugs the sponsor will send a request for FDA
to approve a new drug application

Phase IV
• Post-marketing studies delineate risks, benefits, and optimal use.
• Help to understand possible adverse effects and drug-drug interaction
• The objective of these studies to provide more assurance regarding safety and efficacy on a large population
during practice
• Figure out over dosing and the possibility of identifying new indications

Evaluation of diagnostic test (sensitivity)

Definition
• Diagnostic test: Medical test that provides some evidence for presence or absence of a pathology
• Four outcomes of a diagnostic test:
1. True positive (TP) If you order a test and comes positive for the disease
2. False positive (FP) The patient does not have the disease, but the test comes back positive
3. True negative (TN) If you order a test for a disease and comes negative for the disease (patient does not have the
disease)
4. False negative (FN) The patient has the disease, but the test comes negative
• Uses data of 2X2 table

Have the disease Don´t have the disease

+ TP FP
- FN TN

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Sensitivity (True positive rate) definition:
The proportion of people who test positive and have the disease
OR
The proportion of truly diseased persons in the screened population who are identified as diseased by the screening test
OR
The probability that the test detects a disease actually when the disease is there

• Named as rule out test because it rule out the disease

• Sensitivity = TP/ (TP+FN)
• True positives/ (True positives false negatives)
• High sensitivity means in case of a negative result indicates the absence of the disease

Problem based learning

200 patients are enrolled in a study to evaluate the accuracy of a new ELISA based test for influenza. 100 patients were
diagnosed with influenza by the reference standard culture of respiratory secretion. 80 of those patients with Influenza
had a positive ELISA based test as did 5 patients without Influenza. Calculate sensitivity?

• Total number of patients 200

Have influenza Don´t have influenza
+ 80 5
- 20 95
Total 100 100

• SN= 80/ 80+20= 80/100= 80%

• These values mean that from 100 patient have the disease the test was able to diagnose about 80 people with the
disease
• SN= 1-FN (0) = 1-0 =1
• Sensitivity test for low prevalence diseases
• A mnemonic for the clinical use of sensitivity is SN-N-OUT (sensitive test-negative-rules out disease).

Example adapted from Clinical tests: sensitivity and specificity. BJA education 2008

A test with 100% sensitivity correctly identifies all patients with the disease. A test with 80% sensitivity detects 80% of
patients with the disease (true positives) but 20% with the disease go undetected (false negatives). A high sensitivity is
clearly important where the test is used to identify a serious but treatable disease (e.g. cervical cancer). Screening the female
population by cervical smear testing is a sensitive test. However, it is not very specific and a high proportion of women with
a positive cervical smear who go on to have a colposcopy are ultimately found to have no underlying pathology.

Sensitivity and Specificity Graph

Overview

Gold standard

Have disease Don´t have disease

+ TP (True Positive) FP (False Positive) Positive predictive value

- FN (False Negative) TN (True Negative) Negative predictive value

Sensitivity Specificity

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Double Hump graph

• Cutoff point B has the highest sensitivity which correctly identifies all the sick patients
• Cutoff D would be the most specific test (it identifies only sick people).
• Cutoff C where the 2 curves intersect is the most accurate.

How to determine the best screening test

• Curve E achieves the highest sensitivity (y-axis) without including too many false-positives (x-axis).

Validity of screening test

• Sensitivity: The ability of a test to identify correctly those who have the disease or true positives.
• Specificity: the ability of a test to identify correctly those who do not have a disease or true negatives

Specificity

Specificity (True negative rate) definition:

• The proportion of all people without disease who test negative

OR
• The probability of correctly identifying disease-free persons.
• Used as a confirmatory test after a positive screening test
• SP= TN/(TN+FP)
• Measures only the distribution of persons who are disease-free
• If a test has a high specificity, then a positive result indicates the existence of the disease

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Problem based learning
200 patients are enrolled in a study to evaluate the accuracy of a new ELISA based test for influenza. 100 patients were
diagnosed with influenza by the reference standard culture of respiratory secretion. 80 of those patients with Influenza
had a positive ELISA based test as did 5 patients without Influenza. Calculate sensitivity?
• Total number of patients 200

Have influenza Don´t have influenza

+ 80 5
- 20 95
Total 100 100

• SP= 95/ 95+5= 95/100= 95% specific

• SP= 1-FP rate
• A test with a high sensitivity but low specificity results in many patients who are disease free being told of the
possibility that they have the disease and are then subject to further investigation
so If FP=0 the SP becomes 100 % that reduces the rate of false positive

Sensitivity VS Specificity

Positive and Negative Predictive values

Overview
• Predictive value reflects the diagnostic power of a test
• High PV+ indicates a strong chance that a person with a positive test has the disease
• High PV- means that a negative test in effect rules out the disease

Positive Predictive Value (PPV)

• What is the chance or the given the probability that given a positive test, the patient has the disease
• The probability of disease in a person who receives a positive test result.
• PPV measures only the distribution of persons who receive a positive test result.
Have disease Don´t have disease
+ TP FP
- FN TN

PVD= TP/(TP+FP)
• Positive predictive value focuses on subjects with a positive screening test in order to ask the probability of
disease for those subjects.

Problem based learning

200 patients are enrolled in a study to evaluate the accuracy of a new ELISA based test for influenza. 100 patients were
diagnosed with influenza by the reference standard culture of respiratory secretion. 80 of those patients with Influenza had
a positive ELISA based test as did 5 patients without Influenza

Influenza No Influenza
+ 80 5
- 20 95

PVD= 80/ (80+5) = 80/85= 94%

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 • Among those who had a positive screening test, the probability of disease was 94%

Negative Predictive Value (PPV)

• What is the chance or probability that a patient does not have the disease given a negative test
• NPV= TN/ (TN+FN) (True negative)/(True negative+ false negative)

Have disease Don´t have disease

+ TP FP
- FN TN

• Based on the previous example:

• Negative predictive value focuses on subjects with a negative screening test in order to ask the probability that
subjects with a negative test are truly not diseased.
Influenza No Influenza
+ 80 5
- 20 95

• NPV= 95/ (20+95) = 95/115=83%

• False negative rate= 20/ (20+95) =17%= 1-NPV
• Among those who had a negative screening test, the probability of being disease-free was 83%.

Calculating odds and risks

Definitions
• “Risk” refers to the probability of occurrence of an event or outcome. Statistically, risk = chance of the outcome
of interest/all possible outcomes.
• The term “odds” is often used instead of risk. “Odds” refers to the probability of occurrence of an
event/probability of the event not occurring

Exposure /risk factor Yes NO

Yes a b

c d
NO

• Exposure to risk factor might be:

1. Advantageous in case of treatment
2. Or Not: in case of carcinogens
• (A) means you got exposed so you get the disease
• Outcome Exposure
• Risk (exposed group) = a/(a+b)
• Risk (unexposed group) = c/(c+d)

Risk difference
Absolute Risk Reduction (ARR):
• when the risk of an outcome is decreased by the exposure OR reduction in incidence of associated with treatment
compared to the control group.
• ARR= Risk in the control group - Risk in the Treatment group.
• Example:
• In a study case, 5% of patients on statin had MI. 9% of those on placebo develop MI.
• One got exposed to statin and another to placebo and the outcome remains same- MI
• ARR = 9% - 5% = 4%
• Risk of MI is reduced by 4% in those who take statins.
• The incidence of MI is reduced by 4%.

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Attributable risk (AR):
• is the difference between the risk of an outcome in the exposed group and the unexposed group.
• AR = risk in exposed- risk in unexposed= a/(a+b) - c/(c+d)

Example:
9% exposed to asbestos- bronchogenic carcinoma
2% without exposure- bronchogenic carcinoma
AR = 9% - 2% = 7%

Number needed to treat (NNT):

• The Number Needed to Treat (NNT) is the number of patients you need to treat to prevent one additional bad
outcome (death, stroke, etc.).
• To calculate the NNT, you need to know the Absolute Risk Reduction (ARR); the NNT is the inverse of the
ARR: NNT= (1/ARR)

Example:
• Example if ARR of statin therapy is 4% so NNT = ¼% = 25
• We need to treat 25 people with statin to prevent MI in one patient.
• The smaller the number to treat the better the medication.

Number needed to harm (NNH):

• How many persons on average need to be exposed to a risk factor over a specific period to cause harm in an
average of one person who would not otherwise have been harmed.
• 1/Attributable risk = 1/0.02 = 50

Relative risk used in cohort studies

• The ratio of the probability of an outcome in an exposed group to the probability of an outcome in an unexposed
group.

• Risk ratio measures the association between the exposure and the outcome.

Examples
• 21% of smokers- lung cancer
• 1% non-smokers – lung cancer
• RR = 21%/ 1% =21
• Smokers are 21 times more likely to develop lung cancer than non-smokers.

• 50% of diabetic pts develop CVD

• 10% of control develop CVD
• RR= 50%/10% = 5
• Diabetics are 5 more times likely to develop CVD than the rest of the population.

Relative Risk Reduction (RRR)

• Is the relative decrease in the risk of an adverse event in the exposed group compared to an unexposed group

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Risk in unexposed-Risk in the exposed population
------------------------------------------------------------
Risk of unexposed

c/(c+d) - a/(a+b)
--------------------
c/(c+d)

Example
• 5% of pts on statins develop MI
• 9% pts on placebo develop MI
• RRR = 9 – 5/9= 4/9 = 0.44 or 44%

Odds ratio
• Used in case control studies
• Measure of association between an exposure and an outcome.
• Definition: the odds that an outcome will occur given a particular exposure, compared to the odds of the outcome
occurring in the absence of that exposure. OR
• Odds that group with diseases (cases) was exposed to a risk factor divided by the odss that the group w/o the
disease (control) was exposed.

• a = Number of exposed cases

• b = Number of exposed non-cases
• c = Number of unexposed cases
• d = Number of unexposed non-case

• OR > 1 = Increase likelihood of an event in exposed group

• OR <1 = Decrease likelihood
• OR = No difference between the exposed group & control group

Example:
• Researcher conducts a case-control study to determine risk of lymphoma due to CT scans. 100 people were
selected with Lymphoma, 180 people W/O lymphoma were selected as control. 5 patients with lymphoma had
received a CT scan at some point their life. 2 pts without lymphoma had received a CT scan. Calculate CT scan-

Lymphoma
a 5 b 2
CT scan
C 95 d 98

5 x 98 = 490/180 = 2.6
2 x 95

• Those who had CT scans are 2.6 more likely to develop lymphoma than those who were not exposed to CT
scans.

Incidence and Prevalence

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Incidence
• Measurement of the number of new individuals who contract a disease during a particular period of time.

Incidence rate=
Number of new cases in specific time period
Population at risk at this time period

• Used when working with infectious diseases such as TB and malaria

• Example: In a population of 5000 that is studied over 10 years 500 news cases of Ebola are reported. Hence
incidence rate = 500/5000= 10%

Prevalence
• Measurement of all individuals (new and old) affected by the disease at a particular time

Prevalence rate=
Number of existing cases
Population at risk

• 5000/50000= 10%

• Incidence rate is higher in acute diseases, while prevalence rate is greater than incidence rate in chronic
infectious diseases

Precision and accuracy

Precision VS Accuracy
• precision is the ability of a test to measure something consistently. Think of the clustering of rifle hots at a target
(reliability).
• Accuracy is the degree to which a test measures that which was intended known also as Validity

• Precision measures how close measurements are to each other

• Accuracy measures how close result is to the truth
• Random error  precision in a test.
•  precision lead to  standard deviation.
•  precision  statistical power (1 − β).
• Systematic error accuracy in a test.

Bias
Outline:

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Bias
• Deviation from the truth of inferred results Due to systematic error or favor particular direction
• Bias is a statistical term which means a systematic deviation from the true value.
• It is a sampling procedure that may show some serious problems for the researcher as it cannot be reduced by
mere increase in sample size.
• Bias is the difference between the expected value and real value of the parameter.

Types of Bias
Selection bias (Sampling bias)- Berkson bias
• Type of bias caused by choosing non-random data for statistical analysis
• Case-control studies are susceptible to selection bias, as both the exposure and disease/outcome have occurred by
the time the patient is recruited into the study
• In case control studies, selection bias can occur in the selection cases if they are not representative of all cases
within the population, or in the selection of controls if they are not representative of the population that produced
the cases
• They lack external validity.

Examples:
• Like you pay money to people who are low in their socioeconomic status and enroll them for study and then
collect data and try to generalize it on the rest of the population
• Heart disease being studied in a population that does not subjects above 65 years of age.
• Predicting rates of heart disease by gathering subjects from a local health club
• Using only hospital records to estimate population prevalence (Berkson bias)
• Including people in a study who are different from those who are not included (nonrespondent bias)
Solution:
• Random sampling should be done to eliminate sampling bias.
• Independent sample; weight data

Recall bias
• Subjects fail to accurately recall events in the past, that is going to influence the course of your study.
• Recall bias is a problem in studies that have self-reporting, such as case-control study and retrospective cohort
studies

Example
• Non-smokers with lung cancer report significant exposure to second-hand smoke as a child

Solution
• Conduct a prospective study or confirm objective sources of information.

Sampling bias
• Sampling bias occurs when a sample statistic does not accurately reflect the true value of the parameter in the
target population
• Sampling bias can also occur if sample is too small to represent the target population
• To ensure that a sample is representative of a population, sampling should be random, i.e. every subject needs to
have equal probability to be included in the study.
• In sampling bias, results in a biased sample, a non-random sample of a population (or non- human factors) in
which all individuals, or instances, were not equally likely to have been selected
• Medical sources sometimes refer to sampling bias as ascertainment bias.
• Ascertainment bias has basically the same definition, but is still sometimes classified as a separate type of bias

Late-look bias
• When there is late-look bias, individuals with severe disease are less likely to be uncovered in a survey because
they die fir it.
• Information that was gathered too late to make useful conclusions.

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 • Patients are severely incapable or dying during the study.
Example:
• Survey of patients with pancreatic cancer shows patients with minimal symptoms as they are too sick to respond,
or they die during the survey.
Solution
• Stratify by disease severity

Procedure bias (Experimental bias)

• A process where the scientists performing the research influence the results, in order to portray a certain outcome
• When patients or investigators decide on treatment assignment, can lead to extremely large biases.
• The investigator may consciously or subconsciously assign particular treatments to specific types of patients.
For example:
• One group of patients receives surgical intervention, however, the other group didn´t get any surgical
intervention
• Randomization is the primary design feature that removes this bias.
Attrition bias
• Systematic error caused by unequal loss of participants from a randomized controlled trial (RCT).
• Patients start to drop off during the study

Example 1:
• Study group for a drug to reduce acne, from 200, 120 pts drop off because the drug was not working.
• Remaining 80 of them find that the Drug is working in reducing their acne.

Example 2:
• in an intervention study of diet in people with depression, those with more severe depression might find it harder
to adhere to the diet regimen and therefore more likely to leave the study.

Solution
• Gather as much data from the patients who have dropped out.

Confounding bias
• A situation in which the effect or association between an exposure and outcome is distorted by the presence of
another variable
• Confounder: an extraneous variable that wholly or partially accounts for the observed effect of a risk factor on
disease status. The presence of a confounder can lead to inaccurate results.
Example 1
• Study done to find the link between the drinking coffee and lung cancer
• Usually drinking coffee is associated with heavy smokers, so smoking is considered a confounding variable
Example 2
• Compare the relationship between exercise and heart disease in 2 populations when one population is younger
and the other is older. Are differences in heart disease due to exercise or to age?
Example 3

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 • Pulmonary disease is more common in coal workers than the general population; however, people who work in
coal mines also smoke more frequently than the general population

Solution
• Multiple studies
• Matching
• Meta-analysis

Lead time bias

• Lead-time bias gives a false estimate of survival rates, e.g., patients seem to live longer with the disease after it is
uncovered by a screening test
• False impression of improved survival in a screened population without affecting mortality, because the cancer is
diagnosed earlier in the natural history of the disease, but the patient still dies of the cancer

Example
• At the age of 75 years a man came with back pain and was diagnosed of prostate cancer and died after about 5
years at the age of 80.
• If that man at the age of 60 underwent PSA test and found that the level was more than 24 and had undergone
treatment and died at the age of 80 after 20 years
• We conclude wrongly that it was because of PSA test the patient survived for another 20 years.

Solution
• Adjust survival based on the severity of the disease
• Use life-expectancy to assess benefit.

Observer expectancy effect

• Researcher’s belief in the efficacy of a treatment changes the outcome of that treatment (aka, Pygmalion effect)
• In research, experimenter bias occurs when experimenter expectancies regarding study results bias the research
outcome

Solution
• Use double-blind design, where neither the subject nor the investigators know which group receives the
intervention.
Hawthorne effect
• The bias that happens when people change their behavior during the study
• Is a type of reactivity in which individuals modify an aspect of their behavior in response to their awareness of
being observed.
Example
• You inform the patient that they are being given a drug to reduce BP and being studied for that. The patient
modifies his lifestyle so that the BP lowers.
Solution
• Add a placebo group.

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Susceptibility bias
• Type of selection bias where treatment regimen is selected for a patient based on the severity of their condition
without taking into account other possible confounding variables.
Example
• CAD patients managed surgically compared with the others who receive medical management.
Solution
• Randomize patients and place them both in medical and surgical arm of the study.

Statistical distribution

Definitions
• If you have a sample 1,1,2,4,5,7,7,25
• Mean: sum of the values of the observations divided by the numbers of observations, 52/8= 6.5
• Mode: most frequently occurring value in a set of observations 1,7

• Median: point on the scale which divides a group into 2 parts (upper and lower half); the measurement below
which half the observations fall is 50th percentile (4+5)/2= 9/2= 4.5

Normal bell curve (Gaussian curve)

• The peak of the curve corresponds to the mean of the dataset (note that the mean in the normal probability
distribution also equals the median and the mode).

Positive and Negative skew

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 • A positive skew has the tail to the right, and the mean greater than the median -MeanMedianMode
A negative skew has the tail to the left, and the median greater than the mean-MeanMedianMode.
Standard deviation
• Standard deviation: Average distance from the curve
• SD measures the variability within a single sample
• Example: sample set (1,2,3,4,5)
• Number= 5
• Mean= 3
• Standard deviation = (2+1+0+1+2)/5= 1.2

• When you are value 1 SDs from the mean 65%

• When you are value 2 SDs from the mean 95%
• When you are value 3 SDs from the mean 99%

Standard error
• Estimates the variability between samples
• The smaller the standard error, the better and more precise the study.
• The greater the SD, (high variation in the data), the greater the standard error, and the larger the sample size, the
smaller the standard error.

Standard error of mean (SEM)

• is a method used to estimate the standard deviation of a sampling distribution.

Statistical Hypothesis
Null Hypothesis
• The hypothesis of No association between two variables. No association between the risk and outcome.
• Null hypothesis justify that the findings are the result of chance or random factors
• The hypothesis says that observed difference is entirely due to sampling error
• Use to establish the basis for calculating the probability that the difference occurred purely of chance.

Alternative Hypothesis (H1)

• alternative hypothesis is one in which a difference (or an effect) between two or more variables is anticipated by
the researchers; that is, the observed pattern of the data is not due to a chance occurrence
• It is usually taken to be that the observations are the result of a real effects
H0 H1
H1 Power 1-B Alpha Type 1 error
H0 B Type 2 error Correct

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Example
• A study to compare the action of metronidazole with a placebo on giardia.
• Null hypothesis says no increased rate of resolution.
• Alternative hypothesis says the contrary.

Steps for testing a hypothesis:

1. A NULL HYPOTHESIS suitable to problem is set up

2. An alternate hypothesis is defined, if necessary.
3. A suitable statistical test, using a relevant formula is calculated.
4. The degree of freedom is determined.
• Then we determine P value:
• The p-value is a standard against which we compare our results.
• The probability value (P value) correspond to the calculated value of test and its degree of freedom
• If p ≤ 0.05, reject the null hypothesis (reached statistical significance).
• If p > 0.05, do not reject the null hypothesis (has not reached statistical significance).
Type I error ()
• Rejecting the null hypothesis when it’s really true
• Known as false alarm, type 1 error, false positive error
• Example: Use of Vitamin C improves the recovery of URT infection patients. Reality- it does not
• The chance of type I error is given by the p-value
• P 0.05 means there is less than 5% of chance that the data will show something that is not really there.
• Alpha = probability of making type 1 error
Type II error ()
• Failing to reject the null hypothesis when it is really false
• The chance of a type II error cannot be directly estimated from the p-value
• Known as false negative error, type 2 error
• There was a difference which you did not get.
• You missed the difference and you were blinded.
• Beta= Probability of making type 2 error.
•  is related to statistical power (1 – β), which is the probability of rejecting the null hypothesis when it false
• You can increase the power and decrease  value by:
•  Sample size
•  expected effect size
•  precision of measurement
Note:
• A type I error (error of commission) is generally considered worse than a type II error (error of omission)
• If the null hypothesis is rejected, there is no chance of a type II error.
• If the null hypothesis is not rejected, there is no chance of a type I error.

Core ethical principles

Patient autonomy
• The patient has the right to refuse or choose their treatment. Autonomy can be defined as the ability of the person
to make his or her own decisions.
• Autonomy can be defined as the ability of the person to make his or her own decisions
• Also, autonomy refers to obligation to respect patients as individuals (truth-telling, confidentiality)
• Patient autonomy does allow for health care providers to educate the patient but does not allow the health care
provider to make the decision for the patient
Beneficence
• Explain how physicians provide positive steps such as prevention, removal of harm to the patient
• Beneficence involves balancing the benefits of treatment against the risks and costs involved
Nonmaleficence
• Non-harming or inflicting the least harm possible to reach a beneficial outcome

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 • If a surgery or treatment procedure poses more harm than benefit to the patient, then it is better not to be done.
Justice
• The patients should be fairly and equitably treated
Informed consent
Overview:
• The process of communication between a patient and physician that results in the patient’s authorization of
agreement to undergo a specific medical intervention (American Medical Association)
• Failure to obtain informed consent renders any physician liable for negligence or battery and constitutes medical
malpractice.
When informed consent is required
• The patient must be informed in cases of surgery, anesthesia, other invasive or radiological procedure
• The patient should be able to understand and make a decision
• The patient should be able to understands the risk/ benefit for any procedure
• Benefits: Such as recovery time
• Risks: Inform the patient about all possible risks that the patient may have to face- like puncture of neighboring
carotid artery in this example. This may lead to increase bleeding. There are chances for pneumothorax.
• The patient should know the diagnosis if possible
• It is necessary to let the patient know the purpose of a proposed treatment or procedures
• The alternatives regardless of cost
• Indication of the procedure- Tell the patient why the procedure is being done.
• Nature of the procedure- the patient should be informed about the procedural steps.
Exceptions
• An emergency in which medical care is needed immediately to prevent serious or irreversible harm
• Incompetence in which someone is unable to give permission (or to refuse permission) for testing or treatment
• Waiver- Patient comes up personally and says that he does not want to know about the procedure and asks the
doctor to do what is best.
• Therapeutic privilege- If we tell something to the patient, he may commit suicide, so rather not tell him about it.
• Note: Patient cannot demand unnecessary treatment from the physician and the doctor cannot carry on with the
same treatment if it has failed already.

Consent for Minors

Overview
• The general rule is that minors are not capable of giving consent for medical treatment.
• As a result, the consent of a minor for medical treatment is ineffective, and the physician must secure the consent
of the minor’s parent or other person standing in loco parentis prior to treating the minor.
Minor
• A minor is generally any person < 18 years old.
Emancipated minors
1. When a minor is validly married;
2. When an individual reaches the age of 18 years;
3. During the period when the minor is on active duty with the armed forces
4. Self-supporting
5. Has children
Parental consent is not required for the following cases
6. Emergency situation
7. Prescribing oral contraceptives
8. Treating STDs
9. Medical care in pregnancy
10. Drug addiction
Decision-making capacity
Decision capacity
• The ability of health care subjects to make their own health care decisions.
• You must not assume that because a patient lacks capacity to make a decision on a particular occasion,

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 • Capacity is to use that information in making the decision – a person should be able to weigh up the pros and
cons of making the decision. Communicate their decision – if a person cannot communicate their decision – for
example, if they are in a coma – the Act specifies that they should be treated as if they lack capacity.
How to asses capacity?
• Understand the information relevant to the decision;
• Retain that information;
• Use or weigh up that information as part of the process of making the decision;
• Communicate their decision by talking, using sign language or other means of communication.

Components of decision-making capacity

• Decision is consistent with patient’s values and Goals
• Patient is Informed (knows and understands)
• Patient Expresses a choice
• Decision is not a result of altered Mental status (eg, delirium, psychosis, intoxication), Mood disorder
• Decision remains Stable over time
• Patient is ≥ 18 years of Age or otherwise legally emancipated
Confidentiality
• Confidentiality is the right of an individual to have personal, identifiable medical information kept private.
• Such information should be available only to the physician of record and other health care and insurance
personnel as necessary
Exceptions to patient confidentiality
• If there is a serious risk to the patient or another person
• Potential physical harm to others is serious and imminent
• Likelihood of harm to self is great
• No alternative means exist to warn or to protect those at risk
• Physicians can take steps to prevent harm
• Although physicians must always maintain confidentiality about their patients. Psychologists can (or must) break
confidentiality, and take other appropriate actions, as warranted, if:
1. You are a danger to yourself and threaten to harm yourself (e.g., suicidal).
2. You threaten to harm another specific person (e.g., assault, kill).
3. Children/ elderly abuse
4. Epileptic patients and other impaired automobile drivers.
5. Reportable diseases HIV, Syphilis, Chlamydia, (Anthrax, small box), Hepatitis A, B, C, Rabes, lymes and
tularemia
6. Preventable diseases Measles, mumps, rubella, varicella

Healthcare
Standard insurance
• The insurance company helps patient pay for health care in exchange for a periodic payment by patient
(premium) and patient shares in payment by means of Deductible, Copayment and Blue Cross Blue Shield
HMO health maintenance organization
• Limited insurance provider that provide medical care for fixed annual fee
• is a prepaid group practice that either hires physicians or contracts with physicians to provide services.
• Physicians are paid for the number of patients they are responsible for, not for how much they do for each patient
• Physicians make money when patients stay well and do not need to use services.
• HMOs often require members to select a primary care physician (PCP), a doctor who has a direct access to
medical services. PCPs are usually internists, pediatricians, family doctors, geriatricians, general practitioners
(GPs)

PPO Preferred provider organization

• Network of providers supply discounted treatment for plan members
• Its most common type of health plan
• The network includes physicians, hospitals with negotiated discounts
• PPO network of physicians no referral needed

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Government methods of payments for services
Medicare
• Program pays health care costs for the elderly (age >65), disabled, and dependents of disabled.
Types of Medicare
• Part A: pays for hospital care
• Part B: pays for physician services and basic medical bills (doctor´s fees, diagnostic testing)
• Part C: (parts A + B = Combo) delivered by approved private companies
• Part D: Prescription Drugs
• Everybody gets (A)but you have to opt for the others
Medicaid
• Medicaid payments to providers are generally far below standard fees (poor and immigrants)
• A joint state/federal program that covers all care, including hospital stays, physician services, medication, and
nursing homes
• If poor and over age 65, Medicare is first used, then Medicaid
Compensation
• Fee for service
• Overtreat is pitfall
• Capitation fixed amount of money per patient Regardless test, time, healthy patient
• Capitation is a payment arrangement for health care service providers.
• It pays a set amount for each enrolled person assigned to them, per period of time, whether or not that person
seeks care.

The role of human factor in health care

• Applying human factors to healthcare reduces medical errors and allows clinicians to deliver better care to their
patients and that helps in:
• Improve patient safety and satisfaction
• Standardization improves process reliability (eg, clinical pathways, guidelines, checklists).
• Reduce clinician burnout
• Simplification reduces wasteful activities (eg, consolidating electronic medical records).
• Boost process efficiency
• Mitigate the risk of error
PDSA cycle

• Is shorthand for testing a change by developing a plan to test the change (Plan), carrying out the test (Do),
observing and learning from the consequences (Study), and determining what modifications should be made to
the test (Act).
Quality measurements in health care
Outcome measures
• Measure impact on the patient such as mortality rates, readmissions rates, Average HbA1c of patients with
diabetes and surgical site infection rates
Balancing measures
• These are the metrics a health system must track to ensure an improvement in one area isn’t negatively impacting
another area (impact on other systems and outcomes)
• Example: Incidence of hypoglycemia among patients who tried an intervention to lower HbA1c
• Financing
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 • Patient satisfaction

Processing measures
• Performance of system as planned
• Example:
• Reducing time in registration or rooming the patient
• Percentage of diabetic patients whose HbA1c was measured in the past 6 months
Structural measures
• Used to assess infrastructure of capacity, systems, and processes (Physical equipment, resources, facilities).

Swiss cheese model

• The swiss cheese accident causation model is a theoretical model used in risk analysis, risk management, and risk
prevention.
• To explain the complex and layered health care system and how each healthcare workers could potentially
prevent (and cause) medication errors
• According to this model, a series of barriers are in place to prevent hazards from causing harm to humans.
However, each barrier, such as system alarms, administrative controls, surgeons, nurses, etc, has its unintended
and random weaknesses, or holes, just like Swiss cheese.
• The presence of holes in one of the slices does not normally lead to a bad outcome; but when by chance all holes
are aligned, the hazard reaches the patient and causes harm.

Types of medical errors

• The patient should be informed about any medical error might happen independent of immediate outcome
(harmful or not).

• There are many ways that medical care can go wrong. Errors can be related to the administration of medications,
adverse drug reactions, laboratory testing, surgery, and improper use or failure of medical devices
Active error
• Usually are human errors and involve individuals who are doing a task such as using the wrong IV pump dose
programmed and the effect felt almost immediately
Latent error
• Occurs in processes indirect from operator but impacts patient care (eg, different types of IV pumps used within
same hospital).

Medical error analysis

Retrospective approach: Applied after failure event to prevent recurrence.
Forward looking approach: Applied before process implementation to prevent failure occurrence.

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Public health

Disease prevention strategies

Primary prevention:

• Primary prevention seeks to prevent the onset of specific diseases via risk reduction by enhancing resistance to
the effects of exposure to a disease agent. HPV vaccination

Secondary prevention:
• Secondary prevention includes procedures that detect and treat preclinical pathological changes and thereby
control disease progression. Screening procedures are often the first step to manage existing but asymptomatic
disease (eg, Pap smear for cervical cancer)

Tertiary prevention:
• Tertiary prevention seeks to soften the impact caused by the disease on the patient's function, longevity, and
quality-of-life. Chemotherapy

Quaternary prevention:
• Action taken to identify patient at risk of over-medicalization, to protect him from new medical invasion, and to
suggest him interventions ethically acceptable. electronic sharing of patient records to avoid duplicating recent
imaging studies

Medicaid and Medicare

Medicaid Medicare
Federally funded program Federally funded program
Mainly benefits people who are  65 years or  63 but with Poor or low income
disability, end stage renal failure

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Preventive medicine and Healthcare

Outline:
• HMO is a health insurance plan with a very low and affordable premiums and copayments
• Policyholders are obligated to select their health care professionals from a list of approved health care providers
called PCP

HMO PPO

1. Requires a primary care provider (PCP) 1. There is flexibility in selecting physicians

2. Needs referrer from PLP he could see a specialist 2. No need a referrer to see specialist between the managed
3. Less expensive network
4. Smaller network 3. More expensive
5. Must use network 4. Larger network
6. Network is local 5. Can go off network
6. Can move around

Disease prevention strategies

Primary prevention:
• Primary prevention seeks to prevent the onset of specific diseases via risk reduction by enhancing resistance to
the effects of exposure to a disease agent. HPV vaccination
Secondary prevention:
• Secondary prevention includes procedures that detect and treat preclinical pathological changes and thereby
control disease progression. Screening procedures are often the first step to manage existing but asymptomatic
disease (eg, Pap smear for cervical cancer)
Tertiary prevention:
• Tertiary prevention seeks to soften the impact caused by the disease on the patient's function, longevity, and
quality-of-life. Chemotherapy

Quaternary prevention:
• Action taken to identify patient at risk of over-medicalization, to protect him from new medical invasion, and to
suggest him interventions ethically acceptable. electronic sharing of patient records to avoid duplicating recent
imaging studies.

Medical Malpractice
Definition
• Medical malpractice occurs when a physician fails to act as a reasonable physician would have acted under the
circumstances
• The negligence might be the result of errors in diagnosis, treatment, aftercare or health management.
• For medical malpractice to be established, the patient must be able to prove the presence of the four Ds, which
include negligence or deviation from the standard of care during medical practice by a physician.
• The four Ds of medical malpractice are:
• Duty to patient
• Derelict in Patient care negligence
• Direct cause
• Damages to patient

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 Chapter 5:

Basic Pathology

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Hypoxia

Tissue Hypoxia
The term hypoxia refers to decreased or inadequate oxygenation of a tissue. Anoxia is the complete lack of oxygen supply
to a tissue. The main causes of anoxia are high altitude, cardiac arrest and respiratory failure.
Relationship between PAO2, PaO2 and SaO2:

• Oxygen diffuses from the inspired atmospheric air to the alveoli, to the plasma and penetrates the RBCs to attach
to the heme groups inside hemoglobin, see Figure 1.
• Within the alveoli, oxygen content if increased would increase the partial pressure of oxygen PAO 2.
• When oxygen content within the alveoli is increased, more oxygen will dissolve into the plasma of the pulmonary
capillaries. This will increase the partial pressure of arterial oxygen PaO2.
• Once oxygen reaches the RBC, it will dissolve into the RBC’s membrane and attach to the heme groups. This will
increase the arterial oxygen saturation, known as SaO2.
• The relationship between PaO2 and SaO2 is quite easy to understand. Simply put, if PaO2 decreases, SaO2 will
always decrease.
• PaO2 and SaO2 can be easily measured and are reported in arterial blood gas analyses.
• Total oxygen content in the blood is equal to Hb concentration multiplied by SaO2 plus PaO2 multiplied by 0.0003.
Based on this, three clinically relevant conclusions can be made:
o Total oxygen content in the blood is positively correlated with Hb concentration, PaO2 and SaO2
o Any decrease in these three parameters would decrease total oxygen content in the blood
o Decreased oxygen content in the blood is the main drive for erythropoietin synthesis in the kidneys.

Figure 1: schematic view of gas exchange mechanism in alveolar-capillary interface. Source: Goljan Rapid Review
Pathology 5th edition.

Energy production and oxygen:

• Cellular production of ATP is largely dependent on the presence of oxygen

• ATP synthesis would be decreased in the case of hypoxia
• ATP synthesis occurs in the inner mitochondrial membrane by the process of oxidative phosphorylation
o The role of oxygen in this chain reaction is to receive an electron at the end of the electron transport chain
in complex IV of the oxidative pathway
Clinical presentation of hypoxia:

• Depending on the extent, severity, and speed of hypoxic injury patients can present with cyanosis, confusion,
anxiety, lethargy, tachycardia, tachypnea, seizures or coma
• Severe hypoxic injury can lead to death.
• Cyanosis is appreciable when SaO2 is below 80%
Pulse oximetry:

• A non-invasive tool to measure SaO2

• Accurate for patients without methemoglobinemia and carboxyhemolgobin “emitted wavelengths are suitable only
for normal hemoglobin”
o Presence of these abnormal hemoglobins can result in a false high SaO2
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 Co-oximeter devices emit different wavelengths and can differentiate between the different types of
o
hemoglobin. They will be more suitable in patients with methemoglobin or carboxyhemoglobin
• Pulse oximetry is useful in patients with respiratory failure, severe asthma, obstructive sleep apnea and in patients
under general anesthesia
• Can reliably measure SaO2 between 75% to 100%
Hemoglobin and hypoxic injury:

• Hemoglobin is the single most important factor in determining oxygen content in the blood
• It is also the main carrier of oxygen in the blood
• Anemic patients have low Hb concentration → decreased oxygen content in blood → decreased oxygen delivery
to tissues → hypoxia
• CO displaces oxygen from binding to hemoglobin → hypoxia
• Methemoglobin has low affinity for oxygen → decreased oxygen delivery to peripheral tissues → hypoxia
• Cyanide poisoning prevents extraction of oxygen by the tissue → venous oxygen content is higher than arterial
content
Partial arterial pressure of oxygen and hypoxic injury:

• Hypoxemia is the cause of decreased PaO2

• Oxygen diffusion from the capillaries to tissues is dependent on PaO2
• The arterial plasma has a higher oxygen concentration whereas the peripheral tissue has a lower oxygen
concentration. Therefore, oxygen diffuses from the plasma through the capillary wall into the tissue
Causes of Tissue Hypoxia:
Ischemia and hypoxemia:

• Ischemia is defined as decreased arterial blood flow to peripheral tissue or decreased outflow from that tissue.
Hypoxemia is a decrease in PaO2.
• Atherosclerosis, decreased cardiac output as in HF, and venous thrombosis are the main causes of ischemia
• Possible causes of hypoxemia include respiratory acidosis, decreased PiO2, ventilation perfusion defects,
hemoglobinopathies and other hemoglobin-related disorders
Ischemic injury consequences:

• Decreased perfusion of a tissue can results in atrophy, i.e. decreased cell count and tissue mass
• If ischemia is prolonged, infarction can occur. Infarction is defined as a localized area of tissue necrosis
• Oxygen is needed for many metabolic functions. Therefore, decreased oxygen delivery due to ischemia would lead
to organ dysfunction
Factors affecting PaO2:

• Percentage of oxygen in inspired air “decreased in high altitudes”

• Ventilation/perfusion matching
• Diffusion of oxygen from the alveoli into the pulmonary capillaries

Note: Any abnormality in these three factors would decrease PaO2 → hypoxemia → hypoxic injury

Respiratory acidosis:
Definition:
Carbon dioxide retention by the lungs due to hypoventilation causing an increased PaCO2 and a decreased PaO2.
Etiology: many but here are some common examples

• Respiratory depression due to depression of the CNS centers of respiration as in barbiturates use
• Paralysis of the diaphragm as in amyotrophic lateral sclerosis
• Chronic bronchitis
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Gas exchange parameters in respiratory acidosis:

• PACO2 which is partial pressure of CO2 in the alveoli is increased

• PAO2 which is partial pressure of O2 in the alveoli is decreased → both PaO2 and SaO2 will decrease
• PAO2 – PaO2 “A-a gradient” will remain normal
Decreased PiO2:

• PiO2 is the percentage of oxygen in inspired air

• It is decreased at high altitude and when breathing reduced %oxygen mist
• PAO2 will be low, as well as PaO2 and SaO2
• A-a gradient will be normal
Ventilation/perfusion defects as a cause of hypoxemia:

• Normal V/Q is equal to normal alveolar ventilation (4 liters per minute) / normal pulmonary blood flow (5 liters
per minute) = 0.8
• Ventilation defects are characterized by abnormal ventilation of alveoli that are normally perfused
o Extensive ventilation defects can produce intrapulmonary shunting of blood → PO2 and PCO2 in arterial
are venous blood are same
o Patients with ventilation defects tend to have a large disparity between PAO 2 and PaO2 → increased A-a
gradient
o Fraction of inspired oxygen FiO2 does not affect PaO2 in diffuse ventilation defects
• In pure perfusion defects, alveoli are ventilated but not perfused. Common causes include pulmonary venous
embolus or fat embolus.
o Increased pathologic dead space
o Dead space is defined as areas of the respiratory tract where oxygen and carbon dioxide exchange does
not occur. Physiologic dead space includes the nose, mouth, trachea up to the respiratory bronchioles
o In patients with pure perfusion defects, both PaO2 and PaCO2 are decreased
▪ Loss of oxygen exchange in non-perfused alveoli → low PaO2
▪ Patients breathing faster → loss of CO2 → low PaCO2
o A-a gradient is increased
o Increasing FiO2 can improve hypoxemia in patients with perfusion defects
Diffusion defects:

• Decreased diffusion of oxygen across the alveolar-capillary interface into the pulmonary capillaries
• A-a gradient will be increased
• Interstitial fibrosis and pulmonary edema are classical causes of diffusion defects
High altitude:

• At high altitude, atmospheric pressure is decreased, PiO2 is low, and PAO2 will be decreased
• Ventilation will be increased → increasing V/Q
• PaO2 will be decreased
• Because the subject will breath faster → clearance of CO2 → respiratory alkalosis
• Pulmonary blood flow will increase → increased pulmonary resistance → increased pulmonary artery pressure →
hypertrophy of the right ventricle
• 2,3-BPG concentration will increase → shifting of oxygen-hemoglobin dissociation curve to the right → decreased
affinity for oxygen
• Low PaO2 will increase synthesis of erythropoietin by the kidneys
Anemia as a cause of hypoxic injury:

• Anemia will typically lead to hypoxic injury but not hypoxemia because PaO2 will remain normal
• Anemia is defined as the decrease in hemoglobin concentration in the peripheral blood. Total oxygen content is
decreased in anemia.
• Iron deficiency, increased erythrocyte destruction/hemolysis, decreased production of RBCs, or increased RBCs
sequestration are the main causes of anemia. Anemia is further discussed in Hematology section
• Because PaO2 and SaO2 are normal, you would expect the A-a gradient to be normal.

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Methemoglobinemia:

• Presence of oxidized heme groups (Fe3+ instead of Fe2+).

• Fe3+ is converted to Fe2+ by the action of NADH reductase system in the glycolytic pathway in RBCs
• This pathway is immature in newborns → increased risk of methemoglobinemia
Possible causes of methemoglobinemia:

• Oxidants like nitrite and sulfur containing drugs

• Exposure to fertilizing agents containing nitrates
• Sepsis
Hypoxia in methemoglobinemia:

• PaO2 is normal and A-a gradient will be normal

• Methemoglobin cannot bind oxygen → decreased SaO2 → decreased oxygen content in the blood
• Methemoglobin shifts the oxygen-hemoglobin dissociation curve to the left
Clinical presentation:

• Cyanosis can be seen even at low levels of methemoglobin (< 20%)

• Patients may develop headache, anxiety, dyspnea, tachycardia
• Confusion, lethargy, and lactic acidosis are seen in patients with a methemoglobin level above 40%
• Chocolate colored blood due to increased concentration of deoxyhemoglobin
• Treatment is methylene blue → increases activity of NADH reductase
• Exchange transfusion and hyperbaric oxygen treatment are indicated for unresponsive patients or those who cannot
tolerate methylene blue such as G6PD deficient patients
CO poisoning:

• CO poisoning can occur in patients who use gas heating systems, smokers, or those doing a barbeque indoors
without adequate ventilation
• While PaO2 will be normal, SaO2 will be reduced in a patient with CO poisoning
• CO binds to hemoglobin much stronger than oxygen (100 times stronger). Therefore, heme will not have vacancy
for oxygen to bind and total oxygen content will be decreased → decreased oxygen delivery to peripheral tissues
→ hypoxic injury
• One of the earliest signs of CO poisoning is headache
• Late presentation is characterized by cherry red color skin
ATP and Mitochondrial Pathologies
• Patients with decreased ATP production by the oxidative pathway might develop lactic acidosis due to glycolysis
• The Na/K pump will be disrupted because it is ATP dependent → Na accumulation inside the cell → Na drags
water with it → cellular swelling
• The Ca pump will also be disrupted if ATP production is impaired → calcium accumulation inside the cell →
activation of several enzymes and induction of apoptosis
Reversible cell injury due to low ATP production:

• Cell swelling, loss of microvilli, and membrane blebbing is seen

• The rough endoplasmic reticulum will be swollen → impaired ribosomes → impaired protein synthesis
Irreversible cell injury due to low ATP production:

• If ATP production is not rescued → apoptosis

• The damaged cell will leak intracellular enzymes → elevated liver enzymes in hepatitis or elevated troponins in
MI are classical examples
Mechanism of apoptosis in low ATP state:

• Leakage of cytochrome C from the mitochondria into the cytosol → induction of apoptosis
• Activation of lysosomal enzymes by the increased intracellular calcium → destruction of cell membrane and cell
digestion

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Specific Tissues Susceptible to Hypoxic Injury
Common causes of ischemia:

• Atherosclerosis
• Decreased venous drainage as in testicular torsion and Budd-Chiari syndrome
• Shock
Shock:

• Shock is defined as the decreased perfusion of a vital organ. The main types of shock are hypovolemic, cardiogenic,
septic, neurogenic and anaphylactic
• Hemorrhagic is a specific type of hypovolemic shock
Budd-Chiari syndrome:

• Caused by the blockade of the hepatic vein → results in hepatic infarction

• The most common causes of the blockade of the hepatic vein are:
o Polycythemia vera
o Any condition that may result in a hypercoagulable state
Ischemic brain injury:

• Most commonly affected areas are the watershed or border zones

• These areas receive blood supply from distal branches of two arteries and have limited collaterals
• They are likely to be affected in generalized hypoperfusion states as in shock
• Embolic or thrombotic ischemic brain injury typically affects the anterior, middle or cerebral arteries territories
• Neurons are most vulnerable to hypoxic-ischemic injury (cannot last without oxygen for more than three to four
minutes)
• At the cellular level, the following cells are more likely to be affected in ischemic brain injury:
o Purkinje cells of the cerebellum
o Pyramidal cells of the hippocampus
o Pyramidal cells in cortical zones 3, 5 and 6
Ischemic heart injury:

• The sub-endocardium is not well perfused in comparison to the outer layers of the heart
• Early ischemic heart injury typically affects the sub-endocardium resulting in unstable angina or NSTEMI
GI tract ischemic injury:

• The area around the central vein in the liver (Zone III) is more susceptible to ischemic injury than other areas of
the liver
• The splenic flexure of the colon and rectum are more likely to undergo ischemic injury
Cell Death

Apoptosis:
Definition:
Apoptosis is an energy dependent process where purposeful death of a small group of cells occur. Apoptosis can be
physiologic as with endometrial shredding during menstruation, or pathologic. The cell and nucleus shrink and fragment
resulting in apoptotic bodies. These apoptotic bodies are then engulfed and cleared by macrophages, however without
causing an inflammatory response. During this process, the cell becomes eosinophilic whereas the nucleus becomes
basophilic.
Pyknosis:

• This is the first step in the breakdown of the nucleus in apoptosis

• The nucleus shrinks and DNA condenses into shrunken basophilic mass
Karyorrhexis:

• The second step in the breakdown of the nucleus

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 • The nucleus gets fragmented
• Nuclear membrane ruptures
Karyolysis:

• This is the last step in nuclear breakdown

• The nucleus fades and chromatin dissolute
• DNAses and RNAses breakdown nucleic acids and the nucleus is broken down to molecular building blocks
(laddering of DNA into fragments in multiples of 180 bp)
• The cell now becomes anuclear necrotic cell
Biochemical pathway of apoptosis:

• Caspase activation is required for apoptosis to occur

• Caspase is needed to activate the proteases that break down the cytoskeleton
• Caspase is also responsible for the activation of endonucleases which break down the nucleus
• The activation of caspase is achieved by three main pathways:
o The intrinsic mitochondrial pathway
o The extrinsic receptor-ligand pathway
o The cytotoxic CD8+ T-cell mediated pathway which is in fact part of the extrinsic receptor-ligand
pathway
The intrinsic mitochondrial pathway:

• Important for tissue remodeling during embryogenesis

• The main trigger is the withdrawal of a regulating factor
• Also important for the regulation of cellular immune responses:
o Decreased IL-2 → apoptosis of proliferating effector immune cells
• Exposure to radiation, toxins or hypoxia can also induce apoptosis by this pathway
• Regulated by the Bcl-2 family of proteins, namely BAX, BAK, Bcl-2 and Bcl-xL.
BAX and BAK:

• These proteins are responsible for the formation of pores in the mitochondrial membrane
• This leads to leakage of cytochrome C from the mitochondrial membrane into the cytoplasm
• Cytochrome C activates caspases to induce apoptosis
Bcl-2 and Bcl-xL:

• These are antiapoptotic proteins

• They preserve the mitochondrial membrane and make it impermeable to cytochrome C
• As these are antiapoptotic, activating mutations of these genes can result in carcinogenesis:
o Bcl-2 mutation is implicated in the overexpression of this protein which is seen in follicular lymphoma
with translocation 14;18
o Decreased caspase activation
o Cells gain immortality
o Development of lymphoma
Extrinsic receptor-ligand pathway:

• A ligand binds to its receptors → activation of caspase → apoptosis

• Classical examples include FasL binding to Fas (CD95) receptor or TNF-alpha binding to its receptor
• This pathway is important for normal thymic development → Fas-FasL interaction is needed for medullary
negative selection in the thymus:
o Mutations in Fas receptor are responsible for autoimmunity because of the increased circulation of self-
reacting lymphocytes
o Associated with autoimmune lymphoproliferative syndrome
Cytotoxic CD8+ T-cell pathway:

• Recognition of foreign antigens presented on MHC-I on target cell by CD8+ T-cell

• Release of perforins from the cytotoxic T-cell → formation of holes in target cells

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 • The next step is to release granzyme by the cytotoxic T-cell → granzyme activates caspases → induction of
apoptosis of target cell
Necrosis:
Definition:
Necrosis is cell death mediated by acute inflammation. Necrosis involves a large group of cells, unlike apoptosis which
involves a small number of cells. Necrosis can only be pathologic.
Coagulative necrosis:

• Most tissues, when they undergo ischemic injury, a coagulative infarct occurs
• Ischemia → denaturation of enzymes → blockade of proteolysis
• Cellular architecture is preserved whereas nuclei disappear
• Increased binding of eosin stain in necrotic tissues → eosinophilia

Figure 2: Coagulative necrosis on gross pathology and histology. Source:

https://en.wikipedia.org/wiki/Coagulative_necrosis#/media/File:Histopathology_of_a_pheochromocytoma_with_coagulati
ve_necrosis,_annotated.jpg

Liquefactive necrosis:

• Ischemic injury or infarcts of the brain are liquefactive

• Bacterial abscesses in any tissue are also liquefactive
• The liquefication of the infarcted tissue occurs secondary to the release of lysosomal digestive enzymes by
recruited neutrophils
• In early stages, histology shows cellular debris and macrophages
• Later on, neutrophils are seen.
• Cystic spaces and cavitation are a hallmark of liquefactive necrosis in the brain
Caseous necrosis:

• This type of tissue necrosis is seen with tuberculosis, systemic fungal infections such as histoplasma capsulatum,
and nocardia
• The main trigger of this type of necrosis is the recruitment of macrophages which wall off the infecting
microorganisms
• Granuloma formation

Figure 2: Caseous necrosis in a lymph node due to tuberculosis. Source:

https://en.wikipedia.org/wiki/Caseous_necrosis#/media/File:Tuberculous_lymph_node_with_caseating_granuloma_40X.j
pg

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Fat necrosis:

• Most commonly is due to nonenzymatic traumatic injury to fatty tissues such as to the breast
• Enzymatic mechanisms of fat necrosis include acute pancreatitis → leakage of pancreatic enzymes →
saponification of peripancreatic fat → fat necrosis
o Lipase breaks down triglycerides → free fatty acids can bind to calcium → saponification
• As expected, the nuclei will disappear. You will see dead fat cells without nuclei
• Combined calcium to fatty tissue appears dark blue on H&E stain

Figure 3: Fat necrosis shown in a breast lump. Source:

https://en.wikipedia.org/wiki/Fat_necrosis#/media/File:Breast_tissue_showing_fat_necrosis_4X.jpg

Fibrinoid necrosis:

• Mainly seen in necrosis of blood vessels

• Can be immune mediated as in polyarteritis nodosa or non-immune mediated as with hypertensive emergencies or
preeclampsia
• Immune-mediated fibrinoid necrosis is characterized by the following:
o Immune complex deposition
o Type III hypersensitivity reaction
o Leakage of plasma proteins including fibrin →fibrinoid necrosis from the damaged vessel
• Histologic examination shows thickened and pink vessel walls

Figure 4: Fibrinoid necrosis in a patient with vasculitis. Source:

https://en.wikipedia.org/wiki/Fibrinoid_necrosis#/media/File:Churg-Strauss_syndrome_-_high_mag.jpg

Gangrenous necrosis:

• Can be seen in necrosis of limbs or gastrointestinal tract

• Often seen after chronic ischemia
• If necrosis is solely due to ischemia → dry gangrene
• Superinfection → wet gangrene
• Histologic examination shows coagulative necrosis in dry gangrene and liquefactive on coagulative background in
wet gangrene

Figure 5: Gangrene of the first four toes of the right foot in a patient with diabetes mellitus. Source:
https://en.wikipedia.org/wiki/Gangrene#/media/File:GangreneFoot.JPG

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Infarction
• Venous occlusion can lead to ischemia. The type of infarction seen in that case is described as red infarction
• Tissues with multiple blood supplies such as the liver, lung, intestine, or testes when become ischemic, the
infarct is usually red
• Reperfusion injury is characterized by red infarction as well
• Solid organs with a single arterial blood supply such as the heart or kidneys undergo pale infarction after the
occlusion of the main blood vessel supplying the tissue.
Free Radical Injury

Overview:
Reactive oxygen species (ROS) refers to a class of endogenous highly reactive oxygen and nitrogen bearing molecules. They
can damage cells via membrane lipid peroxidation, protein modification, or DNA breakage.

Sources of Free Radicals:

Endogenous:

• Mitochondria, peroxisomes, lipoxygenases, NADPH oxidase and cytochrome P450 are the main sources of
endogenous ROS
• Metabolism of drugs, redox reactions, and cellular inflammatory responses may cause endogenous pathways to
generate ROS
Exogenous:

• Ultraviolet light or ionizing radiation exposure, exposure to chemotherapeutics, inflammatory cytokines and
environmental toxins are possible causes of exogenous ROS
Antioxidant defences:

• Enzymatic systems including catalase, superoxide dismutase, and glutathione peroxidase eliminate free radicals
• Many of the ROS have a short-half life and can self-decay
• Non-enzymatic mechanisms of scavenging of ROS include glutathione and the antioxidant vitamins A, C and E
• Metal carrier proteins such as transferrin for iron and ceruloplasmin for copper are also antioxidants
Pathogenesis:
• For normal growth and metabolism to occur, a state of homeostasis is needed
• High oxidative stress is associated with random cellular damage or specific signalling pathways activation. This
can lead to cellular ageing, development of certain diseases such as cancer, or apoptosis
• Decreased generation of ROS as is seen in some hereditary immune disorders is characterized by decreased
proliferative responses and defective host defences against microorganisms
Oxygen toxicity:
Prematurity is associated with increased oxidative stress → retinopathy of prematurity and abnormal retinal
vascularization. Bronchopulmonary dysplasia is also associated with increased exposure to oxygen. Reperfusion injury is a
classical example of oxygen toxicity.
Chemotherapeutic toxicity:

• Many drugs can cause oxidative injury for example acetaminophen overdose → hepatotoxicity
• Carbon tetrachloride toxicity:
o Carbon tetrachloride is converted to CCl3 free radical by cytochrome P450
o CCl3 decreases apolipoprotein synthesis → fatty liver and centrilobular necrosis
Metal storage diseases:

• Iron overload in hemochromatosis

• Copper overload in Wilson disease

Pathologic Calcifications
Dystrophic Calcification

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Definition:
This is one mechanism of calcium deposition in the human body and is considered as pathological. The process starts when
there is dead tissue where calcium accumulates despite having normocalcemia. Fat necrosis typically undergoes dystrophic
calcification.
Etiology:
• Trauma, inflammation, varicose veins, necrosis of tumors, infections, and connective tissue diseases may cause
dystrophic calcification
Epidemiology:
• This is the most common type of calcinosis cutis
• 25 to 40% of patients with systemic sclerosis especially CREST may develop calcinosis cutis
• Other associated diseases include dermatomyositis and systemic lupus erythematosus
Pathophysiology:
• Tissue damage → release of phosphate-binding proteins by dying cells → binding of phosphate → deposition of
calcium and development of dystrophic calcification
• Tissue damage leads to chronic inflammation and vascular hypoxia
• TNF, IL-6 and IL-1B contribute to the formation of calcium salts
• Mainly hydroxyapatite and amorphous calcium phosphate
• Histopathology reveals dark blue depositions with hematoxylin and eosin stain or black deposition with von Kossa
stain
Clinical findings:
• Calcifications grow slowly and are usually asymptomatic
• If they are painful → functional impairment
• In systemic sclerosis, most commonly affected sites are forearms, elbows, fingers and knees
• The extremities, buttocks, and underneath lupus lesions are the most common sites of dystrophic calcification in
SLE
Diagnosis:
• Laboratory testing and imaging studies are tailored to find the etiology of dystrophic calcification
• In dystrophic calcification you expect serum phosphate and calcium levels to be normal
Treatment:
• Treatment is difficult so focus should be made on avoiding trauma, smoking cessation, decreasing stress and
exposure to cold
• Smaller calcific lesions respond to warfarin, ceftriaxone, and intravenous immunoglobulin
• Diltiazem at high doses decreases the amount of calcium that enters cells and macrophages of damaged tissues and
is useful in the treatment of dystrophic calcification

Metastatic Calcification
Definition:
Metastatic calcification is defined as the deposition of calcium salts in the presence of an abnormal serum calcium and
phosphate levels. Calcium phosphate product needs to be higher than 70 mg2/dL2 for metastatic calcification to occur.
Etiology:
• The most common cause os chronic kidney failure
• Hypervitaminosis D, hyperparathyroidism, sarcoidosis, milk-alkali syndrome and malignant neoplasms are other
common causes
• Milk-alkali syndrome occurs after the excessive ingestion of foods or antacids that contain calcium
Epidemiology:
• Less common than dystrophic calcification
• Does not always mean that the patient has metastatic cancer
Pathophysiology:
• Lesions are usually located in periarticular regions
Clinical findings:
• Calcific lesions in periarticular regions
Diagnosis:
• Calcium and phosphate levels are elevated
• Serum creatinine level might be elevated in patients with CKD

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 • Malignant neoplasms need to be excluded
Treatment:
• Treatment of the etiology is needed
• Similar to dystrophic calcification, metastatic calcification might respond to diltiazem, warfarin, bisphosphonates,
or ceftriaxone

Growth Adaptations

Hypertrophy:
It is defined as a condition in which non-dividing cells such as muscle cells gain more mass excessive to their capacity.
There is no increase in the number of cells or fibers in the tissue, but the overall size of the organ or structure enlarges.
Physiologic hypertrophy is seen in the muscles of bodybuilders and in the pregnant uterus. The main mediator of muscle
hypertrophy is insulin-like growth factor-1.

• Usually occurs concurrently with hyperplasia

• Pure hypertrophy is usually not a risk factor for malignancy
Hyperplasia:
Hyperplasia is defined as an increase in the number of cells in the tissue. The cells divide rapidly increasing in number and
the overall size of the structure is increased. It can be physiological or pathological.

• Physiological hyperplasia is seen again in the pregnant uterus

• Pathological hyperplasia is seen in benign conditions such as benign prostatic hyperplasia or in potentially
malignant diseases
• Pathological hyperplasia may progress to dysplasia and cancer except benign prostatic hyperplasia
Atrophy:
This is the opposite of hypertrophy wherein the cells start to shrink in size leading to a decrease in the overall size of the
tissue or organ. Can also occur due to a decrease in cell number “apoptosis”.

• Physiological atrophy is seen in the thymus after mid-adulthood

• Disuse atrophy is used for conditions where atrophy takes place in a specific tissue after prolonged disuse
• The cell size decreases by an overall loss of cell organelles, proteins and cytoplasm. This is mediated by a
uniquitin-proteosome degradation mechanism
Metaplasia:
In here, there is a change in the cellular identity by a replacement of one type of healthy cells with other healthy cells in a
tissue or organ. It is triggered by an abnormal stress or inducer. A common example is the metaplasia of the lower
esophagus due to chronic gastroesophageal reflux.

• Mostly affects the surface epithelium

• Reversible
• Can progress to dysplasia and cancer except apocrine metaplasia which does not increase the risk of breast
cancer
• Keratomalacia and myositis ossificans are other examples of metaplasia and are caused by vitamin A deficiency
• Mesenchymal tissues can also undergo metaplasia
Dysplasia:
Dysplasia is a condition where abnormal arrangement of cells takes place due to a change in their usual growth behavior.
This means that there is disordered cell growth and proliferation of precancerous cells.

• Examples include cervical intraepithelial neoplasia

• Longstanding hyperplasia or metaplasia may lead to dysplasia
• Reversible
• If dysplasia persists it can progress to cancer

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Amyloidosis

Systemic Amyloidosis
Definition:
Amyloidosis is the deposition of misfolded proteins in the extracellular space. This causes tissue damage. Amyloid is a
misfolded protein that has beta-sheet arrangement. They appear apple-green under polarized light and stain red with congo
red stain.
Systemic primary amyloidosis:
Immunoglobulin light chain deposition systemically in the form of AL amyloid. It is associated with plasma cell dyscrasias
(diseases) in which plasma cells make large amounts of light chains which then deposit in different organs resulting in end-
organ damage.

• Damaged organs need to be excised and transplanted when possible.

• There is no cure for systemic amyloidosis
Systemic secondary amyloidosis:

• SAA protein systemic deposition in the form of AA amyloid

• SAA is an acute phase reactant → increased in chronic inflammatory states, malignancies and familial
Mediterranean fever.
Familial Mediterranean fever:

• A genetic disease with dysfunction of neutrophils

• Results in secondary systemic amyloidosis
• Seen in patients of Mediterranean origin
• Elevated SAA → deposition of AA amyloid
• Patients typically present with episodes of acute fever, serosal inflammation and symptoms and signs suggestive
of acute appendicitis

Note: Patients with familial Mediterranean fever can develop acute inflammation of the serosal
lining of the heart which can mimic MI.

Clinical findings in systemic amyloidosis:

The symptoms and signs of systemic amyloidosis do not differ much regardless if it is primary or secondary:

• Nephrotic syndrome is seen when the kidneys are involved

o The kidneys are the most commonly involved organs in systemic amyloidosis
• Restrictive cardiomyopathy
• Arrhythmias
• Hepatomegaly
• Enlarged tongue
• Malabsorption
Diagnosis of systemic amyloidosis:

• A tissue biopsy is needed, and the diagnosis is often delayed

• The most commonly biopsied organs are the rectum and abdominal fat pads
• Amyloid is congo-red positive
Localized Amyloidosis
Definition:
Deposition of misfolded protein “amyloid” in a single organ “localized”.

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Senile cardiac amyloidosis:

• An acquired type of local amyloidosis

• Deposition of non-mutated serum transthyretin in the heart
• Transthyretin is abundant in the blood “second most common protein found in the blood”
• Usually asymptomatic
• Seen in more than a quarter of people older than 80 years
Familial amyloid cardiomyopathy:

• A familial type of localized amyloidosis

• Deposition of mutated serum transthyretin in the heart
• Results in restrictive cardiomyopathy
• Seen in African Americans
• 5% of African Americans carry this mutation
Type 2 diabetes mellitus associated amyloidosis:

• Insulin resistance → hyperinsulinemia → overproduction of byproduct amylin → deposition of amylin in the islets
of the pancreas causing amyloidosis
• Eventually, the islets of the pancreas are destroyed, and the patient becomes insulin dependent
Alzheimer’s disease associated amyloidosis:

• Beta-amyloid precursor protein (BAPP) on chromosome 21 encodes for misfolded AB amyloid plaques
• Deposition of AB amyloid plaques in the brain “cortical and subcortical depositions” → development of AD
• Nuclear imaging can confirm the presence of AB amyloid plaques in patients with cognitive decline to increase
the certainty of the diagnosis of AD
• Patients with Down syndrome “trisomy 21” are at an increased risk of developing AD “most patients have AD by
the age of 40 years”
Dialysis-associated amyloidosis:

• Typically affects the joints

• Beta2 microglobulin isn’t filtered from the blood in patients on dialysis
• Deposition of beta2 microglobulin results in joint amyloidosis

Note: beta2 microglobulin is a protein needed for the support of MHC-1 on cell surfaces.

Medullary thyroid cancer and localized amyloidosis:

• Overproduction of calcitonin in medullary thyroid cancer → formation of calcitonin amyloid plaques in the
thyroid
• On fine-need aspiration, presence of tumor cells in an amyloid background increases the probability of medullary
thyroid cancer

Acute Inflammation

Definition
Inflammation is the process of recruiting inflammatory cells and plasma proteins into the interstitial space.

• Acute inflammation is characterized by edema and neutrophils in tissue

• Acute inflammation can be seen post-infection or necrosis
• Necrosis will always lead to acute inflammation
• The main goal of the acute inflammatory response is to clear the pathogens causing the infection or to remove
necrotic debris
• Acute inflammation is part of the innate immune response

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Toll-like receptors:

• Present on cells of innate immune system namely macrophages and dendritic cells
• Also present in adaptive immune system cells
• TLR recognizes pathogen-associated molecular patterns and damage-associated molecular patterns
• For example: CD14 or TLR4 is a TLR on macrophages that recognizes LPS on gram negative bacteria
• When TLRs are bound to their ligand, NF-KB is upregulated → activation of acute inflammation
• Activation of TLRs also result in the release of type 1 interferons such as alpha and beta interferons which inhibit
viral replication within cells
Arachidonic Acid Metabolism
Metabolism of arachidonic acid (AA):

• AA is released from the phospholipid layer of the cell by the action of phospholipase A2
• AA is metabolized by cyclooxygenase or 5-lipooxygenase pathways to produce prostaglandins and leukotrienes
respectively
• Prostaglandins (PGI2, PGD2 and PGE2) increase vascular permeability and cause vasodilation:
o Vasodilation increases the temperature of the end-organ and causes erythema “warmth and erythema
are two of the cardinal signs of inflammation”
o Vasodilation occurs at the arteriole level
o Increased vascular permeability occurs at the postcapillary venule level → results in edema another
cardinal sign of inflammation
o NSAIDs and COX-2 inhibitors inhibit the synthesis of prostaglandins, decreasing inflammation
o PGE2 mediates fever and pain the other two cardinal signs of acute inflammation
• Leukotrienes include LTB4, LTC4, LTD4 and LTE4
o LTB4 attracts and activates neutrophils, the main immune cell involved with acute inflammation
o Other leukotrienes mediate smooth muscle cell contraction causing vasoconstriction and bronchospasm
“involved in the pathogenesis of asthma”
o Leukotrienes increase vascular permeability by causing contraction of pericytes → opening space
between cells
Neutrophils and Mast Cells:
Neutrophil attraction and activation in acute inflammation:

• LTB4 which is a leukotriene attracts and activates neutrophils

• Interleukin 8 activates macrophages which attract neutrophils
• Bacterial products “toxins” can also attract neutrophils
• Tumor necrosis factor and IL1 can also attract and activate neutrophils
• C5A from the complement pathway can attract and activate neutrophils as well
Mast cells:

• Mast cells are also involved with acute inflammatory responses

• They are found in all connective tissues of the body
• They can be activated by tissue trauma, complement proteins C3a and C5a, and cross linking of cell surface IgE
with an antigen
o Cross-linkage occurs when two or more IgE on a mast cell binds the same antigen
o Involved with atopic asthma
• When activated, they release histamine which causes vasodilation and increases vascular permeability
• They are also capable of releasing proteolytic enzymes which can kill bacteria or inactivate bacterial toxins

Note: Mast cells activation has a delayed response which is characterized by the release of
arachidonic acid metabolites including leukotrienes. Because of this, we have a class of asthma
drugs that act as mast cell stabilizers.

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Complement System:
Activation of the complement system:

• The complement system can be activated by three main pathways

• The classic pathway:
o IgG or IgM binds to an antigen
o C1 binds to antigen-bound-IgG or IgM
• The alternative pathway:
o Activation of the complement system is achieved by the direct action of microbial products
• The mannose binding lectin (MBL) pathway:
o MBL binds to mannose which is found on microorganisms
o The bound MBL then activates the complement system
• C3a and C5a activate mast cells causing degranulation and release of histamine
• C5a attracts neutrophils
• C3b is an opsonin which mark cells and pathogens for phagocytosis
The membrane attack complex:

• C3 is converted to C3a and C3b by C3 convertase

• C5 is converted to C5a and C5b by C5 convertase
• C5b then joints C6 to C8 to form MAC. Then, C9 binds to the MAC to induce lysis of the cell
• The MAC can kill pathogens and self-cells
Other inflammatory factors rather than the complement system:
Hageman factor:

• Also known as factor 12 in the coagulation cascade

• An inactive proinflammatory protein produced by the liver
• Produced in exposure to subendothelial or tissue collage
• Increased in severe gram negative sepsis
• Links sepsis/SIRS with disseminated intravascular coagulation by pathologic activation of coagulation cascade
• Hageman factor is capable of activating the complement system, coagulation and fibrinolytic systems in addition
to the kinin system
Kinin system:

• Kinin system converts kinin to bradykinin

• Kinin is a high molecular weight substrate
• Bradykinin results in vasodilation and increases vascular permeability
• Bradykinin can also mediate pain

Note: The function of bradykinin is that of histamine + pain (vasodilation and increased vascular
permeability + pain).

Cardinal Signs of Inflammation:

• Redness (rubor) and warmth (calor) occur due to vasodilation of the arterioles which is mediated by histamine,
bradykinin and prostaglandin
• Swelling (tumor) is caused by increased vascular permeability at the post capillary venule mediated by
histamine, bradykinin, leukotrienes, prostaglandins and tissue trauma
• Pain (dolor) is caused by bradykinin and PGE2
• Fever is caused by the release of IL1 and TNF by macrophages
Mechanism of fever in acute inflammation:

• Release of IL1 and TNF by macrophages

• IL1 and TNF reach the perivascular cells of the hypothalamus to increase the activity of COX

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 • COX increases PGE2 in the hypothalamus which raises the temperature set point
• The core body’s temperature is raised causing fever
Acute Inflammation – An Overview:
Phases of acute inflammation:

• Fluid phase is characterized by edema and the activation of the complement system
• Neutrophil phase is characterized by the recruitment and activation of neutrophils. Peaks at about 24 hours
• Macrophage phase peaks at about 2 to 3 days. When monocytes enter the interstitium, they are called
macrophages
• Acute inflammation can last for days or weeks. As long as the key player is neutrophils, then inflammation is
classified as acute
Neutrophils recruitment and activation: these same steps are followed by macrophages for their recruitment into the
inflammatory site

• The first step is margination. Normally, neutrophils and macrophages circulate in the center of the vessel lumen.
When the blood vessel dilates as in acute inflammation, margination occurs
• Endothelial cells express selectins in areas of inflammation. Selectins bind to neutrophils to allow rolling.
Rolling makes neutrophils slow down so that they can later enter the inflamed tissue
• Cellular adhesion molecules on endothelial cells bind to integrins on neutrophils resulting in neutrophil adhesion
• Neutrophils now transmigrate across the vessel wall at the postcapillary venules. Chemotaxis drives the
neutrophils to move to the infection site
• Neutrophils are attracted to bacterial products, IL8, C5a and LTB4
• Neutrophils phagocytose pathogens which are covered by opsonins such as C3b and IgG
Selectins, integrins, and adhesion molecules:

• P-selectin is released by the action of histamine. P-selectin is stored in Weibel-Palade bodies inside endothelial
cells. Von-Willebrand factor is another protein stored inside Weibel-Palade bodies
• E-selectin is released by the action of TNF and IL1
• Selectins bind to Sialyl Lewis X protein on neutrophils and this results in rolling
• Cellular adhesion molecules are upregulated by endothelial cells in the presence of the major innate immunity
cytokines IL1 and TNF
• Integrins which bind to cellular adhesion molecules are upregulated by C5a and LTB4
Leukocyte adhesion deficiency:

• An autosomal recessive mutation of integrins at the CD18 subunit

• Presents with delayed separation of the umbilical cord after childbirth. After childbirth, blood ceases to pass
through the umbilical cord and it undergoes necrosis. As we have explained, necrosis is always followed by acute
inflammation. In the case of leukocyte adhesion deficiency, neutrophils fail to adhere and they are not recruited
→ delayed separation of the umbilical cord
• Circulating neutrophils increase in numbers because they are entrapped within the intravascular space
• Patients have recurrent bacterial infection and do not form pus. Remember, pus is dead neutrophils
Phagocytosis:

• Neutrophils engulf pathogens and cellular debris and form a phagosome

• Phagosomes merge with the lysosome to make a phagolysosome
• Hydrolysis and enzymatic destruction of the pathogen occurs inside the phagolysosome
• Killing of organisms by phagocytosis can be oxygen dependent (more efficient) or oxygen independent:
o Oxygen dependent phagocytosis occurs in the phagolysosome
o Oxygen is converted to superoxide by NADPH oxidase
o Superoxide is converted to hydrogen peroxide by superoxide dismutase
o Hydrogen peroxide is converted to HOCl by myeloperoxidase
o HOCl kills the microorganism within the phagolysosome
o Oxygen independent killing of microorganisms occur within the lysosome after secondary granules that
contain lsyozome and major basic protein release their contents inside the phagolysosome

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Chediak-Higashi syndrome:

• An autosomal recessive protein trafficking defect

• Microtubule railroad tracks within cells are defective
• Patients present with neutropenia due to impaired cell division, giant granules inside leukocytes and recurrent
pyogenic infections
• The cause of the giant granules in leukocytes is the formation of golgi apparatus granules because newly formed
golgi will fail to travel inside the cell because of the microtubule defect
• The increased risk of recurrent pyogenic infections is explained by the inability to move the lysosome to the
phagosome resulting in merging failure and inability to form phagolysosomes
• Patients with this syndrome have defective hemostasis because platelets cannot degranulate as the granules inside
will fail to move
• Albinism is seen in these patients because melanin cannot travel from melanocytes to the keratinocytes
• Patients also develop peripheral neuropathy because neurotransmitters synthesized inside neuronal bodies cannot
be transported to the axon endings
Chronic granulomatous disease:

• Defective NADPH oxidase → inability to convert oxygen to superoxide → decreased oxygen dependent killing
of microorganisms
• Patients have chronic granulomas
• The disease can be autosomal recessive or X-linked
• Catalase positive organisms are encountered in these patients. They include staphylococcus aureus, p cepacia, s
marcescens, nocardia, and aspergillus
• Other bacteria produce H2O2 which can be converted to bleach by myeloperoxidase → phagocytosis killing will
occur. Catalase destroys H2O2 which make bacteria that produce catalase more likely to cause recurrent
infections and granulomas in patients with chronic granulomatous disease
• Nitroblue tetrazolium (NBT) is the screening test for CGD. If NADPH oxidase is present and functional, the
solution will turn blue excluding CGD
• Patients with recurrent candida infections and a normal NBT could have myeloperoxidase deficiency
Resolution of inflammation:

• Neutrophils undergo apoptosis forming pus within 24 hours after the resolution of the trigger of the inflammatory
response
• Macrophages which come 2 to 3 days after the onset of acute inflammation check the work of neutrophils. They
are also capable of phagocytosis however they kill organisms via oxygen independent mechanism that involves
lysozyme
• If the inflammatory trigger or organism has been neutralized, macrophages secrete anti-inflammatory mediators
IL10 and TGF-beta. These induce healing
• If inflammation is still needed, macrophages will secrete IL8 to recruit more neutrophils to the site
• Macrophages can wall off the infected area to form an abscess
If macrophages recognize that neutrophils cannot neutralize the offending agent “i.e. viral infections”, they will process
antigens and present them via MHC-2 to start chronic inflammation

Chronic Inflammation

Cells Involved with Chronic Inflammation

Definition of chronic inflammation:
Chronic inflammation is a process that involves immune cells “mainly lymphocytes”. It is a delayed response that is more
specific than acute inflammation. It is a form of adaptive immunity. Lymphocytes include T-cells, B-cells and plasma cells.
Stimuli of chronic inflammation:

• The most common cause is a persistent infection

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 o Viruses, mycobacteria, parasites and fungi are the main infectious agents associated with chronic
inflammation
• Autoimmune diseases are characterized by chronic inflammation
• Foreign materials can induce a chronic inflammatory response
• Some cancers are characterized by chronic inflammation “inflammatory breast cancer”
T-cells:

• T and B-cells are both made in the bone marrow

• T-cells migrate to the thymus for their maturation
• Within the thymus, T-cells become specific to a certain antigen and they develop into CD4 helper or CD8 cytotoxic
T-cells
o These are not the only mature T-cells. For example, you also have regulatory T cells which can suppress
immune responses
• Activation of T-cells:
o They recognize antigens presented on MHC molecules by antigen presenting cells, however, a second
signal is needed for their activation
o Helper CD4 T cells recognize antigens presented on MHC II which is present on antigen presenting cells.
MHC II presents extracellular antigens
o CD8 cytotoxic T-cells recognize antigens presented on MHC I which is present on all cells. MHC I
presents intracellular and viral antigens
o B7 present on antigen presenting cells or CD40 found on B cells act as the second signal to activate CD4
cells. B7 binds to CD28 on the T-cell, whereas CD40 binds to CD40L
o CD8 T cells require the release of IL2 from CD4 cells for their activation “IL2 is the second signal for
CD8 T cells”
o Activated CD4 T cells have two types: TH1 and TH2. TH1 secrete interferon gamma to enhance the
phagocytic ability of macrophages and IL2. TH2 release cytokines that attract eosinophils in addition to
anti-inflammatory cytokines such as IL10
▪ TH2 cells also secrete IL4 → class switching to IgG and IgE, and IL5 which attracts eosinophils
and make B-cells mature into plasma cells. IL5 cause class switching to IgA
▪ IL10 inhibits TH1 cells “anti-inflammatory”
Cell killing by CD8 cytotoxic T-cells:

• Activated CD8 cells secrete perforins which make holes in target cells. They also secrete granzymes that activate
caspase pathway inducing apoptosis
• Moreover, they express Fas ligand which binds to Fas receptor on target cell to activate apoptosis
Self-reactive T-cells:

• As T-cells mature in the thymus, some can recognize self-antigens. It is important to kill these T-cells to prevent
the development of autoimmune disease
• A CD8 self-reactive T-cell will recognize self-antigens presented on MHC I. As a second signal will not be
provided, this will result in the apoptosis of the self-reactive T-cell “anergy”
B-cells:

• They are produced by the bone marrow

• Naïve B-cells express IgM and IgD “class switching is needed as explained before”
• B-cells phagocytose antigens and process and present them on MHC II. CD4 helper T-cells recognize this and then
CD40 present on B-cells bind to the helper T-cell as a second signal. This will activate the CD4 T-cell to express
IL4 and/or IL5 which then induce the isotype switching of B-cells to produce appropriate antibodies
• When B-cells are activated, they undergo somatic hypermutation to increase the affinity of the antibody to its
antigen. They also mature into plasma cells “antibody producing cells”
Granulomatous Inflammation
Definition:
This is a specific type of chronic inflammation characterized by epitheloid histiocytes “macrophages with abundant pink
cytoplasm and elongated nuclei”. Macrophages can become multinucleated. Granulomas are surrounded by lymphocytes
and giant cells. They can be classified into caseating and non-caseating granulomas.
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Caseating granulomas:

• Seen in tuberculosis and fungal infections

• Acid-fast bacilli are seen in the case of TB
• GMS silver stain is used to look for fungal organisms
• Macrophages act as antigen-presenting cells. They present foreign antigens on MHC II to CD4 helper cells
• Macrophages also secrete IL12 to induce CD4 helper T-cell to differentiate into mainly TH1 cells
• CD4 helper T-cells secrete interferon gamma → conversion of macrophages into epitheloid histiocytes and giant
cells → formation of granulomas
Same steps occur in both caseating and non-caseating granulomas
Non-caseating granulomas:

• Unlike caseating granulomas, non-caseating ones lack central necrosis

• They are seen as a reaction to foreign materials for example in leaking breast implants
• Sarcoidosis is a common inflammatory condition characterized by systemic non-caseating granulomas
• In Crohn’s disease, you see non-caseating granulomas
• Cat scratch disease is another condition that cause star-shaped granulomas in the neck
• Beryllium exposure can also cause non-caseating granulomas

Note: In ulcerative colitis, the hallmark of the disease is crypt abscess.

Primary Immunodeficiency

DiGeorge Syndrome
• Mutations in chromosome 22q11 cause DiGeorge Syndrome
• It is characterized by failure of development of 3rd and 4th pharyngeal pouches
• Absence of thymus → T-cell deficiency
o Impaired immune response to viral and fungal infections
• Absence of parathyroid glands → hypocalcemia
• Heart, great vessels and facial defects
Severe Combined Immune Deficiency
• Both, T and B-cells are impaired
• Defective cell and humoral mediated immunity
• Caused by defects in cytokine receptors
• The second most common cause is adenosine deaminase deficiency → accumulation of adenosine and
deoxyadenosine in immune cells → cytotoxicity
• Characterized by MHC II deficiency → inability to activate CD4 helper T cells → this impairs the activation of
CD8 cytotoxic and B cells “both require CD4 helper T-cells”
• Patients are at an increased risk of viral, fungal, bacterial and protozoal infections
• Patients are at an increased risk of opportunistic infections and live-attenuated vaccines should be avoided
• Treatment: sterile isolation “bubble babies” and definitive treatment is stem cell transplantation
X-linked Agammaglobulinemia
• Complete lack of antibodies
• Naïve B-cells cannot mature into plasma cells
• Caused by a mutation in Bruton tyrosine kinase. “Bruton agammaglobulinemia” is another name for the disease
• Patients are at an increased risk of recurrent bacterial infections. Because of the lack of IgA, patients are also at
an increased risk of recurrent enteroviral and Giardia infections
• Patients start developing infections 6 months after birth “time required for maternal antibodies to be consumed in
the newborn blood”
• Live attenuated vaccines such as polio vaccine must be avoided

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Variable Immunodeficiency Disease
• Defective B or T-cells result in low levels of immunoglobulins
• Increased risk of bacterial, enteroviral, and Giardia infections
• Present in late childhood, unlike Bruton agammaglobulinemia which presents after six months of birth
• Increased risk of autoimmune disease and lymphoma
IgA Deficiency:
• The most common immunoglobulin deficiency
• Increased risk of mucosal infections
• An association with celiac disease has been described
Hyper IgM Syndrome:
• Mutations in CD40 or CD40 receptor → B-cells cannot activate CD4 helper cells → impaired immunoglobulin
class switching
• Elevated IgM and decreased IgA, IgG and IgE levels
• Patients have recurrent mucosal infections and pyogenic infections. IgG is an opsonin and low levels of this
immunoglobulin has been associated with increased risk of formation of pus
Wiscott-Aldrich Syndrome:
• Defective humoral and cellular immunity associated with thrombocytopenia and eczema
• Mutation in Wiskott-Aldrich Syndrome Protein which is x-linked cause the syndrome
• Patients have recurrent infections
Complement Deficiencies:
• Patients who have decreased levels of C5 to C9 factors are at an increased risk of Neisseria infections “inability
to form membrane-attack complex”
• Deficiency of C1 inhibitor causes hereditary angioedema
o Hereditary angioedema is characterized by massive edema especially periorbital and mucosal
• Mucosal edema can be fatal due to upper respiratory tract obstruction
Autoimmune Disorders

Overview:
Autoimmune diseases are characterized by an overactive immune system or loss of self-tolerance. This means that the
immune system recognizes self-antigens as foreign antigens and an immune response is initiated and sustained against
self-antigens.

• The estimated prevalence of autoimmune diseases in the US is 1%

• Women of childbearing age are at highest risk
• Presence of an autoimmune disease in a patient increases the risk of developing other autoimmune diseases
• The common pathology of autoimmune diseases is exposure to an environmental trigger in a genetically
susceptible subject
Systemic Lupus Erythematosus:
Definition:
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibodies that cause type II
hypersensitivity reaction (killing of cells mediated by antibodies). Type III hypersensitivity reaction (antigen-antibody
complex formation) has also been described in the pathogenesis of SLE.
Clinical Findings:

• Presence of malar “butterfly” rash upon sunlight exposure is classic of SLE

• Kidney disease is seen in patients with SLE. Diffuse proliferative glomerunephritis is common in such patients,
however other types of nephritic or nephrotic syndromes have been described. Kidney damage is a common
cause of death in SLE patients
• SLE is characterized by pleuritis, pericarditis, myocarditis and endocarditis. Libman-Sacks endocarditis is
characteristic

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 • SLE patients can develop immune-mediated hemolytic anemia, thrombocytopenia and leukopenia. Leukopenia
puts them at an increased risk of recurrent and severe infections which can be fatal
• Arthritis is a common finding as well
• Fever and weight loss are seen in many of the autoimmune diseases we discuss here, and SLE is no exception
• Psychosis has been reported and is supposed to be the result of CNS inflammation
Diagnosis:

• In addition to the clinical findings, laboratory testing is quite helpful in autoimmune diseases
• In SLE, you can see ANA (anti-nuclear antibody) which is sensitive for lupus (useful for screening)
• Anti-dsDNA is very specific for SLE
• You can see anti-histone antibodies in drug induced lupus. Drugs that can cause lupus include hydralazine,
procainamide, and isoniazid
• On echocardiography, if you see vegetations seen in endocarditis involving both sides of a valve, the diagnosis of
Libman-Sacks endocarditis can be made which increases the possibility of SLE
Antiphospholipid syndrome associated with SLE:

• APS can be isolated or associated with SLE

• In APS associated with SLE, the main pathology is formation of antibodies that bind to phospholipids. One
example is the anticardiolipin antibody
• Presence of anticardiolipin antibodies can give false positive syphilis test
• Lupus anticoagulant antibodies can give a falsely elevated PTT. However, remember that APS patient is in a
hypercoagulable state
• Patients diagnosed with APS need to be lifelong anticoagulation to lower their risk of stroke, DVT, hepatic vein
thrombosis, and recurrent miscarriages due to placental thrombosis
Sjogren’s Syndrome:
Definition:
Sjogren’s syndrome is a type IV hypersensitivity mediated disease characterized by lymphocyte infiltration and
destruction of the lacrimal and salivary glands. The normal glandular tissue is replaced with fibrous non-functional tissue.
Clinical Findings:

• Patients present with symptoms and signs suggestive of dry mucous membranes “dry eyes, dry mouth, recurrent
dental carries and painful intercourse
• The disease is more common in older women
• The parotid glands may become enlarged because of the fibrosis
• Patients should be screened for SLE to exclude secondary Sjogren’s syndrome
Diagnosis:

• ANA are positive in Sjogren’s syndrome, similar to SLE

• Anti-ribonucleoprotein antibodies are specific. Anti-SSA and anti-SSB are the main examples and they classify
Sjogren syndrome into type A and type B
• Sjogren’s syndrome can be associated with SLE or rheumatoid arthritis in addition to other autoimmune diseases
• Patients with Sjogren’s syndrome are at an increased risk of B-cell lymphoma especially in a patient with late
unilateral enlargement of a parotid gland
Systemic Sclerosis:
Definition:
An autoimmune disease characterized by tissue damage and activation of fibroblasts. Fibroblasts deposit collagen resulting
in fibrosis which thickens the skin making it tight and less mobile.
CREST: also known as limited scleroderma “local skin involvement and delayed visceral organ disease”

• Calcinosis
• Raynaud’s phenomenon (spasm of blood vessels in digits in response to cold or stress
• Esophageal dysfunction
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 • Sclerodactyly
• Telangiectasias
• Positive anti-centromere antibodies
Diffuse Scleroderma:

• Diffuse skin and early visceral organ involvement

• Patients complain of dysphagia to both solids and liquids
• Positive ANA “non-specific”
• Positive anti-DNA topoisomerase I antibodies (SCL-70 antibody) “specific”
Mixed Connective Tissue Disease:
Definition:
Patients have autoimmune tissue damaged with mixed features of SLE, systemic sclerosis and polymyositis. Patients have
anti-U1 ribonucleoprotein antibodies

Tissue Regeneration
• Tissue regeneration is defined as the replacement of damaged tissue with native non-distinguishable new tissue
• Repair, on the other hand, is the replacement of damaged tissue with a fibrous “collagen-rich” scar
• Tissues that lack the ability to regenerate undergo repair when injured
Labile tissues:

• These tissues are capable of continuously regenerating due to the presence of regenerative stem cells
• They include the intestines “stem cell in mucosal crypt”, skin “stem cells in basal layer”, bone marrow “due to
hematopoietic stem cells which are CD34 positive”, and presence of type 2 pneumocytes in the lungs
Stable tissues:

• These tissues do not need to undergo continuous regeneration, however if injured, they are capable of complete
regeneration
• The liver and the proximal tubule of the kidneys are classical examples of stable tissues
• For example a lacerative injury to the liver heals without scarring
• Another example is the regeneration and recovery of kidneys in patients with acute tubular necrosis whom we
put on dialysis temporarily
Permanent tissues:

• These tissues cannot regenerate

• If injured, they will undergo repair “formation of a fibrous scar
• Myocardium, skeletal muscle, and neurons are examples
Granulation Tissue
Granulation tissue is present in the early phase of tissue repair of permanent tissues and skin. It contains fibroblasts,
capillaries, and myofibroblasts.

• Fibroblasts deposit collagen type 3

• Collagenase removes type 3 collagen and replaces it with type I which is stronger and found in scar
• Collagenase requires zinc as cofactor
Types of collagen:

• Type 1 has a high tensile strength and is found in bone

• Type 2 is found in cartilage
• Type 3 is found in granulation tissue and is very pliable. It is replaced by type 1 in final scar
• Type 4 is found in the basement membrane of epithelial tissues
Molecular basis of tissue repair:

• Fibroblast growth factor induces angiogenesis and skeletal development

• VEGF induces angiogenesis “required for granulation tissue formation”

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 • PDGF induces angiogenesis by increasing the growth of endothelium, and increases the growth of fibroblasts and
smooth muscle cells “very important for granulation tissue formation”
• TGF alpha is an epithelial and fibroblast growth factor
• Inflammation is seen after tissue damage. Therefore, we require TGF beta to suppress inflammation and further
induce the growth of fibroblasts for repair
Clinical Correlation
Primary vs Secondary Intention:

• If the wound edges are brought together as in surgical incisions, the wound is considered to heal by primary
intention. This results in minimum scar formation
• If the wound edges are left far away, then the wound heals by secondary intention. Granulation tissue is formed
and a scar is then formed. However, the scar size will be smaller than the original gap because myofibroblasts
contract and shrink the wound
Collagen formation and structure:

• First, alpha collagen strands are made inside the cells. These strands intertwine and make procollagen. Procollagen
leaves the cell into the extracellular space
• The alpha strand consists of Gly-Proline-Lysine repeats
• Hydroxyl groups cross-link prolines and lysine in the alpha strands to make collagen
• Vitamin C is required for the hydroxylation cross-linkage of collagen “vitamin C deficiency is characterized by
impaired tissue repair”
• Copper is the cofactor of lysyl oxidase, the enzyme responsible for the hydroxylation cross-linkage in collagen
Delayed wound healing:

• Vitamin C-deficiency, zinc or copper deficiency, and infection of the wound site can result in delayed wound
healing
• Ischemia, diabetes and malnutrition are disease states associated with impaired wound healing
• Presence of foreign bodies in wounds can delay healing
• If the wound does not heal properly, it can rupture. This is more likely to happen when the wound is in the abdomen
“post abdominal surgery”
Keloid vs hypertrophic scar:

• If the scar is big in size but localized to the wound it is considered as a hypertrophic scar. On the other hand, if the
scar is out of proportion to the wound, it is a keloid
• In hypertrophic scars, the problem is excess type I collagen, whereas in keloids it is excess type III collagen
deposition
• Keloids are more common in African Americans and they tend to occur on the earlobes, upper extremities and face
Neoplasia and Neoplastic progression
Important Definitions Related to Neoplasia
Neoplasia:
A neoplasia is defined as the unregulated, irreversible monoclonal expansion of a single cell. Hyperplasia on the other
hand is regulated and polyclonal.
Desmoplasia:
Firming of a tumor due to the induction of fibroblasts which form collagen.
Carcinoma in Situ:
Dysplastic changes involve the entire thickness of an epithelial surface for example ductal carcinoma in situ of the breast.
Also known as high-grade dysplasia. This is the earliest form of malignancy.

Monoclonality
The hallmark of neoplasia is monoclonal expansion. Monoclonality means that the tumor cells arise from a single parent
cell. To determine monoclonality, one can depend on:
• G6PD isoforms
• Androgen receptor isoforms
• Ig light chain phenotype isoforms

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G6PD isoforms:
• Each X-chromosome encodes a different isoform of G6PD. Because of the random inactivation of X-
chromosome in normal cells, you expect the tissue to have a 1:1 ratio of the two G6PD isoforms. Loss of this
ratio means monoclonality
• Androgen receptor isoforms determine monoclonality in same way
Ig light chain phenotype isoforms:
• Useful in confirming monoclonality in lymphomas
• Light chains consist of K and lambda chains in a fixed 3:1 ratio
• If the kappa to lambda chains ratio is different from 3:1, suspect monoclonality

Benign versus Malignant Neoplasms

Benign neoplasms:
• Localized and generally do not metastasize
• Usually slow-growing
• Mobile and distinct from surrounding tissues
Malignant neoplasms:
• Characterized by local invasion
• Have potential to metastasize
• Usually rapid growing
• Infiltrative and difficult to distinguish from surrounding tissues
• Fixed and immobile
Examples of benign neoplasms:
• Adenomas, papillomas, lipomas, angiomas, chondromas, and osteomas are classical examples
• A mole or a nevus is a benign melanocyte tumor
• Lymphocytes cannot give rise to benign tumors
Examples of malignancies:
• Adenocarcinoma, papillary carcinoma, osteosarcoma, chondrosarcoma, angiosarcoma, and liposarcoma
• Lymphoma and melanoma are malignant tumors that end with the suffix oma “don’t confuse them as being
benign!”

Epidemiology
Leading causes of death in adults:
1. Cardiovascular disease
2. Cancer
3. Cerebrovascular disease
Leading causes of death in children:
1. Accidents
2. Cancer
3. Congenital defects
Therefore, cancer is the second leading cause of death in both adults and children.
Leading cancers in males by incidence:
1. Prostate
2. Lung
3. Colorectal
Leading cancers in males by death toll:
1. Lung
2. Prostate
3. Colorectal
Leading cancers in females by incidence:
1. Breast
2. Lung
3. Colorectal
Leading cancers in females by death toll:
1. Lung

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 2. Breast
3. Colorectal

Note: Squamous and basal cell carcinomas are very common, however they rarely metastasize and
often curable.
Note: There is no screening protocol for lung cancer which explains why it is the leading cancer by
death toll in males and females. It is usually detected late.

General Features of Neoplasia and Cancer

• Cancers that tend to produce symptoms later tend to have worse prognosis
• Cancers that produce symptoms later have higher grade and accumulate more mutations before they are
diagnosed
• Examples of such cancers include ovarian, pancreatic, and lung cancer
• Other cancers typically start to cause symptoms after 30 cell divisions
• As more divisions occur, more acquired somatic mutations are identified

Screening:
Screening aims to detect dysplasia before the development of malignancy. Dysplasia is reversible, e.g. Barrett’s
esophagus. Screening can also aim for the detection of cancers in early stages before the development of clinical
symptoms “where treatment can be curative”.
Examples of common screening tests for cancers:
• Mammography to look for breast cancer and ductal carcinoma in situ
• Pap smear to detect cervical intraepithelial neoplasia and early form of cervical cancer
• PSA and DRE to look for prostate cancer
• Hemoccult test and colonoscopy for colorectal cancer

Carcinogenesis, Oncogenes and tumor genetics

Chemical Carcinogens
Carcinogens are chemical, viral or physical stressors that cause DNA damage resulting in development of neoplasia.
• Aflatoxins derived from aspergillus flavus can cause hepatocellular carcinoma. This fungal organism can
contaminate stored grains. Hepatocellular carcinoma has also been associated with alcohol intake
• Chemotherapeutic agents “especially alkylating agents” are associated with an increased risk of leukemia and
lymphoma
• Squamous cell carcinoma of the oropharynx and upper esophagus may be caused by exposure to alcohol or
tobacco
• Alcohol also increases the risk of pancreatitis → chronic pancreatic inflammation elevates the risk of pancreatic
cancer
• Exposure to arsenic can cause squamous cell carcinoma of the skin
• Lung cancer is seen in smokers because cigarettes contain many carcinogens:
o Arsenic and polycyclic hydrocarbons are the main carcinogens in cigarettes
o Smoking also increases the risk of kidney and bladder carcinoma. Naphthylamine found in cigarettes
are linked to the increased risk of urothelial carcinoma
• Asbestos has been linked to an increased risk of lung cancer and mesothelioma
• Smoked foods which are more common in Japan explains the increased risk of stomach carcinoma “intestinal
type” due to exposure to nitrosamine
• Occupational exposure to vinyl chloride may cause angiosarcoma of liver
• Exposure to nickel, chromium, beryllium or silica may cause lung fibrosis and eventually lung cancer

Note: The most common carcinogenic worldwide is cigarette smoking.

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Oncogenic Viruses
Ebstein-Barr Virus:
• Has been linked to lymphomas: Burkitt lymphoma in African children and CNS lymphoma in patients with HIV-
AIDS
• Nasopharyngeal carcinoma which is more common in Chinese or African males. Unfortunately, early metastases
are common
Herpes Human Virus 8:
• Linked to Kaposi sarcoma a tumor of endothelial cells. There are specific groups that are at an increased risk of
Kaposi sarcoma:
o HIV positive patients with AIDS → risk can be lowered by treating HIV
o Transplant patients → risk can be reduced by reducing immunosuppression
o Older eastern European males → simply take the tumor out to treat
Hepatitis Viruses:
• HBV and HCV which can cause chronic hepatitis can result in hepatocellular carcinoma
HTLV-1:
• May cause adult T-cell leukemia/lymphoma
Human papillomaviruses:
• Squamous cell carcinoma of the anogenital area and adenocarcinoma of the cervix
• Oncogenic HPVs are types 16, 18, 31 and 33

Radiation and Carcinogenesis

Ionizing radiation:
• Seen after exposure to nuclear leak from nuclear reactors or radiotherapy
• Damages DNA by generating hydroxyl free radicals
• May cause acute and chronic myeloid leukemia, and papillary thyroid carcinoma
Non-ionizing radiation:
• Most commonly from exposure to ultraviolet light
• Causes DNA damage by forming abundant pyrimidine dimers which need to be excised by restriction
endonucleases
• May cause BCC, SCC and melanoma of the skin

Note: Patients with xeroderma pigmentosum have defective restriction endonuclease → elevated
risk of BCC, SCC and melanoma after exposure to ultraviolet light.

Note: Most common cause of ionizing radiation in the USA is exposure to radon due to uranium
decay. Exposure to radon is the second most common cause of lung cancer in the USA after
smoking.

Genetics of Carcinogenesis
Proto-oncogenes:
• Proto-oncogenes are required for regular cell growth and differentiation. When mutated, they become oncogenic
• Growth factors, signal transducers, nuclear regulators, and cell cycle regulators are main examples of proto-
oncogenes
• These are all linked to each other which explains why mutations in any or several of them can result in
carcinogenesis:
Growth factors bind to their receptors → induction of signal transducers → cell cycle and transcription
factors/regulators are activated → induction of cell cycle through G1-S-G2-M stages to result in cell division
Growth factors:
• Platelet derived growth factor B overexpression is seen in astrocytoma
• Epidermal growth factor receptor amplification is implicated with breast cancer

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 • Point mutations in RET “neural growth factor receptor” are seen in MEN2A, MEN2B and sporadic medullary
thyroid carcinoma
• Point mutations in stem cell growth factor receptor “KIT” are seen in gastrointestinal stromal tumors
Signal transducers:
• RAS gene family are implicated in carcinomas, melanomas, lymphoma and almost up to 70% of all cancers.
They encode for GTP binding protein
• ABL encodes for tyrosine kinase. Translocation t(9,22) with BCR is seen in some acute lymphoblastic leukemias
and CML
Nuclear regulators:
• Translocation t(8,14) seen in Burkitt lymphoma results in overexpression of C-MYC
• Amplification of N-MYC is implicated with neuroblastoma
• Amplification of L-MYC is implicated with small cell lung carcinoma
Cell-cycle regulators:
• Translocation t(11,14) is seen in mantle cell carcinoma. Cyclin D1 is the involved gene
• Cyclin depdent kinase mutations are linked to melanoma

Note: Loss of function mutations/deletions of tumor suppressor genes or regulators of apoptosis

sustain the growth and give tumor cells immortality.

Tumor Grade Vs stage and Tumor Nomenclature

Benign versus Malignant Neoplasia
Histologic features of benign tumors:
• Organized growth
• Uniform nuclei
• Low nuclear to cytoplasm ratio in favor of more cytoplasm
• Lack of invasion
• Minimum mitotic activity
• Does not metastasize
Histologic features of malignant tumors:
• Disorganized growth
• Nuclear pleomorphism and hyperchromatic nuclei
• High nuclear to cytoplasm ratio in favor of more nuclear element
• High mitotic activity
• Local invasion and/or metastasis

Identifying Cell Types in Neoplasia

Immunohistochemistry:
• Intermediate filaments are cytoskeletal proteins that differentiate cell types from each other. Even if the cell loses
many of its structural or morphological features, their type can still be identified by using immunohistochemistry
staining of intermediate filaments
• The following cell types have these intermediate filaments:
o Epithelial cells have keratin
o Mesenchymal cells have vimentin
o Muscular cells have desmin
o Neuroglia cells have GFAP
o Neurons have neurofilaments
• Immunohistochemistry can be also used to stain specific molecules that can help in determining the type of
cancer:
o Prostate surface antigen in prostatic carcinoma
o Estrogen receptor in ER+ breast cancer
o Thyroglobulin in thyroid follicular carcinoma
o Chromogranin in neuroendocrine cells such as small cell lung cancer and carcinoid tumors

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 o S-100 in melanoma

Note: Both carcinoid tumors and small cell lung cancer originate from neuroendocrine cells.
However, in carcinoid tumors you see well-differentiated cells, whereas in small cell lung cancer
there is poor differentiation.

Tumor Markers:
• Tumors release proteins and other molecules which can be detected in the blood
• These tumor markers can be used for screening, and monitoring response to treatment
• They are also helpful in detecting recurrences especially microscopic recurrences which may not show on
imaging but still be detected by finding a specific tumor marker
• Prostate surface antigen is a good example here. It is used for screening, monitoring response to treatment and
looking for tumor recurrence in patients with prostate cancer

Tumor Grading:
• Based on histologic examination
• Well differentiated tumors have good prognosis. Tumor cells resemble parent tissue
• Poorly differentiated tumors do not resemble the parent tissue and carry poor prognosis
• Cell organization, structure, polarity, mitotic figure, and nuclear morphology are used to assess differentiation
grade

Tumor Staging:
• Based on the tumor’s size, local spread, lymphatic spread and distant metastatic state of the tumor
• Most important factor for prognosis
• Determined after resection of tumor if resectable
• The TNM staging system is the classical example of tumor staging:
o T stands for tumor’s size and depth. The size of tumor is more important for solid organ tumors
whereas the depth of a tumor is more important for tubular organs such as the colon
o N stands for spread to lymph nodes. Lymphatic spread status is the second most important prognostic
factor
o M stands for metastasis. This is the single most important prognostic factor in clinical practice

Tumor Progression

Tumor Progression and Local Spread

Steps required for local invasion of an epithelial tumor:

• Downregulation of adhesion molecules such as e-cadherin

• Attachment of tumor cells to laminin in basement membrane
• Production of collagenase by tumor cells to destroy collagen type IV in the basement membrane
• Binding of tumor cells to fibronectin in extracellular matrix
• Local invasion of blood and lymphatic vessels
Distant Metastasis
Once local invasion of blood and lymphatic vessels occur, the tumor can become metastatic:

• Lymphatic spread is more common for carcinomas

• Hematogenous spread is more common for sarcomas
• Hematogenous spread occurs via the venous system
• Some tumors may metastasize by seeding of a body cavity
Note: Any cavity or space “pleural, pericardial, subarachnoid space or joint space” may show evidence of tumor seeding.
However, the most common site is peritoneum and the most common cause of peritoneum seeding is ovarian carcinoma
“metastasis to omentum causes omental caking”.

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 Chapter :6

Basic Pharmacology

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What is pharmacokinetics • Intravascular administration (e.g., IV) does not
involve absorption, and there is no loss of drug.
Overview Bioavailability = 100%
• With extravascular administration (e.g. oral,
intramuscular, subcutaneous, inhalation), less than
100% of a dose may reach the systemic circulation
because of variations in bioavailability.
Distribution
• The dispersion of a substance throughout fluids
and tissues of the body
• The process of distribution of a drug from the
systemic circulation to organs and tissue
• The distribution usually occurs from Vascular
space blood and plasma to extravascular fat,
muscle, interstitial space
Metabolism (Biotransformation)
• The irreversible transformation of parent
Difference between pharmacokinetics and compound into daughter compounds
pharmacodynamics • The metabolic conversion of drug molecules to
• Pharmacokinetics means (Drug motion) what the more water-soluble metabolites that are more
body does to the drug readily excreted.
• How does the drug concentration change as it • Usually, metabolism lead to production of
moves through different compartments of your compounds that have little or no pharmacologic
body. activity
• Study of drug movements in the body and it • Prodrugs, compounds that have no activity until
describes the drug absorption, distribution and they undergo metabolic activation
drug elimination over • Some compounds are converted to toxic
Components: metabolites such as acetaminophen
1. Absorption • The primary site for drug metabolism is the liver
2. Drug distribution Elimination
3. Metabolism • Removal of the substances from the body
4. Drug elimination • The primary site for drug metabolism is the kidney
• Pharmacodynamics means (Drug power) what the • This elimination will be proportional to the drug’s
drug does to your body plasmatic concentrations.
• How the drug exerts its effect on your body (deals Enzyme kinetics
with potency, drug receptor interactions) Medical terminology
Affinity

• Is a measure of the tightness with which

a drug binds to the receptor, shown by the
Absorption proximity of the curve to the y axis (if the curves
• Process of a substance before entering systemic are parallel); the nearer the y axis, the greater the
circulation affinity
• The bioavailability of the drug depends on the Potency
route of administration • Measurement of drug activity required to produce
• Absorption is faster from I.V  I.M Oral  an effect of given intensity
Dermal

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 •
Vmax reflects how fast the enzyme can catalyze
the reaction.
• KM means affinity or potency
Lineweaver-Burk Equation
• The Lineweaver-Burk equation is a reciprocal
form of the Michaelis-Menten equation.
• This produces a straight line.
• The Y-intercept is 1/Vmax, and the X-intercept is
• A high potent drug produces a strong effect at low −1/Km
concentration, while a drug with low potency
produce the effect but with higher dose
Efficacy
• Measurement of how well a drug produces a
response (effectiveness)

Enzyme kinetics:

• The higher the value of V or S, the closer the

intercept will be to zero
• Slope= Km/Vmax

Enzyme Inhibitors
Competitive inhibitors
• Resemble the substrate and compete for binding to
• Measurements of the rates of enzyme catalyzed the active site of the enzyme.
reactions and identify the factors that affect these
• Km is increased, Vmax is unchanged
rates
The Michaelis-Menten equation
• Describes how the rate of the reaction, V, depends
on the concentration of both the enzyme [E] and
the substrate [S], which forms product [P].
• Km is the substrate concentration required to
produce half the maximum velocity
• A higher Km means a lower affinity of the
substrate for the enzyme. • Competitive inhibition is usually reversible and
• Most enzymatic reactions follow a hyperbolic excess substrate might abolish the inhibition
curve (ie, Michaelis-Menten kinetics) Noncompetitive inhibitors
• Do not bind at the active site. They bind to
regulatory sites on the enzyme.
• Km is unchanged, Vmax is decreased.

Class of inhibitor Km Vmax

Competitive increase No effect
Noncompetitive No effect Decrease

Competitive Competitive Noncompetitive

inhibitors inhibitors, inhibitors
reversible irreversible
Resemble substrate Yes Yes No
Overcome by  (S) Yes No No
Maximus velocity Vmax: Bind active site Yes Yes No
• Increasing the substrate concentration indefinitely Effect on Vmax unchanged  
Effect on Km  unchanged unchanged
does not increase the rate of an enzyme-catalyzed Pharmacodynamics  potency  
reaction beyond a certain point.
• Occur when the enzyme is saturated with substrate Summary

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 • Competitive inhibitors increase Km • Some drugs like to stay in the plasma, Low vd 
• noncompetitive inhibitors decrease Vmax 9L
Volume of distribution • Some drugs like to stay in the extravascular
Outline: compartments, High Vd  40L
m • Clinically used to figure out how much total drug
C = -------- need to give to reach your desired plasma
V concentration

m Amount of drug absorbed into the body

Plasma = ------- • Vd = ---------------------------------------------
Vd Plasma drug concentration
• The volume of distribution of a drug is the
proportionality constant between the amount of • Absorbed: Means amount of drug given I.V
drug in the body and the plasma concentration of
the drug: • Plasma . Vd = I.V dose “mass absorbed”
• The volume that drug would occupy if it were • Volume of distribution in directly proportional to
present throughout the body at the plasma the amount of drug you want to give
concentration. • Size (MW) if high will have low vd
• When we give a certain dose, we found the drug • Plasma (low vd) or extravascular protein binding
concentration isn´t ideal. That´s way we called it (high vd)
apparent volume of distribution • Hydrophilic drugs exhibit low vd, while lipophilic
Clinical uses of volume of distribution drugs show high vd
• The prediction of the loading dose to achieve a • Plasma protein binding may decrease in renal
target concentration. disease due to uremia, hypoalbuminemia, or due to
• Loading Dose = V × Target Concentration drug interactions.
• A second useful application is the ability to • Decreased plasma protein binding leads to an
calculate the half-life. This requires the clearance increase in free plasma fraction causing an
(CL) to be known as well as the apparent volume increase in volume of distribution and a shorter
of distribution (V). elimination half-life.
Apparent volume of distribution • The increase in the apparent volume of distribution
• It’s a constant value not a variable and the shorter elimination half-life cause a
decrease in total plasma concentration.
Examples of apparent volume of distribution
Drug VD Comments
Warfarin 8L Reflects a high degree of
plasma protein binding
Theophylline, 30L Represents distribution in total
Ethanol body water
Chloroquine 15000L Shows highly lipophilic
molecules sequester into total
body fat
NXY-059 8L Highly Charged hydrophilic
molecule

• Is the apparent volume needed to account for the • Another way to think about Vd = “I gave a certain
total amount of drug in the body if the drug was amount of drug and plasma concentration is really
evenly distributed throughout the body and in the low. It appears as this drug into a really large
same concentration as the site of sample collection volume”
such as peripheral venous plasma.
• Volume of distribution (Vd) is a theoretic concept
that relates the amount of drug in the body (dose)
to the concentration (C) of drug that is measured
(in blood, plasma, and unbound in tissue water).
• Volume of distribution (Vd) refers to attribution of
drug in relation to the average healthy person

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Apparent Vd comparisons L
Plasma
Drug • A person has bacterial pneumonia. You decided to
drug give them erythromycin I.V The minimum
binding antibiotic plasma concentration which will inhibit
Case bacterial growth is 20 mg/L. The volume of
1: distribution is 40 L and the oral bioavailability is
Low 25%. what should the oral dose be?
Free drug
Plasma  = 20 mg/ L
Vasc Extra-Vascular
ular Vd = 40 L
Case 2: FA Mus
High Vd F=
cle 25
T
Mass Bound
C = ---------------
Volume
Case 3: Mass = Concentration * volume
Med Vd F Muscle
A Mass (Actual Absorbed Mass) = Mass (Total Mass Admin)
* Bioavailability (route)
Why we do care about plasma drug concentration
• Because we assume that the plasma drug Mass (Total Mass Admin) * Bioavailability (P.O) =
concentration is to the target drug concentration Concentration * vd
• This rule is mostly valid for I.V administration and
can´t apply for local anti-inflammatory drugs,
inhalation, lotion, eye drops Concentration (20mg/L) * Vd (40L) 800
Example: Dose = -------------------------------------------- =--------- =
• A person has bacterial pneumonia. You decided to 3200 mg= 3.2 g
give them erythromycin I.V The minimum Bioavailability (1/4) (1/4)
antibiotic plasma concentration which will inhibit
bacterial growth is 20 mg/L. The volume of Drug Clearance
distribution is 40 L. what should the IV dose be? Definition
• Volume of plasma that is cleared of drug per unite
Plasma= 20 mg/L time
Units
Vd= 40 L • Volume/ time = ml/min
• Clearance is the proportionality factor used to
Amount of drug absorbed into the body determine the rate of elimination
Vd = ------------------------------- • Rate of elimination = CL* concentration
Plasma drug concentration • Mass/ time = vol / time * mass / vol = mass/ time

Mass Clearance
C = ------------- • For every drug, each organ of elimination has its
Volume own clearance (e.g. hepatic clearance, renal
clearance).
Mass = Concentration * Volume • CL total = CL renal * CL hepatic * CL lungs
• Renal clearance (CL) represents the volume of
Amount of drug absorbed= plasma concentration * blood cleared by the kidney per unit time and is a
Apparent volume of distribution constant for drugs with first-order elimination
kinetics.
20 mg
I.V dose = ----------- * 40L = 800 mg

239
 • Total body clearance equals renal plus nonrenal • Drug interaction
clearance. An important relationship is Cl = k × • Distribution and binding characteristics of the drug
Vd.
• Glomerular filtration rate (GFR): is used to make Ionization
clinical decisions regarding drug dose and choice • Many drugs are weak acids or weak bases and can
• Cl = GFR when there is no reabsorption or exist in either nonionized or ionized forms in an
secretion and no plasma protein binding equilibrium, depending on the pH of the
• The advantage of the clearance approach is that environment and the pKa (the pH at which the
clearance applies to all elimination rate processes, molecule is 50% ionized and 50% nonionized)
regardless of the mechanism for elimination • The ionized form is better renally excreted because
• Clearance (Cl) is the volume of blood cleared of it is water soluble.
drug per unit of time
• Cl is constant in first-order kinetics Weak acids Weak bases
phenobarbital, methotrexate, TCAs, amphetamines
aspirin (salicylates)
Rate of drug elimination Treat overdose with sodium Treat overdose with ammonium
CL =------------------------------- = vd X ke bicarbonate to alkalinize urine. chloride to acidify urine.
(elimination rate)
Plasma drug concentration
Drug Half-life
Definition
•Protein-bound drug is not cleared; Cl = free
• Time required for the body to eliminate 50% of the
fraction × GFR
drug
• In addition, for first-order elimination processes,
• Time it takes from the initial concentration C0 to
clearance is a constant, whereas the rate of drug
reach t1/2
elimination is not constant
• 95% of the drug is always eliminated after 4.5
Common clearance pathways
half-lives
1. Renal clearance: Urine (most drugs)
2. Hepatic clearance: Bile (most drugs)
0.693 0.693 * Vd
3. Pulmonary clearance: Air (Inhaled anesthetics)
t1/2 = -------------- =---------------
Creatinine clearance 10
• Volume of blood plasma that is cleared of
8
creatinine per unit time and is a useful measure for
Plasma Conc

GFR 6
• Can determine renal function
4
2
0
0 2 4 6
Time

Ke CL

• t ½ is inversely proportional to Ke
• Where CL clearance and Ke first order
elimination rate constant
• The clearance of the drug (CL) refers to the rate at
which the body eliminates the drug from the body
• The volume of distribution (Vd) refers to the
distribution of the drug around the body
• Liver and kidney disease patients may have
Factors affecting renal clearance problems of excreting a drug
• Drug plasma concentration • Difficulty of excreting a drug increases the half-
• Blood flow to the kidney life and increases the risk of toxicity

240
Clinical significance of t1/2 Key Points:
• It helps determine how much of a drug needs to be • Think of AUC I.V as the amount of drug in plasma
taken and how frequently it needs to be taken if a if 100% had been absorbed = Total mass of the
certain average amount is needed constantly drug administered = Dose before absorption
Elimination half-life:
• Provides an accurate indication of the length of • Think of AUC P.O as the actual amount of drug that
time that the effect of the drug persists in an gets into plasma (Mass after absorption)
individual.
• The greater the half-life of the drug, the longer it Question: Bioavailability
takes to excrete • Metoprolol is a drug that works on the heart. The
• Elimination depends on the amount of the drug oral bioavailability is 50%. If the standard I.V dose
delivered to the liver or the kidney per unite time is 5o mg, what should be the oral dose?
• The greater the Vd the higher the half -life of the • (Assume our goal is to reach the same plasma drug
drug, the longer the duration of action concentration)
Elimination rate constant (K):
• The rate of drug elimination from the body as a Answers
fraction. Method 1 (Wrong)
• This value is constant in first-order kinetics, and
independent of drug concentration AUC route
---------- = Bioavailability (route)
Time Plasma Drug Remaining AUC IV
Conc
0 hr 8 mg/L Fraction % AUC P.O = AUC I.V * Bioavailability (P.O)
1 hr 4mg/L 1/2 50%
2 hr 2 mg/L 1/4 25% (75% AUC P.O (Actual mass in plasma) = 50 mg (total
metabolized) mass given) x 0.5 = 25 mg
3 hr 1 mg/L 1/8 12.5% • In this case if I administered a dose with a total
4 hr 0.5 mg/L 1/16 6.25% mass of 50 mg P.O, after absorption I would only
have 25 mg in my plasma
5 hr 0.25 mg/L 1/32 3.125%
Method 2:
t1/2 definition in zero and first order kinetics
• The order of a reaction refers to the way in which Mass (Actual Plasma Mass) = Mass (Total mass Admin) *
the concentration of drug or reactant influences the
Bioavailability (route)
rate of a chemical reaction. For most drugs, we
Mass After Absorption Mass before Absorption
need only consider first-order and zero-order.
F
• In the zero-order kinetics model that a constant
amount of drug is eliminated per unit time, so the Mass (Actual plasma Mass)
half-life of zero-order kinetics will change with the Mass (Total mass admin-p.o) = --------------------------------
concentration of the drug Bioavailability P.O
• because in first-order kinetics, a constant
proportion is metabolized, the half-life is constant 50mg
for a specific drug Mass (Total administered dose) = --------------- = 100 mg
Drug Absorption overview 0.5
Measurement of Bioavailability
Bioavailability • Pharmacokinetics method:
• The fraction (percentage) of an administered • Based on the assumption that pharmacokinetics
dose of unchanged medicine that reaches the blood profile reflects the therapeutic effectiveness of a
stream (systemic circulation). drug
• Intravascular doses have 100% bioavailability, f = • Plasma level time studies:
1. Based on the assumption that there is a direct
relationship between the concentration of drug in
Main determinates blood or plasma and concentration of drug at the
1. Route of administration site of action
2. Properties of the drug

241
Drug Absorption overview
Overview
• Pharmacokinetics: The change in drug
concentration as it moves through the different
compartments of the body
• Absorption: the movement of a drug from the site
of administration to bloodstream.
• Absorption depends on the route of administration
• Concentration = Drug Mass/ Volume
• Mass= Amount of drug (Units =mg)
• Volume (Units= L, mL, CC)
• Blood volume = 5L Bioavailability of IV vs oral route
• Plasma volume PV = (Blood)- (Cells)= 2.5 L • Upon injection, an active substance reaches the
• PV= BV. (1-HCT) target site after passing the blood circulation.
• 1 CC= 1 Cubic centimeter = 1 ml • So, if 75 milligram (mg) of active substance is
injected into the bloodstream, then 100%
Example corresponds to 75 mg active substance.
• A 10 mg dose of drug X is 100% absorbed, what is • After a tablet or capsule is swallowed, it reaches
the plasma drug concentration? the stomach, then passing through the intestine till
• Amount of drug is 10 mg it reaches the liver.
• Plasma= 10mg/ 2.5L = 4mg/L
• Case1= I.V bolus + 1 Compartment (Plasma) + No
Elimination
• 1 compartment means no distribution
• The goal to administer the drug intravenously to
reach the systemic circulation
• Let’s say total volume 10ml and concentration in
the syringe is 1mg/ml
• Volume in needle 10ml
• Conc in needle 1mg/ml • The amount that actually reaches systemic
• Then amount of drug given (mass) =10 mg circulation (Absolute bioavailability) by oral route
• Blood volume = 5L is extremely low in comparison to IV injection.
• Plasma volume PV = (Blood)- (Cells)= 2.5 L
• Plasma concentration = 10mg/2.5L= 4mg/L
• Note: Serum = Plasma – Clotting factors
• Case2= PO + 1 Compartment (Plasma) + No
Elimination
• The goal to administer the drug by mouth to reach
the systemic circulation
• It will pass to the stomach then to intestine, in this
case we will lose some drug till reach the
circulation
• If we start with 10mg and for example we lost 5
mg, how much drug left?
• Plasma drug concentration= (5 mg remaining)/
(Plasma volume 2.5 L) Bioavailability
• The final drug concentration= 2mg/L • The fraction (percentage) of an administered
• So, when we compare both I.V and oral route, we dose of unchanged medicine that reaches the blood
find the drug concentration achieved by I.V is stream (systemic circulation).
higher (4mg/L) compared with (2 mg/L) • Intravascular doses have 100% bioavailability, f =
1.
• Area under the curve (AUC): Represents the total
drug exposure across time.

242
 -------------------------------
Plasma drug Concentration

• We used the terminology of volume of distribution

to highlight the unbounded fraction of the drug or
how much drug stays in patient´s bloodstream
• The higher Vd, the higher the bounded fraction to
protein in the blood stream
• Drugs that have relatively small Vd (e.g. 5 L)
largely stay in the plasma compartment. Drugs
with a Vd of 15L distribute throughout vascular
and extracellular fluid compartments.
• When drugs bind non-specifically to proteins, their
movement is limited. That is because the large
proteins to which they are bound will not be able
to readily distribute to other parts of the body.
• Drugs will be more quickly distributed to areas of
the body that receive large amounts of blood flow
(e.g. heart, kidneys) than to areas that receive little
blood flow (e.g. skin, adipose)
• Drugs with high plasma protein binding and
narrow therapeutic range, e.g., warfarin and
phenytoin, are prone to drug interactions.

10 mgExample
10 mg Distribution
Case 3 = I.V. bolus + (Plasma+ Extravascular
compartments) + no elimination
Drug Distribution overview
Overview Plasma = 2.5 L
Vascular
• Pharmacokinetics: The change in drug Endothelium
concentration as the drug moves through the
different compartments of the body
Endothelium
• Components of pharmacokinetics: Absorption,
Distribution, Metabolism, Excretion

Mass Extra-vascular = 7.5 L

C= ---------
Volume
Mass
Mass (Actual absorbed mass) = Mass (Total mass admin) * C= -------------
Bioavailability Volume

If given I.V =1 =100% 10mg 4 mg

At t= 0 hr C0= ------------- = ----------------
Distribution Volume L
• The dispersion of a drug throughout your body
from the vascular space into extravascular space Total Mass Absorbed
• Examples of extravascular space: Fat, Muscle, C ideal = ---------------------------------------------------
Interstitial space Volume vd which the drug is distributed
• Distribution is where the drug goes after it is
absorbed and is usually discussed as the volume of
distribution (Vd).

vd = Amount of the drug in body 10mg 10 mg 1 mg

243
At t= 1 hr C1= ------------- = ---------------- = ----------- Clearance CL
- • Volume of plasma that is cleared of drug per unit
2.5 L+7.5 L 10L L of time through the kidney
• Constant fraction of VD in which the drug is
Total Mass Absorbed 10mg contained that is excreted by the kidney per unit of
Vd = --------------------------------------------------- time
Cplasma • Cl is constant in first-order kinetics

• The ideal situation assuming the drug

concentration is the same on both sides Excretion rate
CL rate = -------------------------
• Apparent Vd of plasma protein–bound drugs can plasma concentration
be altered by liver and kidney disease ( protein
binding, Vd). • Consider the mass balance of drug cleared by the
kidney and ultimately excreted in urine
Vd Compartment Drug types • Rate of drug passing through the kidney = rate of
Low Intravascular Large/ Charged molecules, drug excreted in urine
plasma protein bound
Medium ECF Small hydrophilic molecules • ClR X Cp = Qu X Cu
High All tissue including fat Small lipophilic molecules • ClR = renal clearance
• CP = plasma drug concentration
Distribution barriers: • Qu = rate of urine flow
• Blood–brain: permeable only to lipid-soluble drugs • Cu= urine drug concentration
or those of very low molecular weight. Example:
levodopa versus dopamine Qu X Cu Excretion rate
• Placenta: Most of drugs cross through placenta ClR = ------------------ = -------------------
Cp Cp

Rate of (filtration+ secretion- reabsorption)

ClR = --------------------------------------------------------
Plasma drug concentration

Clearance ratio → indication for the mechanism of renal

excretion of the drug

Effect of rate of urine flow on tubular reabsorption and renal

drug secretion
• Rate of urine flow (normal 1-2 ml/ min) will
Renal clearance influence the amount of drug which is reabsorbed
Renal excretion = filtration- Reabsorption + secretion • Urine flow increases→ time for reabsorption
decreases→ drug excretion promoted large fluid
Filtration: intake, use of diuretics etc. increases urine flow
• Metabolized or non-metabolized substances and decreases drug reabsorption.
• Only free drug can be filtered (unbound to
albumin) Glomerular Filtration Rate
• Glomerular filtration rate (GFR) is the measure
Reabsorption: that describes the total amount of filtrate formed
• Lipid soluble drugs cross GIT tract by all the renal corpuscles in both kidneys per
• Phase I and phase II Change the drug and make it minute.
polar so prevent • The glomerular filtration rate is directly
proportional to the pressure gradient in the
Secretion: glomerulus, so changes in pressure will change
• Secretion involves the transfer of hydrogen ions, GFR.
creatinine, drugs, and urea from the blood into the
collecting duct, and is primarily made of water.

244
 • GFR is also an indicator of urine production, • Examples: Atorvastatin, rosuvastatin and
increased GFR will increase urine production, and Simvastatin
vice versa. • Statins is usually metabolized by CYP 3A4
• GFR is equal to the Clearance Rate when any • The interaction is caused by an organic compound
solute is freely filtered and is neither reabsorbed in grapefruit known as furanocoumarin
nor secreted by the kidneys. • CYP3A4 inhibited by furanocoumarins lead to
• The rate therefore measured is the quantity of the increase statins blood concentration
substance in the urine that originated from a
calculable volume of blood Statins and Anti-acids (H2 blockers)
• CYP3A4 inhibited by cimetidine that lead to
Urine concentration X Urine flow increase statins blood concentration
GFR =------------------------------------
Plasma concentration Statins and Macrolides
• Examples: Azithromycin, clarithromycin
• Cl = GFR when there is no reabsorption or • Macrolides are also moderate to potent inhibitors
secretion and no plasma protein binding of CYP3A4.
• Creatinine clearance rate (CCr or CrCl) is the
volume of blood plasma that is cleared Competitive inhibition Statins
of creatinine per unit time and is a useful measure Drug-drug interactions of statins
for approximating the GFR. Statins and grapefruit
• Inulin clearance is used to estimate GFR because it • Statin drugs, also known as HMG-CoA reductase
is not reabsorbed or secreted. inhibitors, work by blocking the enzyme that your
• A normal GFR is close to 120 mL/min. body needs to produce cholesterol
• Examples: Atorvastatin, rosuvastatin and
Chronic kidney diseases Simvastatin
• Risk factors for kidney disease include: • Statins is usually metabolized by CYP 3A4
1. Diabetes • The interaction is caused by an organic compound
2. High blood pressure in grapefruit known as furanocoumarin
3. Family history, older age, ethnic group and • CYP3A4 inhibited by furanocoumarins lead to
smoking increase statins blood concentration.
Competitive inhibition Statins

Drug-drug interactions of statins

Statins and grapefruit

Statins and Macrolides

• Examples: Azithromycin, clarithromycin
• Macrolides are also moderate to potent inhibitors
of CYP3A4
• Statin
drugs, also known as HMG-CoA reductase First and zero order elimination
inhibitors, work by blocking the enzyme that your
body needs to produce cholesterol
Zero-order elimination First-order elimination

245
 •  Plasma drug concentration→ no rate of drug metabolism •  Plasma drug concentration→  rate of drug metabolism
• Rate of metabolism becomes independent of drug concentration • Rate of metabolism is proportional to drug concentration
• Rate of drug metabolism is constant • Half-life is constant
• Rate of elimination is constant, regardless the drug • Rate of elimination is proportional to drug concentration
concentration • Constant fraction of the drug is eliminated per unite time
• Constant amount of the drug is eliminated per unite time • Drug concentration in plasma decreases exponentially with time
• Drug concentration in plasma decreases linearly with time • Examples: Most drugs at most doses
• Examples: Aspirin& Phenytoin& ETOH

4 0 2 (mg/L) / hr
Note: Half-life = Time to metabolize 50% of drug
• First order: constant proportion of the drug is
eliminated per time

10

Plasma concentration
8

0
0 1 2 3 4 5
Time (hr)

First order Vs zero order elimination

Time Plasma conc. Rate of Elimination=
• Zero order: constant amount of the drug is Units mg/L  (plasma)/  time
eliminated per time 0 8 (8-4)/1=4
1 4 2
10 2 2 1
Plasma concentration

3 1 0.5
8 4 0.5 0

6
First order-elimination rate constant and half life
4 • The elimination rate constant K is a value used in
pharmacokinetics to describe the rate at which a
2 drug is removed from the system
0
0 2 4 6 0.693 0.693 * Vd
t1/2 = -------------- =---------------
Time (hr) Ke CL
• t ½ is inversely proportional to Ke
• Where CL clearance and Ke first order
Time Plasma conc Rate of Elimination= elimination rate constant
Units mg/L  (plasma)/  time • The clearance of the drug (CL) refers to the rate at
0 8 2 (mg/L) / hr which the body eliminates the drug from the body
1 6 2 (mg/L) / hr • The volume of distribution (Vd) refers to the
2 4 2 (mg/L) / hr distribution of the drug around the body
3 2 2 (mg/L) / hr

246
 Time Plasma Conc Drug Remaining
0 hr 8 mg/L Fraction %
1 hr 4mg/L 1/2 50%
2 hr 2 mg/L 1/4 25% (75%
metabolized)
3 hr 1 mg/L 1/8 12.5%
4 hr 0.5 mg/L 1/16 6.25%
5 hr 0.25 mg/L 1/32 3.125%

9
8
Half-life = one hour• The enzymes involved in Phase I reactions are
7
primarily located in the endoplasmic reticulum of
6 the liver cell, they are called microsomal enzymes
Plasma Conc

5 • The function of these enzymes:

• introduce reactive and polar groups (Hydrophilic)
4 into their substrates by adding or unmasking
3 functional groups (-OH, -SH, -NH2, -COOH)
2 • Examples of Phase I reactions: Oxidation,
reduction, Alkylation, Decarboxylation and N-
1 Carboxylation
0 • One of the most common modifications is
0 1 2 3 4 5 hydroxylation catalyzed by the cytochrome P-450-
dependent mixed function oxidase system
Time
• Cytochrome P-450 enzymes are located in liver
cells
• Cytochrome P-450 enzymes are at least 33
c (t)= C0 x e -kt different cytochrome P450 (CYP) which are
grouped into 4 main families CYP1-CYP4
c (t 1/2) = ½ C0
• CYP 3A4, CYP 2D6 are the most common
-k t1/2 enzymes
½ C0 = C0 X e
CYP 3A4
ln (1/2) = ln (e-kt ½)
3: Family
-0.693 = -kt ½
A: Subfamily
4: Isozyme
0.693
------------ = t
• Cytochrome P450 enzymes are considered as
K
hemeproteins (containing heme and iron)
Half-life, clearance & Vd Drug + O2+ NADPH → Drug + H2O+ NADP+
• NADPH is supplied from pentose phosphate shunt
0.693 Clearance Total (reducing agent= losing electron)
t ½ = -------- Ke = -------------- • Produced as byproduct G-G-P → G-P-G
Ke Vd • Phase I can turn a nontoxic molecule into a
poisonous one
Other non-P450 phase I reaction
Volume of blood that gets filtered of drug Alcohol metabolism
Clearance Total =-----------------------------------------------= • Alcohol dehydrogenase
L/ hr • Genetic polymorphism might exist
Time Monoamine oxidases
• Metabolism of endogenous amine
Vd= Volume that the drug appears to be distributed in neurotransmitters (dopamine, norepinephrine, and
serotonin)
Decrease Vd means drugs likes to stay in the plasma Hydrolysis

Phase I metabolism
247
 • Genetic polymorphism exists with Pharmacogenomics& Enzymatic polymorphism
pseudocholinesterase Overview
• Example: local anesthetics and succinylcholine Polymorphism
• Genetic differences in drug metabolism are the
Phase II metabolism & Conjugation result of genetically based variation in alleles for
• Conjugation with endogenous substrate (enzymes genes that code for enzymes responsible for the
transferases) to further increase aqueous solubility metabolism of drugs.
• The genes contain abnormal pairs or multiples or
abnormal alleles leading to altered enzyme
function.
• Single nucleotide polymorphism (SNP) Single
changes in one allele of a gene responsible for a
variety of metabolic processes including enzymatic
metabolism

Aldehyde dehydrogenase
• Polymorphic enzyme responsible for the oxidation
of aldehydes to carboxylic acids
• ALDH1 and AlDH2 are the most important
enzymes for aldehyde oxidation
• ALDH2*1/*1 wild-type Homozygous
•
Conjugation with glucuronide, sulfate, acetate and • Heterozygous mutation is 100x slower
amino acid ALDH2*1/*2
• Phase II follows conjugation reactions • Homozygous mutation ALDH2*/*2 allele is non-
(transferases) functional and develops several side effects, also
• Phase II May follow phase I or occur directly increase likelihood of alcohol dependence
• 95% of tylenolol (acetaminophen) is metabolized Asian flush
by phase II enzymes • Buildup of toxic metabolite (Acetaldehyde) due to
• Carcinogenic agents usually catalyzed primarily by deficiency in ALDH2 enzyme
phase I drug metabolizing enzymes, typically • Acetaldehyde causes damage to DNA and proteins
cytochrome P450s. and leads to the inflammation that causes the face
• These reactive intermediates can induce DNA and to turn red when drinking alcohol.
RNA damage, and formation of protein adducts • 40% of east Asian population has ALDH2
• Phase II enzymes classically conjugate these deficiency
hydrophobic intermediates to a water-soluble • ALDH2 Deficiency are at significantly increased
group, thus masking their reactive nature, and risk of liver disease and cancers like esophageal
allowing subsequent excretion cancer and gastric cancer.
• The reactive species are often detoxified by phase
II drug metabolizing enzymes

Phase II metabolizing enzymes

• UDP-glucuronosyl transferases (UGTs)-
Glucuronidation
• Diseases associated with glucuronidation: Gray
baby syndrome
• Glutathione-S-transferases (GSTs)- Glutathione
(GSH) conjugation
• Depletion of GSH in the liver is associated with Clinical presentations
acetaminophen hepatotoxicity
• N-acetyltransferase (NAT) -Acetylation
• Genotypic variations (fast and slow metabolizers)
• Drug-induced SLE by slow acetylators with
hydralazine > procainamide> isoniazid (INH)

248
 Acetaminophen /Ethanol
• Chronic alcoholics are at increased risk of
paracetamol (acetaminophen) due to induction of
liver microsomal enzymes by ethanol with
increased formation of the toxic metabolite of
paracetamol.

Anti-seizures meds W/oral contraceptive

• Estrogens and progestogens (active ingredients in
oral contraceptives) are metabolized by
cytochrome P450 3A4.
• Nausea
• Anti-epileptic medications induce cytochrome
• Headache P450 3A4, leading to enhanced metabolism of
• Vomiting either or both the estrogenic and progestogenic
• Hypotension component of oral contraceptives, thereby
• Increase heart rate reducing their efficacy in preventing pregnancy
• Facial flushing
Rifampin (anti-TB) w/HIV meds
Disulfiram • 1/3 of the world has latent TB infection
• Blocks the removal of acetaldehyde from the body • Rifampin induced CYP450 that decrease blood
via ALDH inhibition levels of HIV medications and eventually ended by
treatment failure or viral resistance
Enzyme induction
St. john`s wort w/ allergy meds
Indications:
• Depression
• Anxiety
• Sleep disorders
• Premenstrual syndrome
• St. Johns is a herbal medication is used to
treatment of depression, but it’s not recommended
to take St. Johns with the following drugs
• Antidepressants because its side effects, for
example cause serotonin syndrome when
administered with SSRIs
• Also St. John's wort may reduce levels of
antihistaminic in the body, making them less
effective:
Enzyme induction
• Loratadine (Claritin)
• Increase in the amount of enzyme protein as a • Cetirizine (Zyrtec)
result of some stimulus, whereas enzyme
• Fexofenadine (Allegra)
repression refers to a decrease in enzyme after a
stimulus • St. Johns reduces the effect of digoxin and
increases the effects of sedatives
• Enzyme inductions is usually associated with
decrease in drug concentrations along with
increase metabolites (might be toxic)
• Examples of enzyme inducers (e.g. phenytoin,
carbamazepine, rifampicin) that increase the
ability of liver enzymes in metabolizing other
drugs

249
Adrenergic agonists

Overview:

Receptor Location Physiology

Alpha1 (α1) Vascular tissue • ↑ Heart contraction

smooth muscle • Vasoconstriction (↑BP)
• ↑ Bladder contraction

Alpha2 (α2) Sympathetic nerve endings • Inhibit NE release

• Vasodilation (↓BP)

Beta 1 (β1) Heart • ↑ Heart contraction

• ↑ BP

Beta 1 (β2) • Lung • Bronchodilation

• skeletal muscles • ↑ Uterine relaxation
• Uterine muscles • ↑ Blood Sugar

• Hypertensive urgency
• Opiate withdrawal (Addiction of Benzodiazepine
by preventing overactivation of the sympathetic
system)
• Diabetic autonomic neuropathy.
Side effects:

• Orthostatic hypotension
• Sedation
• Dry mouth
• Sexual dysfunction
Dobutamine (Selective β1agonist):
Mechanism of Action:
• Positive ionotropic agent enhances cardiac muscle
Phenylephrine (Selective Alpha-1 agonist): contractility therefore increase Cardiac output
Mechanism of Action: (↑CO)
• More action on β1>β2
Activation of α1 receptor leads to Increase intracellular Clinical uses:
calcium release- Vasoconstriction • Cardiogenetic shock (Hypotensive)
• Congestive heart failure CHF
Clinical uses:

• Nasal decongestant Side effects:

• Hypotension (Increase peripheral resistance- • Headache
increase Blood Pressure (BP) • Arrhythmia
• Mydriasis (Dilation of eye pupil) • Hypertension
Side Effects: Isoproterenol (β1&β2agonist):
Mechanism of Action:
• Rebound congestion if used for long term • Positive ionotropic agent (when bind to β1
• Headache (Hypertension) receptors) enhances cardiac muscle contractility
Clonidine (Selective α2 adrenergic agonist): therefore increase Cardiac output (↑CO)
Mechanism of Action: • When bind B2 smooth muscle relaxation decrease
total peripheral resistance(↓TPR)
• Bind to α2 receptors at the presynaptic terminal Clinical uses:
• Decreasing net sympathetic outflow though
prevention of NE reuptake which leads to decrease • Heart block/Bradycardia
total peripheral resistance -reduce BP Albuterol, Metaproterenol, Terbutaline (Selective
Clinical uses: β2agonist):
Mechanism of Action:

250
 Bind selectively to β2 receptors • Ipratropium bromide
• Glycopyrrolate
Clinical uses: • Benztropine
• Treatment of Asthmatic patients • Oxybutynin
• Asthma diagnosed by (bioconstruction--allergy-cough- Mechanism of Action:
swelling-short of breath) • Prevent Acetylcholine to bind to cholinergic
• Albuterol is a drug of choice for asthma due to its receptors
significant effect in relaxation of bronchi smooth muscle • Atropine is irreversibly block muscarinic
wall receptors
• COPD
Clinical use
• Bronchitis
Drug Organ Application
Ritodrine (Selective β2agonist):
Mechanism of Action:
Atropine Eye Mydriasis
Relaxation of uterine smooth muscle by binding to β2
receptors
Clinical Uses: Heart Treatment of Bradycardia
• premature labor-Reduce premature contraction
Epinephrine, Norepinephrine and dopamine (Mixed
adrenergic agonist):
Homatropine Eye Mydriasis
Mechanism of Action:
• Natural endogenous neurotransmitters
• Epinephrine stimulates α1α2,β1,β2
Clinical uses: Tropicamide Eye Mydriasis

• Acute anaphylactic reactions (Hypersensitivity

reactions). This effect mediated by Scopolamine CNC Motion sickness
➢ Binding to β2 mediated bronchodilation
➢ β2 mediated decrease in release of inflammatory
mediators
➢ β2 mediated α1, α2 resulted in vasoconstriction and Benztropine CNC Parkinson
decreases of mucosal edema
• Hypotension (shock) septic shock
• Respiratory stress (bronchodilation) Ipratropium Respiratory Asthma, COPD
• Glaucoma system

• Asthma
• Norepinephrine less effect on B2 (strong α1,2) Oxybutynin Genitourinary Urinary incontinence
used for:
• Hypotension (shock)
• Reduced renal perfusion
Glycopyrrolate GIT, Preoperative
Dopamine:
• At low doses, selectively bind to D1 receptors in Decrease GIT motility
the kidney resulting vasodilation and increase
renal blood flow
• At medium doses, bind to β1 receptors in the heart Note:
• At high dose binds to α receptors leading to • Atropine causes relaxation of the sphincter
vasoconstrictionClinical uses: muscle-Pupil dilation
• Hypotension • Atropine induces Cycloplegia
• Heart failure • Atropine uses to relief Bradycardia and AV
• Cardiogenic shock conduction block
Anticholinergic drugs: • Atropine, homatropine, Tropicamide used to
• Atropine/homatropine induce mydriasis prior to retinal exams
• Scopolamine • Ipratropium used to prevent bronchospasm
• Tropicamide associated with COPD and asthma

251
 • Glycopyrrolate is used as pre-operative medication
to reduce salivary & respiratory secretions
• Oxybutynin used to decrease urinary incontinence,
mild cystitis by reducing bladder spasm
Urinary incontinence more common in women
• Benztropine is used to treat Parkinson disease by
decreasing Acetylcholine effects
• Cogentin (benztropine) is a drug used as an
adjunct therapy in Parkinson's disease (PD) to
treat.

Adverse Effects:
• Blurry vision (Blind like a bat)
• CNS toxicity delusions, hallucinations (Mad as
hatter)
➢ Anticholinergic side effects are the most
common cause of drug
➢ -induced delirium in the elderly • Effect of Sympathetic and Parasympathetic on
• Decrease salivation, secretions (Dry as bone) different brain organs
Nervous System:
• Decrease sweating- Increased body temperature
(Hot as hell)
• Cutaneous vasodilation (Red as a beet)
• Tachycardia
• Bronchodilation decrease airway secretions.

Autonomic nervous system pharmacology

Outline:
• Nervous System
• Comparison between Sympathetic and
Parasympathetic
• Structural differences between Sympathetic and
Parasympathetic systems

Sympathetic Parasympathetic
Neurotransmitters • Epinephrine (E) Acetyl Choline (Ach)
• Norepinephrine (NE
Receptors Alpha 1 Muscarinic Receptors

Alpha 2 M1
Beta 1 M2
Beta 2 M3
M4
M5
Nicotinic Receptors

Nn (Neuronal)
Nm (Neuromascular)

252
Structural differences between Sympathetic and parasympathetic systems:

Structural comparison between Sympathetic and Parasympathetic:

Sympathetic Parasympathetic

Point of CNS origin Lumbosacral (T1-L5) Craniosacral, Cranial nerves (3,7,9.10)

Preganglionic Short Long
Release ACh Release ACh
Post-ganglionic Long to target Short on -Near target
Release NE Release ACh

Effect of Sympathetic and Parasympathetic on different brain regions:

Organ Sympathetic Parasympathetic

Eye Mydriasis Miosis

Heart ↑Heart rate ↑Contractility ↓Heart rate ↓Contractility

↑SV, AV node
Lung Broncho vasodilation Broncho constriction
GIT ↓ GIT motility ↑ GIT motility
Blood vessels Vasoconstriction Vasodilatation
Genitourinary system Inhibition of bladder contraction (Urination) Bladder contraction
Contraction of the uterus Relaxation of the uterus
Help ejaculation of the semen from penis Erection of the penis
Sweet glands Sweating
Adrenal glands Release of E, NE
Kidney Increase blood pressure (Increased renin release)
Skeletal muscles Increase contractility
Glycogenolysis
Pancreas Decrease in insulin secretion
Lipolysis in fat cells

Cholinergic drugs

Overview:
• Acetylcholine (Ach) is a preganglionic neurotransmitter for both sympathetic and parasympathetic system
• ACH is the postganglionic neurotransmitter for parasympathetic system
• Somatic nervous system uses Ach to induce muscle contraction through Nicotine receptors
• General steps for Ach synthesis:

1. Acetyl COA is added to choline to produce Acetylcholine

2. Acetylcholine is taken and stored inside the vesicles to protected from degradation
3. Once there is action potential, Ach will be released into synaptic cleft and bind to two types of cholinergic
receptors
➢ Muscarinic receptors (M)
➢ Nicotinic receptors (N)
Muscarinic receptors Nicotinic receptors

• Ganglia of peripheral Nervous system • Autonomic ganglia

• Heart • Adrenal medulla
Location • Smooth muscle • Neuromuscular Junction (NMJ)
• Brain

4. Acetylcholine is degraded by Acetylcholinesterase

Direct acting cholinergic drugs (Direct Agonist-Cholinergic agonist):
• Bethanechol.
• Carbachol.

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 • Pilocarpine.
• Methacholine.
Mechanism of Action:
Bind to cholinergic receptors like Ach
Bethanechol • postoperative ileus
• Stimulate bowl movement
• Stimulation bladder
contraction

Carbachol. • Glaucoma to initiate miosis

• Decrease intraocular
pressure

Pilocarpine • Open angle Glaucoma

(allow contraction ciliary
muscle of eye ball
• Stimulation secretion in the
lacrimal sweat and saliva
glands

Methacholine • Challenge test for asthma

diagnosis

Note:

• Methacholine challenge test or asthma challenge test

• Methacholine provoke bronchoconstriction, or narrowing of the airways lead to decrease FEV1, EV1/FVC ratio
Adverse Effects:
• Due to excessive cholinergic stimulation
• Decrease in blood pressure (stimulation of Vagus nerve)/Diarrhea
• Urination (increase bladder contraction)
• Miosis
• Bronchoconstriction

• Excitation of skeletal muscle

• Lacrimation
• Salivation and sweating
Indirect adrenergic agonist
Overview:
Indirect acting adrenergic agonists:
Amphetamine
Mechanism of Action:

• Increases the release of norepinephrine, dopamine & serotonin from nerve terminals
Clinical uses:

• ADHD (Attention deficit hyperactivity disorder)

• Narcolepsy
• Suppress appetite
Ephedrine
Mechanism of Action:

• Increases the release of norepinephrine, dopamine & serotonin from nerve terminals
Clinical uses:

• Urinary incontinence
• Bronchospasm
• Hypotension

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Cocaine
Mechanism of Action:
• Prevent the reuptake of monoamines such (NE, dopamine and serotonin) as into presynaptic neurons (constant
stimulation of NE)
• Act on α receptors -Vasoconstriction
• Sodium channel blocking properties (Local anesthesia)
• NOTE: Avoid using β-Blockers in patients with Cocaine overdose, because Cocaine induce unopposed α1 activation which eventually leads to massive
hypertension

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Chapter 7:

Cardiology

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Fetal Erythropoiesis the loop represent the opening and closure of the mitral and
Definition: aortic valves.
Erythropoiesis is the process of the production of red blood
cells. The main drive for erythropoiesis is tissue hypoxia. The pressure-volume pressure also gives important
information about some important cardiac parameters such
During fetal embryogenesis, new organs and tissues are
being developed and their oxygen demand increases. This as the systolic volume (SV), the end diastolic volume, end
systolic volume, end diastolic pressure, and end systolic
results in a state of relative hypoxia which activates
volume and pressure.
different signaling pathways such as SCF, GCs, BMP4 and
Hedgehog to activate erythropoiesis.
Differences between Fetal and Adult Hemoglobin:
There are few important differences between fetal and
adult hemoglobin, which can be found in the following
table.
Fetal hemoglobin adult hemoglobin
Composition α2γ2 α2β2
life span in days 80 120
affinity for oxygen Higher Lower
binding of 2,3-bpg Lower Higher
Figure 3: During diastolic filling, the volume of blood in
the left ventricle keeps increasing. Eventually, the mitral
The purpose of these differences is to facilitate the valve is closed and this represents the end of diastole.
extraction of oxygen from maternal hemoglobin to fetal Pressure starts building up in the left ventricle during
hemoglobin across the placenta. systole until a point where it surpasses that of the systemic
circulation and the aortic valve opens. Pressure stops
Organs of Fetal Erythropoiesis: building up, and volume is decreased until the end of
Fetal erythropoiesis occurs in different organs depending systole when the aortic valve closes. At this point, the
on the gestational age. pressure inside the left ventricle is still high, but because
systole has ended it will drop immediately to the baseline,
• The yolk sac is responsible for erythropoiesis in
the mitral valve opens, and diastolic filling starts. The
the first 3 to 8 weeks
stroke volume is equal to the end diastolic volume – the
• Instead of two α and two γ chains, hemoglobin
end systolic volume. Source:
produced by the yolk sac has two α and two ε
https://upload.wikimedia.org/wikipedia/commons/1/1c/Car
chains
diac_Pressure_Volume_Loop.jpg
• Liver takes over from 6 weeks to birth
• The spleen becomes able to produce red blood Pressure-Volume Loops in Pathologic Cardiac Conditions:
cells from the tenth week of gestation to the 28th Pathologies that have an impact on the cardiac cycle such
week as those associated with increased afterload, preload, or a
• The bone marrow starts erythropoiesis from the decrease in end systolic or diastolic volumes will result in a
18 weeks of gestation and during adulthood characteristic pressure-volume loop.
• While the bone marrow is capable of
erythropoiesis during fetal life after 18 weeks of The following examples of pathologies show how the
gestation, severe hypoxic stress during fetal life pressure-volume loop is different based on the
can shift erythropoiesis to the spleen. hemodynamic consequences of the pathology.
Pressure-Volume Loops in Cardiology
Definition
The pressure-volume loop is a diagram or a plot of
pressure versus volume. The work done by a pump system,
such as the heart, can be effectively assessed in terms of
efficiency from a pressure-volume loop.
Normal Pressure-Volume Loop
The normal pressure-volume loop is traced from the right
lower corner, to the top right corner, followed by going to
the left top corner, then the left bottom corner, and finishes
back at the right lower corner of the loop. The corners of

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 • And when the aortic valve closes and we end at
the end-systolic volume, it will be smaller than
normal
• Accordingly, the stroke volume is increased
Cardiac Cycle
Definition
The cardiac cycle is a group of events that occur
sequentially within the heart when the heart beats. It
describes how the blood circulates through pulmonary and
systemic circulations in relation to heart beating.
To understand the cardiac cycle, we need to use four
different diagrams:
Figure 4: Normal (black) and pathologic cardiac pressure-
volume loops. Source: • An illustration of the four heart chambers
https://commons.wikimedia.org/wiki/File:Cardiac_cycle_( • Pressure curves that show how the pressure
pressure_volume_loop).svg changes overtime
• Electrocardiogram
In the diagram above, we see three pathologies: • A phonogram to correlate all the above with the
different heart sounds
Blue Loop:
Atrial Systole
• The end-diastolic-volume is normal.
• This event starts at the end of diastole. The atria
• Pressure keeps building up during isovolumetric
contract to pump any remaining blood to the
contraction and it surpasses the pressure
maximum of the normal curve ventricles
• Because of this, you see a slight increase in the
• At some point, systolic ejection occurs but the
pressure inside the atrium, see the yellow curve,
remaining time of systole is much shorter
segment a
• The aortic valve closes earlier than expected, and
• An electrical impulse is generated from the SA
it goes down to baseline. The end-systolic volume
node which travels to the AV node. The atria
is much larger as compared to normal
contract slightly later than they are depolarized
• Accordingly, when afterload is increased, the
because they allow more blood to pour to the
aortic pressure is increased, the end systolic
ventricles first. Therefore, this part of the cycle
pressure is increased, and the stroke volume is
corresponds to the P and PR intervals on the ECG
decreased
• In normal conditions, this event should not be
• This might be seen in aortic stenosis
associated with any heart sounds. In patients with
Green Loop:
hypertrophic congestive heart failure, massive
• Here, it is better to start with the normal point of pulmonary embolism or cor-pulmonale, a fourth
the curve, where the end systolic volume is heart sound will be heard during this time period
• Volume keeps adding up and it surpasses that of of the cardiac cycle.
the normal curve, so the end-diastolic volume in
this pathology is larger than normal Isovolumetric Contraction
• The pressure changes are not significant or • This is the beginning of systole. The following
abnormal changes happen in the heart and are illustrated in:
• Accordingly, the main abnormality here is o The atrioventricular valves close
increased preload and an increase in stroke o This is the interval between the closure
volume of the atrioventricular valves and the
• This might be seen in aortic regurgitation, where opening of the semilunar valves
more blood is escaping into the left ventricle after • The pressure curve shows a rapid build-up in
the closure of the aortic valve pressure in the ventricle, red curve, which
Orange Loop: surpasses the diastolic arterial blood pressure, of
• Here, contractility is increased for some reason 80 mmHg
• More blood volume will be pumped out of the
o The opening of the semilunar valves is
heart
dependent on the ventricular pressure

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 surpassing the afterload pressure, i.e. the • The second heart sound, S2 “dup”, will occur
arterial pressure during this phase. It occurs due to the closure of
• On the ECG, this event corresponds to the QRS the semilunar valves. S2 is normally split because
complex, which is due to ventricular the aortic valve closes before the pulmonary
depolarization valve
• The normal heart sound, S1 “lub”, is heard during Rapid Ventricular Filling
this event. It occurs due to the closure of the • The AV valves open and blood flows rapidly
atrioventricular valves from the atria to the ventricles
Rapid Ejection • Accordingly, the ventricular volume is increasing
• This event can be seen as mid-systole rapidly whereas the ventricular pressure and atrial
• During this phase, the semilunar valves open and pressure are unchanged
a large amount of blood volume is pumped out of • This does not correspond to any ECG events
the ventricles in a short time period • In pathologic conditions where the ventricular
• On the pressure curve, if you trace the red curve filling is so rapid and vigorous, as occurs in
you see that the pressure is still rising in the dilated congestive heart failure, an abnormal S3
ventricles but now it matches that of the systemic might be heard
circulation. The peak of this pressure curve is Diastasis:
what we measure in systolic arterial blood
• Also known as reduced ventricular filling
pressure
• Any remaining blood in the atria flows to the
• This event does not correspond to any ECG ventricles until they are full, however this occurs
features or heart sounds more slowly
Reduced Ejection • The ventricular volume will increase further, but
• This event marks the end of systole slowly. No changes in ventricular or atrial
• Because the ventricles are undergoing pressure
repolarization and are at full contraction, the • No ECG events or heart sounds during this phase
pressure is not building up anymore. Instead, it Cardiac and Vascular Function Curves
starts dropping. As long as the pressure is above Definition:
that of the systemic circulation, the semilunar It has been known that cardiac function and systemic
valves will remain open. Once the pressure drops
vascular function are related to each other. The
below 80 mmHg for the systemic circulation, the experimental study of this interrelationship between these
aortic valve will close, and this marks the end of two systems resulted in the development of what is known
systole. as the cardiac and vascular function curves.
• You will see on the pressure curve that the
Cardiac Function Curves
pressure of the ventricles starts to drop during this
The cardiac function curve explains how cardiac output
phase and most of the blood is ejected. The nadir
changes depending on the right atrial pressure. Figure 1
of the volume curve corresponds to the end-
shows cardiac function curves in different conditions.
systolic-volume.
• This event corresponds to the T-wave on the ECG
• You would not expect to hear any heart sounds
during this period
Isovolumetric Relaxation
• This can be seen as the opposite of isovolumetric
contraction. Meaning, the ventricular pressure
will drop further, the atrioventricular and
semilunar valves are closed, and the myocardium Figure 5: In normal conditions, the red curve, you see that
is undergoing relaxation. The atria are being B is
at 0 mmHg pressure in the right atrium, cardiac output
filled with blood. approximately 5 L/min. If you increase the sympathetic
• The pressure curves will show a drop in nervous system tone, the contractility of the heart increases
ventricular pressure to almost zero, and no and cardiac output is increased. When you decrease the
change in ventricular volume, hence the name sympathetic nervous system tone, the contractility of the
isovolumetric. heart decreases and the cardiac output drops. Source:
• This does not correspond to any ECG events http://www.pathwaymedicine.org/cardiac-function-curve

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Conditions that alter the inotropy of the heart: Affected heart sounds:
• Right-sided heart sounds are more intense
• Increased catecholamines, digoxin, and exercise
increase inotropy Hand Grip
• Heart failure with reduced ejection fraction,
opioids, and sympathetic inhibition decreases Mechanism of effect of handgrip
inotropy • Hand grip increases the total peripheral resistance
Vascular Function Curves: • Afterload is increased
These curves try to explain how systemic venous return to • It becomes more difficult for blood to be ejected
the right atrium varies with right atrial pressure. See Figure from the left ventricle to the aorta
2. • Accordingly, forward murmurs will decrease in
intensity, whereas backward flow murmurs will
increase in intensity
Affected murmurs:
• Forward flow murmurs such as aortic stenosis
and HOCM will decrease in intensity
• Regurgitant murmurs such as mitral regurge,
aortic regurge, and ventricular septal defect
murmurs will increase in intensity
Figure 6: When the circulating volume or venous tone is
• The click of mitral valve prolapse will occur later
altered, you see that venous return to the right atrium is
also changed. Source: Second Phase of Valsalva Maneuver and Standing Up
http://www.pathwaymedicine.org/vascular-function-curve
Mechanism of effect
Conditions that alter venous return: • Decreased preload leads to less blood return to
the heart
• The right atrial pressure will be altered at a given • In HOCM, left ventricular volume is decreased as
cardiac output depending on how much blood is is stretching of the left ventricular walls
being return to the right atrium
• The left ventricular outflow obstruction is
• Increased fluid infusion or increased sympathetic increased
nervous system tone will result in increased
• The intensity of the HOCM murmur is increased
venous volume and venous tone respectively
• Because there is less blood to be pumped, the
• Acute hemorrhage will decrease the circulating
forward flow murmur of aortic stenosis is
volume
decreased
Conditions that alter the total peripheral resistance:
Affected murmurs
• Vasopressors increase the total peripheral
• Most murmurs will decrease in intensity
resistance
• Increased intensity of HOCM murmur
• Exercise decreases the total peripheral resistance
• Earlier onset of the mitral valve prolapse click,
Effect of Maneuvers on Heart Murmurs and Sounds
and the click will be louder
Inspiration
• While inspiration increases right-sided heart Rapid Squatting
murmurs, left-sided heart murmurs are increased Mechanism of effect
with expiration • Venous return will increase as is preload
Mechanism of effect of inspiration • Afterload is also increased
• Inspiration decreases the intrathoracic pressure • In HOCM, the left ventricular volume is
• Venous return increases increased as is stretching of the left ventricular
• Right atrial pressure decreases wall
• Preload is increased • The left ventricular outflow obstruction is
• Pulmonary blood volume increases decreased
• Blood flow from the pulmonary circulation to the • More blood is available to be pumped
left atrium decreases Affected murmurs
• Accordingly, right-sided heart murmurs will
increase intensity, whereas, left-sided heart
murmurs will decrease in intensity

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 • Most forward murmurs such as aortic stenosis Fetal Shunts and Their Importance
and backward murmurs like mitral regurgitation The following table summarizes the main fetal shunts and
will increase in intensity their importance to the fetus.
• The murmur of HOCM will decrease in intensity Shunt Importance to the fetus
• The click of mitral valve prolapse will be delayed ductus venosus Shunting of oxygenated blood from the umbilical
and softer vein to the inferior vena cava
Foramen ovale Shunting of oxygenated blood from the right
Fetal Circulation atrium to the left atrium to be pumped to the
Flow of Blood in the Fetal Circulation systemic circulation
ductus arteriosus Shunting of the deoxygenated blood from the
• The umbilical vein receives oxygenated blood main pulmonary artery to the descending aorta to
from the placenta: be delivered to the placenta via the umbilical
o PO2 is 30 mmHg arteries for reoxygenation

o Oxygen saturation is 80%

• Blood flows through the umbilical vein to reach In the next table, we show the fate of the different fetal
the liver: structures related to the circulatory system in postnatal life.
o Most of the blood is shunted via the
ductus venosus to the systemic fetal structure postnatal structure
Ductus venosus Ligamentum venosum
circulation bypassing the hepatic Ductus arteriosus Ligamentum arteriosum
circulation Foramen ovale Fossa ovalis
• Blood enters the inferior vena cava to reach the Urachus Median umbilical ligament
Umbilical arteries Medial umbilical ligaments
right atrium: Umbilical vein Ligamentum teres hepatis also
o Most of the blood is directed to the left known as round ligament
atrium via the foramen ovale
• Blood goes down to the left ventricle to be Transition from Fetal to Postnatal Circulation
pumped to the aorta to supply the systemic • At birth, the infant takes a breath
arterial circulation • Pulmonary arterial resistance is decreased →
• Deoxygenated blood from the body enters the blood can now go to the lungs from the
superior vena cava to reach the right atrium: pulmonary arteries
o The blood goes to the right atrium to be • Left atrial pressure becomes higher than the right
pumped into the pulmonary artery atrium → shunting from the right atrium to the
o The ductus arteriosus connects the main left atrium is no longer possible
pulmonary artery with the descending • Foramen ovale closes
aorta
• Oxygenation saturation becomes much higher
o Because fetal pulmonary artery
than that of the fetal circulation → less
resistance is high, most of the blood will
prostaglandins → closure of the ductus arteriosus
bypass the lungs and enter this shunt to
Patency of the Ductus Arteriosus
go to the descending aorta
• In some pathologies, you might want to close the
• The two umbilical arteries receive the
ductus arteriosus or keep it open
deoxygenated blood from the aorta and go to the
• For example, if the infant has an isolated patent
placenta for oxygenation
ductus arteriosus, you might think about
providing an intervention to close it.
Indomethacin promotes closure of the PDA
• On the other hand, you might want to preserve
the patency of the ductus arteriosus in some
congenital heart defects. You would administer
prostaglandins E1 or E2
Coronary Artery Circulation
Overview:
The circulation of blood in the blood vessels that supply
the heart is referred to as the coronary circulation. The
coronary arteries supply oxygenated blood to the heart
Figure 7: Fetal circulation. Source: muscle, whereas the cardiac veins drain blood from the
https://commons.wikimedia.org/wiki/File:2139_Fetal_Circ heart muscle.
ulation.jpg
• 5% of cardiac output

261
 • Resting myocardium extracts 70% of oxygen Left Circumflex Artery
from blood within the coronary arteries • Originates from the left coronary artery
• Working myocardium extracts 90% of oxygen • Supplies the lateral and posterior walls of left
• Coronary perfusion occurs during diastole ventricle
• During systole, coronary arteries are compressed. • Supplies the anterolateral papillary muscle
If the coronary arterial supply is insufficient, this • If occluded → lateral myocardial infarction,
can lead to ischemia anterolateral papillary muscle rupture
Left Anterior Descending Artery
• Originates from the left coronary artery
• Supplies the anterior two thirds from
interventricular septum, anterolateral papillary
muscle, and anterior surface of left ventricle
• If occluded → anterior myocardial infarction,
anterolateral papillary muscle rupture
• Most common site of coronary artery occlusion
Left Marginal Artery
• Originates from the circumflex artery
• Travels across the left margin of the heart to the
apex
Heart Sounds
Figure 8: Anatomy of the coronary arteries and blood Overview:
supply distribution of the heart. Source: Heart sounds are heard with a stethoscope during cardiac
https://diseasespictures.com/coronary-artery-disease/ examination. The normal heart sounds occur due to the
closure of the atrioventricular or semilunar valves. The
Right Coronary Artery abnormal heart sounds occur during diastole and are
• Originates from the aorta related to the dynamic filling of a pathologic ventricle.
• Supplies the SA node
Where to Listen:
• If occluded → bradycardia or heart block
In Figure 1, you can see the main places that you are
Right Marginal Artery
supposed to put your stethoscope on while auscultating the
• Originates from the right coronary artery
heart.
• Supplies the right ventricle
• If occluded → inferior wall myocardial
infarction/ischemia
Posterior Descending Artery
• Originates from the right coronary artery in 82%
of people
• Originates from the left circumflex artery in 8%
of people
• Originate from both right coronary artery and left
circumflex artery in the rest of people
Figure 9: A. Right upper sternal border. P Left upper
• Supplies AV node, the posterior one third of the
sternal border. T. Left lower sternal border. M. Apex
interventricular septum, posterior two thirds of
ventricles, and posteromedial papillary muscle • The aortic area or right upper sternal border lies
• If occluded → heart block, posterior wall between the first and second intercostal spaces
myocardial infarction/ischemia, posteromedial
• Opposite to it, the left upper sternal border is the
papillary muscle rupture pulmonic area
Left Coronary Artery
• If you go down to the left lower sternal border in
• Originates from the aorta the fourth intercostal space, you find the tricuspid
• Gives rise to the left circumflex artery, left area
anterior descending artery, and left marginal • Finally, you should finish your auscultation by
artery listening to the apex of the heart which is in the
• If occluded → massive anterolateral myocardial mid-clavicular line in the fifth intercostal space
infarction

262
Normal Heart Sounds: • Onset of symptoms in the 3rd or 4th decade of
Normal heart sounds are S1 “lub” and S2 “dub”. They life
occur due to the closure of the atrioventricular and • Prognosis is improved in patients who undergo
semilunar valves. S2 is normally split. surgical or percutaneous valve replacement/repair
• The 5-year survival rate, if unoperated and
S1:
severe, is 44%
• This sound occurs due to the closure of the Etiology and Pathophysiology
atrioventricular “mitral and tricuspid” valves • The most common cause is rheumatic fever
• It can be heard more clearly at the mitral or • Other less common causes include malignant
tricuspid area carcinoid disease, SLE, and rheumatoid arthritis
S2: • Normal mitral valve orifice area is 4 to 6 cm2
• Symptoms start to occur when the mitral valve
• This sound occurs due to the closure of the orifice area is 2.5 cm2 or less
semilunar valves “aortic and pulmonic” • Left atrial pressure increased → transudation of
• Because the aortic valve closes before the fluid into lung interstitium
pulmonic valve, there is splitting • Hemoptysis can occur
• It can be heard in the upper right or left sternal • Pulmonary hypertension can develop because of:
borders clearly • Retrograde transmission of left atrial pressure
Abnormal Heart Sounds: • Pulmonary arteriolar constriction
When the left ventricle is stiff, or the left ventricle is • Obliterative changes in the pulmonary
dilated/there is increased return of blood to the left vasculature
ventricle, additional abnormal heart sounds might be heard. • Pulmonary interstitial edema
S3: Clinical Findings:
• When the condition progresses, patients develop
• During rapid ventricular filling, after S2, a third dyspnea and fatigue
sound can be heard in patients with: • Atrial fibrillation due to left atrium dilatation
o Dilated congestive heart failure • Hemoptysis
o Massive pulmonary embolism • Symptoms and signs of right heart failure because
• It occurs due to rapid and vigorous flow of blood of severe pulmonary hypertension → very late in
from the left atrium to the left ventricle the disease process
S4: • In Figure 1, you can see the main places that you
are supposed to put your stethoscope on while
• During atrial systole, right before S1, a fourth auscultating the heart.
heart sound can be heard in patients with:
o A stiff left ventricle
o Congestive hypertrophic heart failure
It occurs due to the striking of the stiff ventricle by the
blood ejected from the left atrium during atrial systole.
Valvular Heart Disease: Mitral Stenosis
Definition
• Mitral stenosis occurs when the mitral valve Figure 10: A. Right upper sternal border. P Left upper
opening is narrowed. Blood flow from the left
sternal border. T. Left lower sternal border. M. Apex
atrium to the left ventricle is obstructed. Because
the mitral valve is open during diastole, you
• If you hear a diastolic murmur at the mitral area,
would expect to find abnormalities on the most likely diagnosis is mitral stenosis
auscultation of the heart during this phase.
• S1 is louder
Epidemiology
• There is a diastolic snap followed by the diastolic
• The currently estimated incidence is 1 in 100,000.
murmur
Because the most common cause of mitral
stenosis is rheumatic fever, and the later has been • The diamond-shaped low-frequency murmur is
declining, the incidence of mitral stenosis is also best heard with the bell of the stethoscope
declining. • A second murmur can be heard during atrial
systole
• Mitral stenosis is more common in females

263
Murmur Grading • Rheumatic fever and ischemic heart disease are
• Grade I: the murmur is barely audible other common causes of mitral regurgitation
• Grade II: The murmur is soft • Patients with acute mitral regurgitation have the
• Grade III: the murmur is easily audible following abnormalities:
• Grade IV: the murmur is loud o Increased end diastolic volume
o Decreased end systolic volume
o Increased total stroke volume
Note: The more severe the mitral o Most of the blood is pumped backward
valve stenosis, the earlier the into the left atrium
opening snap will be heard. o Accordingly, increased left atrial
pressure
o Preload is increased, whereas, afterload
is decreased
Diagnosis and Treatment
• Patients with chronic mitral regurgitation have
In addition to auscultation, echocardiography provides
the following abnormalities when
valuable information about the mitral valve pathology,
decompensated:
allow for the measurement of different parameters related
o Dilated left ventricle and left atrium
to hemodynamics, and can assess in determining the
o Decreased total stroke volume
severity of mitral stenosis.
o Higher end systolic and end diastolic
Treatment options include: volumes
o Elevated left atrial and left ventricular
• Decreasing preload with diuretics, beta-blockers, pressures
and calcium channel blockers o If untreated, cardiogenic shock
• Valve repair by a catheter Clinical Findings:
• Valve replacement • When the condition progresses, patients develop
Valvular Heart Disease: Mitral Regurgitation dyspnea and fatigue
Definition • Atrial fibrillation due to left atrium dilatation
Mitral regurgitation occurs when there is mitral valve • Hemoptysis
insufficiency, so that the mitral valves do not keep closed • Symptoms and signs of right heart failure because
during systole. This can be seen in patients with left of severe pulmonary hypertension → very late in
ventricular dilatation. The left atrium is also usually the disease process
enlarged in patients with mitral regurgitation. • Systolic dysfunction is rarely seen
In Figure 1, you can see the main places that you are
Epidemiology supposed to put your stethoscope on while auscultating the
Mitral regurgitation can be classified into acute and heart.
chronic. Chronic mitral regurgitation is seen in patients
with rheumatic fever, whereas, acute regurgitation might
be seen in patients with acute myocardial infarction. The
incidence of mitral regurgitation is 5 in 10,000.

• 2nd most common valvular disease

• Myxomatous degeneration is a more common
cause than rheumatic fever in the United States
• More common in females
Risk factors:
• Advanced age
• Low body mass index Figure 11: A. Right upper sternal border. P Left upper
• Renal disease sternal border. T. Left lower sternal border. M. Apex
• Prior myocardial infarction
• History of mitral valve stenosis • If you hear a holosystolic murmur at the mitral
area, the most likely diagnosis is mitral
Etiology and Pathophysiology: regurgitation
• The most common cause is myxomatous • S1 is normal, whereas S2 is unsplit
degeneration • Third heart sound, S3 gallop

264
Diagnosis and Treatment: In Figure 1, you can see the main places that you are
In addition to auscultation, echocardiography provides supposed to put your stethoscope on while auscultating the
valuable information about the mitral valve pathology, heart.
allow for the measurement of different parameters related
to hemodynamics, and can assess in determining the
severity of mitral regurgitation.

Treatment options include:

Medical treatment with nitrates or antihypertensives to
decrease afterload
Intra-aortic balloon counter-pulsation in acute MR with
hemodynamic instability
Anticoagulation for patients with atrial dilatation and atrial
fibrillation
Valve surgery for replacement or repair Figure 12: A. Right upper sternal border. P Left upper
sternal border. T. Left lower sternal border. M. Apex
Valvular Heart Disease: Tricuspid Regurgitation
• If you hear a holosystolic murmur at the tricuspid
Definition
area, the most likely diagnosis is tricuspid
• When there is damage to the tricuspid valve or regurgitation or ventricular septal defect
leaflets, tricuspid regurgitation can occur. Blood
• Third heart sound, S3 gallop
backflow through the tricuspid valve from the
Diagnosis and Treatment:
right ventricle to the right atrium.
• In addition to auscultation, echocardiography
Epidemiology
provides valuable information about the tricuspid
• The estimated incidence of tricuspid regurgitation
valve pathology, allow for the measurement of
is 9 per 1000 different parameters related to hemodynamics,
• Equal occurrence in males and females and can assess in determining the severity of
• Age of onset varies based on the etiology: tricuspid regurgitation.
• Ebstein anomaly: at birth or early childhood Treatment options include:
• Rheumatic valvular disease: 15 years and early
adulthood • When there is a structural deformity of the valve,
• Carcinoid, bacterial endocarditis, or heart failure: or significant destruction by bacterial endocarditis
older adults → annuloplasty or valve replacement
• The prognosis of the patient is dependent on the • If tricuspid regurgitation is secondary to left-
presence of pulmonary hypertension and dilated sided heart failure → treat left-sided heart failure
cardiomyopathy rather than on the mere presence to alleviate tricuspid regurgitation
of tricuspid regurgitation Valvular Heart Disease: Tricuspid Stenosis
Etiology and Pathophysiology: Definition:
• Acquired causes of tricuspid regurgitation Tricuspid stenosis is caused by rheumatic fever and is
include: rheumatic fever, endocarditis, carcinoid, usually associated with mitral and aortic stenosis. The
trauma, SLE, and right ventricular dilatation damaged tricuspid valve will allow regurgitation during
secondary to pulmonary hypertension systole in addition to the characteristic murmur heard
• Chronic tricuspid regurgitation → right because of stenosis in diastole.
ventricular volume overload
• If untreated → right-sided congestive heart Epidemiology:
failure: • The condition is rare and affects approximately
o Hepatic congestion 1% of the population
o Ascites • It is more common in females
o Peripheral edema • Mortality rate is 5%
Clinical Findings:
Etiology and Pathophysiology:
• Patients present with dyspnea on exertion
• Rheumatic valvular disease affects the tricuspid
• Orthopnea
valve and results in structural alterations
• Ascites
• This leads to improper excursion of the valve
• Peripheral edema
leaflets

265
 • Tricuspid valve stenosis always occurs with Valvular Heart Disease: Mitral Valve Prolapse
concomitant aortic and mitral valve stenosis Definition:
• Right atrial pressure increases → right atrial Because of the sudden tensing of the chordae tendinea, the
enlargement mitral valve might prolapse in late systole. This is the most
• Because of the elevated right atrial pressure, the common valvular lesion.
patient develops hepatomegaly and peripheral
edema Epidemiology
• Pulmonary blood flow is decreased • More common in people with heritable
connective tissue disorders such as Marfan and
Clinical Findings: Ehlers-Dantos syndromes
• Fatigue • It is found in up to 4% of the general population
• Signs suggestive of venous congestion: • Female to male ratio is 2:1
hepatomegaly and ascites • Most patients are asymptomatic, however up to
• Atrial fibrillation 10% progress to severe mitral regurgitation
• Dyspnea • Even if mitral regurgitation occurs, the prognosis
• Because the condition commonly occurs along is still excellent when compared to mitral
with mitral stenosis: regurgitation without history of mitral valve
o Hemoptysis and orthopnea are less prolapse
severe when compared to mitral stenosis Etiology and Pathophysiology
alone because of decreased pulmonary • The exact cause is unknown; however, it is more
blood flow common in people with inherited connective
In Figure 1, you can see the main places that you are tissue disorders
supposed to put your stethoscope on while auscultating the
• Myxomatous degeneration of the mitral valve
heart. leaflets → redundancy of the anterior and
posterior leaflets and chordal apparatus → mitral
valve prolapse in late systole
• If mitral regurgitation is severe → elevated left
atrial pressure and volume → atrial fibrillation →
pulmonary congestion → pulmonary
hypertension → right-sided heart failure
Clinical Findings
• Mitral valve prolapse can be primary or
syndromic
Figure 13: A. Right upper sternal border. P Left upper • Primary mitral valve prolapse rarely progresses to
sternal border. T. Left lower sternal border. M. Apex become symptomatic
• Symptomatic patients have symptoms and signs
• Increased intensity of the first heart sound due to mitral regurgitation
• In the tricuspid area, a tricuspid opening snap In Figure 1, you can see the main places that you are
followed by a rumbling low-frequency diastolic supposed to put your stethoscope on while auscultating the
murmur can be heard with the bell of the heart.
stethoscope
• The intensity of the murmur increases with
inspiration
Diagnosis and Treatment:
In addition to auscultation, echocardiography provides
valuable information about the tricuspid valve pathology,
allow for the measurement of different parameters related
to hemodynamics, and can assess in determining the
severity of tricuspid stenosis and concomitant mitral or
aortic valve disease. Figure 14: A. Right upper sternal border. P Left upper
sternal border. T. Left lower sternal border. M. Apex
Treatment options include:
• In the mitral area, you can hear a medium-pitched
Tricuspid stenosis requires valvular repair or replacement crescendo late systolic murmur after a mid-
of the valve systolic click
266
 • The murmur’s intensity increases when the contractility of the myocardium is decreased this
patient stands up can also lead to systolic dysfunction
• The murmur’s intensity decreases when the • Because of increased LV mass, the myocardial
patient does a hand grip maneuver oxygen demand increases. Coronary blood flow is
Diagnosis and Treatment: usually decreased, which leads to ischemia →
In addition to auscultation, echocardiography provides angina pectoris
valuable information about the mitral valve pathology, and Clinical Findings:
allow for the measurement of different parameters related • Syncope
to hemodynamics. • Angina
• Dyspnea on exertion
Treatment options include: In Figure 1, you can see the main places that you are
supposed to put your stethoscope on while auscultating the
• Asymptomatic patients with minimal disease heart.
require no treatment
• Patients with severe mitral regurgitation require
surgical management
Valvular Heart Disease: Aortic Stenosis
Definition:
The obstruction of the blood outflow across the aortic
valve is known as aortic stenosis. It is currently believed
that a period of latent asymptomatic aortic stenosis of 10 to
20 years precede symptomatic stenosis. Mortality is very
high. Figure 15: A. Right upper sternal border. P Left upper
sternal border. T. Left lower sternal border. M. Apex
Epidemiology:
• Aortic sclerosis is a precursor to calcific
• In the aortic area: a crescendo-decrescendo
degenerative aortic stenosis. It is present in up to
systolic ejection murmur and a soft S2. Ejection
30% of those older than 65 years
click might be audible
• The prevalence of aortic stenosis in the elderly is
• Murmur radiates to the carotid arteries
up to 9%
• S4 gallop
• Survival rate after the onset of symptoms in
Diagnosis and Treatment:
patients with severe aortic stenosis who are
In addition to auscultation, echocardiography provides
medically treated is 50% at two years
valuable information about the aortic valve pathology, and
Etiology and Pathophysiology:
allow for the measurement of different parameters related
• The etiology is age dependent. Etiologies that are to hemodynamics.
common in patients younger than 70 years of age:
from most common to least common Treatment options include:
o Bicuspid AV
o Rheumatic fever • Aortic valve replacement
o Degenerative calcific stenosis Murmurs
o Hypoplastic
o Unknown Aortic Regurgitation
• The etiology on those older than 70 years: from • Due to aortic root dilatation, bicuspid aortic
most common to least common valve, or damage to the aortic valve leaflets
o Degenerative
• Blood flows backward to the left ventricle during
o Bicuspid diastole
o Rheumatic fever
• If left untreated, can progress to left heart failure
o Hypoplastic
• Patients have a wide pulse pressure (SBP – DBP)
• Aortic valve stenosis → outflow tract obstruction
Characteristics of the murmur
→ increased LV systolic pressure → left
ventricular hypertrophy → normal systolic • High-pitched blowing early diastolic decrescendo
function but decreased diastolic compliance murmur
• If untreated → LV EDP rises → increased • S1 intensity is decreased
pulmonary capillary pressure → diastolic • See the following figure to know where the
dysfunction → decreased cardiac output. If the murmur is best heard

267
 • Rapid upstroke and depolarization
• Voltage-gated sodium channels open
Phase 1:

• Initial repolarization
• Voltage-gated sodium channels close
• Voltage-gated potassium channels begin to open
Phase 2:

Figure 16: The aortic regurgitation murmur is heard at the • A plateau phase
right upper sternal border, also known as the aortic area. • Calcium influx through voltage-gated calcium
Source: First Aid 2018 channels balance potassium efflux
• Calcium influx triggers release of calcium from
Patent Ductus Arteriosus sarcoplasmic reticulum → myocyte contraction
• The ductus arteriosus might remain open after Phase 3:
birth because:
o It is an isolated occurrence where the • Rapid repolarization
DA failed to close • Massive potassium efflux
o It has been kept open on purpose • Closure of voltage-gated calcium channels
because the infant’s life is dependent on Phase 4:
mixing between venous and arterial
• Resting potential
blood because of a congenital heart
defect • Increased potassium permeability via potassium
o The latter is achieved by administering channels
prostaglandins E1 and E2 In Figure 1, you can see the different phases of myocardial
o Also seen in congenital rubella or action potential.
premature babies
Characteristics of the murmur:

• Continuous machine-like murmur heard at the left

infraclavicular area
• S2 is obscured. Murmur is loudest at S2
• See the following figure to know where the
murmur is best heard

Figure 17: The different phases of the cardiac myocyte

action potential and related channels. Source:
https://commons.wikimedia.org/wiki/File:Action_potential
_ventr_myocyte.gif

Pacemaker Action Potential

Figure 2: The PDA murmur is best heard at the The SA and AV node show automaticity in generating
infraclavicular area. Source: impulses.
https://www.easyauscultation.com/cases-
anatomy?coursecaseorder=2&courseid=29 Phase 0:

Cardiac Conduction System • Upstroke

• Voltage-gated calcium channels open
Myocardial Action Potential
• Voltage-gated sodium channels are permanently
The bundle of His and Purkinje fibers are capable of
inactivated → delayed conduction velocity at AV
generating an action potential which is characterized by
node
five different phases:
The pacemakers of the heart do not have the phase 1 and 2
Phase 0: of the myocardial action potential.

268
Phase 3: o 100 msec delay → allows enough time
for ventricular filling
• Repolarization • Bachmann bundle
• Calcium channels are inactivated • Bundle of His
• Potassium channels are open → potassium efflux • Left and right bundle branches
Phase 4: • Purkinje fibers
SA node has the highest pacemaker rate, followed by the
• Slow spontaneous diastolic depolarization
AV node, bundle of His, and the slowest is from the
• Occurs due to If also known as funny current
Purkinje fibers and ventricles.
• If channels allow for slow sodium and potassium
influx The Purkinje fibers have the highest speed of conduction
• Responsible for the automaticity of SA and AV followed by the atria, ventricles and slowest at the AV
nodes node.
• Slop of phase 4 is decreased when acetylcholine
or adenosine are administered → bradycardia Pathway of Conduction: Depolarization
• The slop is increased when the sympathetic tone The order of depolarization is as follows:
is increased → faster depolarization →
tachycardia 1. SA node
Figure 2 shows the action potential of a pacemaker. 2. Atria → P-wave on ECG
3. AV node → PR interval on ECG
4. Bundle of His → Q from QRS complex
5. Right and left bundle branches → R from QRS
complex
6. Purkinje fibers → S from QRS complex
7. Ventricles → ST segment which is isoelectric
Repolarization:
The order of repolarization is as follows:

Figure 18: The different phases of a pacemaker action 1.The atrial repolarization occurs during the QRS
potential. Source: complex, hence it is not seen on ECG
2. The ventricles undergo repolarization from
https://www.cvphysiology.com/Arrhythmias/A004
outward to inward
3. Ventricular repolarization is responsible for the
Anatomy of the Cardiac Conduction System:
T-wave on ECG
Figure 4 shows the normal ECG.

Figure 19: Anatomy of the cardiac conduction system.

Source:
https://commons.wikimedia.org/wiki/File:Cardiac_conduct Figure 20: Normal ECG. Source:
ion_system.jpg https://commons.wikimedia.org/wiki/File:SinusRhythmLa
bels.svg
• SA node, near the entrance of the superior vena
cava Brugada Syndrome
o Dominant pacemaker of the heart
Definition
• AV node, in the posteroinferior part of the Brugada syndrome is a rare inherited disease that
interatrial septum predisposes the patient to ventricular fibrillation and
o Blood supply through the PDA, which
arises from the RCA in 80% of people
269
sudden cardiac death without significant or identifiable • Genetic testing to look for mutations in SCN5A
ventricular structural abnormalities. gene
• Electrocardiogram, which shoes three distinct
Epidemiology types of ECG as depicted in Figure 1
The estimated prevalence of Brugada syndrome is 0.14%.
Ethnic differences in incidence have been reported.

• Brugada syndrome is eight times more common

in men
o This is due to increased penetrance in
men
o The probability of inheriting a mutated
gene is equal in both genders
• Age of onset is from 30 to 50 years, i.e. young
men
• Age of sudden cardiac death as the presenting
feature is 41 years in average
• Brugada syndrome puts the patient at an Figure 21: ECG in Brugada syndrome. Type 1: pronounced
increased risk of polymorphic ventricular
elevation of the J point, covered type ST elevation, and an
tachycardia which can evolve into ventricular inverted T-wave in leads V1 and V2. Type 2: saddleback
fibrillation and cardiac arrest ST-segment elevation. Type 3: ST segment elevation is
Etiology and Pathophysiology less than 1 mm. Source:
• Mutations in the SCN5A gene which encodes the https://emedicine.medscape.com/article/163751-
voltage-gated sodium channel are reported in up workup#c1
to 30% of the cases
• Mutations in other genes that encode other Treatment
protein channels involved with the myocyte • Placement of an implantable cardioverter
action potential phases are reported in the defibrillator
remainder of the cases How to read an ECG:
• The mutations typically result in loss of function What is an ECG?
of the sodium channels, i.e. abnormal phase 0 and • The ECG (electrocardiogram) registers the heart’s
phase 1 electrical activity
• The loss of sodium voltage-gated channels is • The individual action potentials of the myocardial
more pronounced in the right ventricle → right cells are average and a final vector is measured
bundle branch block • Therefore, the ECG is the average of billions of
• A repolarization gradient is present in patients microscopic electrical signals
with Brugada syndrome which is responsible for • The three important components of ECG are:
ST segment elevations on ECG o P-wave which is atrial depolarization
Clinical Findings o QRS complex which results from
• Syncope ventricular depolarization
• Cardiac arrest o T-wave which represents ventricular
• Nightmares repolarization
• Family history of sudden cardiac death • The three important intervals on ECG are:
• Cardiac arrest occurs during sleep or rest | cardiac o PR interval which is due to AV node
arrest in HOCM occurs during exercise delay → prolonged in AV blocks
• Physical examination is normal o The ST segment which represents the
isoelectric depolarized ventricles →
Diagnosis: important in MI and other conditions
• Laboratory testing is essential to exclude where it can be elevated or depressed
electrolyte abnormalities known to present with o QT interval which can be prolonged in
ST segment elevations some conditions
• Patients with symptoms of acute coronary
syndrome should undergo CK-MB and troponin
testing

270
Before Starting to Read the ECG o III: observes from the left arm to the left
• You should always check the identification leg
information on the top left of the ECG to make o AVL: points to left arm
sure you have the right ECG for the right patient o AVR: points to right arm
• Check the ECG parameters which are o AVF: points to the feet
standardized as the following: • It is important to understand how an electrode is
• Paper speed: 25 mm/s → one small red square = observing the heart to understand:
0.04 ms → one large red square = 0.2 ms o Whether measured depolarization will
• Sensitivity: 10 mm/mV be a positive or a negative deflection
• Filter frequency → 40 Hz o The determination of the heart axis as
• The routine ECG should have six limb leads and we will see later
six chest leads Figure 2 shows the observation vectors of the six limb
• These important things are shown in Figure 1. leads.

Figure 23: How the different limb leads observe "look at

the heart". Source:
Figure 22: You should check the patient's identification https://nl.ecgpedia.org/images/8/8b/ECGafleidingen.jpg
information on top left in blue, the parameters of the ECG
on the bottom left underlined with yellow and that there are The 7+2 Plan
six chest and six limb leads. In most cases, only limb lead In Figure 3, we see a normal ECG. In order for us to be
II is given like a long trace. Source: familiar with the process of reading an ECG, we will refer
https://nl.ecgpedia.org/images/7/76/Normaal_ecg.jpg to this figure in each step.

ECG Electrodes
• There are four extremity electrodes and six chest
electrodes
• However, there are six limb leads and six chest
leads on the ECG
• Extremity electrodes:
o LA: left arm
o RA: right arm
o N: neutral and usually left leg Figure 24: Blue underline: step 1, dark-red line: step 2,
o F: left foot bright-red line: step 3, orange vertical lines: step 4. Steps 5
• The chest electrodes are electrodes V1 to V6 to 7+2 are explained in the text. Source:
How do we have four extremity electrodes but six limb https://en.ecgpedia.org/images/8/82/Nsr.jpg
leads?
Step 1: Rhythm
• It is easy to understand why we have six chest
• The goal of this step is to determine whether your
leads on the ECG
patient has a sinus rhythm or not
o Each chest electrode is measuring the
depolarization wave in one frontal plane • If there is a P-wave before every QRS complex,
one can assume this is a sinus rhythm
• Limb leads:
o I: observes from the right to the left arm • Refer to Figure 3, blue underline
o II: observes from the right arm to the o This ECG shows a p-wave before every
left leg QRS complex and therefore has a sinus
rhythm

271
Step 2: Rate o In our example, all of them are positive,
• Figure 3, dark-red line hence the heart axis is normal
• The next step is to determine the heart rate • Left heart axis deviation is when the heart axis is
• Method 1: counting the large red squares: between -30 and -90 degrees:
o Use the sequence 300-150-100-75-60- o Positive in lead I and negative in leads
50 II and AVF
o Count the difference between two QRS • Right heart axis deviation is when the heart axis
complexes is between 90 and 180 degrees:
o Work best for regular rhythms o Lead I is negative, whereas, lead AVF is
o If the second QRS complex is between positive
two lines, take the mean of the two Step 5: P-wave Morphology
corresponding numbers from the above • Now we go back to the blue underline in Figure 3
sequence to study the morphology of the p-wave
o Based on this method, the heart rate in • The morphology is important as it can indicate
Figure 3 is: right or left atrial enlargement
75 + 60 • A normal p-wave has the following
= 68 beats/min
2 characteristics:
• Method 2: counting small red squares and use the o Max height: 2.5 mm in leads II and III
following equation: o Positive in leads II and AVF and
1500 biphasic in V1
HR (beats/min) =
number of small squares o P-wave duration < 0.12 seconds
o HR from method 2 in our example will • In our example, we can conclude that the p-wave
be 1500/22 = 68 beats/min is normal in morphology
Step 3: Conduction Step 6: QRS Morphology
• In Figure 3, bright-red line, you see three • The QRS complex should be narrow as described
important intervals that are used to assess the before
conduction on an ECG: • Q-waves are minimal if present → if prominent,
o PR interval “from beginning of p-wave i.e. old MI
to start of QRS complex” which is • Micro-voltage QRS is one that is less than 5 mm
indicative of how fast AP is transmitted in height or depth in a chest lead
via the AV node → normal PR: 0.12 to • R wave propagation is important. It should
0.20 seconds become larger from V1 to V5. R wave should be
o QRS duration which indicates how fast at its maximum height in lead V5
the ventricles depolarize → should be • In our example, the QRS morphology is normal
really fast if depolarization occurs via Step 7: ST Morphology
the normal conduction pathway → < 0.1 • The ST segment represents ventricular
seconds repolarization
▪ Wide QRS complexes might • ST segment should be isoelectric as in our
be seen in LBBB, RBBB, or example
ventricular rhythms • Elevation of ST segment is indicative of acute
o QT interval which is indicative of how
ischemia, acute pericarditis, HOCM, PE, Brugada
fast the ventricles are repolarized → < syndrome, LVH or acute myocardial infarction
0.45 seconds in men and 0.46 seconds
• ST segment depression is seen in LVH with strain
in women
pattern, digoxin overdose, hypokalemia, and
• In our example, we can find the three intervals to ischemia
be as follows:
• T-wave morphology is also checked in this step
o PR interval: 0.12 second
• If you identify a T-wave abnormality such as a
o QRS duration: 0.08 second
o QT interval: 0.36 second flat T-wave or a negative T-wave, it must be
present in two consecutive leads to be considered
Step 4: Heart Axis
as abnormal
• This is depicted by the orange lines in Figure 3
• Our patient has normal T-wave morphology
• Look at the QRS in leads I, II, and AVF.
• The normal heart axis is in the direction of leads
I, II and aVF:

272
Step 7+1: Compare to a Previous ECG • Abnormal fast accessory pathway allows for
• Whenever examining an ECG, it is always faster conduction from atria to ventricle via
advisable to compare the current ECG with a bundle of Kent
previous one • The impulse bypasses the normal conduction
• You need to determine whether the patient has a pathway, the AV node
new abnormality or an old one • Because the action potential will also be
• Treatment is different for acute versus chronic conducted through the AV node but with delay,
arrhythmias you end up with the following characteristics on
Step 7+2: Conclusion the ECG:
• This is perhaps the most difficult step of them all o Delta-wave because the bundle of Kent
• You need to show a concise and well-written is faster in conduction
conclusion that shows the results of the o Shorter PR interval
previously mentioned seven steps o Widened QRS because the conduction
• The conclusion in our example is as follows: was in part via the accessory pathway
• “Normal sinus rhythm with HR of 68 beats/min, • This can result in reentry tachycardia →
normal PR, QRS and QT intervals, normal heart supraventricular tachycardia
axis, normal PR and QRS morphology, and no ST
segment abnormality”
Wolff Parkinson White Syndrome
Definition
Wolff Parkinson White (WPW) syndrome is a medical
condition characterized by the presence of one or more
atrioventricular accessory pathways. These pathways are
faster in conduction speed when compared to the AV node
and put the patient at an increased risk of orthodromic re-
entrant tachycardia and atrial fibrillation. Figure 25: Failure of normal insulation of the ventricles
and atria during embryogenesis result in the formation of
Epidemiology the accessory pathway depicted here. This accessory
• The estimated incidence of preexcitation pathway has a faster speed of conduction than AV node
syndrome in the United States is from 0.1 to 3 per and does not have a delay period. Source:
https://en.wikipedia.org/wiki/Wolff–Parkinson–
1000
White_syndrome#/media/File:WPW.jpeg
• Preexcitation syndrome is the presence of a delta-
wave on ECG without the other abnormalities
that are characteristic of WPW syndrome Clinical Findings
• The incidence of confirmed WPW syndrome in • Asymptomatic if the heart rate is normal
the united states is 4 per 100,000 per year • When supraventricular tachycardia develops:
Location of the accessory pathway from most common to o Palpitations
least common: o Dizziness
o Dyspnea
• Left free wall o Presyncope
• Posteroseptal Diagnosis
• Right free wall The ECG shows the characteristic delta-wave when in
• Anteroseptal sinus rhythm. Patients with atrial fibrillation and WPW
Most patients with WPW syndrome will develop a syndrome will have a rapid polymorphic wide-complex
reciprocating tachycardia. Up to 30% of them will also tachycardia that is irregular. This is a dangerous arrhythmia
develop atrial fibrillation. Only 5% of WPW syndrome and most antiarrhythmics are contraindicated.
patients develop atrial flutter.

• There is a slight male to female predominance

• Onset is usually in infancy or early childhood
• The prognosis is excellent if the syndrome is
recognized and treated Figure 26: Delta-wave in a patient with WPW syndrome.
Also notice the shortened PR interval. Source:
Etiology and Pathophysiology https://en.ecgpedia.org/wiki/Ventricular_pre-
• This is a congenital defect excitation_(Wolff-Parkinson-White_pattern)

273
Treatment: Pathophysiology:
Patients with atrial fibrillation and WPW syndrome:

• Procainamide or amiodarone
• Avoid: adenosine, diltiazem, verapamil, or beta-
blockers → block AV node and facilitate
conduction via accessory pathway
Definition treatment:

• Radiofrequency catheter ablation

Atrial Fibrillation
Definition
Atrial fibrillation is a supraventricular tachycardia where
there is uncoordinated activation of the atria that is irregular
Figure 27: Mechanism of re-entry current in the
and does not originate from the SA node and is associated
pathogenesis of atrial fibrillation.
with rapid ventricular response. The rapid, irregular
ventricular response can cause hemodynamic compromise.
• Multiple micro-re-entry automatic areas or
Epidemiology circuits are present in the atria
• Atrial fibrillation is the most common cardiac • Some of these APs are conducted via the AV
arrhythmia node, others are blocked → chaotic rapid
• It is associated with a five-fold increase in the ventricular response
risk of embolic stroke • Patients with such micro-circuits are more likely
• It worsens the prognosis of heart failure and to develop atrial fibrillation when under
myocardial infarction sympathetic nervous system activation
• The prevalence increases with age • The atria no longer contract → blood stasis →
clot formation
Etiology and Pathophysiology
Common causes of atrial fibrillation: Clinical Findings
• Patients can be asymptomatic
• Cardiac causes: • Most common symptom is palpitations
o Myocardial infarction or ischemia • Patients have an irregularly irregular tachycardia
o Hypertension on palpation of the pulse
o Epicardial disease, myocarditis, or • Symptoms and signs suggestive of the etiology:
endocarditis o Heat intolerance, hypertension,
o Heart failure agitation, tremors → hyperthyroidism
o Iatrogenic: post ablation, o Angina → myocardial
catheterization, surgery, or device ischemia/infarction
implantation • Symptoms or signs suggestive of embolic disease
o Atrial septal defect → atrial dilatation such as stroke
o Ebstein anomaly → atrial dilatation • Hypotension and syncope → hemodynamic
o Dilated cardiomyopathy and valvular compromise
disease → atrial dilatation
Diagnosis
• Noncardiac causes:
o Antiarrhythmics • Laboratory testing help in identifying the cause.
o Beta agonists → sympathomimetics Check electrolytes, troponins, CK-MB, thyroid
o Drugs that increase QT interval function tests, and liver and kidney function tests
o Electrolyte abnormalities • Imaging of the heart with echocardiography to
o Sarcoidosis exclude structural heart disease, valvular disease,
o COPD and intra-atrial thrombi
o Pneumonia • ECG: using the 7+2 step plan:
o Pulmonary embolism o Absent p-waves
o Obstructive sleep apnea o Atrial rate: 400 to 600, ventricular rate
o Hyperthyroidism is 75 to 175 beats/min
o QRS duration is narrow →
supraventricular tachycardia with AV
nodal conduction

274
 o Heart axis might point to left or right o Flecainide
depending on the cause → left • Electrical cardioversion
ventricular hypertrophy → left axial • Radiofrequency catheter ablation
deviation Anticoagulation: see table below:
o QRS might show evidence of old MI, or
%
LVH stroke
o ST segment could be depressed → Item Score Total Recommendations
per
ischemia, or elevated → infarction year
CHF 1 0 0 Aspirin
o T-wave inversion → acute myocardial Hypertension 1 1 1.3 Aspirin +
infarction as the cause of atrial clopidogrel
fibrillation Age > 75 years 2 2 2.2
Warfarin:
DM 1 3 3.2
o Comparison to a previous ECG is Stroke or TIA 2 4 4
INR 2 to 3
important for categorization MI or PAD 1 5 6.7
Or:
Age 65 – 74 1 6 9.8
Apixaban,
years
dabigatran,
Female 1 7 9.6
edoxaban,
8 6.7
rivaroxaban
9 15.2
CHA2DS2VASc score: C: CHF, H: Hypertension, A2: age
above or equal to 75 which takes two points, D: DM; S:
Figure 28: ECG in atrial fibrillation. Source: stroke which takes two points, V: vascular disease such as
https://en.wikipedia.org/wiki/Atrial_fibrillation#/media/Fil MI or PAD, A: age from 65 to 74, and Sc: sex which is
e:Atrial_Fibrillation.png female to take one point.

The following table summarizes the categorization of atrial Atrial Flutter

fibrillation: Definition
Atrial flutter is a supraventricular tachycardia that results
Category of AF Definition
First documented First episode to be documented. No previous when there is a reentry mechanism that involves the atrial
episode ECG or normal previous ECG tissue around the tricuspid area. If the AV node conduction
recurrent Two or more episodes of AF that are separated is too fast, the patient’s cardiac output will be diminished,
in time
paroxysmal If recurrent AF keeps converting to sinus rhythm and the patient can develop hemodynamic compromise.
without any intervention
persisting An AF episode that lasts more than 7 days Epidemiology
permanent An AF episode that persists despite electrical or
chemical cardioversion
• Much less common than atrial fibrillation
• Represents 10% of supraventricular tachycardia
Treatment • 200,000 new cases of atrial flutter per year in the
Rate control treatment: United States
• More common in men
• Control rate without attempting to correct Etiology and Pathophysiology
permanent AF Cardiogenic causes such as coronary artery disease,
• Beta blockers and digoxin. Adenosine might be congestive heart failure, and hypertension. Noncardiogenic
used causes include pulmonary embolism, electrolyte
• Avoid beta blockers and calcium channel abnormalities, digitalis toxicity, and COPD.
blockers in patients with AF and Wolff Parkinson
White syndrome Pathophysiology:
• Target ventricular rate is < 100 beats/min
Rhythm control treatment:

• Converting the rhythm back to sinus rhythm

• Helpful in the other types of AF mentioned rather
than permanent AF and in patients with
hemodynamic compromise
• Restoration of sinus rhythm + intra-atrial
thrombus without anticoagulation = arterial
embolism
Figure 29: Mechanism of re-entry current in the
• Chemical cardioversion:
pathogenesis of atrial flutter versus atrial fibrillation.
o Amiodarone

275
 Source: Treatment:
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&sour Rate control treatment:
ce=images&cd=&cad=rja&uact=8&ved=2ahUKEwiX3bjo
kOPdAhVBSxoKHdR5AyAQjRx6BAgBEAU&url=https • This is more important here because 2:1 and 1:1
%3A%2F%2Fwww.pinterest.com%2Fpin%2F3882947991 AV nodal conduction can result in hemodynamic
12793734%2F&psig=AOvVaw1_10EIPyM05Wsj3Lrvf_lJ compromise → decreased cardiac output
&ust=1538410744955803 • Beta-blockers or calcium channel blockers
• Target ventricular rate is < 100 beats/min
• Can also lead to blood stasis in the atrium and Rhythm control treatment:
might be associated with an increased risk of
embolic events • Converting the rhythm back to sinus rhythm
• In patients with hemodynamic compromise
Clinical Findings
• Restoration of sinus rhythm + intra-atrial
• Patients can be asymptomatic thrombus without anticoagulation = arterial
• Most common symptom is palpitations embolism
• Symptoms and signs suggestive of the etiology: • Chemical cardioversion:
o Heat intolerance, hypertension, o Amiodarone
agitation, tremors → hyperthyroidism o Flecainide
o Angina → myocardial
• Electrical cardioversion
ischemia/infarction
• Radiofrequency catheter ablation more successful
• Symptoms or signs suggestive of embolic disease and is favorable → definitive treatment
such as stroke
Anticoagulation:
• Hypotension and syncope → hemodynamic
compromise • Patients might benefit from anticoagulation
Diagnosis treatment. Follow same recommendations as for
• Laboratory testing and echocardiography to atrial fibrillation
identify the cause of atrial flutter Atrioventricular Node Blocks
• ECG: using the 7+2 step plan: Definition
o Sawtooth pattern p-waves The conduction of the AP from the atria to the ventricles is
o Atrial rate: up to 350, ventricular rate is via the atrioventricular (AV) node. When the AV node is
dependent on AV conduction: 1:1 rare; disturbed, this conduction pathway becomes abnormal. The
2:1 or 3:1 common. The slower the disruption of the conduction of AP at the AV node is known
ventricular response, the more visible as an AV node block. The severity of such a block can be
the sawtooth pattern seen as incomplete or complete.
o QRS duration is narrow →
supraventricular tachycardia with AV Incomplete AV block is defined as an AV block that delayed
nodal conduction or transiently blocks the conduction from the atria to the
o Normal heart axis or heart axis ventricles. Complete AV block indicates that the atria and
deviation the ventricles are depolarizing independently from each
o QRS might show evidence of old MI, or other, i.e. dissociation between p-waves and QRS
LVH complexes.
o ST segment could be depressed → First degree AV block
ischemia, or elevated → infarction • Prolongation of the PR interval, i.e. > 0.20 sec
o T-wave inversion → acute myocardial
• Every P wave is followed by a QRS complex
infarction as the cause of atrial
• Prevalence in those older than 90 years is 16%
fibrillation
• Caused by degeneration of the conduction system
• Asymptomatic → no treatment is required

Figure 30: ECG in atrial flutter. Source: Figure 31: First degree AV block. PR interval is 0.36 sec.
https://en.wikipedia.org/wiki/Atrial_flutter#/media/File:Atr Source: https://en.wikipedia.org/wiki/Heart_block
ial_flutter34.svg

276
Second degree AV block • Ischemia and Lyme disease are possible causes
• Two types • Treated with a pacemaker
• Mobitz type I: “Wenckebach”
o Progressive lengthening of the PR
interval
o One P wave is not conducted to the
Figure 34: Third degree AV block. Complete dissociation
ventricles → not followed by a QRS
between p-waves and QRS complexes. Source:
complex
o After the “dropped” beat, the pattern is https://en.wikipedia.org/wiki/Heart_block
repeated again
Ventricular Fibrillation
o Because the PR interval is different, the
rhythm is regularly irregular Definition
o The condition is benign and does not Ventricular fibrillation (VF) is a cardiac arrest rhythm.
require treatment There is chaotic depolarization of the ventricles and the
heart is not contracting, i.e. in cardiac arrest. If untreated,
the prognosis is immediate death.
Ventricular fibrillation in a conscious patient! Check for a
technical problem, the patient is not in VF
Figure 32: Second degree AV block Mobitz type I.
Progressive lengthening of PR interval and one P wave is ECG Findings
not followed by QRS complex. Source: • Complete erratic arrhythmia without any
https://en.wikipedia.org/wiki/Second- identifiable waves or complexes
degree_atrioventricular_block

• Mobitz type II:

o One of the P waves is suddenly not Figure 35: Ventricular fibrillation. Source:
conducted to the ventricles “sudden https://commons.wikimedia.org/wiki/File:De-
somewhat random dropped beats” Rhythm_ventricular_fibrillation_(CardioNetworks_ECGpe
o The PR interval is constant and does not dia).png
lengthen progressively
o The condition is commonly associated Treatment
with AV node ischemia • If the patient develops VF in front of you while
o Can progress to complete third-degree on ECG monitoring, immediate defibrillate and
AV block start CPR
o Treatment is placement of a pacemaker • If the patient is brought to you in cardiac arrest:
o Check the pulse
o Start CPR
o Stop and check for rhythm, VF,
Figure 33: Second degree AV block Mobitz type II. defibrillate
Sudden drop of a QRS complex. Source: o Check for pulse, if no pulse
https://en.wikipedia.org/wiki/Second- o CPR again
degree_atrioventricular_block o And repeat this algorithm
AVNRT and AVRT
Third degree AV block AVNRT
• The AV node is not conducting atrial Atrioventricular nodal re-entry tachycardia (AVNRT) is a
depolarization to the ventricles anymore type of a supraventricular arrhythmia, i.e. narrow QRS
• The atria and ventricles beat independently of complex. This is a nodal rhythm.
each other
• Complete dissociation between the p-waves and • ANRT is the most common type of a regular non-
QRS complex sinus tachycardia
• The QRS complexes are still narrow because they • More common in females
tend to start from the bundle of His, however, Etiology and Pathophysiology
they can be slightly variable in morphology • The patient has a normal pathway and an
between one beat and the other abnormal pathway within the AV node
• Atrial rate is faster than ventricular rate
277
• The normal pathway can undergo rapid Clinical Findings
depolarization, but normal speed of repolarization Patients present with palpations due to tachycardia and
• The abnormal pathway depolarizes slowly but dizziness. The heart rate is from 180 to 250 beats/min.
can undergo repolarization very fast
- Impulse coming from Diagnosis
SA node ECG findings:
- Chooses the normal AV
node pathway Atrial and ventricular rate of 180 to 250 beats per minute
- AV node depolarizes
fast
- Impulse is passed down Normal sinus rhythm → an atrial ectopic beat → AVNRT
to the bundle of His
- Conduction via the Narrow QRS complexes
accessory pathway also
happens at the same Pseudo S-wave which occurs because the atrial
time
- The fast depolarization depolarization vector is in the opposite direction of the
via the normal pathway measuring lead
cancels the slow impulse
coming from the
accessary pathway
- Normal ECG
- An atrial premature beat
occurs
- The normal AV node
pathway is still not fully Figure 36: Regular narrow QRS complex tachycardia with
repolarized pseudo S-waves. AVNRT. Source:
- The abnormal pathway
has fully repolarized https://nl.ecgpedia.org/images/1/12/Avnrt_ecg.jpg
- The impulse goes down
this pathway Treatment
- It takes long for the
impulse to reach the • Adenosine terminates the arrhythmia
bundle of His which is • Carotid sinus massage
important for the next
step in the pathogenesis
AVRT
• The pathophysiology is somewhat similar to
- Because the impulse
took enough time for the AVNRT with few differences:
rest of the AV node to o The accessory pathway is not in the AV
be fully repolarized, a node
re-entry current occurs
- The impulse goes down o The accessory pathway connects the
the Bundle of His to atria and ventricles
depolarize the ventricles o Could be seen in patients with bundle of
- But also goes up to the
atria to depolarize them Kent
- An atrial echo, i.e. • Two patterns:
pseudo S-wave is seen
on the ECG
o Retrograde conduction from the
ventricles to the atria via the accessory
pathway. Each QRS is preceded by a P-
wave. Narrow QRS complex. Also
known as orthodrome AVRT
- The impulse that was
o Anterograde conduction from the atria
sent to the atria is now to the ventricles via the accessory
back to repolarize the pathway. Wide QRS complexes.
ventricles via the
accessory pathway again Retrograde p-waves after the QRS
- AVNRT develops complex
Summary of SVTs
Figure 2 shows the origin of the different types of
supraventricular tachycardias.

278
 Treatment of Supraventricular Tachycardia with
Hemodynamic

Compromise
• A very fast ventricular response rate in a patient
with SVT → decreased cardiac output →
hemodynamic compromise
• The following treatment options assume that you
want to provide rhythm control in atrial
Figure 37: Summary of the different types of fibrillation, or rate control and abolishing of
supraventricular tachycardias and their origin. Source: arrhythmia in other SVTs
https://en.ecgpedia.org/index.php?title=File:SVT_overview • If intravenous access is not established yet:
.svg o Synchronous DC shock at 1J per kg
o Not converted to sinus rhythm? →
Management of Supraventricular Tachycardias synchronous DC shock at 2J per kg
Diagnosis Algorithm: o Not converted to sinus rhythm? →
It is important to differentiate between supraventricular and amiodarone
ventricular tachycardias, and to further classify the • If intravenous access is established:
supraventricular tachycardia into one of the following major o Adenosine 100 µg/kg → slows
types: conduction at AV node
o Wait for 2 minutes
• Atrial fibrillation o No response? → adenosine 200 µg/kg
• Atrial flutter and wait for 2 minutes
• AVNRT o No response? → adenosine 300 µg/kg
• AVRT o No response? → synchronous DC shock
or amiodarone
Narrow QRS complex
tachycardia Treatment of Supraventricular Tachycardia without
Hemodynamic

Regular rhythm? Compromise

• Start with vagal nerve stimulation maneuvers:
No Yes o Valsalva maneuver
o Carotid sinus massage →
Atrial fibrillation P-wave present?
glossopharyngeal afferent, vagal
No Yes efferent
o Immersion of head in cold water
AVNRT
Atrial rate > • If the arrhythmia is not controlled:
ventricular rate?
o Follow adenosine protocol as explained
No Yes above 100, followed by 200, followed
by 300 µg/kg
RP shorter than PR Atrial flutter • If still not controlled:
o Consider beta-blockers, calcium channel
blockers such as verapamil,
AVNRT synchronous DC shock, or amiodarone
AVRT
Treatment of Supraventricular Tachycardia with WPW
Syndrome
Figure 38: Diagnosis algorithm of SVTs. Orange boxes • Accessory pathway in WPW syndrome is not
have the definitive diagnosis. blocked by CCBs, adenosine, and beta-blockers
• AV node is blocked by these drugs → if used,
conduction via the accessory pathway will be
enhanced → degeneration into ventricular
tachycardia
• Accordingly, treat with amiodarone or
procainamide to abolish the arrhythmia

279
Prevention of SVTs This classification gives you an idea which congenital
• Most SVTs can be prevented by chronic beta- heart defects need to be corrected during neonatal period,
blockers or CCBs which can be corrected during infancy, and which ones can
• Digoxin in patients with atrial fibrillation wait until childhood.
• Radiofrequency catheter ablation → definitive
treatment Right to Left Shunt
• These typically present during infancy or
Classification of Congenital Heart Defects neonatal period
Definition • Cyanosis is marked
• The embryogenic development of the heart is a • Those that belong to “CHD incompatible with
complex phenomenon. Because of the normal postnatal circulation” classification need to keep
connection between the right and left atria via the the PDA open and corrected urgently
foramen ovale and ductus arteriosus in fetal • They can be diagnosed prenatally with recent
circulation, most congenital heart defects cause advances in ultrasonography
problems to the baby after birth. Truncus arteriosus
• Based on the type of defect, the presentation with
cyanosis might be early in life, “blue babies”, or • More of mixing of arterial and venous blood
later in life, “blue kids”. In other cases, cyanosis rather than a true right-to-left shunt
might not be an important feature. • Truncus arteriosus fails to divide into pulmonary
trunk and aorta
Classifications
• Lack of aorticopulmonary septum formation
• The classical classification of congenital heart
during organogenesis
defects into cyanotic and acyanotic defects is
outdated, however it is still in use by many • Associated with a VSD
physicians and textbooks. Cyanotic heart defects
result in cyanosis during infancy or short after
birth, whereas, acyanotic defects may result in
cyanosis later in life during childhood.
• The following classification of congenital heart
defects is based on the direction of shunting of
blood.
Figure 39: Persistent truncus arteriosus. Source:
Right-to-left left-to-right doi:10.1016/j.carpath.2010.02.006
Truncus arteriosus Ventricular septal defects
Transposition of the great arteries Atrial septal defects
Tricuspid atresia Patent ductus arteriosus Transposition of great vessels
Tetralogy of Fallot Eisenmenger syndrome
Total anomalous pulmonary venous • Belongs to “CHD incompatible with postnatal
return
Ebstein anomaly
circulation”
Others: coarctation of the aorta • Shunting of blood is required for postnatal life →
VSD, PDA or patent foramen ovale
• Aorta leaves RV, pulmonary trunk leaves LV
A more recent classification is based on the clinical • Systemic and pulmonary circulations are separate
consequences and pathophysiology of the congenital heart
• Failure of aorticopulmonary septum to spiral
defect is given below.
• Urgent corrective surgery
CHD
CHD with CHD with CHD with CHD
incompatible
increased decreased obstruction silent
with
pulmonary pulmonary and no until
postnatal
flow flow shunt adulthood
circulation
Transposition Bicuspid
Tetralogy Aortic
ASD of the great aortic
of Fallot stenosis
arteries valve
Total Anomalies
Tricuspid Coarctation anomalous of
VSD
atresia of aorta pulmonary coronary
venous return arteries
Truncus Ebstein WPW
arteriosus anomaly syndrome
Figure 40: Transposition of the great vessels. Source:
PDA https://en.wikipedia.org/wiki/Transposition_of_the_great_
vessels#/media/File:D-tga-575px.jpg
280
Tricuspid atresia • Asymptomatic at birth
• Depending on size, may present within the first
• Absence of the tricuspid valve few weeks of life, or remain asymptomatic
• Hypoplastic right ventricle throughout life
• ASD and VSD are both required • Large VSD → increased pulmonary blood flow
Tetralogy of Fallot → increased pulmonary venous return to the left
atrium → LV volume overload → heart failure
• Most common cause of early childhood cyanosis
• Pulmonary infundibular stenosis
• Right ventricular hypertrophy → boot-shaped
heart on chest radiograph
• Ventricular septal defect
• Overriding aorta
• Pulmonary stenosis → right to left shunt through
VSD → let spells during crying or exercise
Figure 42: VSD. Source:
https://en.wikipedia.org/wiki/Ventricular_septal_defect#/m
edia/File:Ventricular_septal_defect-en.png

Atrial septal defects

• A defect in the interatrial septum

• Most common type is ostium secundum
o Usually an isolated finding
Figure 41: Tetralogy of Fallot. 1. Pulmonary atresia. 2. • Ostium primum
RVH. 3. Overriding aorta. 4. VSD o Rare and occur with other CHDs
• Atrial septum is missing tissue
Total anomalous pulmonary venous return o In patent foramen ovale, the ovale fails
to close
• Belongs to “CHD incompatible with postnatal • Can be symptomatic or result in heart failure in a
circulation” mechanism similar to VSDs
• An ASD or a PDA is required to maintain life
after birth
• The pulmonary veins drain into the superior vena
cava instead of the left atrium
• Needs urgent corrective surgery
Ebstein anomaly

• Downward displacement of the tricuspid valve

leaflets into the right ventricle Figure 43: ASD. Source: First Aid 2018
• Tricuspid regurgitation
• Usually associated with a patent foramen ovale Patent ductus arteriosus
→ right to left shunt and cyanosis
• Associated with accessory conduction pathways • When a newborn takes his or her first breath:
• Can lead to right-sided heart failure Decreased pulmonary vascular resistance →
increased oxygen saturation → decrease in
• Risk factor: in-utero exposure to lithium
prostaglandins → closure of the ductus arteriosus
Left to Right Shunts between the aorta and pulmonary trunk
• These typically present during childhood • If the above events do not lead to the closure of
• Cyanosis is rare. Usually acyanotic at the DA, then a PDA becomes evident
presentation • Left to right shunt because aortic pressure is
• Belong to “CHD with increased pulmonary flow” higher than pulmonary pressure
category • Right ventricular hypertrophy → right-sided heart
Ventricular septal defects failure
• Uncorrected → late cyanosis in lower extremities
• Most common CHD
281
 • Indomethacin → closes PDA | prostaglandins E1 Transposition of the Great Arteries
and E2 → keep PDA open Cause
• The cause of this congenital heart defect is the
failure of the aorticopulmonary septum to spiral
around its vertical axis.
Description
• The aorta originates from the right ventricle
• The pulmonary artery originates from the left
ventricle
Figure 44: PDA. Source: • Considered as a form of vascular discordance
https://en.wikipedia.org/wiki/Patent_ductus_arteriosus#/me with atrioventricular concordance
dia/File:Patent_ductus_arteriosus.svg

Eisenmenger syndrome

• The previously mentioned left-to-right shunts are

associated with increased pulmonary blood flow
• Increased pulmonary blood flow → pulmonary
arteriolar remodeling and increased resistance →
pulmonary arterial hypertension → right
ventricular hypertrophy → RV pressure exceeds
that of LV → right to left shunt → Eisenmenger
syndrome
• Causes cyanosis and clubbing
• Associated with polycythemia Figure 46: Transposition of the great arteries. Source:
Coarctation of the Aorta https://en.wikipedia.org/wiki/Transposition_of_the_great_
• Belongs to “CHD with obstruction to blood flow vessels#/media/File:D-tga-575px.jpg
without shunt” category
• Most common site of narrowing is at the insertion Pathophysiology
of ductus arteriosus “juxtaductal” • Right to left shunt
• Associated with another CHD: bicuspid aortic • At birth, the systemic and pulmonary circulations
valve will become parallel
• Also associated with Turner syndrome • Deoxygenated systemic blood will be forwarded
• Hypertension in upper extremities, weak delayed to the aorta
pulse in lower extremities • Oxygenated pulmonary venous blood will be
• If uncorrected → intercostal arteries enlarge → forwarded to the pulmonary artery
collateral circulation, → they erode ribs → ribs’ • A VSD or a PDA is required to be compatible
notched appearance on chest radiograph with postnatal circulation
• Because afterload is increased → heart failure • The oxygenated blood is mixed with the
• Increased risk of intracerebral hemorrhage due to deoxygenated blood to perfuse systemic
berry aneurysm association circulation
• Possible risk of endocarditis

Figure 47: Schematic representation of the separation of

the systemic and pulmonary circulations in complete
transposition of the great arteries. Source:
doi:10.1016/j.carpath.2010.02.006
Figure 45: Coarctation of the aorta. Source:
https://en.wikipedia.org/wiki/Coarctation_of_the_aorta#/m
edia/File:Coarctation_Of_Aorta.png

282
Treatment o Also, pulmonary hypertension if large
• Prostaglandins to maintain the patency of the VSD and uncorrected
ductus arteriosus • If pulmonary arterial hypertension is severe →
• Rashkind balloon atrial septostomy reversal of the shunt to become right to left →
• Urgent corrective surgery: Eisenmenger syndrome
o Right atrium is connected to the left • Patients can be asymptomatic, develop symptoms
ventricle in neonatal period, infancy, childhood, or remain
o Left atrium is connected to the right asymptomatic throughout life
ventricle Cardiac Auscultation
Ventricular Septal Defects • Holosystolic murmur at left lower sternal border
Cause • Palpable thrill
The ventricular septum, the wall that separates the left • Normal heart sounds
from the right ventricle, contain an opening. This Treatment
might be caused by Down syndrome, incomplete • No treatment is required, unless:
looping of the heart, or mutations in NKX2.5 gene. o Development of heart failure
o VSD with pulmonic stenosis
Description
o Large VSD that has caused pulmonary
• An opening exists between the right and left hypertension
ventricles o VSD with aortic regurgitation
• Five major types: • If the patient meets any of these criteria, surgical
o Subaortic intervention is required
o Membranous: most common CHD, and
• Infants who are symptomatic should receive
represent 70% of all VSDs
digoxin, loop diuretics, and ACE inhibitors to
o Inlet or an AV canal: associated with
prevent cardiac remodeling and decrease preload
AV septal defect
Atrial Septal Defects
o Muscular: found in 20% of VSDs
Cause
o Garbode: communication between left
There is missing tissue in the septum that separates the left
ventricle and right atrium → due to
and right atria. It is associated with the following diseases:
absence of AV septum
• Down syndrome
• Ebstein anomaly
• Fetal alcohol syndrome
• Lutembacher syndrome
• Holt-Oram syndrome
Description
• An opening exists between the right and left atria
• Four major types:
o Ostium secundum ASD: most common
type of ASD, 10% of all CHDs
▪ Enlarged foramen ovale,
limited growth of septum
secundum, or excessive
Figure 48: VSDs and their classification. Source: resorption of septum primum
https://en.wikipedia.org/wiki/Ventricular_septal_defect#/m ▪ If combined with mitral valve
edia/File:Vsd_simple-lg.jpg stenosis → Lutembacher
syndrome
Pathophysiology ▪ Symptomatic after 40 years of
• Left to right shunt age
• Systole → LV contraction → LV pressure ▪ Can result in pulmonary
exceeds RV → shunting of blood from LV to RV hypertension in 50% of those
→ increased pulmonary blood flow > 40 years
• Eventually, more blood will be returning to the o Patent foramen ovale:
left ventricle → LV overload ▪ Asymptomatic
▪ Can be associated with a
paradoxical embolism

283
 ▪ Associated with migraine • Other genetic disorders such as CHARGE
o Ostium primum ASD: Less common syndrome and Loeys-Dietz syndrome
that ostium secundum: Description
▪ Associated with an AV septal • The normal communication between the aorta
defect and pulmonary trunk fails to close after birth
▪ Associated with Down • The ductus arteriosus connects the aorta and the
syndrome pulmonary artery bifurcation area
o Sinus venosus ASD: rarest type of
ASDs

Figure 49: ASD types: 1. And 2. Sinus venosus ASD, 3.

Ostium secundum ASD, 4. ASD involving coronary sinus, Figure 50: PDA. Source:
5. Ostium primum ASD. Source: https://en.wikipedia.org/wiki/Patent_ductus_arteriosus#/me
https://en.wikipedia.org/wiki/Atrial_septal_defect#/media/ dia/File:Patent_ductus_arteriosus.svg
File:Schematic_drawing_of_various_types_of_atrial_septa
l_defect.png Pathophysiology
• Left to right shunt
Pathophysiology
• Oxygenated blood from the aorta escapes to the
• Left to right shunt pulmonary artery
• ASD > 9 mm → blood shunts from LA to RA → • If the PDA is large, pulmonary blood flow
RV overload → RVH → right-sided heart failure increases significantly → pulmonary arterial
• Coronary artery disease in late 40s → increased hypertension during neonatal period →
stiffness of LV → increased filling pressure of congestive heart failure
left ventricle during diastole → increased left to • In patients with transposition of the great arteries,
right shunt through ASD a PDA is required for compatibility with postnatal
• Both mechanisms lead to increased pulmonary physiology
blood flow → and if severe enough pulmonary • The infant can develop tachycardia, dyspnea,
hypertension cardiomegaly due to ventricular dilation, a
• Can result in Eisenmenger’s syndrome widened pulse pressure, and an increased cardiac
• Dilated right atrium → atrial fibrillation output
• The diagnosis is confirmed by transesophageal
Cardiac Auscultation
echocardiogram
Cardiac Auscultation • S1 and S2 are obscured by the loud machinery-
like continuous murmur
• Fixed splitting of S2
• Murmur best heard at the left infraclavicular area
• Systolic ejection murmur at pulmonic area due to
increased flow of blood through the valve Treatment:
Patent Ductus Arteriosus: • NSAIDs such as indomethacin promotes the
Cause closure of PDA
The ductus arteriosus is normally present during fetal life. Eisenmenger’s Syndrome
After birth, it is supposed to close. If it fails to close, then Definition
the term patent ductus arteriosus is used to describe the Eisenmenger’s syndrome is a process in which a long-
anomaly. The cause can be unknown in some cases. Risk standing left to right shunt caused by a congenital heart
factors include: defect causes severe pulmonary hypertension and reversal
of the shunt into a cyanotic right to left shunt.
• Preterm birth
• Congenital rubella
• Down syndrome

284
Etiology • Most deaths occur during or within the first week
• Any left to right shunt congenital heart defect that after delivery
causes increased pulmonary blood flow can lead • If a woman with Eisenmenger’s syndrome
to Eisenmenger’s syndrome becomes pregnant and the termination of
• Examples include atrial septal and ventricular pregnancy is not accepted:
septal defects, and patent ductus arteriosus • Hospitalization after the 20th week of gestation
Pathophysiology until delivery
Damage and
A CHD with left
Increased RV Increased Coarctation
scarring of of the Aorta
blood flow and pulmonary pulmonary
to right shunt
pressure blood flow Definition
capillaries and
Coarctation
arterioles of the aorta is a congenital malformation
where the aorta is narrowed around the area of insertion of
Reversal of the ductus arteriosus.
RV pressure Right
shunt to Pulmonary
exceeds that of ventricular
become right
LV hypertrophy Pathophysiology
hypertension
to left
Classification of coarctation of the aorta is given in the
table below.
Figure 51: Pathogenesis of Eisenmenger's syndrome.

Clinical Findings
location of notes
• Cyanosis narrowing
• Polycythemia Preductal Proximal to DA - Blood flow distal to
insertion the narrowing is
• Nail clubbing see Figure 2 dependent on PDA
• Syncope - Closure of PDA at
birth → symptoms
• Heart failure during neonatal
• Ventricular and atrial arrhythmias period
- Hypoplastic
development of the
aorta
ductal At the site of DA
insertion
postductal Distal to DA - Most common type
insertion in adults
- Associated with
notching of ribs
- HTN in upper
limbs, weak pulses
Figure 52: Nail clubbing of fingers in a patient with in lower limbs
Eisenmenger's syndrome. Source:
https://en.wikipedia.org/wiki/Eisenmenger%27s_syndrome
#/media/File:ClubbingFingers1.jpg

Diagnosis
• Echocardiography confirms the reversal of the
shunt
• Catheterization can be used to confirm the
diagnosis of pulmonary hypertension Figure 53: A. Ductal CoA, B. Preductal CoA, C. Postductal
Treatment CoA. Source:
• The only curative treatment for this complication https://en.wikipedia.org/wiki/Coarctation_of_the_aorta#/m
of acyanotic CHDs is heart-lung transplantation edia/File:Coarctation_and_PDA.png
• Accordingly, the current recommendation is to
correct any acyanotic CHD that does not close by • In preductal CoA:
itself and is large enough to cause future issues by o Blood pressure might show discrepancy
age of 2 years between right and left arms if the
coarctation is very proximal
Eisenmenger’s Syndrome and Pregnancy
• In postductal CoA:
• Maternal mortality can be as high as 60% in those
with Eisenmenger’s syndrome o Hypertension in upper extremities
o Weak pulses in lower extremities

285
 o Collaterals enlarge → dilated intercostal organogenesis, or sequential chamber localization such as
arteries → ribs’ notching on chest the spiral rotation of the great blood vessels.
radiograph
• Coarctation of the aorta is more common in boys Fetal Alcohol Syndrome
and in girls Diagnostic criteria:
• Girls with Turner syndrome are at an increased • Minor facial anomalies such as short palpebral
risk fissures, thin vermilion border of upper lip, or
• The condition is often associated with bicuspid smooth philtrum
aortic valve, in 50% of the cases • Prenatal or postnatal growth deficiency
Clinical Findings
• Head circumference at 10th percentile or smaller,
• In mild cases, symptoms and signs might occur structural brain anomalies, recurrent nonfebrile
only in late childhood or during adulthood seizures
o Dyspnea
• Neurobehavioral impairment
o Dizziness
• Alcohol exposure during pregnancy
o Fatigue
Associated CHDs:
o Cold legs and feet
o Legs intermittent claudication • VSD
o Upper extremity hypertension • PDA
o Weak pulses in lower limbs
• ASD
• In severe cases, symptoms might be present soon
• Tetralogy of Fallot
after birth:
Congenital Rubella Syndrome
o Upper limbs hypertension and lower
Clinical features:
limbs hypotension
• If the coarctation occurs before the left subclavian • Sensorineural hearing loss
artery: • Ocular abnormalities such as cataract or infantile
o Normal pulses and blood pressure in the glaucoma
right arm • History of maternal exposure to rubella virus
o Weak pulses and decreased BP in left Associated CHDs:
arm
o Weak and delayed pulses in the legs • PDA
Diagnosis • Pulmonary artery stenosis
• Chest radiograph reveals notching of ribs in Down Syndrome
adults Neonatal features:
• Magnetic resonance imaging angiography can
confirm the diagnosis • Excess neck skin
• Catheterization can reveal the narrowing or show • Hypotonia
a bicuspid aortic valve • Flat faces
• Measurement of BP in upper and lower • Dysplastic ears
extremities • Epicanthic fold
Treatment • Increased gap between first and second toes
• Adults who are asymptomatic should receive • Protruding tongue
conservative treatment Chromosome 21 trisomy
• Patients with arterial hypertension should
undergo surgical resection of the narrowed part Associated CHDs:
• Angioplasty with stent graft to dilate the • AV septal defects
narrowed artery
• VSD
• Prognosis is good, however, there is a risk of re-
• ASD
stenosis at the site of a previous coarctation
Maternal DM
Congenital malformations associated with maternal DM:
CHDs and their Associations
Mechanism of Association • Caudal regression syndrome
There are different environmental factors, exposures, and • Holoprosencephaly
certain genetic or chromosomal disorders that are known to • Neural tube defects
increase the risk of congenital heart defects (CHDs) by
interfering with the processes of embryogenesis,

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Associated CHDs: • Truncus arteriosus
• Tetralogy of Fallot
• Transposition of the great arteries
• VSD Regulation of BP and Blood Flow to Organs:
Marfan Syndrome: Baroreceptors
Clinical features: The regulation of the blood pressure is made possible by
two mechanisms:
• Large ear lobes • Fast mechanism which involves neural pathways
• Enophthalmos and the baroreceptors
• Micrognathia • Slower mechanism that involves hormonal
• High palate changes among other changes
Associated CHDs: Location of the receptors:
• The aortic arch which transmits pressure
• Mitral valve prolapse information via the vagus nerve to the solitary
• Thoracic aortic aneurysm/dissection nucleus of medulla
• Aortic regurgitation due to aortic root dilatation • The carotid sinus at the region of common carotid
Prenatal lithium Exposure: bifurcation which transmits information via the
Associated CHDs: glossopharyngeal nerve (Herring’s nerve) also to
the solitary nucleus of medulla
• Ebstein anomaly Mechanism of BP regulation:
Turner Syndrome: • A decreased blood pressure decreases the stretch
Neonatal features: on the baroreceptor
• This decreases afferent baroreceptor firing to the
• Webbed neck solitary nucleus
• Low hair line • This is an inhibitory pathway → decreased firing
• Prominent ears = loss of inhibition on the sympathetic pathway
Single X chromosome (XO) • Increased efferent sympathetic firing and
decreased efferent parasympathetic stimulation
Associated CHDs: • Vasoconstriction → blood pressure is elevated
• Coarctation of the aorta – neonatal presentation • The activation of the sympathetic nervous system
also has an effect on the SA node → increased
• Bicuspid aortic valve
automaticity due to faster diastolic depolarization
Williams Syndrome: of SA node → increased heart rate
Clinical features: Carotid massage:
• The carotid sinus baroreceptors can be massaged
• Mild to moderate intellectual disability
to increased the parasympathetic tone and
• Broad forehead decrease the sympathetic tone temporarily
• Short nose • Increased pressure on the carotid sinus leads to
• Full cheeks increased stretch
• Wide mouth with full lips • Increased afferent baroreceptor firing
Deletion of a segment on chromosome 7 • Increased parasympathetic stimulation at the AV
Associated CHDs: node
• Slower heart rate
• Supra-valvular aortic stenosis Cushing reflex:
22q11 Syndromes • Patients with increased intracranial pressure
Clinical features: might have a triad of hypertension, bradycardia,
and respiratory depression
• Cleft palate, bifid uvula • It might seem unreasonable how hypertension is
• Learning difficulties combined with bradycardia in this triad
• Immune deficiency • The following mechanism explains this
• Hearing loss observation:
DiGeorge (21q11.2 deletion) syndrome Increased ICP → pressure on cerebral arterioles
→ cerebral ischemia → increased brain pCO2 →
Associated CHDs: activation of central reflex sympathetic system to

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 increased brain perfusion (remember CPP = mean Heart - NO, CO2 and hypoxia → vasodilation
Brain - CO2 and low pH → vasodilation
arterial pressure – intracranial pressure) → Skeletal - CO2, low pH, adenosine, lactate, and increased
hypertension muscle potassium → vasodilation
Kidneys - Myogenic and tubuloglomerual feedback
Skin - Sympathetic stimulation → temperature control
The elevated blood pressure put more stretch on
the peripheral baroreceptors → increased afferent
baroreceptor firing → increased parasympathetic Mean Arterial Pressure
stimulation of the AV node → bradycardia The mean arterial pressure as was explained before is
important in determining cerebral perfusion pressure. The
following equation is used to calculate the mean arterial
Chemoreceptors
pressure.
• When the Cushing reflex was explained, we
mentioned central receptors that were concerned 2 DBP + SBP
with the PCO2 of brain interstitial fluid. MAP = ~ 93.33 mm Hg in healthy people
3
• These are central chemoreceptors and they are
also capable of responding to pH of brain Where MAP: mean arterial pressure, DBP: diastolic blood
interstitial fluid and arterial CO2 but do not pressure, and SBP: systolic blood pressure
respond to PO2
• The peripheral chemoreceptors are found in the Hypertension
carotid and aortic bodies Definition
• They are stimulated by hypoxia (PO2 < Hypertension can be defined as a persistent systolic blood
60 mmHg), hypercapnia and acidemia pressure of 140 mmHg or more; and/or a diastolic blood
pressure of 90 mmHg or more; on two different occasions.
Normal Cardiac Pressures
The following Figure 1 shows the normal pressures, in mm Essential Hypertension
Hg, of the different cardiac chambers and major blood Up to 90% of hypertensive patients have essential
vessels. Different types of heart failure are related to hypertension where a cause is not identifiable.
changes in these pressures.
The most likely mechanism is unexplained increased
cardiac output or increased total peripheral resistance
Most cases of essential hypertension are responsive to
current antihypertensive treatments
Therefore, if the patient is diagnosed with resistant
hypertension, the possibility of secondary hypertension
becomes high
Secondary Hypertension
Figure 1: Normal cardiac and major blood vessel pressures When a cause such as renovascular, renal, or endocrine
in mmHg. Notice: blood pressures in the ventricles and the disorder, is identified, the patient will be diagnosed with
aorta or pulmonary artery have a systolic and a diastolic secondary hypertension.
value. Source:
https://www.pinterest.com/pin/14496030029159021/?lp=tr •
Up to 10% of hypertensive patients have
ue secondary hypertension
• 85% of those with resistant hypertension have
Autoregulation secondary hypertension
• Resistant hypertension: failure to achieve a target
• Changes in blood pressure can be large
arterial pressure despite optimum dose of
• Accordingly, there are local organ-specific
antihypertensive medications
mechanisms that allow for autoregulation of
Chronic Kidney Disease
blood flow to that organ
• Approximately, 5% of all hypertensive patients
• The goal is for blood flow to remain constant
over a range of perfusion pressure • 10% of resistant hypertension cases
The table below summarizes the different mechanisms of • Two important pathogenic mechanisms:
autoregulation of blood flow in different body organs. o Renal failure → intravascular volume
overload → hypertension
Organ Autoregulation mechanisms o The activation of the renin-angiotensin
- Hypoxia → vasoconstriction
- The lungs are unique in that they are the only
system
Lungs
organ where hypoxia causes vasoconstriction • Patients with CKD also have:
- Blood is shifted away from hypo-ventilated areas

288
 o Increased sympathetic nervous system Cushing’s Syndrome
tone • 0.5% of all hypertensive patients
o Endothelial dysfunction • Increased cortisol production which can be due to
o Reduced concentration of NO which is excessive pituitary production of ACTH, ectopic
responsible for vasodilation secretion of ACTH, or adrenal gland
o Increased thickening of arterial wall adenoma/cancer
o These changes lead to vasoconstriction • Pathogenesis of hypertension:
→ hypertension • Mineralocorticosteroid activity of
• Treatment options either block the renin- cortisol → water and sodium retention
angiotensin system, decrease the sympathetic • Activation of renin-angiotensin-
tone “beta-blockers”, or decrease volume aldosterone system
overload “diuretics” • Increased reactivity to catecholamines
• Potassium sparing diuretics are contraindicated and vasopressin
Renovascular Disease • Reduced activity of NO synthase, and
• Approximately, 5% of all hypertensive patients the kallikrein-kinin system which
• 20% of resistant hypertension cases produce endogenous vasodilators
• Atherosclerosis (90%) and fibromuscular Hyperthyroidism
dysplasia (10%) with the latter being more • Overproduction of T3 and T4
common in younger patients • Activation of the sympathetic nervous system and
• Fibromuscular dysplasia → string of beads increased sensitivity to catecholamines →
• Same pathogenesis like CKD hypertension
The diagnosis of renovascular hypertension is suspected Medications
when the patient has: • Decongestants that contain sympathomimetics
such as ephedrine or pseudoephedrine can elevate
• Severe hypertension with DBP > 120 mmHg the blood pressure
• Resistant hypertension Other causes of secondary hypertension include coarctation
• Hum on the auscultation of the abdomen of the aorta in patients younger than 30 years of age, and
• A difference in the size of the kidneys on illicit drug use such as cocaine.
ultrasonography
• Or hypertension with an increase in serum Pathophysiology
creatinine after a trial of ACE inhibitors • Elevated blood pressure → increased pressure on
Primary Hyperaldosteronism arterial walls → smooth muscle cell proliferation
• Approximately 1 to 3% of hypertensive patients and stenosis of blood vessels → decreased
• Adrenal gland adenoma and idiopathic bilateral diameter of blood vessel → further elevation in
adrenal gland hyperplasia → increased secretion blood pressure
of aldosterone • Increased shear forces on endothelium →
• Patients with resistant hypertension and endothelial dysfunction → cholesterol deposition
hypokalemia should be screen for in injured blood vessels’ walls → further
hyperaldosteronism especially if younger than 40 vasoconstriction → elevated blood pressure
years of age • Eventually, all of the above leads to increased
• Aldosterone → sodium and water retention → afterload → left ventricle needs to work harder →
volume overload → hypertension left ventricular hypertrophy → heart remodeling
Pheochromocytoma → heart failure
• 0.1 to 0.5% of all hypertensive patients
Risk Factors
• An adrenal gland medulla tumor of chromaffin While an exact cause of essential hypertension is not
cells → overproduction of catecholamines → found, certain risk factors are known to increase the risk of
hypertension hypertension:
• Can be also para-aortic in location
• 5 Ps: • Advanced age
• Paroxysmal hypertension • Obesity
• Palpitation • Diabetes mellitus
• Perspiration • Sedentary lifestyle
• Pale • Tobacco smoking
• Pulsating headache • Excessive salt intake

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 • Excessive alcohol intake emergency is a SBP > 180 mmHg and/or a DBP > 120
• Family history mmHg with evidence of end-organ damage.
• Ethnicity:
• African American more often than Etiology:
Caucasian • Most patients with hypertensive crises have an
• Least common in Asian established diagnosis of hypertension
• Noncompliance is a common cause
Complications
• Use of sympathomimetics such as decongestants
Coronary artery disease:
or illicit drugs
• Elevated blood pressure results in endothelial
dysfunction which increases the risk of coronary Epidemiology:
artery disease and myocardial infarction • 1 to 2% of those diagnosis with hypertension will
Left ventricular hypertrophy: have a hypertensive emergency or urgency in
their lifetime
• This occurs because of the increased afterload • The most common types of hypertensive
• Can result in heart failure emergency are:
Stroke: • Acute pulmonary edema
• Cardiac ischemia
• Increased risk of hemorrhagic stroke, ischemic • Neurologic emergencies
stroke, and lacunar infarcts
Aortic dissection: Pathophysiology:
• Elevated blood pressure damages the intima of • End-organ damage in hypertensive emergencies
the major blood vessels including the aorta → occur by the following mechanism:
aortic dissection Mechanical stress on vascular walls →
Peripheral vascular disease: endothelial damage and release of pro-
inflammatory mediators → increased vascular
• Same pathogenesis of coronary artery disease permeability and activation of coagulation
Ocular complications: cascade in the microvasculature → micro-clots
and hypoperfusion to the target organ
• In hypertensive emergency → papilledema can be
seen Specific Types of End-Organ Damage in Hypertensive
• Chronic hypertension can lead to hypertensive Emergencies:
retinopathy. Acute aortic dissection:
Discussed in detail in Neurology – Visual • Clinical findings include tearing mid-sternal chest
Disorders – Retinal Disorders – Hypertensive pain
Retinopathy • Intravenous esmolol is indicated.
Renal disease: • Lower SBP < 120 mmHg in 5 to 10 minutes!
Acute pulmonary edema:
• Chronic hypertension leads to afferent and
• Patients present with dyspnea and basal crackles
efferent arteriolar stenosis which is known as
• Intravenous nitroglycerin, clevidipine, or
hypertensive nephrosclerosis
nitroprusside
• The glomerular filtration rate will decrease
• Lower by 25% of presenting BP within first hour,
• Activation of the renin-angiotensin system in then more gradually
essential hypertension
• Beta-blockers are contraindicated
• Development of chronic kidney disease and
Acute myocardial infarction:
eventually renal failure
• Symptoms and signs suggestive of MI
Hypertensive Crises: • ECG findings suggestive of MI
Definitions: • Lower BP with esmolol
Hypertension can be defined as a persistent systolic blood • Target BP < 140/90 mmHg
pressure of 140 mmHg or more; and/or a diastolic blood • Maintain DBP > 60 mmHg for adequate coronary
pressure of 90 mmHg or more; on two different occasions. perfusion
Hypertensive urgency is a SBP > 180 mmHg and/or a DBP Acute renal failure:
> 120 mmHg without end-organ damage. Hypertensive • Symptoms and signs of acute renal failure such as
decreased urinary output

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 • Administer intravenous clevidipine, fenoldopam, HTN stage 2 Nonpharmacologic therapy, and
one or two antihypertensives
or nicardipine
Eclampsia or pre-eclampsia:
• Pregnant woman with pregnancy induced Lifestyle Modifications
hypertension or chronic hypertension Known as nonpharmacologic therapy of hypertension in
• Eclampsia → delivery the most recent guidelines.
• Pre-eclampsia: BP can be lowered with Nonpharmacologic effect on sbp in hypertensive patients
hydralazine, labetalol, or nicardipine intervention
weight loss - 5 mmHg
• ACEi, angiotensin receptor blockers, and dash diety pattern - 11 mmHg
nitroprusside are contraindicated dietary sodium < 1,500
- 5 mmHg
Emergency caused by pheochromocytoma or use of mg/day
aerobic exercise 90 t0 150
sympathomimetics: min/week
- 5 mmHg
• Intravenous clevidipine, nicardipine, or resistance training - 5 to 9
mmHg
phentolamine reduced alcohol
Acute intracerebral hemorrhage: < 2 per day drinks for
• Focal neurological deficits, headache, fever, men - 4 mmHg
< 1 per day drink for
meningism women
• Adequate brain imaging with non-contrast CT
scan
Antihypertensives
• Intravenous hypertensives to lower SBP < 140
mmHg within 1st hour First-line agents
• Nicardipine or labetalol are first-line treatments Thiazide diuretics:
Acute ischemic stroke: •
Blocks sodium/chloride reabsorption → sodium
• Not recommended to lower BP unless: is excreted in urine → drags water with it →
o > 220/120 mmHg decreases intravascular volume
o > 180/110 mmHg in patients • Hydrochlorothiazide
undergoing fibrinolytic therapy
• Very effective in African American patients
• If meet the above criteria, intravenous labetalol is
• Can cause hyponatremia and hypokalemia
indicated
• Use with caution in gout
• Over correction of BP → decreased cerebral
• Hypercalcemia
pressure perfusion → worsen ischemia
ACE inhibitors:
Diagnosis and Treatment of Hypertension • Inhibit ACE which decreases the production of
Diagnosis angiotensin II → decreased vasoconstriction and
The diagnosis of hypertension is confirmed when two decreased production of aldosterone → decreased
separate readings show stage 1 or stage 2 hypertension in sodium reabsorption and retention of water
two separate occasions. • Also dilate the efferent arterioles in the
glomerulus → blood flows faster so that proteins
Classification including albumin are not filtered → less kidney
SBP mmHg DBP mmHg
Normal < 120 and < 80 damage → renal protective especially in diabetes
Elevated 120 to 129 and < 80 mellitus
HTN stage 1 130 to 139 or 80 to 89
HTN stage 2 > 140 or > 90
• The above mechanism decreases GFR →
therefore, ACE inhibitors are contraindicated in
renovascular hypertension “patients with
This classification is based on the most recently published hypertension secondary to renal artery stenosis”
guidelines, where the threshold for the diagnosis of • Drugs end with “pril”
hypertension was lowered. • Side effects: hyperkalemia, angioedema, dry
cough, avoid in pregnancy
Treatment Option per Classification ARBs:

recommendations
• Angiotensin II receptor blockers → vasodilation
normal Promote healthy lifestyle → decreased afterload
elevated Nonpharmacologic therapy • Do not cause dry cough or angioedema
htn stage 1 Nonpharmacologic therapy, and
Pharmacology therapy with one antihypertensive • Do not combine with an ACE inhibitor

291
CCBs: The word “atherosclerosis” summarizes the pathogenesis of
the disease. Atherosis refers to the accumulation of fat and
• Vasodilators macrophages, whereas sclerosis is used to describe the
• Nifedipine and amlodipine formation of a fibrosis layer of smooth muscle cells,
Second-line agents leukocytes, and collagen deposition.
Beta-blockers:
Epidemiology
• Blocks cardiac beta-receptors → effect on AV It is difficult to estimate the incidence or prevalence of
node → decreased CO atherosclerosis itself; however most epidemiological studies
• Blocks vascular beta-receptors → vasodilation of focus on the incidence of coronary and peripheral arterial
arteries and veins → decreased afterload and disease as an indicator of atherosclerosis incidence.
preload respectively
• Blocks sympathetic stimulation of renin • More than 400,000 Americans die each year
production by the kidneys → less aldosterone → because of coronary artery disease
less sodium reabsorption → diuresis • Approximately, 785,000 Americans develop an
• Metoprolol initial MI each year
• Side effects: bronchospasm, bradycardia, fatigue, • More 470,000 Americans develop a recurrent MI
hypertriglyceridemia, low HDL, sedation, each year
hypoglycemia, mask hypoglycemic symptoms in • Ischemic heart disease is the leading cause of
diabetic patients death in the Western world
Vasodilators: • In North American and Europe, 27 million
individuals are affected with peripheral arterial
• Hydralazine in pregnant women with disease
hypertension Risk Factors
• Vasodilation → reflex tachycardia • Dyslipidemia:
• Can be associated with drug-induced lupus-like o Hypercholesteremia
syndrome o Elevated LDL
Target BP o Low HDL
Important principles in treating hypertension: o Elevated triglycerides
• Hypertension
• The new guidelines state that all HTN patients • Lifestyle:
regardless of comorbidities should have a BP < o Smoking
130/80 mmHg o Overweight or obesity
• Once pharmacologic treatment is started, it is for o Sedentary lifestyle
lifetime o Unhealthy diet
• Beta-blockers and thiazide diuretics decrease o Alcohol
mortality o Stress
• ACE inhibitors are first-line treatment of • Nonmodifiable risk factors:
hypertension in diabetics o Older age
• Always try to start with a thiazide diuretic, unless o Family history of early heart disease
diabetic then start with ACEi • Metabolic:
o If not controlled, consider adding o Diabetes mellitus
another different class such as a beta- o Inflammation disorders
blocker Pathophysiology
o If not controlled, consider adding a third Three important processes:
antihypertensive such as calcium
channel blockers “nifedipine” or • Fatty streaks formation
“amlodipine” • Atheroma formation
Atherosclerosis • Atherosclerotic plaques formation
Definition Fatty streaks formation: sequential stages
Atherosclerosis is a term used to describe a vascular
pathology that is characterized by thickening of the intimal 1. Chronic endothelial injury by hyperlipidemia,
layer of the arteries and the accumulation of fat. The fatty hypertension, smoking, or other factors
material is found in the central core of the atherosclerotic 2. Endothelial dysfunction characterized by
plaque. increased permeability, enhanced leukocyte
adhesion, and migration of monocytes

292
 3. Smooth muscle cell emigration from the media to • Aneurysms
the intima and the activation of the macrophages • Ischemic stroke or ischemic heart disease
which release inflammatory mediators • Myocardial infarction
4. Engulfment of fat by macrophages → formation • Carotid artery stenosis secondary to thrombosis
of fatty streaks • Embolic disease
Atheroma formation: happens after stage 4 of fatty streaks Diagnosis
formation • The diagnostic approach is dependent on the
5. Smooth muscle cell proliferation, deposition of presenting symptoms and signs of the patient
collagen, deposition of extracellular lipids • For example, a patient presenting with symptoms
Atherosclerotic plaque formation happens after atheroma suggestive of coronary artery disease will need:
formation process o ECG
o Imaging studies such as CTA, MRA, or
6. The plaque consists of a vascular epithelium, imaging studies of the heart to assess
arterial smooth muscle cells, lymphocytes and a cardiac function such as
core of: cell lesions, foam cells, calcium, echocardiography
cholesterol, and other fatty substances o Catheterization of the coronary arteries
7. The plaque is pale-yellow in color due to the Treatment
deposition of carotenoid pigments • Lipid lowering drugs such as statins
The following figure summarizes the different processes • Control of modifiable risk factors such as
involved in atherosclerosis. hypertension, diabetes, smoking, hyperlipidemia,
obesity, and sedentary lifestyle
The goals of treatment are:

• Lower the risk of thrombosis

• Prevent atherosclerotic complications
• Reduce modifiable risk factors to slow the
progression of the process
• Symptomatic relief for example for anginal pain
• Direct widening of a stenotic artery or removal of
the diseased part such as carotid artery
endarterectomy

Clinical Findings Abdominal Aortic Aneurysm

The major arteries are affected in this order: Definition
An aneurysm is the dilation of a blood vessel in respect to
• The aorta, especially abdominal part the original artery. An abdominal aortic aneurysm (AAA)
• Coronary arteries is an aortic diameter at least 1.5 times the normal diameter
• Popliteal arteries at the level of the renal arteries. The normal diameter at
• The carotid arteries that level is 2.0 cm, accordingly, a segment of the
Symptoms include: abdominal aorta that is 3.0 cm or more is an aneurysm.
Most common site is infrarenal.
• Angina → coronary artery disease
• Claudication → peripheral arterial disease
• Symptoms of hyperlipidemia:
o Xanthomas: nodules of lipid-laden
histiocytes in the eyelids
o Lipid deposition in tendons →
tendinous xanthoma
o Lipid deposition in cornea → corneal
arcus
• Ischemic stroke or TIA
• Or the patient might be asymptomatic
Figure 54: An abdominal aortic aneurysm illustration.
Complications: could also be the presentation of the
Source:
disease
https://en.wikipedia.org/wiki/Abdominal_aortic_aneurysm

293
Epidemiology • An incidental finding on ultrasonography,
• AAA is the 14th leading cause of death in the abdominal CT or MRI
United States • Most remain silent until they rupture
• AAA rupture is responsible for 4500 deaths each • If symptomatic before rupture, they can present
year in the United States with:
• AAA is more common in those 65 years or older o Abdominal pain and tenderness
• The condition is four times more common in men o Evidence of embolic disease
• Equal incidence in white and black people o A pulsatile mass in the abdomen
Ruptured aneurysm:
Risk Factors
• Nonmodifiable: • Sudden death in 5% of the patients
o Age: • Shooting abdominal pain or back pain
▪ 1% of those aged 55 to 64 • A pulsatile abdominal mass
years | increase by 3% each
• Severe hypotension and hemodynamic
decade after 64 years compromise
o Male gender:
• 50% of the patients remain alive by the time they
▪ Four times more common in
arrive to the hospital
males
• 50% of those survival the urgent repair procedure
▪ 10 years earlier in onset in
males Diagnosis
o Positive family history increases the risk • It is important to confirm the diagnosis before
by four times AAA rupture
o Genetic disorders such as Marfan • A physical examination that reveals a pulsatile,
syndrome, and Ehlers-Dantos syndrome expansile mass should raise the suspicion of an
• Modifiable: AAA
o Smoking is more important than all the • Abdominal ultrasonography, CT or MRI
above risk factors performed for other purposes can detect an AAA
o Atherosclerosis • Abdominal ultrasonography is the screening
o Hypertension modality of choice for AAA
o Less common in patients with diabetes • CT angiography has a 100% sensitivity for AAA
mellitus detection – only in hemodynamically stable
Risk of rupture of AAA: patients
• Smoking Men aged between 65 to 75 years who
• Three important factors: size of AAA, expansion are asymptomatic should be screened once by
rate, and sex of the patient
abdominal ultrasonography
• AAA size: diameter in cm | annual risk of rupture
o < 4 | 0%
o 5 – 7.9 | 3 – 40%
o > 8 | up to 50%
• A AAA that expands 0.5 cm or more over six
months → high risk of rupture
o Most important risk factor for rapid
expansion is smoking
• Uncontrolled hypertension Figure 55: Measurement of abdominal aortic diameter by
Pathogenesis ultrasonography. Source:
• Atherosclerotic changes in the abdominal aortic https://en.wikipedia.org/wiki/Abdominal_aortic_aneurysm
wall #/media/File:Ultrasonographic_measurement_of_aortic_di
• Degradation of the tunica media by a proteolytic ameter_at_the_navel.svg
process
• Increased activity of matrix metalloproteinases
• Elimination of elastin → aortic arterial wall is
more amenable to high blood pressure induced
injury
Clinical Findings
• Most patients are asymptomatic

294
 Figure 56: A contrast-enhanced abdominal CT scan Debakey
Type I Type II Type III
showing an abdominal aortic aneurysm that is 4.8 cm in classification
diameter. Source: stanford
Type A Type B
classifical
https://en.wikipedia.org/wiki/Abdominal_aortic_aneurysm Percentage 70% 30%
#/media/File:Contrast- Figure 57: An illustration of the different types of aortic
enhanced_CT_scan_demonstrating_abdominal_aortic_ane dissection. Source:
urysm.jpg https://en.wikipedia.org/wiki/Aortic_dissection

Treatment Epidemiology
Nonsurgical treatment: • Incidence 30 per one million per year
• Mortality rate in type A aortic dissection if
• Cessation of smoking untreated is 50% by the 3rd day
• Beta-blockers → reduce expansion rate • Mortality rate in type B aortic dissection if
• Modification of risk factors such as untreated is 10% at 30 days
atherosclerosis and hypertension Risk Factors
• Only for AAAs that are less than 5.5 cm in • Nonmodifiable:
diameter o Age 60 to 70 years
AAA with diameter between 3.0 to 4.0 cm: o Male gender
o Bicuspid aortic valve
• Imaging surveillance every two to three years o History of Marfan syndrome (could be
(ultrasonography)
younger than 40 years)
AAA with diameter between 4.0 to 5.4 cm:
• Modifiable:
• Imaging surveillance very six to twelve months o Hypertension (most important risk
(ultrasonography) factor)
Surgical repair indications in unruptured AAA: o Smoking

• AAA > 5.5 cm in diameter

• Any AAA that expands by 0.5 cm or more in six Note: One of the hypertensive
months emergencies that can be encountered
• Some surgeons consider 5.0 cm to be the in clinical practice is aortic
threshold for indication of surgical repair dissection with severe hypertension
Invasive interventions:

• Surgical repair, via transabdominal route

Pathogenesis
• Endovascular repair: insertion of an endograft Different pathogenesis mechanisms can lead to aortic
into the lumen of the AAA dissection. The most straightforward mechanism is
Aortic Dissection
depicted below.
Definition
Aortic dissection is an injury to the innermost layer of the
aorta where blood starts to flow between the layers of the
aortic wall. Severe Blood flow into A false lumen is
Intimomedial tear
hypertension aortic wall formed

Distal
End-organ Compression
Malperfusion prolongation
ischemia of true lumen
of false lumen

295
The other mechanism of an aortic dissection does not • Control of hypertension and other risk factors
involve an intimomedial tear and is depicted below. • Thoracic endovascular aortic repair (TEVAR) in
complicated cases only
Complicated type B aortic dissection:
Severe Intramural Double-barrel
Evolution into AD
hypertension hematoma aorta
• Evidence of thoracic aortic rupture, mal perfusion
to end organs, or rapid expansion
• Candidates for TEVAR
The mechanism of aortic dissection in atherosclerosis is the Ischemic Heart Disease
following:
Definition
• Atherosclerotic degeneration of the descending Ischemic heart disease is an inclusive term that refers to
thoracic aorta → ulceration of the intima and acute coronary syndromes (ACS), coronary artery disease
medial layers of the aorta → the formation of an (CAD), and coronary heart disease (CHD). While CAD and
intramural hematoma → evolution into an aortic CHD are used interchangeably, they are two different terms
dissection from a pathological point of view. CHD is the consequence
• This is common in older patients with severe of CAD.
atherosclerosis
Clinical Findings Epidemiology
• Tearing, sudden-onset chest pain radiating to the • Leading cause of death and disability in the world
back • Responsible for one in every six deaths in the
• Unequal BP in arms Western world
• Severe hypertension → this is a hypertensive • CHD prevalence in those older than 20 years is
emergency 6.4%
• Hemodynamic compromise or shock in few • Prevalence in men older than 20 years is 8%,
patients whereas the prevalence in women is 5% (1.5:1
Diagnosis male to female ratio)
• Chest radiograph shows mediastinal widening. If • The prevalence of myocardial infarction in that
you suspect an aortic dissection, do not waste age group is 3%, with a 2:1 male to female ratio
your time with this imaging test Risk Factors:
• CT angiography • Family history of early heart disease
• Age > 45 in men, 55 in women
• Hypertension
• Smoking
• Male gender
• Diabetes mellitus
• Atherosclerosis – PAD, CAD, or other forms of
atherosclerosis-related diseases
Figure 2: A contrast-enhanced CT scan showing an aortic
dissection in the ascending aorta, Stanford type A aortic Pathogenesis:
dissection. Source: The pathogenesis of CHD consists of two main processes:
https://en.wikipedia.org/wiki/Aortic_dissection#/media/Fil
• Decreased oxygen delivery
e:DissectionCT.png
• Increased oxygen demand
Treatment Therefore, an imbalance between coronary perfusion
In any patient with aortic dissection: (CAD) and the oxygen demand of the heart muscle is the
main drive for CHD. The mechanism of CAD is the same
• IV Esmolol to lower blood pressure to SBP < 120 of atherosclerosis in other arteries and is given in Figure 1.
mmHg in 5 to 10 minutes
• Sodium nitroprusside
Stanford type A:

• Open heart surgery

Stanford type B:

• Medical treatment with beta-blockers

296
 Diagnosis:
• ECG can be normal when patients are not in an
anginal attack
• Cardiac enzymes such as troponins and CK-MB
are normal
• Echocardiography to assess regional and global
cardiac function
Stress tests:

• Exercise ECG:
Figure 58: Pathogenesis of CAD. o Treadmill is used
o Maximum heart rate should be 220 –
As it has been shown above, CHD is the consequence of age
CAD. As the blood supply is compromised from one step o Look for chest pain, hypotension,
to the next in the pathogenesis of CAD, certain effects arrhythmias, and other ECG
happen in the cardiomyocytes. Figure 2 shows the abnormalities
pathogenesis of CHD. ▪ ST segment depression
o Neither specific nor sensitive for CHD
• Stress echocardiography or myocardial perfusion
tests are more sensitive and specific for CHD →
regional myocardial wall motion
• If positive in any of these tests, go for cardiac
catheterization to confirm the diagnosis of CAD
and CHD
Pharmacologic stress test:

• Can be used after exercise testing or when the

patient cannot do an exercise stress test
• Adenosine, dipyridamole
o They cause coronary artery vasodilation
→ increased blood flow rate and
velocity in normal vessels but not in
stenotic vessels → a steal of flow
Figure 59: Pathogenesis of CHD. Source: http://dx.doi.org/ pattern on perfusion nuclear studies of
10.1055/s-0032-1333543. the heart or ST-segment changes
• Dobutamine
Oxygen demand increases in these patients because of the
o A cardiac inotrope → increases oxygen
following reasons:
demand → similar to exercise
• Left ventricular hypertrophy induced by chronic Treatment:
hypertension Nonpharmacological therapy:
• Increased sympathetic nervous system tone
• Same as nonpharmacological therapy of
Clinical Findings:
hypertension:
• Chest pain – anginal type, substernal with o Weight loss
possible radiation to the jaw or arms o Smoking cessation
• Exertion dyspnea or chest pain o Decrease salt intake
• Stable angina occurs when there is > 70% o Avoid sedentary lifestyle
occlusion of a coronary artery o DASH diet
• Pain resolves with rest within 1 to 5 minutes Risk modification therapy:
• Physical examination is mostly normal, except for
signs suggestive of hypertension, hyperlipidemia • Statins:
or other risk factors o Lipid lowering drugs
• Nitroglycerin relieves the pain very quickly by o Increase HDL and decrease LDL
inducing venous vasodilation, decreasing preload o Anti-inflammatory properties

297
 • Pharmacological treatment of hypertension and • The absence of NO increases the sensitivity of
diabetes mellitus smooth muscle cell (SMC)
Specific treatments of CHD: • Moreover, endothelial damage results in exposure
of subendothelial collagen to circulating platelets
• Aspirin • The activation of platelets and coagulation
o Secondary prevention of arterial cascade results in the release of thromboxane A2,
thrombosis serotonin, and histamine. These are
• Cardiac-specific beta-blockers such as metoprolol vasoconstrictors → increase contractility of SMC
o Decrease oxygen demand by decreasing Why vasospasm occurs at rest or during sleep?
HR
• Nitrates such as nitroglycerin • At rest, the parasympathetic nervous system is
o Decreases preload activated
Revascularization: • Acetylcholine is released:
o Direct vasoconstrictor of the coronary
• If the patient still has symptoms of CHD despite arteries
medical treatment, then revascularization should o Also activates the production of NO by
be considered NO synthase → eventual effect in
• Perform a coronary angiography normal people is vasodilation
• Choose the appropriate method: CABG versus o Because NO synthase activity is
PTCA decreased in patients with variant
• PTCA: angina → rest and the release of
o Moderate-sized viable myocardium acetylcholine result in unopposed
vulnerable to severe ischemia on sudden vasospasm
noninvasive Diagnosis
o Angiographic evidence of a major blood • ECG if performed during the attack can reveal
vessel occlusion supplying that area that ST-segment elevation. This is transient
is > 1.5 mm in diameter o Occurs secondary to transmural
• CABG: ischemia not infarction
o Complex CAD • Coronary catheterization:
o 3-vessel disease o Most definitive test
o 2-vessel disease with LAD artery o IV ergonovine → vasospasm →
disease confirms the diagnosis
o Avoid in 1-vessel disease without LAD Treatment:
disease • Calcium channel blockers → blocks contractility
Prinzmetal’s “Variant” Angina of vascular smooth muscle cells → vasodilation
Definition: • Nitrates
This is a special type of angina that occurs at rest or even Acute Coronary Syndrome
during sleep. It is caused by vasospasm of an already Definition:
narrowed coronary artery due to the contraction of smooth Acute coronary syndrome is an inclusive term that includes
muscle cells. The condition could also occur in healthy unstable angina, non-ST elevation myocardial infarction,
coronary arteries. The symptoms are very brief when and ST-elevation myocardial infarction. These conditions
compared to typical angina pectoris. can be seen as a continuous spectrum where unstable angina
can progress to NSTEMI and NSTEMI may progress to
Pathogenesis STEMI.
Decreased Increased
Endothelial NO Decreased contractilityPathogenesis
dysfunction synthase NO of vascular • ACS is most commonly caused by atherosclerosis
activity SMC • The pathogenesis of unstable angina, NSTEMI,
and STEMI is similar with slight differences
• Endothelial dysfunction occurs because these • ACS in unstable angina occurs by the following
coronary arteries are more often already mechanism:
undergoing atherosclerotic changes An atherosclerotic plaque in a narrowed coronary
• Decreased NO synthase activity leads to artery ruptures → stimulation of platelet
decreased production of NO. NO is a vasodilator aggregation and thrombus formation → severe
occlusion of the coronary artery, however it does

298
 not reach 100% → decreased oxygen delivery to age > 65 TIMI score is used to
3 cad risk factors: estimate the rate of end-point
myocardial cells → decreased contractility and - family history adverse events such as
electrical stability due to failure of production of - htn mortality, recurrent MI, or
ATP by myocardiocytes - dm requiring urgent
- smoking revascularization in the next
• NSTEMI occurs by the following mechanism: - hypercholestorelmia 14 days
Infarction of the innermost layers of the heart due prior documented coronary stenosis >
50% TIMI score of 1 has a 4.7%
to prolonged decreased perfusion 2 anginal events in last 24 hours rate of such complications,
• STEMI occurs when there is a transmural use of aspirin in last 7 days whereas a TIMI score of 6 or
infarction elevated cardiac enzymes more has a 40.9% of
developing an adverse event
• ACS is a problem of decreased oxygen delivery in the next 14 days
with unchanged oxygen demand
Patients who score high
Clinical Findings might be candidates for PCI
Unstable angina:
Treatment:
•Patients report new-onset angina or a change in
the character of their previous angina
• Pain occurs at rest, increases in intensity, and Treatment of unstable angina and NSTEMI:
may last longer than 10 to 15 minutes Aspirin 162 to 325 mg
• Other anginal pain characteristics are also
present: Acute anti-ischemic treatment (MONA):
o Radiation to arm, neck, or jaw
o Associated with dyspnea •Morphine
• Patients have diaphoresis, nausea, dizziness, and •Supplemental oxygen
can be tachycardic or hypotensive •Nitroglycerin
• Other patients might have severe hypertensive → •ACE inhibitors or ARBs
this is one form of hypertensive emergency •Recently, beta-blockers and statins were added to
• Decreased peripheral oxygen saturation this group
NSTEMI: Conservative treatment:

• Same as unstable angina, but the pain is longer in • Low and moderate risk patients
duration and is more severe • Start clopidogrel
• This happens because unstable angina is known • Initiate anticoagulation with unfractionated
to progress to NSTEMI after 20 minutes if heparin, enoxaparin, or fondaparinux
coronary perfusion is not restored spontaneously Invasive treatment:
or by an intervention
STEMI has a similar clinical presentation to NSTEMI. •Initiate a second antiplatelet such as clopidogrel
with or without an IV GP IIb/IIIa inhibitor
Diagnosis • Consider a P2Y12 receptor inhibitor in patients
Unstable angina: undergoing PCI
• Perform PCI → implant a stent in some patients
•ECG: ST-segment depression or T-wave • Initiate anticoagulation
inversion Long-term treatment:
• Cardiac biomarkers must not be elevated
NSTEMI: • Lifestyle modifications
• Aspirin
• ECG: Same as unstable angina • P2Y12 receptor inhibitor for one year
• Cardiac biomarkers are elevated: troponins • Statins regardless of LDL level
STEMI: • Beta-blockers
• ECG: ST-segment elevation or new left bundle • ACE inhibitors or ARB
branch block • Aldosterone antagonists
• Cardiac biomarkers are elevated: troponins or Treatment of STEMI:
CK-MB based on the evolution of the MI • PCI is recommended in all patients
The Thrombosis in Myocardial Infarction (TIMI) Risk • CABG in selected patients
Score for Unstable Angina and NSTEMI: • Fibrinolytic therapy which has its own indications
and contraindications
1 point for each risk factor Notes and interpretation

299
 • Long-term treatment is similar to that of other • Nausea
types of ACS • Vomiting
Evolution of Myocardial Infarction • Pain in left arm or jaw
Definition: • Dyspnea
Myocardial infarction occurs when coronary artery • Fatigue
perfusion is disrupted for a long period, usually over 20
minutes. This occurs secondary to rupture of a coronary
artery atherosclerotic plaque and subsequent thrombosis. Note: The diagnosis of acute MI is
Thrombosis can result in near-complete or complete confirmed when the patient has
occlusion of the affected coronary artery. Because there is characteristic ST-segment deviations
irreversible damage to the myocardium, cardiac enzymes and an elevation in cardiac
such as CK-MB and troponins will be elevated. biomarkers.

Types:
• The two types of acute coronary syndrome that
are related to myocardial infarction are ST- Evolution over Time:
segment elevation MI and non-ST-segment 0 to 24 hours:
elevation MI (STEMI versus NSTEMI) Gross:
• STEMI: Figure 1A
o Complete sudden occlusion of a • The heart is grossly normal. It might have a pale
coronary artery discoloration if tetrazolium stain is used
o Transmural infarction – involves the full Light microscopy:
thickness of the myocardial wall
• Early coagulative necrosis
o ST-segment elevation or new LBBB on
• Release of necrotic cell contents into blood
ECG. Q-waves
stream → elevated cardiac biomarkers
• NSTEMI: Figure 1B
• Microscopic hemorrhages, edema, and wavy
o Near-complete, prolonged occlusion of
fibers
a coronary artery
o Subendocardial infarction • Neutrophils
o Inner third of the sub-endocardium is • Reperfusion injury:
known to be vulnerable to ischemia o In some cases, reperfusion might result
o ST-segment depression on ECG in hypercontraction of myofibrils
• Both have elevation in cardiac biomarkers, unlike o This occurs due to the generation of free
unstable angina radicals and increased calcium influx
Possible complications:

• During this period, ventricular arrhythmias can

occur
• This occurs because of conduction abnormalities
secondary to failure of ATP generation due to
A B hypoxia
Figure 1: A. STEMI. B. NSTEMI. Source: • Heart failure
https://www.123rf.com/photo_55067905_stock-vector-
• Cardiogenic shock
ecg-of-non-st-elevation-myocardial-infarction-nstemi-and-
1st to 3rd day:
detail-of-ecg-p-wave-pr-segment-pr-interval.html and
Gross:
https://www.123rf.com/photo_55067904_stock-vector-
ecg-of-st-elevation-myocardial-infarction-stemi-and-detail- • Hyperemia is prominent
of-ecg-p-wave-pr-segment-pr-interval-qrs-.html Light microscopy:
• The coronary arteries are affected more • Extensive coagulative necrosis
commonly in this order: LAD > RCA > • Acute inflammatory response with neutrophils
circumflex abundance
Clinical Findings: Possible complications:
• Severe retrosternal pain – can be silent in a
patient with diabetes mellitus • Post-infarction fibrinous pericarditis
• Diaphoresis

300
3rd to 14th day: Epidemiology
Gross: • Prevalence of acute MI in adults is 3%
• MI is two times more common in males
• Hyperemic border • Mortality is estimated to be around 40%
• Central yellow-brown soft tissue in the affected
area Pathology
Light microscopy:
Prolonged Necrosis of Necrosis to
ischemia subendocardium subepicardium
• Macrophages are found at this stage
• Granulation tissue formation starts
Possible complications:
• The rupture of an atherosclerotic plaque results in
• Ventricular wall rupture → tamponade acute thrombus formation
• Papillary muscle rupture → mitral regurgitation • This, if not resolved, can lead to prolonged
• Interventricular septal rupture ischemia
• Left ventricular pseudoaneurysm which increases • Necrosis of the sub-endocardium precedes that of
risk of rupture the sub-epicardium by few hours
14th day to several months: • If the patient has chronic coronary heart disease,
Gross: it can take longer than usual to develop a
transmural infarct
• The affected artery undergoes recanalization • Patients with recurrent intermittent occlusion
• The affected myocardial area is gray white “recurrent unstable angina” tend to have a longer
Light microscopy: period before they develop a transmural infarct
• Longer period in the above two scenarios is in
• A contracted scar tissue terms of hours, not days
Possible complications:

• Dressler syndrome
o Might be immune-mediated
o Associated with high levels of
antimyocardial antibodies
o Symptoms occur fever, malaise,
pleuritic chest pain, and decreased
appetite
o Diagnosed by echocardiography Figure 60: Pathogenesis of MI "occlusive thrombus" and
o Treatment: NSAIDs over four to six unstable angina which can progress to MI "non-occlusive
weeks thrombus". Source: DOI: 10.1016/j.jacc.2018.08.1038
• Heart failure
• Arrhythmias Clinical Findings
• True ventricular aneurysm → blood stasis → • Retrosternal chest pain that radiates to upper
mural thrombus formation extremities, jaw, or epigastric region
• Dyspnea and fatigue
Acute Myocardial Infarction • Diaphoresis, nausea and vomiting
Definition: • Palpitations secondary to arrhythmias
Acute myocardial infarction occurs when there is acute • Cardiogenic shock and hypotension
myocardial injury with clinical evidence of myocardial • Severe hypertension might be also seen →
ischemia and a rise or a fall in cardiac biomarkers in hypertensive emergency
temporal relation to the onset of symptoms plus one of the Cardiac Biomarkers
following: CK-MB:

• Symptoms of MI • Rises after 6 to 12 hours of acute MI

• Diagnostic ECG findings • Peaks at 16 to 24 hours
• Development of pathological Q-waves on ECG • Not specific to cardiac muscle – also found in
• Direct visualization of the thrombus on skeletal muscle
angiography • Return to normal after 48 hours → useful in
detecting a re-infarction

301
 • Because it takes too long to be elevated, it is not
the recommended biomarker in the confirmation
of the diagnosis of acute MI
Troponins:

• Cardiac troponin I is specific to the heart → it is

elevated only in cardiac injury Figure 62: Point 1 is the onset of the Q-wave, point 2 is "J-
• Rises after 4 hours of acute injury point". Source: DOI: 10.1016/j.jacc.2018.08.1038
• Peaks at 24 hours
• Return to normal in 7 to 10 days → appropriate The following table summarizes the ECG findings in
for detection of late presentation MI. Not STEMI based on the infarct location.
appropriate for confirmation of a re-infarction Infarct location Occluded artery leads with st elevation
detection anteroseptal LAD V1 and V2
anteroapical Distal LAD V3 and V4
• The most recent definition of acute MI only takes anterolateral LAD OR V5 and V6
troponins into account CircumflexHo
lateral Circumflex Limb leads I and AVL
inferior RCA Limb leads II, III, and
AVF
V1 to V3 ST depression
Supplementary leads
posterior PDA
V7 to V9 show ST
elevation
Treatment
Aspirin 325 mg
Acute anti-ischemic treatment (MONA):

•Morphine
Figure 61: Changes in troponin I and CK-MB after MI •Supplemental oxygen
onset over time. Source: •Nitroglycerin
https://www.grepmed.com/images/1921/ami-biomarkers- •ACE inhibitors or ARBs → decrease afterload →
enzymes-peaks-trends-ckmb-cardiology decrease mortality
• Beta-blockers → decrease oxygen demand by
Electrocardiographic Detection decreasing HR and afterload
• Gold standard diagnostic test in the first six hours • Statins
of MI • Anticoagulation
• ST-segment elevation in STEMI and T-wave Reperfusion therapy:
changes or ST-segment depression in NSTEMI,
see table below • Recommended in all patients with STEMI of < 12
• New left bundle branch block hours duration
ECG Finding Notes
ST elevation - > 1 mm in leads specific to the infarcted area
• PCI is first-line if the patient meets the following
except in V2 and V3 timeframe:
- Men with ST elevation V2 and V3: o Max time from first medical contact to
o > 2 mm
- Women with ST elevation in V2 and V3:
ECG diagnosis < 10 min
o > 1.5 mm o Max delay from STEMI diagnosis to
ST depression - > 0.5 mm in two consecutive leads PCI < 120 minutes
t-wave changes - Hyperacute: peaked T-waves
- T-wave inversion in two consecutive leads
▪ If not, consider fibrinolysis
Other findings - New LBBB • PCI in NSTEMI:
- Pathologic Q-waves o Hemodynamically unstable patients or
- Poor R wave progression → evolving or old
transmural infarct cardiogenic shock
Table: ECG findings in acute MI. Source: DOI: o Chest pain refractory to MONA
10.1016/j.jacc.2018.08.1038 o Life-threatening arrhythmias
o Acute mechanical complications of MI
• ST-segment deviation is determined by o Acute heart failure
comparing the point of onset of the Q-wave to the • Fibrinolytic therapy in patients who are not
point of onset of the ST-segment “J-point”, see candidates for PCI
Figure 3

302
 o Streptokinase, alteplase, reteplase, or Complications of MI
tenecteplase Overview
o If you consider the patient a candidate • Acute MI patients need to be admitted to an
for fibrinolysis, start fibrinolysis as soon intensive care unit or a cardiac intensive care unit
as STEMI is diagnosed, preferably at for close monitoring
the prehospital setting • Reperfusion therapy is the main preventive
Absolute contraindications to fibrinolytic therapy: measure against mechanical complications of MI
o Previous ICH • The adequate and early recognition of these
o Ischemic stroke 6 months ago complications is life-saving
o CNS neoplasms or AVM Classification
o Major trauma, head injury, or surgery Category Examples
one month ago Mechanical - Cardiogenic shock
o GI bleeding one month ago - Rupture complications
o Bleeding disorder - Acute mitral regurgitation
o Aortic dissection - Pseudo/true ventricular
o Liver biopsy or LP 24 hours ago aneurysm
• Relative contraindications to fibrinolytic therapy: electrical - Bradyarrhythmias: AV block,
o TIA 6 months ago sinus bradycardia, asystole
o Oral anticoagulant therapy - Tachyarrhythmias: atrial
o Pregnancy fibrillation, PVC, ventricular
o SBP > 180 mmHg and/or DBP > 110 tachycardia, ventricular
mmHg fibrillation
o Advanced liver disease - Bundle branch blocks
o Infective endocarditis inflammatory - Post-infarction pericarditis
o Active peptic ulcer disease - Dressler syndrome
embolic - Mural thrombus in true
ventricular aneurysm
ischemic - Re-infarction

Congestive Heart Failure and Cardiogenic Shock

• Reperfusion therapy decreases the risk in the
acute setting
• Congestive heart failure might develop:
o Loss of ability to contract of the left
ventricle
o Decreased cardiac output
o End-organ hypoperfusion in cardiogenic
Figure 63: PCI versus Fibrinolysis for STEMI. shock
Recommendations based on the timeframe. Source: • Treatment:
https://doi.org/10.1093/eurheartj/ehx393 o ACE inhibitors to decrease afterload
o Aldosterone antagonists
Long-term treatment: o Diuretics
Arrhythmias
• Lifestyle modifications Sinus arrhythmias:
• Aspirin
• P2Y12 receptor inhibitor • Sinus tachycardia or bradycardia is corrected by
• Statins identifying the cause
• In selected patients: • Tachycardia might be caused by sympathetic
o Beta-blockers nervous system activation, or secondary to
o ACE inhibitors, ARBs, or aldosterone hypotension
antagonists • Bradycardia secondary to sinus node ischemia
Atrial fibrillation:

303
 • Dilation of the left ventricle → mitral • Treatment: IV fluids to increase preload, followed
regurgitation → left atrial dilation → by pericardiocentesis
development of atrial fibrillation Interventricular septal rupture
• Or secondary to atrial ischemia
• The patient has an irregularly irregular pulse • 0.3% of MI patients
• Treatment consists of: • Responsible for 5% of all MI-related deaths
o Rhythm control in hemodynamically • Occurs within the first week post-MI
unstable patients with amiodarone or • Hypotension is pronounced
synchronized DC cardioversion • Treatment: emergency surgery to fix the
o Rate control with beta-blockers if not ventricular septum
contraindicated Papillary muscle rupture
o Anticoagulation
PVC: • 0.3% of MI patients
• The ischemic myocardium is more prone to • Occur within the first week post-MI
generation of premature ventricular complexes • Patients develop shortness of breath, pulmonary
• These PVCs can degenerate into ventricular edema, and hypotension
tachycardia or ventricular fibrillation • Soft-holosystolic murmur due to mitral
Ventricular fibrillation: regurgitation
• The conduction system becomes dysfunctional in • Treatment: mitral valve replacement, and reduce
ischemic myocardium the afterload by administrating sodium
• Ventricular fibrillation is a cardiac arrest rhythm nitroprusside
True ventricular aneurysm
• Treatment is immediate defibrillation
• Patients with recurrent ventricular fibrillation • Rare in the era of PCI
might need an implantable defibrillator • If it occurs, there is blood stasis within the
aneurysm → mural thrombosis → increase risk of
• Ventricular tachycardia is treated with
amiodarone embolic phenomena
AV blocks: • Treatment: anticoagulation

• Occurs secondary to AV node ischemia Pericarditis:

• AV blocks types IIb and III “complete AV block” • Immune-mediated
are dangerous • Early onset post-MI pericarditis
• Treatment is the implantation of a pacemaker • Later-onset Dressler Syndrome
Asystole: • Treatment: NSAIDs, especially aspirin
• This can occur in massive myocardial infarction Re-infarction:
• Exclude other causes of cardiac arrest such as • Recurrence of MI symptoms
hypoxia, hypothermia, electrolyte imbalances, • Rise in CK-MB; troponins are not very useful
hemorrhage because they remain elevated from the first MI
• Non-shockable rhythm for up to 10 days
• Treatment: follow BLS and ACLS algorithms • Consider reperfusion therapy: PCI
Cardiomyopathies
Rupture Complications Definition
Free wall rupture: Cardiomyopathies are diseases that affect the myocardium
and result in structural or functional abnormalities. While
• Occurs in 0.2% after the introduction of PCI in
the pathogenesis of these conditions is different, they share
routine practice
a similar clinical presentation and are identified by the same
• Responsible for 15% of all MI-related deaths diagnostic approach. The main four types are: dilated,
• Peak time is in the 3rd to 5th day post MI hypertrophic, restrictive, and arrhythmogenic right
• Older, women, with totally occluded LAD and Q- ventricular cardiomyopathy.
waves on ECG are more likely to develop a free
wall rupture Dilated Cardiomyopathy
• Patients develop recurrent chest pain, • Most common type, representing 60% of
hypotension secondary to tamponade, or sudden cardiomyopathies
death
• Characterized by a dilated and poorly functioning
• Echocardiography confirms the diagnosis left, or both, ventricles

304
 • Can be classified into primary and secondary • T-wave or ST segment changes
disease • Pathological Q waves
• While hypertension, valvular disease, and • Wide QRS complexes
ischemic heart disease can cause a dilated left • Type 1 AV block
ventricle, the condition is not recognized as a • None of these findings are specific or sensitive
dilated cardiomyopathy Echocardiography:
• More common in men
• Annual incidence is 0.54 per 100,000 in children • Diagnostic
• Annual incidence in adults is 7 per 100,000 • M-mode shows LV dilation and hypokinetic
• The prevalence of dilated cardiomyopathy in the walls
United States is 36 per 100,000
Etiology:

• Beriberi
• Familial or genetic dilated cardiomyopathy
• Myocarditis induced dilated cardiomyopathy
• Peripartum cardiomyopathy
• Stress-induced cardiomyopathy
• Drug-induced cardiomyopathy:
o Anthracyclines – doxorubicin
o Cyclophosphamide Figure 64: M-mode echocardiography showing a dilated
o Cocaine left ventricle and diffuse hypokinetic walls. Source: DOI:
o Alcoholic cardiomyopathy 10.4330/wjc.v6.i6.478
Pathology:
Catheterization:
• Dilated thin ventricles
• Normal or non-occlusive atherosclerotic plaques •To measure cardiac pressures
in coronary arteries •To exclude coronary artery disease as the possible
• Histopathological findings: cause
o Interstitial and perivascular fibrosis Treatment:
o Myocardial necrosis at the sub-
endocardium • Beta-blockers – decrease mortality
Clinical findings: • ACE inhibitors – decrease mortality
• Spironolactone
• Symptoms and signs of congestive heart failure • Patients with ventricular or supraventricular
• Cardiomegaly on radiological examination in an arrhythmias respond to beta-blockers and
asymptomatic patient amiodarone – no effect on mortality
• Abnormal ECG findings in an asymptomatic • Diuretics – no effect on mortality
patient • ICD is indicated in selected patients to prevent
• Chest discomfort that is not relieved by sudden cardiac death
nitroglycerin
Specific Types of Dilated Cardiomyopathy
• Peripheral edema occurs late in the disease Myocarditis and dilated cardiomyopathy:
• Mainly systolic dysfunction
• In case of viral-induced cardiomyopathy, the • A possible long-term complication of viral
patient might describe flu-like illness prior to the myocarditis is inflammatory dilated
onset of cardiac symptoms: cardiomyopathy
o Myocarditis • Also characterized by fibrosis similar to
o Coxsackievirus B idiopathic dilated cardiomyopathy
• Patients might develop ventricular arrhythmias • Histopathological examination of a biopsy is
• S3 gallop on auscultation needed to confirm the diagnosis
• Severely reduced ejection fraction on • PCR can be used to confirm the presence of
echocardiography coxsackievirus B
• Murmur of mitral regurgitation Peripartum cardiomyopathy:
ECG findings:
• Life-threatening condition

305
 • Last month of pregnancy up to 6 months • Fibrosis can affect the SA and AV nodes →
postpartum arrhythmias and sudden death
• Unknown mechanism → possible role of • If the immune response was adequate → fibrosis
prolactin of the myocardium with indeterminate clinical
• A diagnosis of exclusion significance
• A systolic form of heart failure • Also associated with mega-colon, dilated
• Treatment is challengeable because most esophagus, achalasia
pharmacological treatments of heart failure are Hypertrophic Cardiomyopathy
contraindicated during pregnancy • A heterogenous group of different inherited
Stress-induced cardiomyopathy: cardiomyopathies
Pathology:
• Also known as Takotsubo cardiomyopathy
• History of intense emotional or physical stress • An autosomal dominant genetic disorder
followed by LV contractile dysfunction • Mutations in approximately 10 different genes for
• ST-segment elevation on ECG sarcoplasmic proteins
• Cardiomyopathy is transient and reversible • Mutations in beta-myosin heavy chains and other
Drug-induced cardiomyopathies: myosin binding proteins account for up to 80% of
the cases
• Anthracyclines are antineoplastic drugs
• Asymmetrical or symmetrical hypertrophy of the
• Highly effective in different cancers
left ventricle
• Can cause cardiac dysfunction
• Left free ventricular wall hypertrophy plus
o Acute or subacute cardiotoxicity interventricular septal hypertrophy → left
o Chronic cardiotoxicity
ventricle outflow tract obstruction
o Late-onset cardiotoxicity decades after
• Histopathological findings:
discontinuing anthracyclines
o Cardiomyocyte hypertrophy
• Echocardiography for screening of patients on o Disarray and enlarged nuclei
antineoplastic therapy o Hyperchromasia
• Treated with ACE inhibitors, beta-blockers and o Increased content of interstitial collagen
spironolactone
• Diastolic dysfunction due to impaired filling
• Dexrazoxane is a cardioprotective agent used in
patients receiving anthracycline chemotherapy
Alcoholic cardiomyopathy:

• One of the most common types of dilated

cardiomyopathies
• Related to duration and dose of alcohol
consumption
• Good prognosis if the patient discontinue alcohol
consumption
Arrhythmogenic cardiomyopathy:
Figure 65: Septal and left-ventricular hypertrophy in
• Right ventricular dysplasia hypertrophy cardiomyopathy. Source:
• Genetic form of dilated cardiomyopathy https://en.wikipedia.org/wiki/Hypertrophic_cardiomyopath
• Fibrosis and fatty infiltration of the right ventricle y#/media/File:Hypertrophic_obstructive_cardiomyopathy.p
ng
• Ventricular tachycardia and ventricular
fibrillation
Clinical findings:
Chagas disease:
• Syncope during exercise
• A parasitic infection that affects multiple organ
Mechanism: asymmetric septal hypertrophy →
systems
systolic anterior motion of the mitral valve →
• Caused by Trypanosoma cruzi infection outflow obstruction → possible syncope
• Significant fibrosis in the left ventricular • Sudden cardiac death in a young athlete
myocardium in some patients → ventricular
• S4 secondary to a stiff left ventricle during late
dilation → chronic heart failure
diastole
• Systolic murmur

306
 • Diagnosis is confirmed by echocardiography and
ECG findings of LVH and septal hypertrophy
Treatment:

• Beta-blockers are first-line therapy

o Negative inotropes
o Improved ventricular relaxation →
increased diastolic filling → increased Figure 66: Amyloid deposits in a patient with secondary
stroke volume → increased CO amyloidosis due to familial Mediterranean fever. Source:
• Calcium channel blockers have also some role DOI: 10.4330/wjc.v6.i6.478
• The goal is to decrease the left ventricular
outflow tract gradient to less than 50 mmHg Hemochromatosis:
• Definitive treatments include alcohol septal • Iron overload and deposition in sarcoplasmic
ablation, and septal myectomy reticulum of the heart
Restrictive Cardiomyopathy • Autosomal recessive disorder
• Impaired ventricular filling and reduced diastolic • Multi-system manifestations
volume • Treatment is by repeated phlebotomy
• Normal or near-normal systolic function Sarcoidosis:
• Changes in restrictive cardiomyopathy are • Systemic infiltrate disease
functional, not structural • Noncaseating granulomas infiltrate the
• 5% of all pediatric cardiomyopathies myocardium
Pathology: • Restrictive cardiomyopathy → can progress to
dilated cardiomyopathy
• Infiltrative conditions of the myocardium result in • Associated with ventricular tachycardia and AV
impaired ventricular filling block type 3
• Can be primary diseases such as in Loffler’s • Steroids improve symptoms but do not prevent
endocarditis and idiopathic restrictive sudden death
cardiomyopathy • Patients who develop a complete AV block
• Infiltrative diseases that can cause secondary should be treated with a permanent pacemaker
restrictive cardiomyopathy include:
o Hemochromatosis Heart Failure:
o Sarcoidosis Definition
o Glycogen storage disorders Heart failure results when there are structural or functional
o Fabry’s disease abnormalities of the ventricles that impair their filling or
o Amyloidosis ejection of blood. Patients with heart failure present with
Clinical findings: dyspnea, fatigue, limited exercise tolerance, and fluid
retention.
• Signs and symptoms of congestive heart failure
• Distended jugular veins Systolic HF:
Amyloid heart disease:
• Heart failure with reduced ejection fraction
• Near-normal LV dimensions • LVEF < 40%
• Increased myocardial wall thickness • Increased end-diastolic volume
• Infiltrative cardiomyopathy • Decreased contractility
• Low-voltage QRS complexes • Patients with systolic HF tend to have diastolic
• No treatment and poor prognosis HF elements too
• Most common cause is CAD
Diastolic HF:

• Heart failure with preserved ejection fracture

• LVEF > 50%
• Normal end-diastolic volume
• Increased end-diastolic pressure
• Seen in patients with HCM

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Classification:
ACC/AHA stages of hf nyha functional classification
A High risk of HF | No None
structural heart disease | No
symptoms of HF
B Structural heart disease | No I No limitation of physical
symptoms or signs of HF activity
C Structural heart disease with I No limitation of physical
prior or current symptoms of activity
HF II Slight limitation of
physical activity Figure 67: Pitting edema in HF. Source:
III Marked limitation of https://commons.wikimedia.org/wiki/File:Pitting_Edema.jp
physical activity
IV Unable to carry out any g
physical activity
D Refractory HF IV Unable to carry out any Left heart failure:
physical activity

• Orthopnea
Epidemiology: Increased venous return when supine → increased
• Lifetime risk of HF is 20% of those 40 years or pulmonary vascular congestion
older • Paroxysmal nocturnal dyspnea
• 650,000 new HF cases per year in the US • Pulmonary edema
• Incidence is 20 per 1000 in those aged 65 to 69 Increased pulmonary venous pressure →
years pulmonary venous distention → transudation of
• African Americans have a higher incidence of HF fluid in the lungs. Hemosiderin-laden
• Mortality remains 50% within 5 years of macrophages in the lungs
diagnosis Right heart failure:
Risk Factors:
• Hepatomegaly
• Hypertension is the most important modifiable
Increased central venous pressure → increased
risk factor for HF
resistance to portal flow
• Obesity, insulin resistance and diabetes mellitus
• Jugular venous distention
• Metabolic syndrome
• Peripheral edema
• Atherosclerotic disease Increased peripheral venous pressure → fluid
Pathophysiology: transudation
• The pathophysiology of systolic HF is Diagnosis:
summarized here: • Echocardiography for the classification of HF
Decreased LV contractility → decreased cardiac into systolic, diastolic, and combined
output → activation of renin-angiotensin-
• Measurement of ejection fraction by
aldosterone system and sympathetic nervous
echocardiography
system → increased sodium and water retention
• BNP levels are elevated in HF and it is a good
→ increased preload → increased cardiac output
biomarker
if compensated HF
• Other diagnostic testing based on etiology for
Decreased LV contractility → pulmonary venous instance MRA, CTA, and angiography is the
congestion → impaired gas exchange, pulmonary cause is ischemic heart disease
edema, and decreased right ventricular output → Treatment:
increased systemic venous pressure → peripheral AHA Stage A:
edema
• Goals are to prevent vascular and CAD, and
Clinical Findings: prevent LV structural abnormalities
General symptoms: • Promote healthy lifestyle modifications
• Pitting edema • ACE inhibitors or ARB especially in DM patients
• Fatigue • Statins as appropriate
• Dyspnea AHA Stage B:
• Jugular venous distension • Goal is to prevent HF symptoms and prevent
• S3 heart sound further cardiac remodelling
• ACE inhibitors or ARB

308
 • Beta-blockers Pathophysiology:
• In selected patients, ICD or revascularization • Decreased end-organ perfusion → hypoxic injury
treatment • Decreased kidney perfusion can result in acute
AHA Stage C: kidney failure
• Hypoperfusion can be secondary to hypotension
• Goal is to control HF symptoms, prevent • Lactic acidosis:
hospitalization, and prevent mortality In absence of oxygen, pyruvate is converted to
• Patients with systolic HF: lactate
o Diuretics to treat fluid retention • Oliguria
o ACE inhibitors or ARBs • CNS dysfunction
o Beta-blockers
o Aldosterone antagonists Important Parameters in Shock:
o In selected patients: hydralazine, Cardiac output:
digitalis, CRT, ICD, or
• This is dependent on the stroke volume and heart
revascularization
rate
• Patients with diastolic HF:
• It is decreased in cardiogenic shock
o Diuretics
Systemic vascular resistance:
o Treatment of comorbidities such as
HTN, CAD or DM • The arterioles and arteries have smooth muscle
AHA Stage D: cells
• Control symptoms • These can constrict when the sympathetic
nervous system is activated as in shock
• Heart transplantation
Treatments that reduce mortality: • When this happens, the systemic vascular
resistance is increased
• ACE inhibitors and ARBs • In some types of shock, the systemic vascular
• Beta-blockers except in decompensated HF resistance will be decreased
• Spironolactone Pulmonary capillary wedge pressure:
• Hydralazine and nitrate therapy in selected
• A pulmonary catheter is wedged into a small
patients
pulmonary arterial branch and inflated
Treatments used only for symptomatic relief:
• The pressure is measured
• Thiazide and loop diuretics • It is an estimate of left atrial pressure
Shock Basics: Common Symptoms and Signs:
Definition: • Hypotension
The current definition of shock considers tissue • Oliguria
hypoperfusion/decreased oxygen delivery to be the • Tachycardia
definition of shock without relying on blood pressure
• Altered mental status
alone. Accordingly, shock state is present when cellular
hypoxia develops which leads to organ dysfunction and
failure. Note: The symptoms of shock come
Classification: from our understanding of the
Causes pathophysiology, i.e. end-organ
Hypovolemic - Hemorrhage dysfunction secondary to
- Third-space losses hypoperfusion
- Vomiting and diarrhea
obstructive - Tamponade
- Massive PE
- Tension pneumothorax
cardiogenic - Acute MI Treatment Principles:
- Myocarditis or cardiomyopathies
- Valvular heart disease
Patient presents with signs of hypoperfusion:
distributive - Septic shock
- Neurogenic shock • ABC
- Adrenal crisis • Intravenous access
cytotoxic - Cyanide poisoning
- CO poisoning • CBC, renal function, electrolytes, lactate
• ABG, ECG, chest radiograph depending on the
presenting symptoms

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 • Cardiac enzymes or echocardiogram if you Pathophysiology:
suspect cardiogenic shock
Assess volume status:

• Classify patients into three main categories

• Hypovolemic, cold extremities
• Hypovolemic, warm extremities and signs of
infection Figure 68: Cardiogenic and obstructive shock are
• Hypervolemic, history of cardiovascular event characterized by decreased cardiac output with
Hypovolemic patients with cold peripheries: hypervolemia. Peripheral vascular resistance is usually
unchanged. Source:
• Control ongoing losses https://www.nejm.org/doi/full/10.1056/nejmra1208943
• Replace volume loss
• Consider transfusion Cardiogenic shock:
• Consider vasopressors only in unresponsive cases
Hypovolemic patients with warm peripheries and signs of •Myocardial damage → impaired cardiac pump
infection: function → decreased stroke volume →
decreased cardiac output → cardiogenic shock
• Septic shock • Decreased cardiac output also leads to coronary
• Replace volume loss artery hypoperfusion and exacerbate myocardial
• Antibiotics ischemia
• Consider vasopressors early in the disease • Heart rate and afterload are increased because of
• If unresponsive, consider inotropes, activated the release of catecholamines → increased
protein C, and corticosteroids myocardial oxygen demand → worsen
• Vasopressin in refractory cases myocardial ischemia
Hypervolemic shock with history of cardiac disease: • Tachycardia → no enough time for diastolic
filling of the heart → diastolic dysfunction on top
• Cardiogenic shock of systolic dysfunction
• Correct volume status • Activation of RAAS system → fluid retention by
• Reverse ischemia by PCI or fibrinolysis as the kidneys → further increase in preload →
indicated pulmonary congestion
• If unresponsive, consider vasodilators and Obstructive shock:
inotropes
Cardiogenic and Obstructive Shock • Inadequate ventricular filling secondary to
Definition: cardiac compression or severe obstruction to
Cardiogenic shock is a state of tissue hypoperfusion ventricular inflow or outflow
secondary to ventricular damage. Cardiac pump function is • Cardiac tamponade → decreased ventricular
impaired. filling → decreased stroke volume → decreased
cardiac output and hypotension → reflex
Obstructive shock is characterized by impaired ventricular vasoconstriction and increased intracardiac
filling. It occurs because of cardiac compression or severe pressures
obstruction to the ventricular outflow or inflow. • A massive pulmonary embolism → obstruction of
pulmonary vessels → increased right-sided
Epidemiology: pressures and low cardiac output → right
Cardiogenic shock: ventricular failure
• Number one cause of death in CAD Hemodynamic Profile:
• Incidence is 8% in ACS Type/etiology
cardiogenic
CO
Decreased
Preload
Increased
Afterload
Increased
Contractility
Decreased
• Mainly left ventricular failure (75% of the cases) pe Decreased Decreased Increased Normal
• Reperfusion therapy reduces mortality tamponade Decreased Decreased Increased Normal
Obstructive shock:
Clinical Findings:
• 2% of cardiogenic shock is obstructive, i.e. • Symptoms and signs of tissue hypoperfusion such
cardiac tamponade as AMS, oliguria, and pulmonary edema
• Symptoms and signs suggestive of acute coronary
syndrome or MI

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 • History of other cardiac disease such as Hypovolemic Shock:
myocarditis, cardiomyopathies, valvular heart Definition:
disease Hypovolemic shock is a state of end-organ hypoperfusion
• S3 due to loss of circulating volume. Hypotension is seen in
• Symptoms and signs suggestive of cardiac patients with hypovolemic shock which activates the
tamponade: sympathetic nervous system to raise blood pressure by
Recent MI → ventricular free wall rupture → cardiac and vascular mechanisms.
sudden death or shock state = cardiac tamponade
• Symptoms of DVT and chest pain → pulmonary Epidemiology:
embolism • A major cause of death in trauma
• Upper extremities hypertension with weak pulses • A complication of surgery
in the lower limbs → coarctation of the aorta • Also seen in patients with gastrointestinal losses
• History of trauma, dyspnea, and shock → tension or burn patients
pneumothorax • Trauma patients tend to have a mixed picture of
Diagnosis: hypovolemic, neurogenic and obstructive shock
• Hypotension • Trauma-related mortality and morbidity are
• Estimate cardiac output, which should be low related to the occurrence of hypovolemic shock
• Measure central venous pressure, which will be Pathophysiology
high
• Perform echocardiography:
o In cardiogenic, expect to see large
poorly contracting ventricles
o In cardiac tamponade: pericardial
effusion, small ventricles, dilated IVA
o In massive PE: dilated right ventricle,
small left ventricle
• ECG:
o STEMI or NSTEMI
o Decreased voltage in tamponade Figure 69: Hypovolemic shock is characterized by a
decreased circulating volume and increased peripheral
Treatment: vascular resistance. Source:
Cardiogenic shock: https://www.nejm.org/doi/full/10.1056/nejmra1208943
• Early revascularization
• Loss of circulating volume → hypotension and
• Intra-aortic balloon pump
pain due to tissue injury → activation of the
• Left ventricular assist device sympathetic nervous system → increased heart
Obstructive shock: rate, cardiac contractility, and peripheral vascular
• Needle or catheter drainage of tamponade resistance → beneficial in early stages of shock
• Fluid and vasoactive drugs while awaiting • Prolonged activation of the sympathetic nervous
decompression system → hypermetabolic state in end-organs →
o Dopamine increases renal perfusion worsen local ischemia
o Dobutamine increases cardiac output • These compensatory mechanisms fail when
o Norepinephrine volume loss is > 25%
• Massive PE is an indication for thrombolytic • When volume loss is > 40% → if not corrected
therapy within 2 hours → activation of systemic
Unresponsive patients with cardiogenic shock: inflammatory cascade → irreversible tissue
damage and increased risk of reperfusion injury
• If early revascularization does not improve the Because of this, early correction of severe
hemodynamic profile, other treatments might be hypovolemic shock is mandatory
considered Hemodynamic Profile
• Inotropes Type/etiology CO Preload Afterload Contractility
Hypovolemic Decreased Decreased Increased Normal
• Vasodilators only if the patient is not severely
hypotensive

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Clinical Findings: Sepsis:
• Symptoms and signs of tissue hypoperfusion such
as AMS, oliguria, and pulmonary edema Presence of two SIRS criteria plus a known or suspected
• Symptoms and signs suggestive of the source of infection.
mechanism of volume loss: Severe sepsis:
o Concealed or open hemorrhage
o Major trauma • Hypotension:
o Vomiting or diarrhea o SBP < 90 mmHg, MAP < 70 mmHg, or
o Third-space losses a reduction in SBP of 40 mmHg from
o Dehydration baseline
• Hypotension when > 30% circulating volume is • Serum lactate > 2 mmol/L
lost • Signs of organ dysfunction
• Tachycardia when > 15% circulating volume is Septic shock:
lost
• Narrow pulse pressure Any sepsis-induced hypotension that does not respond to
fluid replacement therapy and requires vasopressors to
Diagnosis:
maintain end-organ perfusion.
• Hypotension
• Lactic acidosis
• Decreased central venous pressure
The table below shows the stages of hypovolemic shock. Note: Recent definitions of sepsis
and septic shock have removed the
Stage Volume BP HR Other definitions of SIRS and severe
loss
I < 15% Normal Normal - Pallor sepsis in light of recent advances in
750 ml the understanding of septic shock
II 15 – 30% Increased Normal or - Increased
750 – DBP slightly RR
pathogenesis.
1500 ml Narrow elevated - Sweating Sepsis is defined as a life-
pulse threatening end-organ dysfunction
pressure
III 30 – 40% SBP < 100 Tachycardia - Marked
secondary to a dysregulated patient
1500 – mmHg tachypnea response to infection.
2000 ml Septic shock is seen in patients with
IV > 40% SBP < 70 Extreme - Severe
> 2000 ml mmHg tachycardia tachypnea sepsis who develop hypotension that
needs vasopressors to be maintain
Treatment MAP > 65 mmHg and have a serum
• ABC lactate of > 2 mmol/L despite
adequate volume replacement
• Control ongoing losses
therapy.
• Start volume replacement with crystalloids
• Consider blood transfusion in hemorrhagic
patients
• Avoid vasopressors if possible Epidemiology:
Septic Shock • Because of recent changes in the definitions of
Definitions: sepsis and septic shock, it is difficult to know the
The conventional understanding of sepsis and other related incidence of sepsis
pathologies lead to the definition of four important • Septic shock has a mortality rate > 40%
conditions, or stages. • Gram-negative bacteria cause 38% of the cases
• Gram-positive bacteria are responsible for 52% of
SIRS: the cases
Systemic inflammatory response syndrome is characterized • Fungi are becoming a more common cause of
by the presence of at least two of the following: sepsis and septic shock

• Temperature < 36C or > 38.3 C

• HR > 90 beats/min
• RR > 20 per minute or PaCO2 < 32 mmHg
• WBC count < 4000 per mm3 or > 12,000 per mm3

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Pathophysiology: • Acute respiratory distress syndrome
• Disseminated intravascular coagulation
• Acute tubular necrosis
• Multi-organ dysfunction syndrome
• Death
Diagnosis:
• Hypotension
• Lactic acidosis
Sequential organ failure assessment score:
Parameter interpretation of results
PaO2:FiO2 < 300 mmhg
Figure 70: Septic shock is characterized by marked platelets < 100,000 per mm3
vasodilation and decreased peripheral vascular resistance. hypotention requiring Patients who meet 2 or more of these
Source: vasopressors criteria have a high risk of
gcs < 12 development of multi-organ failure,
https://www.nejm.org/doi/full/10.1056/nejmra1208943 bilirubin > 2 mg/dl poor outcome, and possibly death
creatinine > 2 mg/dl, or
• Release of TNF-α and IL-1 in septic shock is urine output < 500 ml/day
believed to play a major role
• TNF- α is produced by activated macrophages in Treatment:
response to microbial antigens • ABC
• Increase in TNF- α → increase in IL1-beta, IL-6, • Initial resuscitation with IV fluids
IL-8, thromboxane, and eicosanoids → activation • Identification of the source of the infection
of the coagulation and complement systems → • IV antimicrobials to cover gram-negative, gram-
decreased myocardial contractility positive and fungal organisms implicated in
• Activation of NO synthase → increased NO sepsis and septic shock
production → vasodilation → decreased Vasoactive medications:
peripheral vascular resistance • IV fluid replacement therapy will not correct the
• Patients also have inability to extract oxygen hypotension in patients with septic shock
from the blood → lactic acidosis despite normal • Norepinephrine is the vasopressor of choice in
venous oxygen saturation septic shock
Hemodynamic Profile: • Patients with low risk of tachyarrhythmias can
Type/etiology CO Preload Afterload Contractility receive high dose dopamine
Septic – Decreased Decreased Decreased Decreased • Low-dose dopamine is indicated in all patients →
before IV
fluids
renal protection by improving perfusion
Septic – After Increased Normal Decreased Decreased • Dobutamine only in patients who do not respond
IV fluids to norepinephrine and dopamine
• Notice that despite adequate fluid replacement,
patients still have a decreased afterload
Neurogenic Shock:
“hypotension” and decreased contractility of the
heart Definition:
A distributive shock with hypotension and bradycardia
• This is characteristic of septic shock
secondary to acute spinal cord injury with disruption of the
• Lactic acidosis does not resolve after fluid
sympathetic nervous system pathways.
replacement therapy because peripheral tissues
are unable to extract oxygen from the blood
Clinical Findings:
• Symptoms and signs of tissue hypoperfusion such
as AMS, and oliguria
• Symptoms and signs of SIRS
• Symptoms and signs suggestive of the source of
infection
• Hypotensive despite adequate fluid replacement
therapy
• Lactic acidosis despite fluid replacement therapy
Complications of septic shock:

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Pathophysiology: • Other vasopressors such as norepinephrine and
ephedrine if dopamine fails to improve the
hemodynamic profile
• Vasopressin
Infective Endocarditis:
Definition:
• Infective endocarditis is a life-threatening disease
where there is damage to the endocardium that
attracts microorganisms to colonize the damaged
part. Infective endocarditis is a multisystem
disease that is usually of a bacterial etiology.
Figure 71: Neurogenic shock is caused by an acute spinal
cord injury and characterized by unopposed vagal tone
Epidemiology:
“vasodilation” due to disruption of the sympathetic nervous
system pathways. Source: • Annual incidence is from 1.5 to 11.6 per 100,000
https://www.nejm.org/doi/full/10.1056/nejmra1208943 • Untreated → 100% mortality rate
• Treated → 25% mortality rate
• Brain, cervical or high-thoracic spinal cord injury • Most patients are older than 50 years of age in the
→ loss of sympathetic stimulation to the blood developed world
vessels → unopposed vagal tone → vasodilation • Two thirds of patients are males
→ decreased peripheral vascular resistance Risk factors:
• The level of spinal cord injury must be above the
6th thoracic vertebra • Rheumatic valvular heart disease
• Bradycardia or no reflex tachycardia • Prosthetic valves or other cardiac devices
Hemodynamic Profile: • Congenital heart disease such as mitral valve
Type/etiology CO Preload Afterload Contractility prolapse
Neurogenic Decreased Decreased Decreased Decreased • Injection drug use
• Human immunodeficiency virus infection
Clinical Findings: • Most cases (80%) are attributed to streptococcus
• Symptoms and signs of tissue hypoperfusion such and staphylococcus infections
as AMS, and oliguria o Staphylococcus aureus
• Severe hypotension with bradycardia o Streptococcus viridans
• Hypotension is sudden • Enterococci species are also reported in infective
Respiratory consequences of spinal cord injuries: endocarditis
• Injuries at C5 or below → paralysis of intercostal Pathophysiology:
muscles → diaphragmatic breathing Pathogens
Adherance to
Persistence
Prolifeartion Detachment
abnormal and formation of vegetation
• Injuries above C3 → paralysis of the diaphragm access
bloodstream
cardiac
of bacterial
colonization
of infected particles -
surfaces vegetations embolism
→ immediate respiratory arrest
Patients will also have history of trauma and focal
neurological deficits based on the level of injury. •
This mechanism explains how the involvement of
the endocardium occurs in patients with infective
Diagnosis: endocarditis
• Sudden severe hypotension with bradycardia in a • Patients also have involvement of other organs
spinal cord injury patient is diagnostic • The main mechanism is dislodgement of infected
• Spinal cord MRI can detect the injury, even if vegetations → embolism to distant organs
small Systemic pathology in infective endocarditis:
Treatment: • Embolization to the brain → embolic stroke with
• ABC conversion to hemorrhagic stroke or pyogenic
• Initial resuscitation with IV fluids brain abscess
Vasoactive drugs: • Embolization to the lungs → septic pulmonary
foci
• Dopamine
• Embolization to the spleen → splenic infarcts
• Atropine in patients with bradycardia
• Activation of the immune system and the
formation of immune complexes → deposition of

314
 immune complexes in the retinal blood vessels → • Should be performed in all patients suspected to
Roth spots have infective endocarditis
• Peripheral finger infarcts • Transthoracic and transesophageal
• Petechiae, cutaneous infarcts, and Osler’s nodes echocardiography
are immune-mediated • Identification of vegetations among other findings
Osler’s nodes: Diagnostic Criteria
• Arteriolar intimal proliferation Modified Duke Criteria for IE:
• Diffuse perivascular infiltration by neutrophils Major clinical criteria:
• Immune complexes
Janeway lesions: A. Blood culture positivity for typical
microorganisms or persistent bacteremia
• Septic emboli B. Echocardiographic evidence of valvular
• Presence of bacteria, neutrophils, necrosis and vegetation or new valvular regurgitation
subcutaneous hemorrhage C. Serology: positive for C. burnetii
Minor clinical criteria:
A. Predisposing condition such as intravenous drug
use or cardiac lesion
B. Arterial embolism
C. Septic pulmonary emboli
D. Mycotic aneurysm
E. Intracranial hemorrhage
F. Subconjunctival hemorrhage
G. Janeway’s lesions
Figure 72: Systemic pathology in infective endocarditis. Interpretations of the results:
Source: DOI: 10.1038/nrdp.2016.59
Definite IE:
Causative organisms: • Proven IE by histopathology, or
• Native valves: • Two major criteria, one major and three minor
o Streptococcus viridans criteria, or five minor criteria
o HACEK group Possible IE:
• Prosthetic valves: • One major and one minor criterion, or
o Streptococcus epidermis if less than 60
• Three minor clinical criteria
days post-surgery
Rejected IE:
o Other streptococci if > 60 days post-
surgery • Established other diagnosis, or
Diagnosis: • Resolution of IE symptoms with antibiotics in 4
Blood culture and identification of causative organisms: days or less, or
• No pathologic evidence of IE at surgery
• Patients who present with symptoms and signs • Does not meet the criteria of possible IE
suggestive of infective endocarditis should get
blood cultures withdrawn before starting Treatment:
antimicrobial treatment • Antimicrobial treatment
• Patients with negative blood cultures can undergo o Streptococcus viridans and bovis:
the following tests to identify the causative ▪ Penicillin
organism: ▪ Ceftriaxone
o Serology testing ▪ For four weeks, or two weeks
o Histopathology if combined with gentamicin
o PCR o Enterococci:
o Immunohistology ▪ Ampicillin + gentamicin
Echocardiography: ▪ For six weeks
o Staphylococci:
• This is the second most important diagnostic test ▪ Nafcillin
in infective endocarditis ▪ Cefazolin

315
 ▪ Vancomycin Acute rheumatic fever:
▪ Nafcillin + gentamicin +
rifampin for prosthetic valve • Colonization, adhesion, and invasion of the
IE pharyngeal epithelium by group A beta-hemolytic
o HACEK: streptococcus (GAS)
▪ Ceftriaxone • Macrophages process GAS antigens and present
▪ Ampicillin them to B and T cells
▪ Ciprofloxacin • Generation of cross-reactive B and T cells which
o Fungi: recognize self-antigens and attack them
▪ Amphotericin • Activated cross-reactive B-cells secrete cross-
▪ Long-term suppressive therapy reactive antibodies, whereas activated cross-
• Surgery in selected patients reactive T-cells result in cellular-mediated
immune responses
Acute Rheumatic Fever and Rheumatic Heart Disease • Damage to the heart, brain (chorea), joints
Definition: (arthritis) and skin (erythema marginatum and
Acute rheumatic fever is a systemic autoimmune response subcutaneous nodules)
to pharyngitis caused by streptococcus pyogenes “group A Carditis mechanism in acute rheumatic fever:
streptococcus bacteria”. Rheumatic heart disease is the
long-term sequalae of cardiac damage caused by acute • Cross-reactive antibodies and activated T-cells
rheumatic fever. bind to laminin and glycoproteins on the valve
surface, or VCAM1 respectively
Epidemiology: • This leads to tissue damage and an inflammatory
• The incidence of acute rheumatic fever and response characterized by the recruitment of
rheumatic heart disease in the developed world is macrophages
low • The consequences of carditis are as follows:
• The incidence is quite high among low-income o Elongation and fusion of chordae
and middle-income countries, i.e. 155 per tendinea
100,000 per year in children aged 5 to 14 years o Valvular thickening and calcification
Risk factors: o Collagen deposition
o Dilation of the annular rings
• Acute rheumatic fever is more common in • These changes can eventually result in valvular
children aged 5 to 14 years stenosis or regurgitation
• Rheumatic heart disease is more common in • Mitral > aortic >> tricuspid valve
adults in their 20s or 30s • Regurgitation is the early lesion. Stenosis in late
• Acute rheumatic fever has equal frequency in presentation
males and females
• Rheumatic heart disease is more common in
women
• Increased exposure to streptococcus pyogenes,
i.e. living in crowded places, appears to be a risk
factor.
Pathophysiology:

Figure 74: Mechanism of carditis in acute rheumatic fever.

Source:
https://www.ncbi.nlm.nih.gov/books/NBK425394/pdf/Boo
kshelf_NBK425394.pdf
Figure 73: Pathogenesis of acute rheumatic fever. Source:
https://www.ncbi.nlm.nih.gov/books/NBK425394/pdf/Boo
kshelf_NBK425394.pdf

316
Clinical Findings minor
carditis - Prolonged PR interval
Acute rheumatic fever: arthralgia - Polyarthralgia
Fever - > 38.5
• Arthritis: markers of - ESR > 60 mm
o Mainly large joints inflammation - CRP > 3 mg/dL
Evidence of preceding - Increased or rising anti-streptolysin O
o Knees, ankles, elbows and wrists streptococcal infection titer
o Multiple joints are affected, sequentially - Anti-DNASE B
or at the same time - Positive culture of group A B-hemolytic
streptococci
o Migratory polyarthritis - Positive rapid group A streptococcal
o Rapid response to anti-inflammatory carbohydrate antigen test
response (NSAIDs or glucocorticoids) • The diagnosis is confirmed when there is
o Sterile synovial fluid with documentation of preceding streptococcal
lymphocytosis infection plus:
• Carditis: o Two major, or
o Can result in pancarditis o One major and one minor, or
o Most often endocarditis with valvular o Three minor
disease (mitral regurgitation) • Evidence of carditis is taken from
o MR findings on auscultation: echocardiography and ECG
▪ Pansystolic murmur • Biopsy might reveal Aschoff bodies:
o Cardiomegaly secondary to atrial o Granuloma with giant cells
dilation o Enlarged macrophages with ovoid,
• Chorea: wavy rod-like nucleus
o Sydenham’s chorea o Known as Anitschkow cells
o Also known as St. Vitus’s dance
o 30% of acute rheumatic fever cases
o Involuntary non-rhythmic purposeless
movements of trunk and limbs
o Usually more pronounced on one side
• Erythema marginatum and subcutaneous nodules:
o 10% of patients have skin
manifestations Figure 75: Aschoff bodies. Source:
o Erythema margination: bright pink, https://en.wikipedia.org/wiki/Aschoff_body#/media/File:R
blanching, non-pruritic macules on the heumatic_heart_disease_-_3b_-_very_high_mag.jpg
trunk and proximal limbs
o Subcutaneous nodules: painless small
Treatment:
nodules that develop over bony
• Penicillin for the eradication of GAS infection
prominences (elbows) or extensor
tendons • Prophylaxis against acute rheumatic fever
o Patients usually have three to four
nodules at time of presentation Acute Pericarditis
• Fever Definition
• Arthralgia without arthritis Acute pericarditis is an inflammatory condition of the
pericardium.
• Elevated acute phase reactants
• Prolonged PR interval on ECG Epidemiology
Diagnosis: • 0.1% of patients hospitalized because of chest
Based on Jones criteria for the diagnosis of acute rheumatic pain
fever. Chronic rheumatic valvular disease is discussed in • 5% of patients admitted to emergency department
the lectures titled: mitral regurgitation, mitral stenosis, for chest pain not caused by MI
aortic regurgitation, and aortic stenosis. • More often in men
Category criteria
• Most patients are 20 to 50 years old
Major • Low mortality, but can be associated with high
carditis - Clinical or subclinical morbidity
arthritis - Polyarthritis
- Chorea • 30% recurrence
- Erythema marginatum Predictors of high morbidity in acute pericarditis:
- Subcutaneous nodules

317
 • Fever > 38 C ECG findings:
• Subacute onset
• Cardiac tamponade • Stage I: diffuse concave ST-segment elevation
• Large pericardial effusion • Stage II: normalization of ST-segment, PR-
segment depression, flat T-waves
• Unresponsiveness to NSAIDs
Pathophysiology • Stage III: symmetric diffuse T-wave inversions
Etiology: • Stage IV: normal ECG
Treatment
• Viral: • NSAIDs for pain and inflammation control
o Adenovirus • Resolves within 2 to 6 weeks
o Coxsackievirus A and B
• Corticosteroids only in patients who do not
o Echovirus respond to NSAIDs
o Epstein-Barr virus
o Hepatitis
Cardiac Tamponade
o HIV
o Mumps Definition
Cardiac tamponade is characterized by the accumulation of
• Bacterial:
fluid in the pericardial space, which results in reduced
o Hemophilus
ventricular filling and hemodynamic compromise. The
o Legionella
condition can result in pulmonary edema, shock and death.
o Meningococcus
o Neisseria Epidemiology
• Fungal • Incidence is 2 cases per 10,000
• Parasitic • 2% of penetrating injuries to the chest
• Noninfectious: • Male to female ratio is 7:3 in children
o Idiopathic • Slight male predominance in adults
o Post-MI • Medical emergency
o Dressler syndrome
• Prognosis:
o Neoplastic
o 1-year mortality in malignancy-related
o Drug-induced: hydralazine, isoniazid,
cardiac tamponade is 76.5%
procainamide
o 1-year mortality in non-malignancy
o Rheumatic fever
cardiac tamponade is 13.3%
o Inflammatory conditions
Pathophysiology
o Collagen vascular diseases
Etiology:
o Uremia and Gout
Pericardial inflammation → increased pericardial fluid → % of cases
pericardial effusion malignant diseases 30 – 60
uremia 10 – 15
idiopathic pericarditis 5 – 15
Clinical Findings Infectious diseases 5 – 10
coagulopathy 5 – 10
• Chest pain: Connective tissue diseases 2–6
o Retrosternal Anatomy:
o Duration of hours to days
o Sharp and stabbing in nature •The pericardium is a two-layer structure
o Worse when supine, improved when surrounding the heart
sitting up • The normal pericardial fluid volume is 20 to 50
o Worsened with inspiration mL
o Radiation to jaw, neck, and arms Phases of hemodynamic changes in cardiac tamponade:
o No response to nitroglycerin
• Friction rub in 85% of patients • Phase I:
• Fever Impaired relaxation of the ventricles → impaired
diastolic filling of the ventricles → the
Diagnosis intraventricular filling pressures are still higher
• Pleuritic chest pain plus friction rub plus than the intrapericardial pressure
characteristic ECG findings and a pericardial • Phase II:
effusion on echocardiography is diagnostic of Further accumulation of fluid in the pericardium
pericarditis → intrapericardial pressure exceeds

318
 intraventricular filling pressures → reduced • Bowed catheter sign on chest radiography after
cardiac output the insertion of a central venous catheter in
• Phase III: children
Further decrease in cardiac output → • Cardiac tamponade is a clinical diagnosis, but
equilibration of pericardial and left ventricular echocardiography can provide some valuable
pressures information:
Pathophysiology: o Massive pleural effusion
o Early diastolic collapse of the right
• Systemic venous return is decreased because of ventricular free wall
the compression of the heart → impaired venous o Swinging of the heart in the pericardial
return to the right atrium → right atrium and sac
ventricle collapse o Inferior vena cava plethora
• Accumulation of blood in the pulmonary venous
network → pulmonary venous congestion and
reduced cardiac output because of decreased
return to the left atrium
• Rapid accumulation of 150 mL can severely
decrease cardiac output
• Slow accumulation of up to 1000 mL will result
in minimum hemodynamic changes and
insignificant effect on diastolic filling of the
ventricles
o Adaptive stretching of the pericardium
Clinical Findings Figure 76: Massive, bottle-shaped heart in a patient with
• Symptoms and signs of obstructive shock and cardiac tamponade. Source: Chest 1996: 109:825
end-organ hypoperfusion:
o Dyspnea Laboratory testing:
o Decreased urine output
o Altered mental status • Indicated for the etiological diagnosis
o Cold and clammy extremities • For instance, troponins might be elevated in
• Physical findings: patients with cardiac tamponade secondary to
o Elevated jugular venous pressure myocardial infarction or cardiac trauma
o Tachycardia and tachypnea • PT and PTT might be abnormal
o Hepatomegaly • ESR, RF, and antinuclear antibodies are indicated
o Diminished heart sounds in patients with connective tissue disorders
• Beck triad: • Renal profile might be abnormal in patients with
o Increased jugular venous pressure uremic pericarditis
o Hypotension ECG:
o Diminished heart sounds
o Seen in patients with acute cardiac •
Sinus tachycardia
tamponade •
Low-voltage QRS complexes
• Pulsus paradoxus: •
Electrical alternans
More than 12 mmHg drop in blood pressure An alteration in the QRS complex voltage. It is
during inspiration caused by the movement of the heart, i.e.
• Kussmaul sign: swinging, in the pericardial space. Can be also
Paradoxical increase in jugular venous pressure seen in patients with myocardial ischemia or
during inspiration acute pulmonary embolism.
• Ewart sign: • PR segment depression
Dullness to percussion, bronchial breathing Swan-Ganz catheterization:
sounds, and bronchophony below the angle of the
left scapula • Insert the catheter into a major vein
Diagnosis • In patients with cardiac tamponade, you will find
Imaging: the following pressures to be near equalization:
o Right atrial pressure
• Chest radiography shows cardiomegaly o Right ventricular diastolic pressure

319
 o Pulmonary arterial diastolic pressure • 90% of the cases are sporadic
o Pulmonary capillary wedge pressure • Can be seen in some genetic diseases such as:
which is indicative of the left atrial o Carney syndrome: cardiac and
pressure cutaneous myxomas, endocrine
Treatment hyperfunction, and hyperpigmentation
• Pericardial drainage is indicated in all cases of o Caused by a mutation in the tumor
cardiac tamponade suppressor gene PRKAR1A on
• If the patient is hemodynamically stage, drainage chromosome 17q22-24
can be delayed up to 24 hours from diagnosis o Peak incidence in the thirties
• Indications for urgent surgical drainage of the Gross Pathology
pericardium in cardiac tamponade: • 75% in the left atrium and 18% in the right atrium
o Type A aortic dissection • Pedunculated growths
o Ventricular free wall rupture in acute • The left atrial cavity might be filled with the
MI tumor in extreme cases
o Trauma • Most tumors arise at the area of the fossa ovalis
o Purulent cardiac tamponade • Average diameter of 5 to 6 cm
Pericardiocentesis: • Soft consistency with a smooth thrombotic
General principles: surface

• Do not drain more than 1 L of fluid

• If there is still fluid accumulation after
withdrawing 1 L, place a prolonged catheter for
drainage
• Delayed pericardiocentesis should be performed
within 12 to 24 hours from diagnosis
Urgent pericardiocentesis:

• A scoring system is used to determine which Figure 77: Gross appearance of a myxoma. Source: DOI:
patients need urgent pericardiocentesis 10.3238/arztebl.2014.0205
• The following features score high on this scoring
system: Histopathology
o Malignant disease or tuberculosis as the • Multipotent mesenchymal cells
cause of cardiac tamponade • Myxoma cells:
o Orthopnea or pulses paradoxus o Multi-nucleated cells
o Rapid worsening of symptoms o Eosinophilic cytoplasm
o Left atrial collapse on echocardiography o Surrounded by a myxoid stroma
• The scoring system is too complex for the • Cystic formation
USMLE Step 1, but you should be aware of the • Hemorrhages and fibrosis
above high-risk features of cardiac tamponade • Calcifications
• This is to determine who needs urgent • Gland formation
pericardiocentesis, the indications of urgent
surgical drainage are described above Rhabdomyoma
• Patients who score 6 or more on this scoring The most common primary cardiac tumor in children.
system need urgent or immediate Epidemiology
pericardiocentesis
• Up to 60% of primary cardiac tumors in children
• Associated with tuberous sclerosis and congenital
Primary Cardiac Tumors
heart defects
Myxoma • Spontaneous regression in 50% of the cases
A benign primary tumor of the heart mainly affecting left Gross Pathology
atrium.
• Single or multiple tumors
Epidemiology • Circumscribed
• 50 to 70% of primary cardiac tumors • Whitish
• Middle aged women • Few centimeters in size
• 10% of primary cardiac tumors in children
320
 • Most commonly occur in the left ventricle or in • Auscultation for bruits over major arteries
the interventricular septum • Temporal artery biopsy in giant cell arteritis
Histopathology • MRI
• Focal hamartomatous accumulation of striated Giant cell arteritis:
cardiomyocytes
• Not a true neoplasm Definition:
Clinical Findings A granulomatous arteritis of the aorta, carotid, and major
• Weight loss, fever and other constitutional carotid branches such as the temporal artery. Usually
symptoms occurs in women older than 50 years.
• Blockage of the mitral or tricuspid valves
resulting in a stenosis-like syndrome Clinical findings:
• Intermittent heart failure
• Jaw claudication
• Embolic phenomena especially with myxomas
• Diplopia
Diagnosis • Temporal artery beading
• Echocardiography is the first diagnostic test in a • Tenderness on palpation of the temporal artery
patient suspected to have a primary cardiac tumor • Can lead to irreversible blindness → ophthalmic
• Transesophageal echocardiography has better artery occlusion
sensitivity and specificity than transthoracic • Associated with polymyalgia rheumatica
echocardiography Diagnosis:

• Focal granulomatous inflammation on biopsy

• Increased ESR
Treatment:

• High-dose corticosteroids
• Started before temporal artery biopsy
• Prevent blindness

Figure 78: A right atrial tumor, most likely a myxoma.

Source: DOI: 10.3238/arztebl.2014.0205

Treatment
• Despite being benign tumors, tumor resection
must be performed as soon as possible
• Simple tumor resection: Figure 79: Granulomatous changes on temporal artery
o Gentle handling of the tumor to avoid biopsy in a patient with giant cell arteritis. Source:
dislodging and breaking https://commons.wikimedia.org/wiki/File:Giant_cell_arteri
o The tumor should be removed with its tis_--_low_mag.jpg
root in toto
o The defect in the heart is closed with Takayasu arteritis
patch material
• Curative Definition:
Vasculitis A granulomatous arteritis of the aorta and its branches.
Definition Occurs in patients younger than 40 years.
These are immune-mediated inflammatory diseases that
affect the arteries. They are classified based on the size of Clinical findings:
the affected blood vessels. They are systemic diseases.
• Asian women
Large Vessel Vasculitis • Weak upper extremity pulses
Assessment: • Fever
• Night sweats
• Palpation of peripheral pulses • Arthritis, myalgia
• Bilateral blood pressure assessment • Skin nodules

321
 • Ocular disturbances • Chronic kidney disease
Diagnosis: Diagnosis:

• Granulomatous thickening and narrowing of the •Biopsy reveals transmural inflammation of the
aortic arch arterial wall with fibrinoid necrosis
• Elevated ESR • Different stages of inflammation
Treatment: • Renal microaneurysms
Treatment:
• High-dose corticosteroids
• High-dose corticosteroids
• Cyclophosphamide

Figure 3: Multiple microaneurysms in a patient with

polyangiitis nodosa. Source:
Figure 80: Narrowing of the right subclavian artery in a https://ucsfmed.wordpress.com/2017/01/25/polyarteritis-
patient with Takayasu arteritis. Source: nodosa/
https://pt.m.wikipedia.org/wiki/Ficheiro:Takayasu_Arteriti
s.jpg Buerger disease:

Medium-Sized Vessel Vasculitis Definition:

Assessment: Also known as thrombo-angiitis obliterans. Occurs in
• Myalgia young (< 40 years) heavy-smoker men. Affects middle
sized arteries, veins and nerves.
• Arthritis
• Fever Clinical findings:
• Weight loss
• Cutaneous, cardiovascular, mucous membranes, • Intermittent claudication
renal, ENT, nervous system, chest • Gangrene
Polyarteritis nodosa: • Autoamputation of digits
• Superficial nodular phlebitis
Definition: • Raynaud phenomenon
Transmural inflammation of middle-sized arteries. Diagnosis:
Involves renal and visceral arteries but does not involve
• Biopsy reveals segmental thrombosing vasculitis
pulmonary arteries. Occurs in middle-aged men. Up to one
Treatment:
third of the patients have hepatitis B.
• Smoking cessation
Clinical findings:
Small-Sized Vessel Vasculitis
• Fever Wegener’s granulomatosis:
• Weight loss
• Malaise Definition:
• Headache A focal necrotizing vasculitis that affects the lungs, upper
• Abdominal pain and melena airways, and kidneys.
• Hypertension secondary to renal artery stenosis
• Neurologic dysfunction such as seizures and Clinical findings:
stroke
• Cutaneous eruptions

322
 • Perforation of nasal septum, chronic sinusitis, Treatment:
otitis media and mastoiditis
• Hemoptysis • Cyclophosphamide
• Cough • Corticosteroids
• Dyspnea
• Hematuria
• Red cell casts
Diagnosis:

• Biopsy reveals necrotizing granulomatous

vasculitis of the lungs and upper airway.
Necrotizing glomerulonephritis Figure 5: Granulomatous eosinophilic necrosis in a patient
• Elevated levels of PR3-ANCA also known as c- with Churg-Strauss syndrome. Source:
ANCA https://en.wikipedia.org/wiki/Eosinophilic_granulomatosis
• Chest radiography shows large nodules _with_polyangiitis#/media/File:Churg-Strauss_syndrome_-
Treatment: _high_mag.jpg

• Cyclophosphamide Microscopic polyangiitis

• Corticosteroids
Definition:
A necrotizing vasculitis affecting small to medium-sized
vessels. Involvement of the pulmonary capillaries. Can
affect the lung, kidneys, and skin
Clinical findings:

• Palpable purpura
• Symptoms and signs related to affected organs
• Can cause pauci-immune glomerulonephritis
Figure 4: c-ANCA in a patient with Wegener’s
Diagnosis:
granulomatosis. Source: https://en.wikipedia.org/wiki/C-
ANCA •Biopsy reveals necrosis without granuloma
formation
Churg-Strauss syndrome: • Elevated levels of MPO-ANCA also known as p-
Definition: ANCA
Treatment:
A necrotizing vasculitis affecting small to medium-sized
vessels. Often associated with asthma and eosinophilia. • Cyclophosphamide
Also known as eosinophilic granulomatosis with • Corticosteroids
polyangiitis.
Clinical findings:

• Asthma
• Sinusitis
• Purpura and skin nodules
• Peripheral neuropathy such as foot drop
• Symptoms of affected systemic organs Figure 6: p-ANCA in a patient with microscopic
• Can cause pauci-immune glomerulonephritis polyangiitis or Churg-Strauss syndrome. The difference is
Diagnosis: that the latter will also have granulomas on
histopathological examination. Source:
• Biopsy reveals granulomatous necrotizing https://en.wikipedia.org/wiki/P-
vasculitis with eosinophilia ANCA#/media/File:P_anca.jpg
• Elevated levels of MPO-ANCA also known as p-
ANCA Henoch-Schoenlein purpura
• Elevated IgE levels
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Definition: Ca channel blockers
Mechanism of action
Vasculitis with immunoglobulin-A deposits in small • Block L-type Ca2+ channels in heart and blood
vessels. This is the most common childhood systemic vessels
vasculitis and is often preceded by an upper respiratory • Act on vascular smooth muscle, reduce
tract infection. contraction of the arteries cause vasodilation
Clinical findings: • Act on cardiac muscles (Myocardium), they
reduce the force of the contraction of the heart
• Triad of: (Negative inotropic)
o Palpable purpura on the legs and
buttocks Calcium channel blockers classification
o Arthralgia or arthritis • Dihydropyridines acts on vascular smooth muscle
o Abdominal pain due to GI involvement. • Non-dihydropyridines act on the heart
Can lead to intussusception
Diagnosis:

• Biopsy reveals IgA immune complex deposition Calcium channel

blockers
and IgA nephropathy classification
Treatment:

• Resolves spontaneously
• Selected patients might benefit from steroids
Non-
Dihydropyridines
dihydropyridines

Amlodipine
Clevidipine Diltiazem
Nicardipine Verapamil
Nifedipine

Clinical uses
Figure 7: Palpable purpura in a child with Henoch- 1-Hypertension
Schoenlein purpura. Source: • Directly dilates peripheral resistance arterioles,
https://commons.wikimedia.org/wiki/File:Purpura2.JPG leading to a reduction in total peripheral vascular
resistance & reduced arterial blood pressure
Behçet syndrome
2-Arrhythmias- Atrial fibrillation
Definition: 3-Classical angina
• Dilate peripheral arterioles which reduce
A small-vessel vasculitis that is more common in Turkish
afterload
and eastern Mediterranean individuals.
4-Prinzmetal angina
Clinical findings: • Drug used Diltiazam or Verapamil
• Dilate the main coronary arteries
• Recurrent aphthous ulcers • Potent inhibitor of coronary artery spasm
• Genital ulcers
• Uveitis • Prinzmetal's variant angina (PVA) is due to
• Erythema nodosum vasospasm of coronary artery and characterized
• Can be preceded by history of HSV or parvovirus by recurrent episodes of chest pain (angina) that
infection usually occur when a person is at rest, between
• Attacks can last up to four weeks midnight and early morning.
Diagnosis: 5-Raynaud’s phenomenon
• Dihydropyridines except Nimodipine used to
• Immune complex depositions treat Raynaud’s phenomenon since it works on
• Association with HLA-B51 vascular smooth muscle

324
Side effects
Dihydropyridines Non-Dihydropyridines K+ channel opener
• Flushing • cardiac depression
• Dizziness • AV block
• Peripheral edema • Hyperprolactinemia
• Constipation Hyperpolarization of
• Gingival hyperplasia smooth muscle

Drug interaction
• Cimetidine (80% increase in nifedipine plasma Arteriole vasodilator
levels)

Vasodilators Decrease TPR

Hydralazine
MOA
Increase cGMP Decrease BP
Clinical uses
Smooth muscle • Severe hypertension cases
relaxation • Baldness (Topical minoxidil)
• Insulinoma (Diazoxide)
Side effects
Arteriole vasodilator • Hypertrichosis (Excess hair)-Minoxidil
• Peri cardiac effusion -Minoxidil
• Hypotension
Decrease TPR • Reflex tachycardia
• Hyperglycemia (Block insulin release)

Sodium Nitroprusside
Decrease BP MOA
Clinical uses Release NO
• Congestive heart failure
• Hypertension (sever cases in hospitals)
• Hypertension during pregnancy (since it’s not Increase cGMP
teratogenic)
Side effects Arteriole
• Hypotension vasodilator
• Reflux tachycardia
• Peripheral edema
• Lupus like symptoms (hydralazine and Decrease TPR
procainamide)
Contraindications
• Angina or coronary artery disease because reflex Decrease BP
tachycardia might increase myocardial oxygen
consumption

Minoxidil, Diazoxide
MOA

325
Clinical uses o Mesenteric ischemia
• Hypertensive emergency o Claudication
• Angina
• CHF Pathophysiology
Side effects • Atherosclerosis = Unhealthy blood cholesterol
• Cyanide toxicity levels. This includes high LDL cholesterol (called
• Hypotension "bad" cholesterol) and low HDL cholesterol
Milrinone ("good" cholesterol).
Mechanism of action
• Inhibits cAMP phosphodiesterase activity in Risk factors for atherosclerosis
myocardium and vascular smooth muscle • High blood pressure
• Smoking
In Cardiomyocytes In Vascular smooth • Insulin resistance
muscle
• Diabetes
 cAMP accumulation • Overweight or obesity
• Lack of physical activity
 cAMP accumulation
 Ca2+ influx • Unhealthy diet
Inhibition of MLCK activity
 Inotropy and chronotropy
Treatment plan
Non-pharmacological
• Lifestyle can cause increase in cholesterol- lack
General vasodilation
of exercise or high intake of saturated fatty acids
• Diet and exercise are first line of treatment.
• Decreases blood viscosity by reducing plasma Pharmacological
fibrinogen concentrations and increasing • Treatment goal is to ↓ LDL cholesterol and
fibrinolytic activity. atheroma plaque formation
Drug names
Clinical uses • Lovastatin
• Congestive heart failure • Pravastatin
• Short term use in decompensated heart failure • Atorvastatin
• Rosuvastatin
Adverse effects • Simvastatin
• Arrhythmias
• Hypotension Mechanism of action
• Inhibit conversion of HMG-CoA to mevalonate, a
Statins cholesterol precursor, results in:
LDL and atherosclerosis • ↓ liver cholesterol
• LDL and atherosclerosis • ↑ LDL-receptor expression
• When patient present high levels of LDL- LDL • ↓ plasma LDL
could be oxidized by free radicals leading to • ↓ VLDL synthesis results in: ↓ triglyceridemia
deposit on the endothelial basemen membrane
• The macrophages will engulf the oxidized LDL Side effects
and degrade it forming foam cells • Myalgia, myopathy (check creatine kinase)
• As the fatty streak enlarges over time, necrotic • Rhabdomyolysis
tissue and free lipid accumulates, surrounded by • Hepatotoxicity (check liver function tests)
epithelioid cells and eventually smooth muscle
cells, an advanced plaque with a fibrous cap. Drug interactions and contraindications
• The plaque eventually begins to occlude the • Pregnancy and teenagers
blood vessel, causing ischemia and infarction in • Gemfibrozil (↑ rhabdomyolysis)
the heart, brain, or extremities. • Cytochrome P450 inhibitors enhance toxicity of
• By time the plaque becomes unstable leading to statins
rupture and thrombosis causes:
o Myocardial infarction
o Acute ischemic stroke

326
Bile acid resins • ↑ plasma HDL
Examples
• Cholestyramine Side effects
• Colestipol • Flushing, pruritus, burning pain (use aspirin 30
• Colesevelam minutes before) Due to vasodilation of blood
vessels
Mechanism of action • Hepatotoxicity
• Prevent intestinal reabsorption of bile acid → • Hyperglycemia (acanthosis nigricans)
Complexation of bile acid in the guts, leads to: • Hyperuricemia (predispose patient to gout)
1. ↑Enterohepatic recirculation of bile salts Note:
2. ↑ Synthesis of new bile salts by the liver • A severe deficiency in niacin causes the disease
3. ↓ Liver cholesterol pellagra, which is characterized by dermatitis,
4. ↑LDL-receptor expression diarrhea, and dementia
5. ↓blood LDL
PCSK9 inhibitors
Clinical Uses Examples:
• Hyperlipidemia • Alirocumab
• Bile acid malabsorption • Evolocumab

Adverse effects Mechanism of action

• ↑ VLDL and triglycerides • Monoclonal antibody
• GIT upset • PCSK9 is a serine protease produced by the liver
• Malabsorption of lipid-soluble vitamins (A, D, E which binds LDL receptors and creates a complex
and K) to be targeted for lysosomal degradation
• Hyperglycemia • PCSK9-LDL complex inhibits LDL receptor
• Cholesterol gallstone recycling to the cell surface, resulting in
decreased cellular reuptake of LDL-C and
Fibrates increased levels of free LDL-C in the plasma.
Examples:
• Gemfibrozil Clinical use
• Bezafibrate • Lower LDL
• Fenofibrate • Increase HDL
• Atherosclerosis Cardiovascular disease
Mechanism of action • Familiar hypercholesterolemia (Heterozygous,
• Bind to the PPARα (Peroxisome proliferator Homozygous)
activated receptors) and increase expression of
lipoprotein lipases, results in: Adverse effects
• ↓ Triglyceride • Myalgias and injection site reactions
• ↓ LDL • Delirium
• ↑ HDL in most patients • Dementia and neurocognitive effects

Clinical Uses Anti-arrhythmic drugs class I

• Used in hypertriglyceridemia

Adverse effects
• Gallstones
• Myositis

Niacin (Vitamin D3-Nicotinic acid)

Mechanism of action
Class 1A
• Inhibit lipolysis
• Decrease hepatic VLDL, results in: • Antiarrhythmic drugs mean eliminates irregular
heartbeat while, proarrhythmic means promotes
• ↓plasma VLDL
irregular heartbeat
• ↓ plasma LDL

327
 • This type of action potential is found in non- • prolongs QT interval of action potential and
nodal, cardiomyocytes (e.g., atrial and ventricular increases the risk of torsade de pointes
myocytes; purkinje tissue). Disopyramide
• Sinoatrial and atrioventricular nodes (nodal tissue • The same mechanism of action of quinidine
action potential) do not depend on fast sodium Side effects
channels for depolarization • Stronger anticholinergic effects
Mechanism of action • Dry mouth
• Class 1A are Na channel blockers (Especially fast • Constipation
Na+ channels) that are responsible for the rapid • Urinary retention
depolarization (phase 0) of fast-response cardiac • Blurred vision
action potentials • Torsade de pointes
• Effective in “state-dependent” blockade Class 1B
• Blocks K+ channel (prolongs repolarization), ↑ • Block fast Na+ channels
action potential duration and effective refractory • Block both activated and inactivated Na+
period channels, but preferred for inactivated channels
• Quinidine causes muscarinic receptor blockade, • Decrease the slope of Phase zero and phase 4
which can ↑ HR and AV conduction. • Slow conduction in hypoxic and ischemic tissues
Examples (Partially depolarized tissue)
• Quinidine • Decrease action potential
• Procainamide Examples
• Disopyramide • Tocainaide
• Lidocaine
Quinidine
• Mexiletine
Lidocaine
Clinical uses Clinical uses
• Atrial fibrillation, flutter; supraventricular &
• Acute Ventricular arrythmia (Post myocardial
ventricular tachyarrhythmias
infarction)
Side effects
• Open-heart surgery
• Cinchonism due to anticholinergic effects (GI,
• Digoxin toxicity–ventricular arrhythmias
tinnitus, ocular dysfunction, CNS excitation)
Side effects
• Hypotension
• CNS drowsiness and nystagmus
• Thrombocytopenia
• Slurred speech
• Risk for torsades de pointes from prolonging
• convulsions and seizures
QRS and ↑ QT interval
• Note: Lidocaine is used IV use because of first-
• Procainamide associated with lupus-like
pass metabolism
syndrome (rash/ arthralgia/fever)
• Disopyramide associated with heart failure Tocainide
• Ventricular arrhythmias, such as sustained
Procainamide
ventricular tachycardia
• The same mechanism of action of quinidine Side effects
Clinical uses
• Bradycardia
• Ventricular arrythmias (Ventricular fibrillation,
• AV node blockage
ventricular tachycardia)
• Hypotension
• Super ventricular arrythmia
Side effects • Ventricular tachycardia
• Most of the side effects due to acetylation of • Pulmonary fibrosis
acetylation of procainamide • Bone marrow aplasia
Mexiletine
• Systemic lupus erythematosus (SLE)–like
syndrome that lead to polyarthralgia, myalgia and • Same uses as lidocaine
pleurisy Side effects
• Pericarditis, pleuritis • Nystagmus
• Hematotoxicity (thrombocytopenia, • Pancytopenia
agranulocytosis)

328
Phenytoin MOA
• Antiarrhythmic drug properties and is a potential • ↓ IK (delayed rectifier current) slowing phase 3
treatment option for patients with refractory (repolarization) of AP
ventricular arrhythmia • ↑ AD and ERP, especially in Purkinje and
• Phenytoin has a narrow therapeutic range ventricular fibers
Side effects
• Nystagmus Clinical uses
• Ataxia • Atrial fibrillation
• Gingival hyperplasia • Atrial flutter
Class 1C • Ventricular tachycardia
• Block Na channels in Purkinje tissue
• Block K channels in ventricular myocytes Side effects
• Has minimum effect in action potential • Pulmonary fibrosis (Restrictive lung disease)
Clinical uses FEV1/FVC ratio
• Supraventricular • Blue pigmentation of the skin (“smurf skin”)
• Ventricular arrythmia • Phototoxicity
Examples • Corneal deposits
• Flecainide • Hepatic necrosis (ALT/AST mentoring)
• Propafenone • Thyroid dysfunction
Side effects • Blue decolorization
• Bronchospasm • Photosensitivity
• Bradycardia
• Proarrhythmic, especially post-MI Bretylium

Anti-arrhythmic drugs class II III IV MOA

Prolong ventricular action potential
Class II Beta blockers Side effects
Examples Hypotension
• Sotalol Clinical uses
• Propranolol • Refractory ventricular fibrillation
• Esmolol • Ventricular tachycardia
MOA
• revent β-receptor activation, which would Class VI (Ca+ channel blockers)
normally ↑ cAMP
• ↓ SA and AV nodal activity Examples
• Block K channel (Sotalol) • Verapamil (Cardiac tissue)
• Esmolol decrease automaticity (Decrease HR and • Diltiazem (Periphery)
AV conduction) • Nifedipine (Periphery)
• ↓ Slope of phase 4 (diastolic currents) of AP in
pacemakers MOA
Block slow cardiac Ca2+ channels
Clinical uses ↓ phase 0, ↓ phase 4
• Esmolol (IV) is used in acute SVTs during ↓ SA, ↓ AV nodal activity
surgery
Clinical uses
• Ventricular arrythmia (Sotalol)
• Supraventricular arrythmia (Atrial fibrillation/
• Supraventricular arrythmia (atrial fibrillation,
atrial flutter) Atrial flutter)
Class III (K+ channel blockers) • Rate control in atrial fibrillation
Examples
• Amiodarone Atrial fibrillation
The primary goals for treatment are:
• Ibutilide
1. Ventricular rate control with beta
• Dofetilide blockers, CCBs, or digoxin
• Sotalol (can be considered as class III since it 2. Anticoagulation
blocks K channels)

329
Side effects Summary for anti-arrhythmic drugs
• Bradycardia
• Hypotension
• Dizziness
• Constipation

Magnesium Sulfate
MOA
• Unknown
• Stabilize the cardiac cell membrane
Ivabradine
Clinical uses Mechanism of Action
• For torsade de pointes Pacemaker action potential:
• Digoxin induced arrythmia • Depolarization of pacemaker cells is mediated by
voltage-gated calcium channels in phase 0
Side Effects • There are no phase 1 or 2 in the AP of a
• Paralysis pacemaker
• Respiratory paralysis • Phase 3 is repolarization which is mediated by
• Flushing and Headache opening potassium channels for potassium efflux
• Bradycardia • Phase 4 is unique in pacemaker action potential:
o Slow spontaneous diastolic
The following drugs might precipitate torsade de depolarization
pointes: o Due to If channels which allow for slow
• Potassium-channel blockers (class 1A and class sodium and potassium influx
III) o Responsible for the automaticity of SA
• Antipsychotics (thioridazine) and AV nodes
• Tricyclic antidepressants Mechanism of action:

Adenosine • Ivabradine inhibits If channels → reduces cardiac

pacemaker activity
MOA • Prolongs the slow diastolic depolarization phase
• Activate acetyl choline sensitive potassium • Reduces heart rate without reducing inotropy →
channel in SA/AV node reduces cardiac oxygen demand
• Activates adenosine receptors causes Gi-coupled Indications:
decrease in cAMP
• ↓ SA and AV nodal activity • Stable coronary arterial disease in patients who
cannot take beta-blockers
Clinical uses • Chronic heart failure with systolic dysfunction
Side Effects:
• SVT Supraventricular tachycardia
• Luminous phenomena: enhanced brightness in a
Side effects fully maintained visual field
• Chest pain Possibly related to the inhibition of If channels in
• Dyspnea the retina
• Flushing • Bradycardia
• Headache • AV block
• Adenosine is antagonized by methylxanthines • Headache
(theophylline and caffeine)
Introduction to hypertension management
Non-pharmacological treatment
• Lifestyle changes
• Decrease Na intake less than 4-gram day
• Weight loss
• Reduce alcohol

330
 • Exercise(daily) • ↑ LDLs and TGs
• Low saturated diet (Instead fruits and vegetables)
• Reduce stress Cautions in use:
• Asthma
Pharmacological treatment • Vasospastic disorders
When to treat: • Diabetics (alteration of glycemia and masking of
• Failed non-pharmacological treatment tachycardia due to hypoglycemic events)
• SBP 140-180 or DBP 90-110mmHg
• Start with a single drug at low dose ACE inhibitors
• 4-6 weeks period for apparent results in case of Drugs
ineffective, consider increasing dose/ add another • Captopril
• Use only one drug from one class then consider • Enalapril
combination treatment • Lisinopril
• For elderly patients start low and go slow • Ramipril

Treatment guidelines Overview

• ↓ Total peripheral resistance (TPR) BP = CO
x TPR
• ↓ CO
• ↓ body fluid volume
• ↓ BP may result in homeostatic regulation:
• Reflex tachycardia (↑ sympathetic activity)
• Edema (↑ renin activity)

Thiazides
• Decrease intravascular volume
• Increase urinary excretion of potassium
• Increase Cl- and Na+ excretion
• Examples: Hydrochlorothiazide

Side effects
• Decrease renal perfusion
• Hypokalemia Angiotensin II vasoconstrictor
• Hyperglycemia
• Hyperlipidemia
• Hyper uremia Aldosterone release from the adrenal
• Hypercalcemia gland
B-blockers
• Decrease heart rate and decrease CO
• Decrease renin release  blood pressure and  sodium
• Vasodilation decrease preload decrease CO reclamation by the kidney.
• Block release renin
Mechanism of action
Examples: • Block angiotensin-converting enzyme, preventing
• Propranolol the conversion of angiotensin I to angiotensin II,
• Bisoprolol therefore:
• Metoprolol • Decrease (Glomerular filtration rate) GFR by
• Atenolol preventing constriction of efferent arterioles
• Prevent AT1-receptor stimulation
Side effects • ↓ aldosterone, vasodilation
• Cardiovascular depression • prevent bradykinin degradation (Bradykinin is a
• Fatigue potent vasodilator)
• Sexual dysfunction

331
Clinical uses: • Hypertension with diabetes mellitus: ACE
• Hypertension (Due to its potent vasodilatation inhibitors/ARBs
effect) • Hypertension in asthma: ARBs, Ca+2 channel
• Heart failure (slow the progression of heart blockers, thiazide
failure) • Hypertension in pregnancy: Methyldopa,
• Post-myocardial infarction patients Hydralazine, Labetalol, Nifedipine

Adverse effects Antianginal drugs

• Persistent cough due to bradykinin release Overview
• Angioedema (Tongue and swollen lips)
• Postural hypotension Cardiac ischemia:
• Protein urea • Secondary to coronary artery disease
• Dizziness • Due to imbalance of myocardial oxygen supply
• Low neutrophils and demand,
• Most common in middle age men and
Drug interaction postmenopausal
• K-sparing diuretics can result in hyperkalemia
• NSAID Angina pectoris
• Squeezing or pressure-like sensation in the chest
Contraindication that patients have during myocardial ischemia.
• Contraindication in bilateral renal artery stenosis • Angina is caused by an imbalance of O2 supply
• Pregnancy (Teratogenic effects) vs. demand, resulting in myocardial ischemia

Angiotensin receptor blocker (ARBs)

• Used for treatment of hypertension

Drugs
• Losartan
• Valsartan Types of Angina:

MOA 1-Stable angina

• Block angiotensin receptor II directly to prevent • Most common type is caused by coronary artery
persistent cough associated with bradykinin atherosclerosis with luminal narrowing >75%.
• Chest pain developed due to increased cardiac
Adverse effects demand (exertional or emotional) and is relieved
• Hyperkalemia by rest or nitro-glycerine (vasodilation).
• Fetal renal toxicity
2-Unstable angina
Vasodilators • Typically occur at rest
• ↓ TPR via arteriolar dilation • Due to nonocclusive coronary arterial thrombi,
characterized by increased frequency or intensity
Examples: • This form of angina has a high risk for
• Hydralazine myocardial infarction
Side effects: • +/− ST depression with T-wave inversion on
• Edema ECG
• Reflex tachycardia
3-Prinzmental angina
Hypertension treatment for special cases • Chest pain occur at rest due to coronary artery
• Primary essential hypertension: Thiazides, ACE vasospasm
inhibitors, ARBs, dihydropyridine Ca+2 channel • Electrocardiogram shows transient ST segment
blockers elevation (transmural ischemia).
• Hypertension with heart failure: Diuretics, ACE • Triggered by smoking, cocaine, alcohols and
inhibitors/ARBs triptans

332
 • Respond to Nitro-glycerine and Ca2+ channel • Reflex tachycardia
blockers • Fluid retention

Note: Drugs that decrease mortality in patients with stable B-blockers

angina include aspirin, nitroglycerin, and beta blockers. 1. Decrease cardiac oxygen demand by:
•  Heart rate
Angina pectoris treatment guidelines • Contractility
• Lowering blood pressure
• ↓ oxygen requirement by ↓ TPR, CO, or both
(nitrates, CCBs, and beta blockers) 2. Increase myocardial perfusion by
• Increase diastolic perfusion time
• ↑ oxygen delivery by ↓ vasospasm (nitrates and • Used in angina of effort and acute treatment of
CCBs). unstable angina
• β-blockers are contraindicated in vasospastic
Nitrates angina
Examples: Nitro-glycerine, Isosorbide Dinitrate, Isosorbide • Examples: propranolol, metoprolol, atenolol
Mononitrate Ca+2 channel blockers
• Nitroglycerin: sublingual, transdermal, and IV • Dilate peripheral arterioles which reduce
formulations afterload
• Isosorbide: oral, extended release for chronic use • Diltiazem or Verapamil used for Prinzmetal
• Nitroglycerin is the preferred drug for acute angina through dilation the main coronary arteries
management of both stable and vasospastic • Potent inhibitor of coronary artery spasm
angina. Ranolazine
• Anti-ischemic with anti-anginal effect through
inhibition of the inward Na+ current in cardiac
MOA:
myocytes, thereby decreasing calcium
Nitrates release nitric oxide (NO)
accumulation

Activates guanylate cyclase in vascular smooth muscle

cells

Causes elevated cyclic guanosine monophosphate (cGMP)

levels

Causing smooth muscle relaxation

(vasodilation)
decreased end diastolic pressure and improvement of
diastolic coronary flow
Vendodilation
• Ranolazine does not affect heart rate or
contractility.
↓ preload → ↓ cardiac work → ↓ oxygen
requirement Side effects:
Clinical uses: • Constipation
• Angina • Dizziness
• Acute coronary syndrome • Headache
• Pulmonary edema • Nausea
• QT prolongation
Side effects
• Orthostatic hypotension Diuretics
• Flushing Types of hypertension
• Headache

333
 Essential Secondary • Idiopathic hypercalciuria (Thiazides
Represent 95% Represent 5%
contraindicated in case of hypercalcemia)
High blood pressure that is not medical condition that causes high • Nephrogenic diabetes insipidus
related to another medical blood pressure, usually occurring in
condition. the kidneys, arteries, heart, or
endocrine system. Side effects
• Hypokalemia and alkalosis
Risk factor for hypertension o Renal artery stenosis
o Obesity o Fibromuscular dysplasia • Hypercalcemia
o Family history more in white or younger • Hyperuricemia
o Race African people
American o Cushing syndrome • Hyponatremia
o Lack of exercise o Primary aldosteronism • Hyperglycemia
o Smoking o Hyperthyroidism
o Coarctation of aorta
• Hyperlipidemia

Malignant hypertension Drug interactions

• CNS: Seizures, strokes, encephalopathy • Thiazides are sulfa drugs, therefore avoid in sulfa
• Eyes: Hemorrhage allergy
• Lung: Pulmonary edema
Loop diuretics
• Heart: MI, aortic dissection
• Kidneys: Nephropathy, increased BUN/
Examples: Furosemide
Creatinine
(Lasix)= last six hours
MOA:
Antihypertensives drugs
• Inhibit
• Diuretics
cotransport
• ACE inhibitors system
• B-blockers (Na+/K+/2Cl−) of
Vasodilator thick ascending
limb of loop of
Diuretics Henle.

Clinical uses:
• Used for rapid high-volume diuresis in cases such
as
o Pulmonary edema
o Congestive heart failure
o Liver cirrhosis
• Hypertension
• Hypercalcemia
Thiazides
Side effects
Examples: Hydrochlorothiazide, Chlorthalidone • Hypokalaemia and metabolic alkalosis
• Hypocalcaemia
MOA • Hypomagnesemia
• Work in the distal convoluted tubule of the • Hyperuricemia
nephron (Na+/Cl− transporter inhibition) lead to: • Ototoxicity
• ↑ luminal Na+ and Cl− in DCT • Nephritis
• ↑ diuresis • Gout
• ↑ Na+ and K loss
• Blockage of sodium uptake here by thiazide Drug interactions
diuretics leads to increased calcium reabsorption. • Thiazides are sulfa drugs, therefore avoid in sulfa
allergy
Clinical uses
• Hypertension
• CHF

334
 Chapter 8:

Endocrinology

335
Insulin • This triggers the exocytosis of insulin granules
Synthesis and insulin is secreted into the blood
• Pancreatic β-cells synthesize preproinsulin in the
rough endoplasmic reticulum
• It is then cleaved into the parent insulin molecule
known as proinsulin, which is seen in Figure 1
• Proinsulin is stored in secretory vesicles which
are called “insulin granules”
• When it is time to release insulin, proinsulin is
cleaved into insulin and C-peptide
• Accordingly, in hyperinsulinemic states where
the source of insulin is endogenous “insulinoma”, Figure 82: The mechanism of insulin secretion by the
the levels of insulin and C-peptide are elevated pancreatic beta-cells.. Source:
• On the other hand, when the source of insulin is https://www.researchgate.net/publication/233888660_The_
exogenous, only insulin levels are elevated molecular_mechanisms_and_pharmacotherapy_of_ATP-
sensitive_potassium_channel_gene_mutations_underlying_
neonatal_diabetes/figures?lo=1

• Oral intake of glucose results in a stronger insulin

response than IV glucose:
o Oral intake of glucose stimulates the
release of glucagon-like peptide 1 and
glucose-dependent insulinotropic
polypeptide “incretins”
o They increase the sensitivity of the β-
cell to glucose
• The β-cell also have alpha- and beta-adrenergic
receptors:
o Alpha-2-adrenergic receptors decrease
the release of insulin
Figure 81: Proinsulin structure. Source:
o Beta-2-adrenergic receptors increase the
https://en.wikipedia.org/wiki/Insulin#/media/File:Insulin_p
release of insulin
ath.svg
Function
Regulation • When insulin is released from the pancreatic β-
• The pancreatic β-cells have GLUT-2 on their cells, it binds to insulin-receptors with tyrosine
membrane kinase activity
o GLUT-2 is a two-way glucose • This has two important effects:
transporter o The activation of phosphoinositide-3
o Transport of glucose is independent of kinase pathway which is responsible for
insulin glycogen, lipid and protein synthesis
• When elevated levels of glucose are present, it “insulin is an anabolic hormone” and for
will enter the β-cell and undergo glycolysis the transport of GLUT-4 glucose
transporters to the cell-membrane
• The ATP/ADP ratio will increase which will
“glucose is needed for the anabolic
close ATP-sensitive K channels
process”
o Sulphonylureas increase insulin
secretion by closing these channels o The activation of the RAS/MAP kinase
pathway which is responsible for cell
regardless of the ATP/ADP ratio
growth and DNA synthesis
• Once the ATP-sensitive K channels close,
potassium can no longer go out of the cell → the • Therefore, insulin has the following anabolic
responses:
β-cell is depolarized
o Increased glucose transport in skeletal
• Voltage-gated Ca channels open to allow for
muscle and adipose tissue
calcium to enter the β-cell → increasing
o Increased glycogen synthesis and
intracellular calcium
storage
o Increased triglyceride synthesis

336
 o Increased protein synthesis in muscles Hypothalamic-Pituitary Axis:
o Increased cellular uptake of potassium Anatomy
and amino acids → needed for protein
synthesis
o Decreased lipolysis and glucagon
release
o Increased sodium retention by the
kidneys
• While glucose crosses the placenta, insulin does
not → therefore, it is important to have other
types of GLUT that are insulin-independent

Note: Exercise can also increase the

expression of GLUT-4 in striated
muscle

Figure 84: The hypothalamic-pituitary axis: Source:

http://biochemistry2.ucsf.edu/programs/ptf/mn%20links/H
PA%20Axis%20Physio.pdf

Anatomy of the posterior segment:

Figure 83: The effects of insulin on glucose transport in • The hypothalamus synthesizes ADH and oxytocin
insulin-dependent glucose uptake. Source: in the large-bodied neurons found in the
https://en.wikipedia.org/wiki/Insulin#/media/File:Insulin_g paraventricular, supraoptic and infundibular
lucose_metabolism_ZP.svg nuclei
• These hormones are transported down through
Glucose Transporters: axons to the posterior pituitary to be released
• GLUT-4 is the main insulin-dependent glucose • They enter the secondary plexus of the
transporter. It is expressed in adipose tissue and hypophyseal portal system and are released in the
skeletal muscles. Accordingly, glucose uptake in major veins that drain the posterior pituitary
these tissues is insulin-dependent gland
• The insulin-independent transporters of glucose Anatomy of the anterior segment:
are:
o GLUT-1 which is found in the RBCs, • The small-bodied neurons found in the preoptic
cornea, placenta and brain nuclei make different releasing hormones
o GLUT-2 which is bidirectional and • These hormones are transported down the axons
expressed by beta-cells, liver, kidney and secreted into the primary capillary plexuses
and small intestine • They act on trophocytes in the anterior pituitary
o GLUT-3 is expressed in the brain and to stimulate the release of different anterior
placenta pituitary hormones into the secondary plexus of
o GLUT-5 transports fructose and is hypophyseal portal system
found in spermatocytes, and the GI tract • Anterior pituitary hormones enter the systemic
o SGLT1 and SGLT2 are sodium-glucose circulation
cotransporters and they are found in the Hypothalamic Hormones:
kidney and small intestine Antidiuretic hormone (ADH):
• The RBCs lack mitochondria → unable to utilize
• This hormone increases water permeability of
other substrates for energy other than glucose
distal convoluted tubule and collecting ducts in
because they are incapable of aerobic metabolism
the kidney → increased free-water reabsorption
• The brain utilizes glucose, however, during
• It is synthesized in the hypothalamus, transported
starvation it can utilize ketone bodies for energy
to the posterior pituitary, and released into the
production

337
 systemic circulation in response to increased • In primary and secondary hypothyroidism →
plasma osmolality TRH levels are elevated → explains how
• In SIADH, ADH levels are elevated despite galactorrhea can develop due to
decreased plasma osmolality hyperprolactinemia
• In central DI, ADH levels are decreased despite Somatostatin:
increased plasma osmolality
Oxytocin: • Inhibits the release of growth hormone
• Somatostatin analogs are used in the treatment of
• Synthesized in the hypothalamus and transported acromegaly
to the posterior pituitary Pituitary Hormones:
• Causes uterine contractions during labor • Six types of cells in the anterior pituitary named
• Milk letdown reflex in response to suckling after the primary hormone they synthesize:
Corticotropin-releasing hormone (CRH): o Adrenocorticotropin cells produce
ACTH
• All releasing hormones are synthesized by the o Thyrotropin cells produce TSH
supraoptic small-bodied neurons in the o Gonadotropin cells produce FSH and
hypothalamus to be transported to the anterior LH
pituitary and stimulate the release of anterior o Cells that produce GH
pituitary hormones o Lactotropin cells produce prolactin
• CRH is increased in stress conditions and Luteinizing hormone (LH):
decreased in chronic exogenous steroid use
• It increases the release of ACTH, MSH and beta- • Stimulates ovulation
endorphin • Gonadal production of sex hormones
Growth hormone-releasing hormone (GHRH): Follicle-stimulating hormone (FSH):

• Stimulates the release of growth hormone from • Stimulates ovarian follicular development
the anterior pituitary • Stimulates the development of spermatozoids
• The GHRH analog tesamorelin is used in the • Stimulates the production of estrogen
treatment of HIV-associated lipodystrophy Thyroid-stimulating hormone (TSH):
Gonadotropin-releasing hormone (GnRH):
• Stimulates the production and release of thyroid
• Stimulates the release of luteinizing hormone and hormones T3 and T4
follicular stimulating hormone from the anterior ACTH:
pituitary
• Hyperprolactinemia suppresses the release of • Stimulates the release of the different types of
GnRH → infertility, decreased libido, adrenal steroids but mainly cortisol
amenorrhea and erectile dysfunction • Increased in Cushing’s disease
• Tonic GnRH administration suppress the • Decreased in secondary adrenal insufficiency
hypothalamic-pituitary-gonadal axis → used in Melanocyte stimulating hormone (MSH):
the treatment of estrogen-dependent tumors
• Stimulates the proliferation and pigmentation of
• Pulsatile GnRH administration causes puberty
melanocytes
and fertility → used in the treatment of infertility
Growth hormone (GH):
Dopamine:
• GH stimulates the production of liver IGF-1 to
• A prolactin-inhibiting hormone and also a stimulate growth of the different body tissues
neurotransmitter
• Overproduction of GH before the closure of the
• Can also decrease the release of thyroid
growth plates → gigantism
stimulating hormone
• Overproduction of GH after the closure of the
• Typical antipsychotics, which are dopamine
growth plates → acromegaly
antagonists, can cause hyperprolactinemia
Prolactin:
because they block the inhibitory effects of
dopamine on the anterior pituitary gland • Has effects on the reproductive and immune
Thyrotropin-releasing hormone (TRH): systems
• Stimulates the production of milk during lactation
• Stimulates the release of thyroid stimulating
hormone and prolactin

338
 • Prolactinoma is the most common type of a Production of Glucocorticoids
pituitary adenoma • Cortisol, the principle mineralocorticoid, is
Adrenal Steroids produced in the zona fasciculata
Anatomy • Pregnenolone, or progesterone are converted to
17-hydroxypregnenolone and 17-
hydroxyprogesterone, respectively, by 17α-
hydroxylase
• 17-hydroxypregnenolone is converted to 17-
hydroxyprogestorone by 3β-hydroxysteroid
dehydrogenase
• 17-hydroxyprogestorone is converted to 11-
deoxycortisol by 21-hydroxylase
• 11-deoxycortisol is converted to cortisol by 11β-
hydroxylase
• 11β-hydroxylase is inhibited by metyrapone
• Accordingly, a deficiency in 17α-hydroxylase
Figure 85: The different layers of the adrenal gland: cause a deficiency in the production of cortisol
Source: and androgens, but not aldosterone
http://biochemistry2.ucsf.edu/programs/ptf/mn%20links/H • On the other hand, a deficiency in 21-hydroxylase
PA%20Axis%20Physio.pdf or 11β-hydroxylase will cause a deficiency in the
production of cortisol and aldosterone, but not
• The main focus here is the zona glomerulosa, androgens
zona fasciculata, and zona reticularis Production of Androgens
• All steroid hormones are derived from cholesterol • Testosterone is produced in the zona reticularis
• ACTH stimulates cholesterol desmolase which and is converted to estradiol by aromatase in the
produces pregnenolone peripheral tissues
• Pregnenolone is then shifted into one of the three • 17-hydroxypregnenolone or 17-
different, but interconnected, pathways to hydroxyprogesterone are converted to
produce aldosterone, cortisol or androgens dehydroepiandrosterone (DHEA) and
• Accordingly, patients with an ACTH-producing androstenedione respectively by 17α-hydroxylase
pituitary adenoma “Cushing’s disease” will have • Androstenedione is converted to estrone by
hypertension “increased aldosterone”, aromatase “which can be inhibited by anastrozole
hypercortisolemia, and increased androgens or exemestane)
• Ketoconazole blocks cholesterol desmolase and • Testosterone is produced from androstenedione
other important steps in steroidogenesis → and is converted to estradiol by aromatase
decreased production of all steroids • Testosterone cab e also converted to
Production of Mineralocorticoids: dihydrotestosterone (DHT) by 5α-reductase
• Aldosterone, the principle mineralocorticoid, is which is the target of the finasteride
produced in the zona glomerulosa Congenital Adrenal Hyperplasia
• Aldosterone production is increased by the • Patients with congenital adrenal enzyme
activation of the renin-angiotensin system or by deficiencies have increased skin pigmentation due
increase in ACTH to the increased production of MSH which is
• Pregnenolone is converted to progesterone by 3β- coproduced and secreted with ACTH
hydroxysteroid dehydrogenase → converted to • They have bilateral adrenal gland enlargement
DEFICIEN LABS BLOOD PRESENTA
11-deoxycortisterone by 21-hydroxylase → T ENZYME PRESSURE TION
converted to corticosterone by 11β-hydroxylase 17α- - ↑ aldosterone - Increased - Ambiguous
and finally converted to aldosterone by HYDROXY - ↓ cortisol because of genitalia
LASE - ↓ androgens hyperaldosteron and
aldosterone synthase - ↓ potassium ism undescende
• Aldosterone synthase is stimulated by angiotensin d testes in
II males
- Lacks
• Enzyme deficiencies “underlined enzymes” result secondary
in congenital adrenal hyperplasia sexual
developme
nt in
females

339
 21- - ↓ aldosterone - Decreased - Most Effects of PTH on the kidneys:
HYDROXY - ↓ cortisol common
LASE - ↑ androgens - Presents in
- ↑ potassium infancy • PTH increases renal calcium resorption and
- Salt phosphate excretion
wasting
- Can lead to
• This is achieved by blocking phosphate
precocious reabsorption in the proximal tubule and
puberty increasing calcium reabsorption in the ascending
- Female
virilization
loop of Henle, distal tubule and collecting tubule
11β- - ↑ 11- - Increased - Female • PTH also promotes the activity of renal 1α-
HYDROXE deoxycortic because of virilization hydroxylase which converts 25-OH-D3 to 1,25-
LASE osterone elevated 11-
- ↓ deoxycortic (OH)2D3
aldosterone osterone • The following changes happen to the urine:
- ↓ cortisol o Decreased urinary calcium
- ↑ androgens
- ↓ potassium o Increased urinary phosphate
o Increased urinary cAMP
Parathyroid Hormone Physiology Effects of PTH and 1,25-(OH)2D3 on the bone:
Synthesis
• There are four parathyroid glands • The rapid phase is mediated by PTH binding to
osteoblasts and osteocytes
• They synthesize preproparathyroid hormone
which undergoes two cleavages to form • Osteocytes form a an osteocytic membrane:
proparathyroid and parathyroid hormone o When PTH binds to osteocytes →
eventually calcium is pumped into the extracellular
space
• The mature parathyroid hormone is a polypeptide
o This results in the rapid increase in
containing 84 aminoacids
ionized calcium and phosphate in the
• The major targets of the parathyroid hormone are
blood
the kidneys, skeletal system (bone) and intestine
• The slow-phase of bone resorption occurs when
• PTH-related peptide is formed by malignancies
osteoclasts are activated
such as squamous cell carcinoma of the lung and
• These osteoclasts digest the bone to release more
has a similar function to PTH
calcium into the blood
Regulation
• 1,25-(OH)2D3 acts on osteoclasts enhancing their
• The main triggers for the release of parathyroid
proliferation and bone resorption
hormone are hypocalcemia, hyperphosphatemia,
and low levels of 1,25-(OH)2D3 • PTH also increases RANK-L (receptor activator
of NK-kB ligand) by osteoblasts and osteocytes.
• Elevated levels of ionized calcium in the blood
RANK-L binds to RANK receptors to stimulate
are a potent inhibitor of PTH release
osteoclasts and calcium release from the bone
• 1,25-(OH)2D3 is another inhibitor of PTH release
Effects of PTH and 1,25-(OH)2D3 on the intestine:
• Accordingly, the main goal of PTH is to maintain
calcium homeostasis as ionized calcium appears • PTH induces the renal production of 1,25-
to be the main regulator of its release (OH)2D3 (calcitriol)
• Mild hypomagnesemia stimulates PTH secretion, • Calcitriol increases the intestinal absorption of
whereas, severe hypomagnesemia inhibits PTH calcium by increased the production of calcium-
secretion binding protein within the intestinal epithelial
• The possible causes of hypomagnesemia are: cells
o Diarrhea Vitamin D
o Alcohol abuse • Vitamin D3 is formed when the cholesterol
o Diuretics precursor (7-dehydroxycholesterol) is exposed to
o Aminoglycosides ultraviolet light in the skin
Function • D3 is converted to 25-(OH)-D3 by the action of
• The main functions of the parathyroid hormone 25-hydroxylase in the liver (an active form of D3)
are aimed into achieving calcium homeostasis • 25-(OH)-D3 is converted to 1,25-(OH)2D3 by the
• To achieve that, the kidneys, bones and intestine action of 1-hydroxylase in the proximal
are affected by PTH convoluted tubules in the kidneys under the
influence of PTH

340
 • 1,25-(OH)2D3 is the most active form of vitamin • Thyroid peroxidase has another important
D3 and is responsible for the slow homeostasis of function at this stage which is to perform a
calcium by increasing intestinal calcium coupling reaction as the following:
absorption and enhancing PTH effects on o Monoiodotyrosine + diiodotyrosine = T3
osteoclasts o Diiodotyrosine + diiodotyrosine = T4
Calcium Homeostasis o T3 and T4 are also bound to
• 99% of total body calcium is stored in the bone in thyroglobulin in the follicular lumen
the form of phosphate and hydroxide salts o They are endocytosed into the thyroid
• A very small portion of calcium is available as follicular epithelial cell
ionized calcium • Thyroid peroxidase is the target of the antithyroid
• The process of calcium homeostasis is dependent drugs propylthiouracil and methimazole
on four important components: • Under the influence of TSH, the thyroid follicular
o Calcium: Hypocalcemia stimulates PTH epithelial cell releases T3 and T4 into the
secretion. Hypercalcemia inhibits PTH circulation, however 99% of both hormones is
secretion bound to thyroid binding protein (TBG)
o Phosphate: Hyperphosphatemia • The release of T3 and T4 from thyroglobulin is
stimulates PTH secretion. facilitated by the action of proteases in the
Hypophosphatemia inhibits PTH thyroid follicular epithelial cell
secretion • Monoiodotyrosine and diiodotyrosine are also
o PTH: PTH increases ionized calcium by bound to thyroglobulin, however they are not
its effects on the bone, intestine and released into the circulation after they are cleaved
kidneys. It induces the production of by the action of the proteases
1,25-(OH)2D3 by the kidneys o Instead, Iodide is removed by the action
o 1,25-(OH)2D3: This active form of of deiodinase and tyrosine and iodide
vitamin D3 is responsible for the become available to start the whole
induction of intestinal absorption of process all over again
calcium and enhances the effect of PTH • While in the blood, the free T4 and T3 get into
on osteoclasts in the slow-phase peripheral tissues. T4 is converted to T3 the active
response of PTH in the bone form of the hormone by the action of 5’-
• Calcium is very important for nerve conduction, deiodinase
muscle contraction and other vital cellular • 5’-deiodinase is the target of glucocorticoids,
functions. Tight calcium regulation is achieved by beta-blockers and propylthiouracil which block
the interplay between these four components the peripheral conversion of T4 to T3
mentioned above
Calcitonin
• This hormone is synthesized by the parafollicular
cells of the thyroid gland
• It opposes the actions of PTH
• Decreases bone resorption of calcium
• It is secreted in response to increased serum
calcium
• It is not important in normal calcium homeostasis
Thyroid Gland Physiology Figure 86: Source and synthesis of thyroid hormones.
Synthesis Source:
• Thyroid follicles synthesize thyroid hormones https://en.wikipedia.org/wiki/Thyroid_hormones#/media/Fi
which are iodine-containing hormones that le:Thyroid_hormone_synthesis.png
control the body’s metabolic functions
• Iodide enters the thyroid follicular epithelial cell Regulation
• Thyroid peroxidase is responsible for the • Thyroid hormones are bound to thyroglobulin
oxidation and organification of iodide within the follicular lumen and thyroid follicular
• Iodine is bound to tyrosine to form epithelial cells
monoiodotyrosine and diiodotyrosine while • The trigger for the endocytosis of the hormone-
bound to thyroglobulin in the follicular lumen bound thyroglobulin and the proteolytic cleavage
of the thyroid hormones T3 and T4 to be released

341
 into the circulation is the pituitary hormone o Increase the basal metabolic rate by
thyroid stimulating hormone (TSH) increased the expression of Na/K-
• TSH is released from the anterior pituitary gland ATPase and the activity of the pump →
in response to thyroid releasing hormone which is increased oxygen consumption and
synthesized by the hypothalamus elevated body temperature →
• These are the positive feedback mechanisms that respiratory rate is increased to meet the
increase the release of T3 and T4 increased oxygen demand
• Free T3 and T4 are the main negative-feedback o Hyperglycemia which is needed to meet
signals in this system. They decrease the the increase in the basal metabolic rate.
sensitivity of the anterior pituitary to TRH This is achieved by increasing
(decreasing TSH) and decrease the release of glycogenolysis and gluconeogenesis
TRH by the hypothalamus o Increased lipolysis
• Another important negative-feedback signal is Vitamin D
achieved by somatostatin which inhibits the Synthesis
release of TSH by the anterior pituitary • 7-dehydrocholesterol, which is a cholesterol
• In Graves’ disease, the thyroid follicular derivative, is found in the skin
epithelial cells release excessive amounts of T3 • When the skin is exposed to sunlight, ultraviolet
and T4 because of the direct activation of the TSH light converts 7-dehydrocholesterol to pre-
receptors by the thyroid stimulating vitamin D3
immunoglobulins (TSI) • Pre-vitamin D3 is converted to vitamin D3
• Total T3 and T4 are not sensitive to thyroid • Vitamin D3 is released into the blood and is
disease because they reflect the 99% of TBG- bound to vitamin D binding protein (DBP)
bound thyroid hormones which are inactive. • Vitamin D3 can be also obtained from animal
Moreover, diseases that increase the amount of sources
TBG or decreases it can also influence the • Vitamin D2 can be obtained from plant sources
interpretation of total T3 and T4 (mushrooms), however it has a much lower
o TBG is increased in pregnancy and oral efficacy than vitamin D3
contraceptive pills use because estrogen • Regardless of the source of vitamin D3
increases TBG (synthesized in the skin or from diet), it will be
o TBG is synthesized by the liver → it bound to DBP to be transported to the liver
will be decreased in hepatic failure and • 25-hydroxylase in the liver converts vitamin D3
in nephrotic syndrome where protein is into a metabolite known as 25-(OH)-D3
lost in the urine • This metabolite is known as calcidiol
o Steroids also decrease TBG • Serum levels of 25-(OH)-D3 are what we measure
Function in vitamin D essays
• Only the small free fraction of thyroid hormones • 25-(OH)-D3 is still not an active endocrine
is active hormone. It needs to be converted to 1,25-
• The target is nuclear receptors → increase gene (OH)2D3 by the activity of 1α -hydroxylase in the
expression in target tissues proximal tubule of the kidney
• T3 has higher affinity for the nuclear receptors • 1,25-(OH)2D3 is known as calcitriol and is the
than T4 → T4 needs to be converted in the active form of vitamin D3
peripheral tissues to T3
• The main functions of T3 include:
o Brain maturation → congenital iodine
deficiency → congenital
hypothyroidism and impaired brain
development
o Bone growth → hypothyroidism in
children can result in short stature
o Beta-adrenergic effects → increase
cardiac output by increasing heart rate Figure 87: Synthesis of vitamin D3 in the skin. Source:
and systolic volume. Increase 10.1007/s00394-012-0430-5
contractility | beta-blockers are used in
thyrotoxicosis to alleviate the beta-
adrenergic effects of T3 Regulation

342
 • Sun exposure is an important up-regulator of vddr-2 Vitamin D receptor Very high doses of
mutations vitamin D3 or 1,25-
vitamin D3 (OH)2D3
• The activation of 25-OH-D3 by the kidneys is vddr-3 Mutations in hormone High-dose 1,25-(OH)2D3
response element-
regulated by parathyroid hormone binding protein
• When calcium levels in the blood are low, PTH
secretion is increased
• This in turn would lead to an increase in the Note: Regardless of the cause of
expression and activity of 1α-hydroxylase → vitamin D deficiency, patients can
increasing the activation of 25-OH-D3 develop severe hypocalcemia which
• Elevated levels of 1,25-(OH)2D3 inactivate further can lead to hypocalcemic tetany.
activity of this active form of vitamin D3 by
increasing the expression of CYP24A1 which Vitamin D3 toxicity:
converts 1,25-(OH)2D3 into inactive metabolites
• Elevated levels of 1,25-(OH)2D3 also • Hypercalcemia
downregulate PTH secretion by the parathyroid • Hypercalciuria
glands • Vitamin D supplementation is controversial in
Physiologic Actions sarcoidosis:
• The main role of vitamin D3 activation is to o Epithelioid macrophages in granulomas
correct hypocalcemia by increasing intestinal have 1α-hydroxylase activity
absorption of calcium and increasing the activity o They can activate 25-(OH)-D3 resulting
and proliferation of osteoclasts in the bone → in vitamin D3 toxicity
increasing bone turnover o At the same time, vitamin D3
• Vitamin D3 also improves myogenesis and supplementation in patients with
contractility hypocalcemia and sarcoidosis is known
• Innate immunity, adaptive immunity, and to lower the risk of type 2 diabetes and
unfortunately autoimmunity is also mediated by cancer
vitamin D3 Accordingly, the current recommendation is to use vitamin
D3 supplementation cautiously in sarcoidosis patients and
Pathophysiology to discontinue vitamin D3 supplementation as soon as
Osteomalacia: possible when the patient develops hypercalcemia to
prevent hypercalcemic renal failure
• Decreased levels of vitamin D3 → vitamin D3
deficiency in an adult
Cushing’s Syndrome
• Impaired mineralization of osteoid → formation
Physiology of Cortisol Secretion by the Adrenal Cortex
of non-mineralized bone
• The bone is weak and may bend or break under
load
• Muscle atrophy → either because of the direct
actions of vitamin D3 on myogenesis or because
of the inability of the patient to lift weights due to
risk of fractures
Acquired rickets:

• Vitamin D3 deficiency in children

• If not treated properly → serious permanent
growth and skeletal abnormalities
Inherited rickets:
The following table summarizes the different types of
vitamin-D dependent rickets, the etiology, and the
treatment.
Etiology Treatment
vddr-1 Inactivating mutation 1,25-(OH)2D3
of 1α-hydroxylase supplementation Figure 88: The hypothalamus-pituitary-adrenal axis.
gene Source: https://antranik.org/adrenocorticotropin-hormone-
acth-including-cortisol/

343
 • The hypothalamus secretes CRH which Epidemiology
stimulates the release of ACTH from the anterior • A rare disorder with an estimated incidence of 3
pituitary gland cases per one million per year
• ACTH stimulates the secretion of cortisol by the • Iatrogenic Cushing’s syndrome is underreported
adrenal cortex Pathogenesis
• A negative feedback loop results in the inhibition • Exogenous corticosteroids which is most
of the release of ACTH by the anterior pituitary commonly iatrogenic
corticotropes and CRH by the hypothalamic o ACTH is suppressed
neurosecretory cells o Bilateral adrenal atrophy
• The release of CRH is increased when the • Primary adrenal adenoma, hyperplasia or
individual is under stress. CRH release follows a carcinoma:
circadian rhythm o ACTH is suppressed
Functions and important notes about cortisol: o Atrophy of the contralateral adrenal
• It is secreted by the adrenal zona fasciculata gland
• ACTH-secreting tumors:
• It is bound to corticosteroid-binding globulin
o Pituitary adenoma → Cushing’s disease
• It has the following functions:
→ elevated ACTH and suppression of
o Increased appetite
cortisol secretion by high-dose
o Elevation of blood pressure by the
dexamethasone test
upregulation of alpha-1 receptors on
o Paraneoplastic → Ectopic ACTH
arterioles. Can also cause excess water
production → elevated ACTH and no
and sodium retention at high
suppression of cortisol with high-dose
concentrations due to its
dexamethasone test
mineralocorticoid effects
Small cell lung cancer and bronchial
o Increases insulin resistance →
carcinoids are two possible causes
diabetogenic
o Increases gluconeogenesis and Pathophysiology
decreases glucose utilization → hence • Excess cortisol results in the different effects
the name glucocorticoid described under the function of cortisol section
o Impairs wound healing and collagen • Hypertension is found in up to 80% of patients
synthesis by decreasing fibroblast with Cushing’s syndrome
activity • Accordingly, it is the most important
o Decreased immunity by the following pathophysiological consequence of Cushing’s
mechanisms: syndrome that needs to be discussed
▪ Inhibition of leukotrienes and • Excess cortisol has a mineralocorticoid effect
prostaglandins production • This increases the tubular reabsorption of sodium
▪ Inhibition of WBC adhesion and water
▪ Blockade of histamine release • Moreover, patients with Cushing’s syndrome
▪ Can cause lymphopenia and have increased sensitivity to norepinephrine
eosinopenia mediated by the upregulation of alpha-1 receptors
▪ Blocks interleukin-2
production Clinical Findings
o Decreased osteoblast activity → • Weight gain and increased deposition of
decreased bone formation → centripetal, supraclavicular and temporal fat
osteoporosis • Hirsutism
• Striae
Definition
• Moon facies
Cushing’s syndrome results from prolonged exposure to
excess glucocorticoids. The most common cause is • Easy bruising
exogenous administration of cortisol “iatrogenic Cushing’s • Menstrual irregularity, amenorrhea and decreased
syndrome”. When the cause of Cushing’s excess ACTH libido
production by the pituitary gland, the term Cushing’s • Depression, emotional lability, irritability, and
disease is used. cognitive decline
• Proximal muscle weakness, reduced bone mineral
density → pathologic fractures
• Impaired glucose tolerance → diabetes mellitus

344
 • Immunosuppression • Slight predominance in females
Diagnosis • The diagnosis is often delayed
Patients with a clinical picture suggestive of Cushing’s Pathophysiology
syndrome should undergo biochemical confirmation of Primary adrenal insufficiency:
hypercortisolism.
• Patients with primary adrenal insufficiency have
• The confirmation of hypercortisolism can be a compensatory increase in ACTH production →
obtained from one of the following tests: increase MSH → hyperpigmentation
o 24-hour urinary free cortisol This is not seen in patients with secondary
o Late-night salivary cortisol adrenal insufficiency where ACT production is
o A dexamethasone suppression test: low
Low-dose dexamethasone is • Acute adrenal insufficiency can occur in patients
administered overnight → no with hemorrhagic shock
suppression is suggestive of Cushing’s • The most common cause of chronic primary
syndrome when ACTH is suppressed adrenal insufficiency “Addison’s disease” in the
western world is autoimmune destruction
High-dose dexamethasone will suppress Metastatic disease is also a common cause
cortisol production in patients with TB is the most common cause of Addison’s
Cushing’s disease but not in those with disease in the developing world
ectopic ACTH secretion • Primary adrenal insufficiency can also occur in
• ACTH can be either suppressed in ACTH- the following conditions:
independent Cushing’s syndrome, or increased in o Associated with autoimmune
ACTH-dependent Cushing’s syndrome polyglandular syndromes
• Patients with ACTH-dependent Cushing’s o Adrenal hemorrhage in septic patients,
syndrome need the following additional those with DIC or endotoxic shock
investigations: “Waterhouse-Friderichsen Syndrome”.
o Pituitary MRI looking for a pituitary Commonly associated with Neisseria
adenoma meningitidis
o If high-dose dexamethasone test does • In patients with primary adrenal insufficiency,
not suppress ACTH, consider the aldosterone production is impaired →
possibility of ectopic ACTH production: hyperkalemia
Chest, abdominal or pelvic MRI to Secondary adrenal insufficiency:
identify the cause
• Secondary to decreased ACTH production by the
Treatment: pituitary gland
• Discontinuation or modification of exogenous • Can be seen in Sheehan’s syndrome or in
cortisol dose destructive tumors of the pituitary gland
• Surgical management accordingly to the cause, • Patients do not have increased MSH
e.g. adrenalectomy in the case of unilateral • The renin-angiotensin-aldosterone axis is intact
adenoma → no hyperkalemia
• Ketoconazole and metapyrone can be used in Tertiary adrenal insufficiency:
patients with pituitary adenoma while waiting for
surgery. • Chronic exogenous steroid use suppresses
Addison’s Disease endogenous mineralocorticoid a glucocorticoid
Definition production by the adrenal glands
Addison’s disease is known as primary adrenal • The sudden discontinuation of exogenous steroid
insufficiency. It results from deficiency of results in adrenal insufficiency
glucocorticosteroids and mineral corticosteroids. Secondary • The renin-angiotensin-aldosterone axis is intact
adrenal insufficiency occurs due to decreased pituitary Clinical Findings
production of ACTH. Tertiary adrenal insufficiency occurs General symptoms and signs:
in patients who are chronic users of steroids who suddenly
stop taking corticosteroids. • Weakness
• Fatigue
Epidemiology • Orthostatic hypotension
• The estimated incidence of Addison’s disease is 1 • Muscle pain
per 10,000

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 • Weight loss • Decreased cortisol and ACTH levels in secondary
• Sugar and salt cravings and tertiary adrenal insufficiency
• GI disturbances o Increased cortisol in response to ACTH
Primary adrenal insufficiency: stimulation test
Treatment
• Hyponatremic hypovolemia → hypotension Primary adrenal insufficiency:
• Hyperkalemia
• Metabolic acidosis • Glucocorticoid replacement therapy
• Skin and mucosal hyperpigmentation see Figure 1 “hydrocortisone or prednisolone”
• Acute → acute adrenal crisis which is a shock • Mineralocorticoid replacement therapy
state “fludrocortisone”
• Chronic → most common cause is autoimmune Secondary adrenal insufficiency:
destruction of the adrenal glands which can be • Glucocorticoid replacement therapy is more
associated with vitiligo; see Figure 2 important than mineralocorticoid replacement
Secondary and tertiary adrenal insufficiency: therapy
• No skin or mucosal hyperpigmentation Tertiary adrenal insufficiency:
• No hyperkalemia • The adrenal gland can recover after few days to
weeks of discontinuation of exogenous
corticosteroids
Primary Aldosteronism
Definition
The increased secretion of aldosterone from the adrenal
gland due to an adrenal gland adenoma or bilateral adrenal
gland hyperplasia is known as primary aldosteronism.
Epidemiology
• 3.5% of hypertensive patients have hypertension
secondary to primary aldosteronism
Figure 89: Mucosal hyperpigmentation in a patient with • Approximately 8.5 million individuals have
primary adrenal insufficiency. Source: primary aldosteronism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636818/f • The most common causes are aldosterone-
igure/F2/ producing adenoma (Conn’s disease), bilateral
adrenal hyperplasia and idiopathic
hyperaldosteronism
• Primary unilateral adrenal hyperplasia is seen in
3% of the patients
• Primary aldosteronism is a possible cause of
treatment-resistant hypertension
Pathophysiology
• In normal circumstances, aldosterone production
is controlled by the renin-angiotensin system
Figure 90: Vitiligo, a common association with Addison's • Aldosterone is synthesized in the zona
disease. Source: glomerulosa
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4540394/ • Other inducers of aldosterone synthesis are
ACTH, serum potassium and dopamine
Diagnosis • Aldosterone facilitates sodium and water
• Measurement of serum electrolytes: retention and potassium excretion
o Hyperkalemia in primary adrenal • Patients with hyperaldosteronism have an
insufficiency elevated blood level of aldosterone independent
o Hyponatremia in primary adrenal of renin
insufficiency
• Hyperaldosteronism results in the following
• Decreased cortisol and elevated ACTH levels in pathophysiologic changes:
primary adrenal insufficiency o Sodium and water retention →
hypertension
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 o Impaired collagen remodeling and Lateralizing adrenal venous sampling:
endothelial dysfunction → left • Unilateral adrenalectomy of the ipsilateral adrenal
ventricular hypertrophy, kidney fibrosis, gland
and fibrotic changes in the blood vessels Bilateral adrenal hyperplasia:
o Increased potassium excretion → • Medical treatment with a mineralocorticoid
hypokalemia receptor antagonist
o Metabolic alkalosis • Spironolactone and eplerenone
Clinical Findings
• Hypertension Neuroblastoma
o Usually severe Definition
o Requires three or more antihypertensive Neuroblastoma is a malignancy originating from neural
drugs crest cells which give rise to the sympathetic nervous
o Patient’s age < 20 years system. Because they originate from an embryogenic stem
o Can cause headaches cell precursor, they are often diagnosed before the age of
• Hypokalemia → can cause fatigue and weakness 18 months. It can arise at any site of the sympathetic
• Polydipsia and polyuria nervous system including the adrenal glands’ medulla.
• No peripheral edema
Diagnosis Epidemiology
Patients presenting with the previously mentioned clinical • A pediatric malignancy that often presents before
picture of treatment-resistant hypertension should get their the age of 4 years
plasma renin and aldosterone levels checked. Patients with • The most common tumor of the adrenal medulla
primary hyperaldosteronism have an increased aldosterone • Annual incidence is 9 per million
to renin ratio. • 650 new cases per year in the United States
Pathophysiology
If positive, a confirmatory test is required: • Most cases are sporadic
• Familial cases are seen in 1% of the patients
• Sodium loading test with oral or intravenous
saline • Associated with the over-expression of the N-
o In normal people, aldosterone levels myc oncogene
should decrease from baseline Dopamin Norepine
o In primary hyperaldosteronism, Tyrosine L-dopa
e phrine
aldosterone levels remain
inappropriately high
If the confirmatory test confirms the diagnosis of primary • Neuroblastomas are functional malignancies that
hyperaldosteronism, the next question is to differentiate secrete catecholamines
between unilateral adrenal adenoma and bilateral adrenal • Large amounts of catecholamines undergo
hyperplasia. metabolism resulting in increased catecholamine
metabolites in the urine and serum
Adrenal CT scan is the imaging modality of choice: • Dopamine is metabolized to homovanillic acid
(HVA), whereas norepinephrine is metabolized
• If a unilateral adrenal nodule is identified and the into VMA
nodule is 1 cm or more in size, this is enough for
• Because of the over production of
the diagnosis of Conn’s disease. No further norepinephrine, some patients might develop
testing is required
hypertension, however this is less commonly seen
• If the nodule size is less than 1 cm or no nodules as compared to pheochromocytoma
are identified, adrenal venous sampling is
• Histopathological examination can show Homer-
indicated Wright rosettes which are also seen in
• If adrenal venous sampling lateralizes elevated medulloblastoma
aldosterone levels to one adrenal gland, unilateral
adrenal hyperplasia is diagnosed
• If adrenal venous sampling is not lateralizing,
bilateral adrenal hyperplasia is confirmed
Treatment
Conn’s disease:
• Unilateral adrenalectomy → curative of
hypertension in up to 30% of the patients

347
 Figure 91: Homer-Wright rosettes. Source:
https://commons.wikimedia.org/wiki/File:Neuroblastoma_
of_the_Adrenal_Gland_(2)_(2274260465).jpg Figure 92: A neuroblastoma in the adrenal gland as seen on
an abdominal CT scan. Source:
Clinical Findings https://radiopaedia.org/images/143309
• The clinical symptoms and signs are largely
dependent on the location of the primary tumor Treatment:
and metastatic disease • Based on the stage of the tumor at the time of the
• Up to 60% of the cases are localized to the diagnosis
abdomen, i.e. adrenal medulla tumors • Localized tumors are treated by primary surgery
• They can present with an abdominal palpable • Patients with metastatic tumors that are
mass, discomfort and pain aggressive are treated with chemotherapy
• Thoracic neuroblastomas are often diagnosed Pheochromocytoma
coincidentally Definition:
• Cervical neuroblastomas can cause Horner’s Pheochromocytomas are rare neuroendocrine tumors that
syndrome secrete catecholamines. They are responsible for up to
• Less likely to develop hypertension than with 0.6% of hypertension cases. Up to 85% of the cases arise
pheochromocytoma from the adrenal medulla and the remainder originate from
• Opsoclonus-myoclonus syndrome the extra-adrenal autonomic neural ganglia. They arise
• The abdominal mass is often firm and has from chromaffin tissues derived from embryogenic neural
irregular shape. It can cross the midline crest cells.
Diagnosis: Epidemiology
• Increased urinary catecholamine metabolites • The estimated incidence is 2 to 8 per million
(VMA and HVA)
• Most common tumor of the adrenal medulla in
• Positive meta-iodobenzylguanidine (MIBG) adults
scintigraphy
• Can be associated with germline mutations NF-1,
• CT scan confirms the presence of an adrenal VHL, and RET (MEN 2A or 2B)
medullary tumor Pathophysiology
• Histological examination is required to confirm • Excessive release of epinephrine, norepinephrine
the diagnosis and for prognostic stratification and dopamine
→ alpha-adrenergic stimulation → intense
vasospasm and hypertension | and
→ beta-adrenergic stimulation → vasodilation,
diaphoresis and tachycardia
• The excessive release of catecholamines is
episodic
• Common triggers of catecholamines’ release
include:
o Spontaneous
o Abdominal palpation during
examination
o Exercise
o Beta-adrenergic blockers

348
 o Intravenous contrasts • 90% originate from non-beta islet cells of the
• The repetitive surges in catecholamines excess pancreas
can lead to catecholaminergic cardiomyopathy • 75% are malignant
o Contraction-band necrosis on • Massive production of vasoactive intestinal
histopathology peptides results in the following:
• 10% are malignant o Chronic watery diarrhea
• They follow the rule of 10’s: o Dehydration
o 10% malignant o Hypokalemia
o 10% bilateral o Achlorhydria
o 10% extra-adrenal o Acidosis
o 10% calcify o Hypotension
o 10% present in children o Hypercalcemia
o Hyperglycemia
Dopami Norepin Epineph • The clinical syndrome caused by VIPomas is
Tyrosine L-dopa
ne ephrine rine
known as Verner-Morrison syndrome, Watery
diarrhea-hypokalemia-achlorhydria syndrome, or
• Dopamine is metabolized to homovanillic acid pancreatic cholera syndrome
(HVA), whereas norepinephrine is metabolized • The term “pancreatic cholera syndrome” is an
into VMA eponym
Clinical Findings • Associated with MEN-1
• Episodic hypertension, tachycardia, diaphoresis, Clinical Findings
headache and feeling of anxiety or panic attacks • Prolonged watery diarrhea → dehydration and
• Related to catecholamine excess hypokalemia
• Orthostatic hypotension on a background of • Lethargy, muscle weakness, nausea and vomiting
paroxysmal or treatment-resistant hypertension • Impaired glucose tolerance
• The symptoms are summarized in the 5 P’s: • Flushing
o Pressure (hypertension) • Achlorhydria
o Pain (headache) Diagnosis
o Perspiration • Elevated fasting VIP plasma level
o Palpitations (tachycardia) • CT scan of the abdomen or somatostatin receptor
o Pallor scintigraphy
Diagnosis • Most tumors are metastatic at time of presentation
• Increased urinary catecholamine metabolites Treatment
(VMA and HVA) • Correction of dehydration
• Plasma catecholamines and metanephrines • Fluid replacement therapy
• Positive meta-iodobenzylguanidine (MIBG) • Octreotide, which blocks VIP, can control the
scintigraphy diarrhea
• CT scan confirms the presence of an adrenal • Curative surgical resection in non-metastatic
medullary tumor tumors
Treatment • Peptide receptor radionuclide therapy is very
• Irreversible alpha-antagonists effective in metastatic disease
“phenoxybenzamine” followed by beta-blockers Hypothyroidism
prior to tumor resection Outline
o Incomplete alpha-blockade before • Definition
giving beta-blockers can result in a • Causes
hypertensive crisis • Clinical Findings
VIPoma • Diagnosis
Definition • Treatment
• VIPoma is a rare endocrine tumor that produces Definition
vasoactive intestinal peptide. Hypothyroidism is the most common hormone deficiency
Epidemiology disorder. It can be congenital or acquired. Another
• Annual incidence is 1 per 10,000,000 classification of hypothyroidism is based on the site of
Pathophysiology endocrine dysfunction: primary thyroid disease, secondary

349
hypothyroidism due to pituitary disease, or tertiary - Painless
hypothyroidism due to hypothalamic disease. Other causes of hypothyroidism include:

Causes • Iodine deficiency

The following table summarizes the most common causes • Drug-induced: lithium and amiodarone
of hypothyroidism. • Thyroid gland downregulation due to increased
iodide intake: Wolff-Chaikoff effect
Pathology notes
Hashimoto - Autoimmune disorder - Most common cause
Clinical Findings
thyroiditis - Antithyroid of hypothyroidism Hypothyroidism is a systemic disease. Almost all body
peroxidase and - Associated with organs are affected.
antithyroglobulin HLA-DR3
antibodies - More commonly
- Early seen in patients with
Clinical findings
hyperthyroidism due non-Hodgkin Metabolic - Weight gain
to follicular rupture lymphoma - Cold intolerance
- Hurthle cells and
lymphoid aggregates - Decreased free water clearance
with germinal centers → hyponatremia
- The thyroid gland is - Decreased basal metabolic rate
enlarged but
Skin and hair - Dry skin
nontender
postpartum - Transient thyroiditis - Coarse brittle hair
thyroiditis - Resolves within 1
year after delivery
- Alopecia
- Can present with - Brittle nails
hyperthyroidism, - Puffy facies
hypothyroidism, or
hyperthyroidism - Generalized non-pitting edema
followed by (myxedema) – rarely seen
hypothyroidism nowadays
- No thyroid gland
enlargement
Gastrointestinal - Decreased GI motility →
- Lymphocytic constipation
infiltrates on Musculoskeletal
histology
- Proximal myopathy with
cretinism - A congenital form of - Patients have pale elevated CK
hypothyroidism puffy faces - Carpal tunnel syndrome
- Can be caused by an - Protruding Neuropsychiatric
autoimmune mediated umbilicus
- Psychomotor retardation
mechanism, thyroid - Protuberant tongue - Fatigue
agenesis, or thyroid - Mental retardation - Weakness
dysgenesis due to poor brain
- Iodine deficiency is a development - Depressed mood
common cause in the - Hyporeflexia
developing world - Myxedema coma due to
subacute - De Quervain’s - This is an
granulomatous thyroiditis inflammatory respiratory depression →
thyroiditis - Thyroiditis post viral condition hypercapnia
infection - ESR is elevated
- Preceded with a flu- - The thyroid gland is
Cardiovascular - Bradycardia → decreased
like illness very tender cardiac output → exertional
- Early hyperthyroidism - Jaw pain dyspnea
followed by reproductive
hypothyroidism
- Menorrhagia and/or
- Hypothyroidism is oligomenorrhea
permanent in 15% of - Infertility
the cases
- Histology reveals
granulomatous Diagnosis
riedel thyroiditis
inflammation • The first test to order in a patient with
- Replacement of - A manifestation of
thyroid gland with IgG4 disease hypothyroidism is TSH
fibrous tissue - Associated with • In primary hypothyroidism, TSH level is
- Inflammatory filtrate autoimmune
- Involvement of pancreatitis,
elevated. In secondary hypothyroidism due to
adjacent structures retroperitoneal pituitary disease, TSH level is low
such as trachea or fibrosis and • The diagnosis is confirmed when free T3 and T4
esophagus noninfectious
- Can mimic anaplastic aortitis levels are low
carcinoma - The thyroid gland is • Patients with hypothyroidism usually have
enlarged, and very
hard
hypercholesterolemia due to the decreased

350
 expression of LDL receptors → decreased LDL • Graves’ disease
clearance → increased cardiovascular disease risk • Iodine deficiency
• Antithyroid peroxidase and antithyroglobulin • Hashimoto thyroiditis
antibodies in Hashimoto thyroiditis • TSH-secreting pituitary adenoma “secondary
Treatment hyperthyroidism”
• Thyroid replacement therapy with levothyroxine Causes of nodular goiter:
Hyperthyroidism
Definition • Toxic multinodular goiter
Hyperthyroidism is the condition of excessive production • Thyroid adenoma
of thyroid hormones (T3 and T4) due to a hyperactive • Thyroid cancer
thyroid gland. • Thyroid cyst
Clinical Findings
Causes Hyperthyroidism is a systemic disease. Almost all body
The following table summarizes the most common causes organs are affected.
of hyperthyroidism.
Pathology notes
Clinical findings
Graves disease - Diffuse thyroid gland - Diffuse goiter Metabolic - Weight loss
hyperplasia - Symptoms and signs - Increased sweating
- Autoimmune disorder of hypothyroidism
- Thyroid stimulating - Exophthalmos and
- Heat intolerance
immunoglobulins bind ocular muscle - Increased synthesis of Na/K
to TSH receptors abnormalities ATPase → increased basal
- Significant damage to - Associated with
the thyroid gland HLA-DR3 and metabolic rate
- TSI is an IgG HLA-B8 Skin and hair - Warm moist skin
immunoglobulin - Fine hair
- Infiltration of
retroorbital space by - Pretibial myxedema in
activated T-cells and Graves’ disease
increased production
of TNF-alpha and
- Onycholysis
interferon gamma Ocular - In Graves disease: periorbital
- Increased osmotic edema, exophthalmos, and
muscle swelling and
muscle inflammation
lid lag
→ exophthalmos - Lid lag occurs due to
- Histology reveals tall, increased sympathetic
crowded, follicular
epithelial cells in a stimulation of the levator
scalloped colloid palpebrae superioris
toxic adenoma - A small single nodule Gastrointestinal - Increased GI motility →
in the thyroid gland
that produces thyroid diarrhea
hormones Musculoskeletal - Proximal myopathy with
uncontrollably normal CK
drug-induced - Amiodarone can cause
hyperthyroidism or - Osteoporosis
hypothyroidism Neuropsychiatric - Hyperactivity
toxic multinodular - Multiple functional - TSH receptor
Goiter nodules mutations in 60%
- Anxiety
- Also known as of the cases - Insomnia
Plummer’s disease - Fine tremors
- Patients can develop
congestive heart - Hyperreflexia “brisk
failure and cardiac reflexes”
arrhythmias Cardiovascular - Tachycardia
- Hyperthyroidism
increases the density - Palpitations secondary to
of beta-1 adrenergic arrhythmias → most
receptors in the heart commonly atrial fibrillation
→ increased
predisposition to - Angina
arrhythmias - Systolic hypertension
- Histology reveals
follicular cells
reproductive - Oligomenorrhea or
distended with colloid amenorrhea
Causes of diffuse goiter: - Infertility
Thyroid storm:

351
 • Incompletely treated/untreated hyperthyroidism • Increased synthesis in response to hypocalcemia
→ acute stress results in severe hyperthyroidism • The chief cells in the parathyroid gland have
• Agitation, delirium, fever, diarrhea, coma and calcium-sensing receptors
tachyarrhythmias • The parathyroid hormone increases calcium
• Tachyarrhythmias can kill the patient absorption by the kidneys and gastrointestinal
Jod-Basedow phenomenon: tract, and increases the activity of osteoclastic
cells to release calcium from the bone
• Thyrotoxicosis in a patient with iodine deficiency • The parathyroid hormone mediates the excretion
who receives iodine in the form of iodine IV of phosphate by the kidneys
contrast Pathophysiology in hypoparathyroidism:
• The thyroid gland is very sensitive “hungry” for
iodine • A patient who is deficient in parathyroid hormone
Diagnosis will develop hypocalcemia, hyperphosphatemia
• The first test to order in a patient with and hypercalciuria. The cause is clear from the
hyperthyroidism is TSH basic understanding of the functions of the
• In primary hyperthyroidism, TSH level is low. In parathyroid hormone
secondary hyperthyroidism due to pituitary Etiology:
disease, TSH level is high
• The diagnosis is confirmed when free T3 and T4 • The most common cause is iatrogenic removal of
levels are high the parathyroid glands in head and neck surgery,
e.g. thyroidectomy
• In Graves’ disease look for thyroid-stimulating
immunoglobulins • Transient hypoparathyroidism can occur
Treatment following thyroid surgery and is believed to be
due to damage to the parathyroid glands,
• Antithyroid drugs such as carbimazole,
hemorrhagic changes, or changes in blood supply
propylthiouracil and methimazole:
o Inhibit the iodiniation of thyroglobulin • Radiation is also a cause of hypoparathyroidism
by thyroperoxidase • Metastatic infiltration, deposition of iron in
o Propylthiouracil also prevents the hemochromatosis, or copper in Wilson’s disease
conversion of T4 to the active form T3 can cause hypoparathyroidism
o Take a while to achieve euthyroidism • DiGeorge syndrome or velocardiofacial
o Propylthiouracil is safe during syndrome is a genetic disorder that is
pregnancy characterized by defective development of the 3rd,
• Beta-blockers: 4th and 5th branchial pouches →
o Symptomatic treatment of palpitations, hypoparathyroidism, cardiac defects, cleft palate,
tremors and anxiety dysmorphic facial features, hypoplasia of the
o Propranolol thymus gland and renal or ocular defects.
• Surgery: o Due to a deletion of locus 22q11,
o The removal of the thyroid gland specifically the gene TBX1
o The patient requires thyroid replacement Pseudohypoparathyroidism type 1A:
therapy afterwards • Unresponsiveness of the kidneys to parathyroid
o Might worsen ocular manifestations in hormone
Graves’ disease
• Hypocalcemia despite hyperparathyroidism
• Radioiodine:
• Presents with shortened 4th and 5th digits, short
o Treatment modality of choice for toxic
stature, obesity, and developmental delay →
thyroid adenoma
Albright syndrome
Hypoparathyroidism
• Inherited from the mother because the paternal
Definition
copy of the Gs protein alpha-subunit is imprinted
Hypoparathyroidism is a state of deficient parathyroid
Clinical Findings
hormone that results in hypocalcemia, hyperphosphatemia
Symptoms:
and hypercalciuria.
Pathophysiology • Cramping
• Tetany
• Twitching
Normal physiology of the parathyroid hormone: • Seizures

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 • Tingling sensation and numbness • Childhood irradiation is a risk factor
Physical examination: • Histology:
o Empty-appearing nuclei with central
• The presence of Trousseau’s or Chvostek’s signs clearing (Orphan Annie eyes)
→ indicative of neuromuscular irritability o Psammoma bodies
• Chvostek’s sign: o Nuclear grooves
o Tapping of the facial nerve results in o Figure 1
contraction of the facial muscles
• Trousseau sign:
o Occlusion of the brachial artery with a
BP cuff results in carpal spasm
• Prolongation of the QT interval
• Hyperactive deep tendon reflexes
Diagnosis
• Hypoparathyroidism
• Hypocalcemia
• Hyperphosphatemia
Figure 93: Histopathology in papillary thyroid carcinoma.
• Hypercalciuria Source:
• Low urine cAMP level https://en.wikipedia.org/wiki/Papillary_thyroid_cancer#/m
Treatment edia/File:Papillary_Carcinoma_of_the_Thyroid.jpg
• Intravenous calcium gluconate
• Oral replacement of calcium and vitamin D Follicular Thyroid Carcinoma:
supplementation should be initiated • Good prognosis
• Calcium citrate is the oral calcium formulation of • Invades thyroid capsule and blood vessels
choice • Hematogenous spread more common than
• Calcitriol, the active metabolite of vitamin D, can lymphatic spread
increase the calcium levels within a few days o To lung and bones
Thyroid Cancer • Associated with RAS mutations
Thyroid Adenoma • Also PAX8-PPAR-γ
The diagnosis of incidental thyroid adenomas is becoming Medullary thyroid carcinoma:
more frequent because of recent advances in imaging. • Parafollicular “C” cells
• 90% or more are small, non-palpable benign • Produces calcitonin
lesions • Sheets of cells in an amyloid stroma
• Most are nonfunctional (cold) nodules o Amyloid stroma stains with Congo red
• Can cause hyperthyroidism in a minority of the o Figure 2
patients (hot) nodules • RET mutations
• Care must be taken to differentiate them from • Associated MEN type 2A and 2B
malignant nodules
Thyroid Cancer:

• Fifth most common cancer in women

• 62000 new cases per year
Clinical Characteristics of Thyroid Cancer
Differentiated thyroid cancer:
Papillary thyroid cancer:
• Most common type of thyroid cancer
• Excellent prognosis (95% cure rate) Figure 94: amyloid stroma in a patient with medullary
• 3:1 female to male ratio carcinoma. Source:
• 30 to 50 years https://commons.wikimedia.org/wiki/File:Medullary_thyro
• Metastases involve cervical lymph nodes id_carcinoma_-_intermed_mag.jpg
• 70% have a BRAF mutation
• Most remain indolent
• RET mutations are also associated

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Undifferentiated thyroid cancer: Subacute Granulomatous Thyroiditis
Anaplastic thyroid carcinoma: Definition:
• Occurs in older patients
Also known as subacute thyroiditis, giant cell thyroiditis or
• Invades local structures de Quervain’s thyroiditis. A painful thyroiditis that has a
• Carries a very bad prognosis 4:1 female to male ratio. Caused by a viral infection.
Diagnosis
Neck ultrasonography is the imaging modality of choice • Most commonly caused by coxsackievirus groups
for a patient presenting with a thyroid nodule. The goal of A and B
ultrasonography is to stratify patients into very low • Most often occurs in women aged 40 to 50 years
suspicion, low suspicion, intermediate suspicion and high • More common in summer
suspicion of malignancy. Clinical features:
Benign nodules characteristics on ultrasonography:
• Purely cystic, or • A prodrome of myalgia, pharyngitis, low-grade
• Spongiform or partially cystic fever and fatigue
• These nodules should be monitored without any • Followed by a tender diffuse goiter and neck pain
surgical intervention that radiates to the ear
Indications of fine-needle aspiration cytology: • Hyperthyroidism is seen in half of the patients:
• Partially cystic nodules with eccentric solid areas Damaged thyroid follicular cells from activated
• Solid isoechoic or hyperechoic nodules “low cytotoxic T lymphocytes → release of large
risk” amounts of T4 and T3
• Solid hypoechoic nodules with smooth margins • Triphasic disease: hyperthyroidism →
“intermediate risk” hypothyroidism → euthyroidism
• Solid hypoechoic nodules with one or more of the Diagnosis:
following features: “high risk”
o Irregular margins • Because most patients present in the initial phase,
o Microcalcifications they have high T4 and low TSH levels
o Rim calcifications • Elevated ESR and CRP
o Extrathyroid extension • Decreased radioactive iodine uptake
o Suspicious lymph nodes
Treatment
• Benign or very low risk nodules should be put
under-surveillance
• Fine-needle aspiration findings of follicular
neoplasia are an indication for surgery
• Other malignant findings are an indication for
surgery
Surgical treatment of differentiated thyroid cancer:
• Small unilateral thyroid cancer with no Figure 95: Subacute granulomatous thyroiditis.
hematogenous or lymphatic spread → lobectomy Microscopic examination showing a granuloma. Source:
• Larger tumors with no metastasis or local https://en.wikipedia.org/wiki/De_Quervain%27s_thyroiditi
extension → total thyroidectomy s#/media/File:Subacute_thyroiditis_-_intermed_mag.jpg
• Evidence of lymph node metastasis → total
thyroidectomy with lymph node dissection Treatment:
• Radioactive iodine as adjuvant treatment in
selected patients • NSAIDs
Undifferentiated thyroid cancer is usually fatal. • If no improvement in pain in one week, consider
steroids “prednisolone”
Thyroiditis Subacute Lymphocytic Thyroiditis
Definition Definition:
Thyroiditis, as the name implies, is the inflammation of the
thyroid gland which can have viral, autoimmune or An autoimmune disease where the thyroid gland is
unknown causes. It can be painful or painless. Most of infiltrated by lymphocytes. Also known as silent sporadic
them present with transient thyrotoxicosis followed by thyroiditis or painless sporadic thyroiditis.
hypothyroidism.
• 4:1 female to male ratio

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 • On histopathological examination, the picture is
similar to postpartum thyroiditis, see Figure 2
Clinical features:

• Small painless goiter

• Triphasic disease: hyperthyroidism →
hypothyroidism → euthyroidism
Diagnosis:
Figure 97: Riedel's thyroiditis. Extensive fibrosis. Source:
• Half of the patients have antithyroid peroxidase https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996929/
antibodies
• Low or absent radioactive iodine uptake Treatment:

• Surgery to relieve pressure symptoms

• Levothyroxine after thyroidectomy
Primary Hyperparathyroidism
Definition:
Primary hyperparathyroidism is the excessive secretion of
parathyroid hormone from one or more of the four
parathyroid glands. The classic disorder is associated with
Figure 96: Subacute lymphocytic thyroiditis. Source: hypercalcemia.
https://www.pathologystudent.com/lymphocytic-
thyroiditis/ Epidemiology:
• Most cases of primary hyperparathyroidism are
Treatment: incidentally diagnosed by biochemical testing in
the United States
• Beta-blockers for symptomatic control of • More common in African Americans
hyperthyroidism • 2:1 female to male ratio
• Levothyroxine when the patient enters the • Incidence is from 81 to 92 per 100,000 per year
hypothyroidism phase Pathophysiology:
Riedel’s Thyroiditis:
Definition:
A rare condition that is also known as fibrous thyroiditis.
Extensive fibrotic changes of unknown etiology of the
thyroid gland and adjacent structures. Figure 98: Causes of primary hyperparathyroidism from
left to right: parathyroid adenoma, parathyroid hyperplasia,
• 4:1 female to male ratio parathyroid carcinoma. Source:
• Most patients are aged between 30 and 60 years https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385896/f
Clinical features: igure/F5/
• Painless rock-hard fixed goiter
• Parathyroid adenoma is the most common cause
• Symptoms of esophageal or tracheal compression
of primary hyperparathyroidism:
• One third of the patients have hypothyroidism o An adenoma of a single parathyroid
Diagnosis: gland
• Positive antithyroid peroxidase antibodies in two o Parathyroid cells are less sensitive to
thirds calcium → increased production of PTH
by individual cells
• Decreased radioactive iodine uptake
• Biopsy for definitive diagnosis, see Figure 3 • Parathyroid hyperplasia involves the four
parathyroid glands:
o The amount of PTH secreted by each
cell is normal
o The number of parathyroid cells is
increased
o The total concentration of PTH is
elevated

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 • Parathyroid carcinoma: hyroid Storm
o A rare cause of primary Definition:
hyperparathyroidism Thyroid storm, also known as thyrotoxic crisis, is a rare
Regardless of the cause, the following pathophysiology condition characterized by an extreme physiological state
occurs: due to severe thyrotoxicosis.

• Hypercalcemia due to the increased mobilization Epidemiology

of calcium from the bone → osteitis fibrosa • Rare
cystica • Very high mortality, can reach 20% despite
• Hypercalciuria → renal stones adequate treatment
• Polyuria due to osmotic diuresis • Most commonly seen in patients with Graves’
• Hypophosphatemia, increased ALP and cAMP in disease
urine Pathophysiology
• Hypercalcemia → neuronal cell damage → • Thyroid storm needs to be precipitated by a
neuropsychiatric disturbances specific cause:
Osteitis fibrosa cystica: o Trauma
• Cystic bone spaces form and are filled with o Surgery
brown fibrous tissue o MI
• Consists of osteoclasts and hemosiderin deposits o Diabetic ketoacidosis
• Hemosiderin deposits occur due to hemorrhage o Pregnancy
• Caused by hyperparathyroidism o Iodinated contrast agents
Clinical Findings o Amiodarone
o Abrupt cessation of antithyroid drugs
• Bone pain due to osteitis fibrosa cystica
• Thyrotoxicosis is the clinical syndrome that
• Abdominal pain due to pancreatitis
occurs when tissues are exposed to high levels of
• Flank pain due to kidney stones
circulating thyroid hormone
• Constipation
• Thyrotoxicosis → increased oxygen consumption
• Neuropsychiatric disturbances and hypermetabolism → increased sympathetic
• Polyuria nervous system activity
Diagnosis:
• Thyrotoxicosis might also lead to an increased
• Elevated parathyroid hormone number of beta1-adrenergic receptors
• Hypercalcemia Clinical Findings
• Hypophosphatemia • High-grade fever
• Hypercalciuria • Cardiovascular dysfunction:
• Very high chloride to phosphate ratio o Tachycardia (> 130 beats/min)
• Radiograph: o Congestive heart failure
o Subperiosteal resorption o Pulmonary edema
o 2nd and 3rd phalanges most commonly o Atrial fibrillation
Treatment: • Central nervous system dysfunction:
• Parathyroid adenoma o Agitation
o Surgical removal of the adenoma o Delirium
• Parathyroid hyperplasia o Psychosis
o All parathyroid glands are removed, and o Extreme lethargy – coma
one of them is implanted back in the o Seizures
muscle • Gastrointestinal and hepatic dysfunction:
• Medical treatment: o Diarrhea
o IV fluids o Nausea and vomiting
o Furosemide which is a loop diuretic o Jaundice
o Thiazide diuretics are to be avoided → • Some patients have a previous history of a
can cause hypercalcemia thyroid storm
o Bisphosphonates Diagnosis
• Very high T3 or T4
• Suppressed TSH
• Other diagnostic tests to identify the etiology
Treatment:

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 • The patient should be admitted to the intensive • IGF-1 is synthesized by the liver
care unit • When the growth plates are closed as in adults,
• Initiate ABCDE elevated IGF-1 levels result in the following
• Initiate appropriate intravenous fluid resuscitation changes:
• Antipyretics, but avoid aspirin → displaces o Large hands and feet
thyroxine from thyroid binding globulin o Prominent jaw and forehead
• Initiate the five “Bs” thyroid-specific therapy • When the growth plates are still open, as in
Block synthesis: children, elevated IGF-1 levels result in
• Propylthiouracil or carbimazole gigantism:
• To prevent formation of further thyroid hormones o Linear increase in size “getting taller”
• The metabolic dysfunctions seen in patients with
Block release: acromegaly are also related to the elevated IGF-1
• Iodine, should be administered 1 hour after the levels:
first step o IGF-1 competes with insulin for insulin
receptor → insulin resistance and
Block T4 to T3 conversion: diabetes mellitus
• Propylthiouracil, propranolol, and corticosteroid o Somatic hypertrophy of body organs
such as macroglossia, acromegalic
Beta-blockers: heart, large kidneys, and bulky skeletal
• Propranolol muscles → could be related to the
binding of IGF-1 to IGF-1 receptor
Block enterohepatic circulation: tyrosine kinase which activates the AKT
pathway → somatic cell growth and
• Cholestyramine
proliferation
Clinical Findings
Acromegaly
Symptoms:
Definition
• Acromegaly is a disorder caused by the excessive • Hypertrophic arthropathy → joint pain
production of growth hormone from the anterior • Carpal tunnel syndrome → wrist pain and
pituitary gland. This results in excessive growth numbness
of body tissues along with other metabolic • Macroglossia → sleep apnea and snoring
dysfunctions. • Compression of the optic chiasm by the pituitary
Epidemiology adenoma → visual disturbances (bitemporal
• The estimated prevalence is 4600 per one million. hemianopia)
The incidence of acromegaly is 116.9 per one • Headaches
million per year. • Erectile dysfunction
• The mean age at diagnosis for men is 40 years, • Hyperhidrosis
whereas for women it is 45 years. Signs:
Pathophysiology • Coarse facial features such as prominent
Etiology: forehead, brow and prognathism, see Figure 1
• Large tongue with widely spaced dentition
• In 95% of the cases, the cause of excessive • Bitemporal hemianopsia on visual field
growth hormone production is a pituitary examination
microadenoma • Acromegalic cardiomyopathy → HF → elevated
• Adrenal, lungs and pancreas tumors can also JVP
cause acromegaly in a minority of patients by • Thick skin, skin tags, hirsutism, and acanthosis
releasing growth hormone or growth hormone nigricans
releasing hormone • Symptoms and signs of HF
• The excessive growth of tissues is mediated by • Large hands with stubby fingers
elevated levels of insulin-like growth factor-1 in • Proximal myopathy
response to the elevated levels of growth
• Genu varum
hormone
• Hypertension
Pathophysiology:
• Increased risk of colorectal polyps and cancer
• The effects of growth hormone are mediated by
insulin-like growth factor-1 IGF-1

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 • Urine osmolality < 300 mOsm/L
• Water intake up to 20 L/day
Epidemiology
• Rare with a prevalence of 1 per 25,000
• Equal occurrence in males and females
• 10% are hereditary
Figure 99: Facial features in a patient with acromegaly. • X-linked nephrogenic DI accounts for 90% of
Compare to the baseline. Source: cases of hereditary DI
https://en.wikipedia.org/wiki/Acromegaly#/media/File:Acr • Central ID is more common than nephrogenic DI
omegaly_facial_features.JPEG Pathophysiology
Central DI:
Diagnosis:
• Increased IGF-1 •
Inadequate synthesis and release of arginine
• Failure to suppress GH after oral glucose vasopressin (AVP)
tolerance test • Secondary to surgery or traumatic brain injury
• A pituitary mass on brain MRI that involves the hypothalamus or posterior
GH suppression test: pituitary gland → destruction of neurons in the
• Administer 100 grams of glucose supraoptic and paraventricular nuclei of the
• Measure GH levels after one hour hypothalamus
• Should be < 5 ng/ml to exclude acromegaly • Becomes symptomatic when more than 80% of
Growth-hormone-releasing-hormone: the neurons are lost
• Elevated levels > 300 ng/ml → extra-pituitary • Other causes include autoimmune disease,
acromegaly pituitary adenomas, and ischemic encephalopathy
Treatment: Nephrogenic DI:
Surgical:
• Failure of the kidneys to respond to AVP
• If the cause of acromegaly is a microadenoma →
endonasal transsphenoidal or trans-nasal • Urine production can be as high as 12 L per day
transsphenoidal microscopic surgery • Inherited in children, and acquired in adults
• Usually curative • Inherited nephrogenic DI is caused by an X-
Medical: linked loss-of-function mutation in the V2R gene
o V2R is expressed mainly in the distal
• If the patient is not cured after surgery or if
surgery is not an option convoluted tubule and collecting tubes
o Responds to AVP by concentrating the
• Somatostatin analogs such as octreotide → act on
urine
somatostatin receptors → inhibition of growth
hormone secretion • Can be drug-induced:
o Demeclocycline, lithium, cisplatin and
• Dopamine receptor agonists such as cabergoline
methoxyflurane
or bromocriptine → can lower GH levels but are
inferior to somatostatin analogs • Also seen in patients with sickle-cell disease,
hypercalcemia, hypokalemia, multiple myeloma,
• GH-receptor antagonist (pegvisomant) → blocks
Sjogren’s disease and amyloidosis
growth hormone receptors in the liver →
The following table shows the main differences between
decreases IGF-1 levels – remember, acromegaly
central and nephrogenic DI.
features are mediated by IGF-1
Note: Most common cause of death Central DI Nephrogenic DI
in acromegaly is heart failure due to causes - Pituitary adenoma - Hereditary
- TBI or surgery - Acquired due
acromegalic cardiomyopathy. - Ischemic to drugs or
encephalopathy infiltrative
Diabetes Insipidus: diseases
AVP or ADH - Low - Normal or high
Definition: levels
Diabetes insipidus (DI) is a group of hereditary and Desmopressin test - Shows response - No response
acquired polyuria and polydipsia diseases. They are
characterized by inadequate arginine vasopressin secretion Clinical Findings
or renal response to AVP. They lead to hypotonic polyuria, • Polyuria, polydipsia and nocturia – classical
and increased thirst. symptoms of DI

• Urine output > 50 mL/kg

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 • Polyuria is urine output > 3 L/day in adults and • Adequate hydration
2L/m2 in children Nephrogenic DI:
• Severe dehydration, fevers, irritability, and
growth retardation in children • Thiazide diuretics → inhibits Na/Cl co-
• If the cause is a CNS tumor: transporter → natriuresis → decreased plasma
o Headaches sodium → activation of RAAS → aldosterone
o Visual defects induces water and sodium retention
• Weakness, lethargy and fatigue • Indapamide → increases proximal tubular water
• Should be differentiated from primary polydipsia reabsorption
and uncontrolled diabetes mellitus • Indomethacin → an NSAID with antidiuretic
Diagnosis: activity
The following diagnostic algorithm can be used when • Amiloride → blockade of ENaC → reduced
approaching a patient with diabetes insipidus. The goal is lithium-induced down-regulation of AQP2 and
to differentiate between central and nephrogenic DI. protects cellular composition of the collecting
duct
• Hydration
Classical symptoms of DI • Discontinuation of the causative drug
SIADH
Definition:
Syndrome of inappropriate antidiuretic hormone secretion
24-hour urine output: (SIADH) consists of hyponatremia, elevated urine
> 50 mL/kg osmolality, excessive urine sodium, and decreased serum
osmolality in an euvolemic patient without edema. Patients
must not be receiving diuretic treatment and must have
No: Consider other
Yes: Order plasma Na, normal cardiac, renal, adrenal, hepatic and thyroid
plasma osmolality and
diagnoses
urine osmolality tests function.

Pathophysiology:
Plasma Na > 143 mEq/L Plasma Na < 143 mEq/L Normal physiology:
Posm > 295 mOsm/kg Posm < 295 mOsm/kg
Uosm < Posm Uosm < Posm
• The supraoptic nuclei of the hypothalamus are
responsible for the production of ADH
Desmopressin test Water deprivation test
• Osmoreceptors located near the nuclei control
Response = CDI No response, go to ADH secretion
•
No response = NDI desmopressin test
When plasma osmolality increases →
osmoreceptors shrink → increased ADH
• The most important tests are 24-hour urine secretion
output, plasma Na and osmolality, urine • Baroreceptors in the aortic arch and carotid sinus
osmolality and water deprivation test sense decreased blood volume/pressure →
• Patients with DI should show no response to increases ADH secretion
water deprivation test, unlike primary polydipsia Etiology:
• Desmopressin test is the last step in the diagnostic • Drugs: MAO inhibitors, and cyclophosphamide
approach and aims to differentiate between CDI
• CNS disorders including stroke, trauma,
and NDI
infection, and hemorrhage
• A more than 50% increase in urine osmolality is
• Malignancies especially small cell carcinoma →
the definition of response in desmopressin test
ectopic ADH production
• Urine specific gravity < 1.006
• Pneumonia, asthma, and atelectasis can cause
Treatment:
SIADH by unknown mechanisms
Central DI:
• Abdominal and thoracic surgery
• Carbamazepine → increases the release of • Iatrogenic “excessive use of desmopressin or
vasopressin from the pituitary gland oxytocin”
• Chlorpropamide → increases the release of Pathophysiology:
vasopressin from the pituitary gland
• Desmopressin

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 • Increased ADH production despite low plasma Treatment
osmolality → increased free-water retention → Patients who are asymptomatic or who have mild
dilutional hyponatremia → increased sodium symptoms of hyponatremia should receive the following
secretion and normalization of extracellular fluid treatments:
volume → euvolemic hyponatremia
• Severe hyponatremia → cerebral edema and • Conivaptan or tolvaptan “V2R receptor
seizures antagonists”, OR
• Rapid correction of hyponatremia → osmotic • Conventional treatment of SIADH:
demyelination syndrome “central pontine o Fluid restriction
myelinolysis” o Diuretics
o Demeclocycline
Clinical Findings: o Maybe normal saline
• The cause of SIADH can be recognized from • Rapid correction is NOT acceptable because most
history and physical examination patients have chronic hyponatremia → can result
• Mild hyponatremia: in osmotic demyelination syndrome
o Headache Patients with advanced symptoms of hyponatremia should
o Lethargy receive the following treatments:
o Slowness
o Nausea • Conivaptan or tolvaptan + 3% saline
o Ataxia Patients with grave symptoms should receive 3% saline:
o Muscle cramps
o Tremors • Rapid correction is acceptable because most
• Advanced hyponatremia: patients have acute hyponatremia.
o Confusion Introduction to Diabetes Mellitus
o Disorientation Definition:
o Vomiting Diabetes mellitus (DM) is a group of metabolic disorders
o Hallucinations characterized by chronic hyperglycemia due to impaired
o Limb weakness insulin secretion, action, or both. DM is a multisystemic
o Dysarthria disease that affects all body organs. The clinical
o Acute psychosis presentation of the patient is dependent on the duration of
• Grave hyponatremia: DM, type of DM and severity of hyperglycemia.
o Seizures
Classification:
o Hemiplegia
The following table summarizes the main characteristics of
o Respiratory depression
DM type 1 and type 2.
o Coma
o Death DM Type 1 dm type 2
Other names - Insulin- - Insulin-independent
Diagnosis dependent DM DM
Bartter and Schwartz diagnostic criteria of SIADH are as Prevalence - 5% of all DM - 90% of all DM
- MODY, drug-
the following: induced, disease of
exocrine pancreas
• Plasma osmolality < 275 mOsm/kg and genetic
syndromes account
• Urine osmolality > 100 mOsm/kg | but usually for the remainder
higher than plasma osmolality 10%
• Euvolemic Genetic - Weak (50% - Strong (90%
predisposition concordance in concordance in
• Urine sodium excretion > 20 mEq/L monozygotic monozygotic twins)
• Plasma sodium < 135 mEq/L twins)
age of onset - Typically, - > 40 years (but can
• Euthyroidism, normal cortisol levels, and no children also occur in
diuretic use children)
Further diagnostic workup is tailored to the specific or body habitat - Thin - Obese or overweight
pathogenesis - Absolute insulin - Insulin resistance
suspected cause of SIADH. Brain CT for example can be deficiency - Down regulation of
ordered to exclude acute intracerebral hemorrhage. - Autoimmune insulin receptors
destruction of β- - Hyperinsulinemia
cells of islets of early in the disease
Langerhans in - Eventually,
the pancreas hypoinsulinemia
occurs → patients

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 - Associated with become insulin- HbA1c:
HLA-DR3 and dependent
DR4 - Islet amyloid • > 6.5% → diagnostic of DM | reflects average
- Can be polypeptide deposits blood glucose over last three months
idiopathic or of 2-hour oral glucose tolerance test:
unknown cause
- Islet leukocytic • The patient consumes 75 grams of glucose in
infiltrate water
typical - DKA - Asymptomatic
presentation - Polyurea, - Incidental • Blood sugar is measured 2 hours later
polydipsia, hyperglycemia • If > 200 mg/dL → diagnostic of DM
polyphagia and - Presenting with DM
weight loss complications
Treatment:
Complications: DM type 1:
Acute DM complications: • Insulin
• Diabetic ketoacidosis can be the presenting DM type 2:
picture in type 1 DM • Diet and exercise
• Hyperosmolar hyperglycemic state can occur in • Manage obesity
type 2 DM. It carries high mortality
• Oral hypoglycemic agents are first-line treatment
Chronic DM complications:
o Metformin is 1st-line:
• Small vessel disease due to nonenzymatic ▪ Increases insulin sensitivity
glycation changes: ▪ Can cause lactic acidosis in
o Diffuse thickening of basement patients with renal disease
membrane especially when serum Cr >
o Retinopathy: hemorrhages, exudates, 1.5 mg/dL
microaneurysms, and vessel ▪ Help patients lose weight
proliferation o Sulphonylureas are 2nd-line:
o Glaucoma ▪ Glyburide, glipizide, and
o Neuropathy glimepiride
o Nephropathy in the form of nodular ▪ Increase insulin production by
glomerulosclerosis → progressive the pancreas by binding to K
proteinuria that starts with channels on beta-cell
microalbuminuria – ACE inhibitors are membranes
renoprotective ▪ Can cause hypoglycemia and
o Arteriolosclerosis → hypertension weight gain
• Large vessel atherosclerosis → CAD, PAD → MI o Thiazolidinediones are 3rd-line:
and gangrene respectively ▪ Reduce insulin resistance
▪ Hepatotoxic → baseline liver
• Osmotic damage:
function tests are indicated
o Increased sorbitol accumulation in
before starting them
organs
o Increased aldose reductase activity with • Insulin might be needed in some patients
decreased sorbitol dehydrogenase Diabetic Ketoacidosis
activity Definition:
o Responsible for peripheral diabetic Diabetic ketoacidosis is an acute complication of diabetes
neuropathy and autonomic diabetic mellitus. It is more commonly seen in patients with type 1
neuropathy DM. Patients present with hyperglycemia, ketosis,
o Also responsible for cataracts acidosis, and dehydration. It is due to absolute insulin
Diagnosis: deficiency in addition to increased levels of the
counterregulatory hormones.
• Normal blood glucose level is 70 to 100 mg/dL
Fasting blood glucose: Pathophysiology:
• Patient is instructed to fast for eight hours • DKA occurs in patients with absolute insulin
overnight deficiency, which explains why it is more
• If > 126 mg/dL → diagnostic of DM common in type 1 DM than in type 2 DM
Random blood glucose: • It is often triggered by one of the following
• If > 200 mg/dL in a patient with polyuria, causes:
polydipsia and polyphagia → diagnostic of DM o Drugs:
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 ▪ Antipsychotics Clinical Findings:
▪ Illicit drugs and alcohol • Most patients present with polyuria and
▪ Corticosteroids, glucagon, polydipsia
pentamidine, • Weight loss, fatigue, dyspnea, vomiting, a
sympathomimetics, and preceding febrile illness, abdominal pain and
thiazide diuretics polyphagia are also common presenting features
o Infection: • Dehydration:
▪ Pneumonia o Tachycardia
▪ Sepsis o Poor skin turgor
▪ Urinary tract infections o Dry mucous membranes
o Lack of insulin due to insulin pump o Orthostatic hypotension
failure, nonadherence to insulin therapy, • Metabolic acidosis:
or new-onset type 1 DM o Deep Kussmaul respirations
o Other causes include myocardial o Fruity smell due to increased acetone
infarction, shock, trauma, arterial • Mental status alterations which can range from
thrombosis, cerebrovascular accident, lethargy to coma
Cushing’s syndrome, or • Symptoms and signs of the precipitating factor
hemochromatosis Diagnosis:
• These stressors elevate the levels of the • Patients with diabetic ketoacidosis have an
counterregulatory hormones (glucagon, increased anion gap metabolic acidosis. The
catecholamines, cortisol and growth hormone) following table summarizes the suspected
• Because of the insulin deficiency, peripheral laboratory findings in mild and severe DKA
tissues are unable to uptake and utilize glucose Mild DKA Severe DKA
for energy production → other sources of energy Anion gap > 10 mEq/L > 12 mEq/L
arterial ph < 7.30 < 7.00
production need to be used serum osmolality Increased Increased
• First source is lipolysis: mental status Alert Coma
o Increased lipolysis elevates free fatty bicarb < 15 mEq/L < 10 mEq/L
serum ketone Positive Positive
acid levels in the blood urine ketone Positive Positive
o They will be converted to acetyl co-
enzyme A and some of this will be • Serum glucose is > 250 mg/dL
utilized by the Krebs’s cycle for energy • Hyperkalemia due to potassium shift to the
production extracellular compartment → total body
o The remainder will be broken down into potassium is depleted
ketone bodies (acetone, acetoacetate, • Nitroprusside agents are used to measure serum
and beta-hydroxybutyrate) ketones
o While some of these ketones can be also • Order tests according to the suspected etiology:
used for energy, they start accumulating o ECG to exclude MI
rapidly → ketosis o Chest radiography
• Decreased glucose utilization and increased o Serum lipase and amylase
proteolysis: o Serum troponin
o Substrates for gluconeogenesis are o Urine and blood cultures
increased • Pseudohyponatremia. Use the following equation
o Increased liver production of glucose by to calculate corrected serum sodium:
gluconeogenesis and glycogenolysis Corrected Na
o This results in hyperglycemia = Measured Na + 0.016 (Measured glucose − 100)
o Glucosuria occurs which results in
osmotic diuresis Treatment:
o Water drags electrolytes with it → • The treatment algorithm of DKA is too
dehydration and eventually impaired complicated at the level of USMLE Step 1
renal function • The principles of DKA treatment are as follows:
• Dehydration → increased lactate level → acidosis o Patients are dehydrated → IV fluids
 ketosis with half normal saline or normal saline
• Dehydration → hyperosmolality depending on the corrected serum Na
level

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 o Patients are in absolute insulin Pathophysiology:
deficiency → start insulin replacement • HHS occurs in patients with relative insulin
therapy after 2 hours of initiation of IV deficiency (type 2 DM) who have limited ability
fluids to drink water
o Potassium supplementation: • It is often triggered by one of the following
▪ If < 3.3 mEq/L → hold insulin causes:
and administer K o Drugs:
▪ If > 5.2 mEql/L → keep ▪ CCBs
monitoring and do not give K ▪ Phenytoin
▪ If in between → keep insulin ▪ Antipsychotics
and administer K ▪ Illicit drugs and alcohol
o Bicarb only in selected patients: ▪ Corticosteroids, glucagon,
▪ Indicated if pH < 6.9 pentamidine,
DKA complications: sympathomimetics, and
thiazide diuretics
• Cerebral edema which occurs in 1% of DKA o Infection:
patients and carried a 24% mortality rate ▪ Pneumonia
o Survivals usually have permanent ▪ Sepsis
neurological sequalae ▪ Urinary tract infections
o Occurs more often in children o Other causes include myocardial
o Risk factors include severe acidosis, low infarction, shock, trauma, arterial
initial bicarb, hyponatremia, severe thrombosis, cerebrovascular accident,
hyperglycemia, rapid hydration, and Cushing’s syndrome, or
retained fluid in the stomach hemochromatosis
o Patients develop new headache, • These stressors elevate the levels of the
persistent vomiting, hypertension, counterregulatory hormones (glucagon,
tachycardia and lethargy catecholamines, cortisol and growth hormone)
• Hypokalemia • Because of the relative insulin deficiency,
• Acute renal failure peripheral tissues are unable to uptake and utilize
• Shock glucose for energy production → hyperglycemia
• Rhabdomyolysis occurs
• Thrombosis • Protein breakdown is sufficient to produce
• Stroke enough substrates for gluconeogenesis and
• Prolonged QT interval glycogenolysis is activated → hyperglycemia
• Pulmonary edema • The low levels of insulin are enough to suppress
• Decreased cognitive abilities in children lipolysis → no ketosis
Prevention of DKA: • Glucosuria occurs which results in osmotic
diuresis
• Proper diabetes education services to children, • Water drags electrolytes with it → dehydration
adult patients, and caregivers and eventually impaired renal function
• Sick day management where patients are • Dehydration → hyperosmolality → severe
instructed to contact their clinical as early as intracellular water depletion
possible • A transient increase in the levels of
• Backup insulin protocol in patients who use proinflammatory cytokines → a prothrombotic
insulin pumps in case of insulin pump failure environment → increased risk of vascular
• Understand the causes of poor adherence to occlusion, mesenteric artery thrombosis,
insulin therapy and correct them myocardial infarction, DIC, CVA, and bilateral
Hyperosmolar Hyperglycemic State femoral artery thrombosis
Definition:
Hyperosmolar hyperglycemic state (HHS) is a life- Clinical Findings:
threatening emergency characterized by marked • Severe dehydration:
hyperglycemia and hyperosmolarity without ketosis. It o Poor tissue turgor
occurs most commonly in adults with type 2 diabetes. o Dry mucous membranes
Mortality can be as high as 50% (in contrast to DKA where o Sunken eyeballs
mortality rate reaches 9%). o Tachycardia with weak pulse

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 • Mental status alterations which can range from Chronic Complications of DM
lethargy to coma (but coma is more common in Definition
HHS as compared to DKA) The main pathology in diabetes mellitus is pathologic
• Seizures changes in the vasculature leading to microvascular and
• Transient hemiparesis that resolves after adequate macrovascular complications. Long-term hyperglycemia is
fluid replacement known to cause long-term damage and eventually failure of
• Symptoms and signs of the precipitating factor different organ systems such as the eyes, nerves, kidneys
and heart.
Diagnosis:
• Blood glucose > 600 mg/dL Pathophysiology:
• Serum osmolality > 320 mOsm/L • The complications of DM can be classified as
• pH > 7.30 microvascular and macrovascular complications
• Mild or absent ketosis and no ketonuria • They occur spontaneously, and the presence of
• Half of the patients will have mild anion-gap microvascular complications increases the risk of
metabolic acidosis the macrovascular complications
• Significant losses in water and electrolytes: • The microvasculature includes the arterioles,
o Severe losses in water, calcium, capillaries and venules
magnesium, and phosphate • The macrovasculature includes the arteries and
o Milder losses in sodium and potassium veins
DKA HHS
Blood glucose > 250 mg/dL > 600 mg/dL • The pathognomonic changes in the
Anion gap > 12 mEq/L Usually normal microvasculature related to DM are:
arterial ph < 7.30 > 7.30
serum osmolality Increased Markedly increased
o Increased thickness of the basement
mental status Alert – lethargic – Coma membrane in the arterioles of the
coma glomeruli, retina, myocardium, skin and
bicarb < 15 mEq/L > 15 mEq/L
serum ketone Positive Negative muscle
urine ketone Positive Negative o Abnormal regulatory systems of
Mortality rate Up to 9% Up to 50% vascular permeability and BP control
Type of DM most Type 1 DM Type 2 DM
commonly assicated o The clinical consequences are
with hypertension, delayed wound healing
• Order tests according to the suspected etiology: and tissue hypoxia
o ECG to exclude MI o Neovascularization occurs due to tissue
o Chest radiography hypoxia and involves the vasa vasorum
o Serum lipase and amylase of the major arteries
o Serum troponin o This can lead to accelerated
o Urine and blood cultures atherosclerosis → the connection
• Pseudohyponatremia. Use the following equation between microvascular and
to calculate corrected serum sodium: macrovascular complications of DM
Corrected Na • Chronic hyperglycemia → non-enzymatic
= Measured Na + 0.016 (Measured glucose − 100) glycation of amino acids
Macrovascular Complications
Treatment • Coronary artery disease
• Vigorous intravenous rehydration o Myocardial infarction is the most
• Electrolytes’ replacement therapy common cause of death in DM
• Intravenous insulin o Due to accelerated atherosclerosis
• Diagnosis and management of the precipitating • Stroke, usually ischemic
factor • Peripheral artery disease → lower limbs ischemia
• Overhydration → acute respiratory distress • These complications can be delayed by adequate
syndrome and/or cerebral edema glucose control
• Cerebral edema is often fatal o HbA1c reflects blood glucose level
• Mortality is high despite adequate treatment average in the last three months
Treatment of cerebral edema: o Should be < 7% to be considered in
optimum control
• 1 to 2 g per kg mannitol over 30 minutes
Microvascular Complications
Diabetic nephropathy:

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 Diabetic retinopathy:

• DM is the leading cause of blindness in the

developed world
• Can be classified into non-proliferative and
proliferative retinopathy
• Non-proliferative retinopathy:
o Advanced end-glycation products
deposit in the medial arteriolar wall of
the retinal blood vessels
Figure 100: Pathogenesis of diabetic nephropathy. Source: o They become constricted → retinal
https://www.nature.com/articles/nrneph.2013.272/figures/1 ischemia
o The ischemic retina undergoes scarring
• In normal physiology, the basement membrane is o Microaneurysms occur
lined with heparin sulphate → negative charged o Exudates and hemorrhages are more
molecule → propels albumin and limit protein often in later stages of non-proliferative
filtrate → albumin moves from the afferent to the DM retinopathy
efferent arteriole, bypassing filtration o Asymptomatic in the early stages
• In diabetic nephropathy, hyaline deposition o Can become threatening of vision if it
occurs which causes thickening of the basement involves the macula → can result in
membrane and early loss of this negative charge macular edema
→ Kiemosteil Wilson’s nodules • Proliferative retinopathy:
• In addition to the thickening of the basement o Prolonged retinal hypoxia → induction
membrane, the following changes also occur in of angiogenesis → neovascularization
diabetic nephropathy as depicted in Figure 1: o The new blood vessels are fragile and
o Mesangial cell expansion and leaky
proliferation o Can lead to retinal detachment and
o Podocytopathy vitreous hemorrhages
o The deposition of advanced glycation • Panretinal laser coagulation can be used in
end products → increased TGF, VEGF, selected cases. Frequent ocular examinations can
proinflammatory cytokines and detect retinopathy in its earlier stages
oxidative stress • Adequate blood sugar control is important
o Dilation of the afferent arteriole • See lecture Neurology – Diabetic Retinopathy,
o Constriction of the efferent arteriole for more details
• The end result of these changes is increased Diabetic neuropathy:
protein filtration, which is the hallmark of
diabetic nephropathy and impaired regulatory • Chronic hyperglycemia results in the deposition
mechanisms of blood pressure of advanced end-glycation products in the blood
• Microalbuminuria is the first sign seen in diabetic vessels supplying the nerves → nerve ischemia
nephropathy and death
• The GFR is increased early in the disease • Sorbitol deposition → osmotic pathology → also
“because of the afferent arteriolar dilation and nerve dysfunction
efferent arteriolar constriction” • Loss of sensory and vibration sensations → can
• Microalbumin concentration in the urine ranges result in the development of a diabetic foot
between 30 to 300 mg/dL “should be zero” • Paresthesia
• An albumin/creatinine ratio in the urine of > 0.20 • The affected dermatomes become severely
is diagnostic of diabetic nephropathy painful due to extreme sensitivity to touch
• Eventually can progress to macroalbuminuria → • Severe diabetic foot with loss of sensation →
can lead to edema destruction of the small bones of the foot →
• GFR will decrease in the end-stage because of Charcot joint deformity
arteriosclerosis of the afferent arteriole → • The paresthesia follows a stock-glove pattern
hypertension starting distally and progressing proximally
• ACE inhibitors are renoprotective in patients with • Involvement of the autonomic nervous system →
DM → they cause vasodilation of the efferent orthostatic hypotension and syncope
arterioles → limit protein loss in urine

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 • Neurogenic bladder due to damage to the Epidemiology
parasympathetic cholinergic nerves • Most comm neuroendocrine tumor of the
• Gastroparesis due to loss of vagal nerve pancreas
stimulation of the stomach → delayed gastric • Annual incidence is 4 per one million
emptying → can result in hypoglycemia | treated • Most commonly sporadic, but can be associated
with metoclopramide, and erythromycin with multiple endocrine neoplasia type 1 (MEN-
• Impotence due to S2 to S4 nerve disease 1) syndrome
• Peripheral neuropathy responds to gabapentin and • If proper localization is possible → the surgical
duloxetine resection of the tumor is curable
Mononeuropathy in DM: Pathophysiology
• Ulnar nerve palsy → claw-like hand with • Sporadic or associated with MEN-1
inability to flex last two digits • Patients with MEN-1 can also have parathyroid
• Radial nerve palsy → hand drop hyperplasia, anterior pituitary adenomas, and
tumors of the duodenum
• Common perineal nerve palsy → foot drop and
loss of dorsiflexion of the foot • The two-hit hypothesis applies to the MEN gene
Cranial nerve palsies: which is a tumor suppressor gene
• Sporadic insulinomas represent 90% of the cases
• Oculomotor nerve involvement: and are characterized by the following:
o Innervates all ocular muscles except the o Less than 2 cm in size in 90% of the
inferior oblique and lateral rectus cases
o It provides parasympathetic innervation o Solitary in 90% of the cases
to the pupils o Benign in 90% of the cases
o In DM, only motor function is impaired. • Insulinomas in MEN-1 are usually multicentric,
The pupils are spared larger in size and known to recur
• Patients develop diplopia, ptosis and ocular pain • Tumor of the beta pancreatic cells
Other complications: • Over-production of insulin results in
hypoglycemia
• Diabetic foot ulcers due to ischemia and loss of
sensation → can result in gangrene → most Clinical Findings
common cause of below-knee amputation in the • CNS symptoms related to hypoglycemia:
US o Visual disturbances
• Delayed wound healing o Altered mental status
o Coma
• Patients are immunocompromised
o Seizures
Management:
• Autonomic symptoms related to hypoglycemia:
• Regular HbA1c monitoring (should be below o Sweating
7.0%) o Palpitations
• Check for microalbuminuria and prescribe ACE o Tremors
inhibitors • Whipple triad: hypoglycemia, symptoms of
• BUN and creatinine to detect kidney disease hypoglycemia, and resolution of symptoms after
• Regular ocular examination with fundoscopy the normalization of glucose levels
• Annual podiatrist consultation for diabetic foot Diagnosis
management and prevention The following diagnostic criteria can be used to diagnose
• Adequate control of dyslipidemia (LDL < 70 insulinoma:
mg/dL)
• Adequate control of hypertension (< 130/80 • Blood glucose < 50 mg/dL with symptoms of
mmHg) hypoglycemia
Insulinoma: • Relief of symptoms after eating
Definition • Plasma insulin increased
Insulinoma is a rare neuroendocrine tumor that results in • Plasma C-peptide increased (low in exogenous
over-secretion of insulin. Patients present with symptoms insulin over-dose)
of hypoglycemia. • Plasma proinsulin increased (low in exogenous
insulin over-dose)
• Negative toxicology screen for sulfonylureas

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Localization is important and is achieved with: • Patients diagnosed with ZES should undergo
further testing to exclude MEN-1
• Intraoperative direct visualization → gold- • CT and MRI for localization of the tumor
standard • Somatostatin receptor scintigraphy is the imaging
• CT or MRI preoperatively of choice
• Intraoperative ultrasonography (100% sensitivity) Treatment
Treatment Medical:
Surgical:
• Histamine-2 receptor blockers
• Tumor resection is curative • Proton-pump inhibitors
Zollinger-Ellison Syndrome • PPIs bind to H/K/ATPase at the luminal aspect of
Definition the gastric parietal cell → interferes with gastric
Zollinger-Ellison Syndrome (ZES) is an endocrinopathy acid secretion
that is characterized by gastrin-secreting tumors that result • Medical treatment is highly effective nowadays
in multiple, refractory and recurrent peptic ulcers of the → surgery is reserved for tumor resection and not
distal duodenum and proximal jejunum. due to peptic ulcer disease complications
Surgical:
Epidemiology
• Annual incidence is from 0.1 to 3 new cases per • Tumor resection not peptic ulcer disease oriented
one million MEN Syndromes
• Slight female predominance Definition:
• Most gastrinomas occur in patients aged between Multiple endocrine neoplasia (MEN) syndromes as the
20 and 50 years name implies are characterized by the presence of multiple
endocrine benign and malignant tumors due to a genetic
Pathophysiology mutation.
• 80% of the cases are sporadic
• 20% associated with MEN-1 MEN Type 1:
• Gastrinomas are derived from the enteroendocrine Overview:
cells and can be found in the pancreas or proximal • Also known as Werner’s syndrome
small intestine
• Tumors in the following endocrine glands:
• They are considered as well-differentiated o Parathyroid glands hyperplasia affecting
neuroendocrine tumors four glands
• Gastrinomas of the pancreas are more likely to be o Anterior pituitary adenoma
malignant o Pancreatic endocrine tumors
• Increased production of gastrin → trophic changes (insulinoma, gastrinomas,
in the parietal cells of the gastric antrum → glucagonoma)
hypersecretion of acid → large and multiple o Fore-gut carcinoid
medically refractory peptic ulcers of the distal • Cause:
duodenum and proximal jejunum o Mutation in the tumor suppressor gene
• They can also occur in the cystic duct, 2nd and 3rd MEN1 located on chromosome 11q13
portions of the duodenum, and the neck of the o MEN1 produces menin
pancreas Routine screening:
Clinical Findings: • Parathyroid hyperplasia which becomes clinically
• Abdominal pain due to peptic ulcer disease apparent at the age of 8 years:
• Diarrhea o Annual serum Ca and PTH
• Gastrinoma which occurs after 20 years of age:
Diagnosis annual serum gastrin
• Elevated fasting gastrin levels → pH of the • Insulinoma which can occur after 5 years of age:
stomach must be measured to exclude insulin levels
achlorhydria as the cause of gastrinemia • Anterior pituitary adenoma which can occur after
• Gastrin levels remain elevated despite the 5 years of age: brain MRI every three years
administration of secretin in secretin inhibitory • Foregut carcinoid which is often seen in those
test older than 20 years: CT scans every three years

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MEN Type 2A: • Carcinoid syndrome cannot occur if the tumor is
Overview: confined to the GI tract → active amines and
polypeptides are metabolized by the liver
• Also known as Sipple’s syndrome • Once metastasis occurs → the metastatic tumor
• Mutations in RET gene on chromosome 10q11.2 cells release serotonin and other active
• Parathyroid hyperplasia affecting one or two polypeptides directly into the blood stream →
glands carcinoid syndrome
• Medullary thyroid carcinoma – typically in • The most commonly released active amines and
patients aged 15 to 20 years peptides in carcinoid syndrome include serotonin,
• Pheochromocytoma histamine, kallikrein, and prostaglandins
• Prophylactic thyroidectomy is indicated • Most of the symptoms of carcinoid syndrome are
• Therapeutic thyroidectomy in patients with due to the secretion of serotonin
medullary thyroid carcinoma • Serotonin increases the motility and secretions of
MEN Type 2B: the GI tract → diarrhea
Overview: • Most of dietary tryptophan is directed for
serotonin synthesis → niacin deficiency
• Mutations in RET gene on chromosome 10q11.2 • Niacin deficiency → Pellagra: dermatitis,
• Pheochromocytoma dementia and diarrhea
• Mucosal neuromas in the tongue, lips and eyelids • Prostaglandins also increase GI motility →
• Associated with marfanoid habitus diarrhea
• Earliest onset of medullary thyroid carcinoma and • Rule of 1/3s:
most aggressive form of the disease o One third metastasize
• Prophylactic thyroidectomy is indicated o One third present with secondary
• Therapeutic thyroidectomy in patients with malignancy
medullary thyroid carcinoma o One third are multiple
Carcinoid Syndrome Clinical Findings
Definition • Diarrhea
Carcinoid syndrome is a group of symptoms caused by the • Cutaneous flushing
systemic release of polypeptides, biogenic amines • Asthmatic wheezing
(serotonin) and prostaglandins from well-differentiated • Right-sided valvular heart disease (tricuspid
neuroendocrine tumors. The term “well-differentiated regurgitation or pulmonic stenosis)
neuroendocrine tumors” refers to what was previously o Limited to the right side because of the
known as “carcinoid tumors”. 10% of well-differentiated breakdown of serotonin by MAO-A in
neuroendocrine tumors result in carcinoid syndrome. the lungs
• Pellagra
Etiology: Diagnosis
• Most commonly due to well-differentiated • Elevated 24-hour urine 5-hydroxyindoleacetic
neuroendocrine tumors of midgut that metastasize acid levels (metabolite from serotonin
to the liver breakdown)
• 68% of the tumors arise from the GI tract • Elevated chromogranin A levels
• 28% arise from the respiratory tract • Synaptophysin – a neuroendocrine tumor marker
• The remainder arise from the ovaries, testicles Treatment
and kidneys Medical:
Epidemiology
• Well-differentiated neuroendocrine tumors are • Somatostatin analogs such as octreotide and
rare lanreotide → inhibit the release of all GI
• Carcinoid syndrome is even rarer (10% of the endocrine hormones including those produced by
well-differentiated neuroendocrine tumors result well-differentiated neuroendocrine tumors
in carcinoid syndrome) • Provide symptoms’ relief in up to 70% of the
• The median age of diagnosis is between 55 and patients
60 years Surgical:
Pathophysiology
• The tumor can be resected if well-localized

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 • Curative in early well-differentiated non- o Nausea and vomiting
metastatic neuroendocrine tumors of the o Increased ICP
respiratory tract Diagnosis
Pituitary Adenoma • The goal of the diagnostic workup is to exclude
Definition: other causes of hyperprolactinemia and confirm
Pituitary adenomas are tumors of the pituitary gland which the presence of a pituitary micro or
are important to study and recognize because they can macroadenoma
hyper-secrete hormones or cause mass effects. • History, examination, and measurement of
A microadenoma is less than 10 mm in diameter. A
thyrotropin levels are indicated to exclude other
macroadenoma is 10 mm or more. A giant adenoma is 40
causes of hyperprolactinemia
mm or more.
• The causes of hyperprolactinemia are:
o Prolactinomas
Epidemiology
o Acromegaly
• The estimated prevalence of pituitary adenomas o Cushing disease
is 1 in 1000 o Hypothalamic disease → loss of
• They are found in 10% of the general population dopamine inhibitory effects
in disease-free people o Medications such as antipsychotics
• Most pituitary adenomas are benign tumors o Pregnancy
• Two-thirds of them secrete excess hormones o Hypothyroidism
• 50% of them are prolactinomas o Chronic kidney disease
• Macroadenomas can cause hypopituitarism o Cirrhosis
• 50% of pituitary adenomas are macroadenomas o Adrenal insufficiency
Epidemiology of prolactinomas: • Prolactin levels > 200 µg/L are almost always
caused by a prolactinoma
• 50% of all pituitary adenomas • MRI is the imaging modality of choice to confirm
• Most frequently in women aged 20 to 50 years the presence of a prolactinoma (90% of them are
Pathophysiology microadenomas)
• The pathogenesis and etiology of pituitary
adenomas are poorly understood
• Prolactin secretion is inhibited by the
neurotransmitter dopamine coming from the
hypothalamus
• Accordingly, most medications used in the
treatment of hyperprolactinemia in pituitary
adenoma are dopamine agonists
• The elevated prolactin levels suppress the
hypothalamic-pituitary-gonadal axis → decreased
libido, infertility and osteoporosis
Figure 101: A pituitary microadenoma (diameter less than
Clinical Findings
10 mm). Source: 10.1001/jama.2016.19699
• The symptoms of pituitary adenomas can be due
to the excess hormone release “mainly prolactin”
or the mass effects of a macroadenoma Treatment
Medical:
• The inhibition of the hypothalamic-pituitary-
gonadal axis results in the following symptoms • Dopamine agonists such as cabergoline and
and signs: bromocriptine
o Decreased libido • Oral contraceptives for those who do not wish to
o Infertility conceive
o Osteoporosis Surgical:
o Oligomenorrhea or amenorrhea
o Galactorrhea • Transsphenoidal surgery can achieve
o Erectile dysfunction normalization of prolactin in 85% of patients with
• The mass effects of macroadenomas include: microadenomas
o Visual disturbances
o Headache

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 • The results are not very good in macroadenomas • The migration course of the thyroid gland starts at
where normalization can be achieved only in 40% the foramen cecum at the base of the tongue,
of patients loops around the hyoid bone anteriorly and
• The recurrence rate within 10 years after surgery inferiorly, and descends anteriorly to the
for macroadenomas is 20% thyrohyoid membrane to reach the final
• Accordingly, the achievement of normalization of infrahyoid location in the neck
prolactin levels with dopamine agonists is first- • Ectopic thyroid tissue can be found in any of
line treatment these locations that the developing thyroid gland
Thyroid Development and Developmental Abnormalities needs to migrate through:
Thyroid Gland Development o The base of the tongue which is the
• The thyroid diverticulum arises in the floor of the most common site. It is known as a
primitive pharynx lingual thyroid. Its removal can result in
• It descends into the neck hypothyroidism if it is the only thyroid
• During embryogenesis, the thyroid gland is tissue the child has
connected to the tongue by the thyroglossal duct o Adjacent to the hyoid bone
• The thyroglossal duct normally disappears or o Midline in the infrahyoid portion of the
form the pyramidal lobe of the thyroid neck
• The foramen cecum is the normal remnant of the o Rarely, the lateral part of the neck
thyroglossal duct Hemiagenesis of the Thyroid Gland
Thyroglossal Duct Cysts • Failure of development of one thyroidal bud
• The most common developmental anomaly of the • Accounts for 0.1% of thyroidal developmental
thyroid anomalies
• It is the most common cause of a midline cervical • The most commonly absent lobe is the left one
mass in children younger than 5 years • It is often incidentally diagnosed on thyroid
• The thyroglossal duct connects the thyroid gland scintigraphy or ultrasonography where half of the
to the tuberculum impar and is supposed to thyroid gland is found to be missing
involute after the 5th embryonal week
• Failure to involute results in a persistent
thyroglossal duct, thyroglossal duct remnants or
thyroglossal duct cysts
• They are usually found at the level of the hyoid
bone in the thyro-hyoid location
• Papillary thyroid carcinoma can arise from a
thyroglossal duct cyst
• The mass moves with swallowing or protrusion of
the tongue

Figure 102: A thyroglossal duct cyst. Source:

https://en.wikipedia.org/wiki/Persistent_thyroglossal_duct#
/media/File:Thyreoglossal_duct_cyst.jpg

Ectopic Thyroid Tissue:

• This is a rare entity
• It results from defects in the early stages of
thyroid embryogenesis

370
 Chapter 9:

Gastroenterology

371
Embryology and Anatomy of the GI Tract • Dilatation of these veins → external hemorrhoids
Embryology: which are painful
• The gastrointestinal tract is very long • Anal fissures are tears in the anal mucosa below
• For it to be confined in the small abdominal the pectinate line:
cavity, a lot of developmental steps that involve o Blood streaks on toilet paper
herniation, return of midgut and rotation need to o Painful pooping
occur o Mostly are located posteriorly
• At the 6th week, the rapidly growing midgut o Associated with chronic constipation
herniates through the umbilical ring (a and low-fiber diet
physiologic hernia) • Squamous cell carcinoma → lymphatic spread to
o The principle is simply to have more the inguinal lymph nodes (external nodes)
space for the midgut to develop
• At the 10th week, the midgut returns to the
abdominal cavity
o First rotation occurs around the superior
mesenteric artery 270 degrees
counterclockwise
• The other two parts of the developing GI tract are
the foregut (before the midgut) and the hindgut
(after the midgut)
• The foregut becomes everything from the
pharynx to the proximal duodenum
o Liver, gallbladder, and pancreas Figure 103: Pectinate line anatomy. Source:
originates from the foregut https://en.wikipedia.org/wiki/Pectinate_line#/media/File:G
o The proximal duodenum buds out (the ray1080.png
different buds develop into these
accessory digestive organs) Anatomical Structure of the GI Tract:
• The midgut becomes the distal duodenum up to The gastrointestinal (digestive) tract starts from the mouth
the first two thirds of the transverse colon (the and ends at the anus. The main purposes of the GI tract are
splenic flexure) to allow food and nutrients to enter the body, pass it to the
• The hindgut develops into last one third of the stomach, early digestion, passing food to the small intestine
colon to the pectinate line for further digestion and absorption, further breakdown of
o The pectinate line separates the GI food in the large intestine and finally exiting the end product
endodermal origin from the skin of the in the form of stool through the anus.
anus which is ectoderm
Area above the pectinate line: The GI Tract:

• The superior rectal artery from the inferior • The mouth, and pharynx (some digestion of the
mesenteric artery supplies the area above the line. carbohydrates starts here)
Venous drainage is via the superior rectal vein → • Esophagus (a tube for food to pass to the
inferior mesenteric vein → portal vein stomach)
• Chronic constipation and straining → dilatation • The stomach which stores food, and starts the
of the branches of the superior rectal vein → process of digestion via proteases and acidic
internal hemorrhoids which are painless secretions
• Tumors above this line are adenocarcinomas → • The duodenum where bile and pancreatic
drainage via the lymphatic vessels to the internal secretions come to help digest food further
iliac lymph nodes (internal nodes) • The jejunum and ileum where further digestion of
Area below the pectinate line: food takes place and absorption of nutrients takes
place
• Perianal perineum is supplied by the pudendal • Colon where broken food starts to form into stool
nerve and pudendal blood supply to be passed by the anus
• Inferior rectal artery from the pudendal artery. Layers of the GI Tract:
Venous drainage is via the inferior rectal vein to Mucosa:
the pudendal vein to the iliac veins and inferior
vena cava

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 • The lining of the GI tract “epithelium” which can • Gastric glands which secrete acid
be stratified squamous, or columnar depending on Duodenum:
which part is being analyzed (form intestinal villi)
o The intestinal villi increase the surface • Villi and microvilli – increase absorptive surface
area of the intestine → more absorption • Brunner glands which secrete bicarbonate and are
• The lamina propria found in the submucosa:
• The muscularis mucosa o Fluid passing from the stomach is acidic
Submucosa: o It is important to neutralize this acidity
for next-step digestive enzymes related
• Contains the submucosal glands which secrete to the breakdown of fats
fluids o Also, to protect the duodenum from
• The Meissner submucosal nerve plexus ulcers’ formation
(important in controlling digestive tract secretions
and hormones Lieberkühn crypts:
Muscularis externa:
o These are important for the small
• Auerbach myenteric nerve plexus (peristalsis and intestine
GI motility) o Continuous regeneration and
Outer layer: replacement of enterocytes is needed
o These crypts have stem cells that are
• Serosa for intraperitoneal structures capable of replacing the enterocytes and
• Adventitia for retroperitoneal structures goblet cells
• Blood vessels and lymphatic run through this o Bacterial pathogens might be present in
layer to supply the GI tract the food, accordingly, Paneth cells
Ulcers versus Erosions: found in the duodenum secrete
defensins, lysozyme and tumor necrosis
• These two pathologies are descriptions of almost factor to provide some innate
the same thing but differ in the depth of the lesion nonspecific immunity
• Erosions are confined to the mucosa Jejunum:
• Ulcers can extend to the submucosa, muscularis
externa or even all the way through the serosa • Plicae circularis and crypts of Lieberkühn
(perforation) Ileum:

• Peyer patches which are lymphoid aggregates in

the lamina propria (important in fighting
pathologic microorganisms)
• Largest number of goblet cells in the small
intestine to secrete mucous and lubricate the
passing food
Colon:

• The villi are absent (no need to absorb any more

nutrients)
• Water absorption still occur to harden the stool
• Abundant goblet cells for lubrication
Blood Supply to the GI Tract:
Figure 104: Layers of the GI tract. Source:
Blood supply and innervation of the developing gut:
https://commons.wikimedia.org/wiki/File:2402_Layers_of
_the_Gastrointestinal_Tract.jpg • The foregut is supplied mainly by the celiac trunk
and innervated by the vagus nerve
Histology: • The midgut is supplied by the superior mesenteric
Esophagus: artery and also innervated by the vagus nerve
• Nonkeratinized stratified squamous epithelium → o A pad of fat exists between the
to protect from abrasions duodenum and the superior mesenteric
Stomach: artery

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 o Protects the superior mesenteric artery • Paraumbilical vein with the small epigastric veins
from being compressed when food is of the anterior abdominal wall
passing through the duodenum • Caput medusae is the clinical sign in patients with
o In severely malnourished people, this portal hypertension
visceral fat might be lost Rectum portosystemic anastomoses:
o Postprandial pain due to intermittent
compression of the superior mesenteric • Superior rectal vein with middle and inferior
artery will result in what is known as rectal veins
superior mesenteric artery syndrome • Anorectal varices can develop in patients with
• The hindgut is supplied by the inferior mesenteric portal hypertension
artery and innervated by the pelvic nerve
• Sympathetic nerve supply of the foregut and
midgut is from the thoracic splanchnic nerves
• Sympathetic nerve supply of the hindgut is from
the lumbar splanchnic nerve
Celiac trunk:

• Common hepatic, splenic and left gastric arteries

• Anastomoses between the left and right
gastroepiploic and left and right gastric arteries

Figure 105: Branches of the celiac trunk. Source:

www.wesnorman.com/celiactrunk.htm

Portosystemic anastomoses:

• Studying these anastomoses is important because

patients with portal hypertension will develop
varices involving these veins
• Mainly, in the esophagus, umbilicus and rectum Figure 106: Portosystemic anastomoses. Source:
Esophagus portosystemic anastomoses: https://pbs.twimg.com/media/BKo3gyTCYAAWyEh.jpg

• Left gastric vein with the azygos vein Ligaments of the GI Tract:
• In portal hypertension, esophageal varices can • These ligaments are important because they
develop connect different GI organs to the abdominal wall
Umbilical portosystemic anastomoses: or to each other
• They keep the different organs in their place

ligament Structures within the ligament Connection Notes

Gastrocolic - Gastroepiploic arteries - Greater curvature of the - Part of the greater omentum
stomach and transverse colon
gastrosplenic - Short gastric, and left - Greater curvature of the - Part of the greater omentum
gastroepiploic vessels stomach and the transverse - Separates the greater and
colon lesser sacs on the left
splenorenal - Splenic artery and vein - Spleen to the posterior
- Tail of pancreas abdominal wall

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 falciform - Ligamentum teres hepatis - Liver to anterior abdominal - A derivative of the ventral
- Patent paraumbilical vein wall mesentery
hepatoduodenal - Proper hepatic artery - Liver to the duodenum - The ligament can be
- Portal vein compressed between thumb
- Common bile duct and index fingers to control
intraoperative bleeding in
Pringle maneuver
- Borders the omental foramen
- Part of the lesser omentum
Gastrohepatic - Gastric blood vessels - Liver to the lesser curvature - Separates the greater from
of the stomach the lesser sacs on the right
- Part of the lesser omentum

• Presents with polyhydramnios in utero

o Esophageal atresia makes the fetus
unable to swallow amniotic fluid
• If not diagnosed antenatally, the diagnosis is
often obvious after the first feeding:
o Drooling and choking associated with
nonbilious vomiting
• The abdomen becomes distended because the
distal TEF allows air to enter the stomach
o Can be confirmed by plain radiography
• Neonates can become cyanosed secondary to
laryngospasm:
o Laryngospasm develops in response to
reflux aspiration
Figure 107: Gastrointestinal ligaments. Source: • The diagnosis can be confirmed by failure of
https://step1.medbullets.com/gastrointestinal/110003/gastr passing a nasogastric tube into the stomach
ointestinal-ligaments H-type tracheoesophageal fistula:

Retroperitoneal Structures: • A TEF without esophageal atresia

• Structures that do not have a mesentery • Resembles the letter H
• Include GI and non-GI structures Pure esophageal atresia without a tracheoesophageal
• Injuries can cause blood or gas in the fistula:
retroperitoneal space
• Esophageal atresia or stenosis
• They are:
o Suprarenal glands • A plain radiograph will reveal a gasless abdomen
o Aorta and inferior vena cava with possible collapse of the stomach
o 2nd to 4th parts of the duodenum
o Pancreas except tail
o Ureters
o Descending and ascending colon
o Kidneys
o Thoracic portion of the esophagus
o Part of the rectum
Developmental Anomalies of the GI Tract
Tracheoesophageal Fistula
Definition:
A congenital malformation of the trachea and esophagus
where there is an abnormal communication between the
two tubes. Tracheoesophageal anomalies can be classified
into the following types.
Types:
Esophageal atresia with distal tracheoesophageal fistula:

• Most common type (85%)

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 • Presentation:
o A defect in the abdominal wall with an
exstrophied bladder and a portion of the
urethra
o Separation of the pubic symphysis
o External rotation of the pelvis
o In females, narrowed vaginal orifice,
bifid clitoris and divergent labia
• Primary closure is the treatment whenever
feasible
Long-term complications:
o Vesicoureteral reflux
o Bladder spasm
o Bladder calculus
o Recurrent urinary tract infections

Figure 108: The different types of TEF. Source:

https://en.wikipedia.org/wiki/Tracheoesophageal_fistula

Ventral Wall Defects:

Failure of rostral fold closure:
Ectopia cordis:

• Very rare with an estimated incidence of 8 per Figure 110: Bladder exstrophy in a female. Source:
million births https://en.wikipedia.org/wiki/Bladder_exstrophy
• The heart is located partially or totally outside the
thorax Failure of lateral folds closure:
• The heart can be found in the neck, chest or Gastroschisis:
abdomen
• Most neonates die and there is no recommended • Definition:
treatment o Extrusion of abdominal contents
• Early surgical intervention might be successful in through an anterior abdominal wall
a minority of the cases defect typically on the right of the
umbilicus without peritoneum or
amnion covering
• Not associated with chromosomal abnormalities
• Often an isolated finding

Figure 109: Complete thoracic ectopia cordis. Source:

https://doi.org/10.1016/s1010-7940(02)00811-4

Failure of caudal fold closure:

Bladder exstrophy:

• 1 in 10,000 to 50,000
• Male to female ratio is 6:1
• Risk of bladder exstrophy in the offspring of an Figure 111: Gastroschisis. Source:
individual with corrected bladder exstrophy is https://en.wikipedia.org/wiki/Gastroschisis
increased by 500 times

376
Omphalocele: • Patients might develop chronic abdominal pain
and chronic pancreatitis
• Definition: Gastrointestinal Hormones and Secretions
o Failure of the lateral walls of the Gastrointestinal Regulatory Substances
abdomen to migrate at the umbilical These are gastrointestinal endocrine hormones (substances
ring which results in midline herniation released into the blood to affect distant targets).
of the abdominal contents into the
umbilical cord. Covered by peritoneum Gastrin:
• Associated with chromosomal abnormalities such Definition and source:
as trisomies 13 and 18
• Associated with other structural malformations of Gastrin is a hormone that is released by G-cells in the
the heart, genitourinary and neural tube systems pyloric antrum of the stomach, duodenum and pancreas. It
is a polypeptide hormone.
Regulation:

• Stomach mechanical distention in response to

food or a change in the stomach’s pH
(alkalization) stimulates the release of gastrin
• Presence of aminoacids and peptides (from food)
and vagal stimulation by gastrin-releasing peptide
also stimulate the release of gastrin
• A very low pH (< 1.5) inhibits the release of
gastrin
Action:
Figure 112: Omphalocele. Source: • It is clear from the mechanism of regulation that
https://en.wikipedia.org/wiki/Omphalocele the main effect of gastrin would be to increase
acid (H+) production by the parietal cells
Congenital umbilical hernia: • To protect the stomach from the increased acid
• Failure of the lateral folds of the abdomen to production, gastrin also stimulates the growth of
close at the umbilical ring which results in a small gastric mucosa
defect • Finally, gastrin is known to increase gastric
• Most often close spontaneously motility in an attempt to move the food from the
Pancreatic Anomalies: stomach to the duodenum
Normal development: Clinical correlation:
• The pancreas is derived from the foregut
• Ventral buds form the uncinate process and main • Conditions that increase the pH of the stomach
pancreatic duct such as chronic proton pump inhibitor use, or
• The dorsal pancreatic bud becomes the body, tail, atrophic gastritis will increase the release of
isthmus and accessory pancreatic ducts gastrin
• Both buds contribute to the pancreatic head • Zollinger-Ellison syndrome results in
Annular pancreas: hypergastrinemia secondary to a gastrinoma
Somatostatin
• Abnormal rotation of the ventral pancreatic bud Definition and source:
which fails to meet the dorsal bud
• A ring of pancreatic tissue is formed which A polypeptide hormone synthesized and released by D
encircles the 2nd part of the duodenum cells which are found in the pancreatic islets and
• It can result in duodenal narrowing → obstruction gastrointestinal mucosa.
and vomiting
Regulation:
Pancreas divisum:
• Its release is increased by increased acidity of the
• Failure of fusion between the ventral and dorsal
stomach juices
parts of the pancreas which is supposed to happen
at 8 weeks • Decreased by vagal stimulation
Actions:
• Mostly asymptomatic and is common in the
general population

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 • Again, the main action of somatostatin is obvious A polypeptide hormone that is released by the small
from its regulation mechanisms, it is to decrease intestine.
gastric acid production and secretion
• It also decreases the production of pepsinogen, Regulation:
pancreatic and small intestine fluid secretion, • Increased release in fasting
gallbladder contraction, insulin and glucagon Action:
release
Clinical correlation: • As the name implies, it increases intestinal
peristalsis by producing migrating motor
• Somatostatin inhibits the release of growth complexes
hormone and other hormones Clinical correlation:
• Octreotide, a somatostatin analog, is used in the
treatment of acromegaly, variceal bleeding and • Erythromycin is used to stimulate intestinal
carcinoid syndrome peristalsis
Cholecystokinin • This antibiotic is a motilin receptor agonist
Definition and source: Vasoactive Intestinal Polypeptide:
Definition and source:
An endocrine hormone released by the I cell of the
duodenum and jejunum. This polypeptide is released by parasympathetic ganglia
found in the gallbladder, small intestine and the different
Regulation:
GI sphincters.
• Increased release by presence of fatty acids and Regulation:
aminoacids in the duodenum
Actions: • Increased release by mechanical distention of the
GI tract and vagal stimulation
• The name of the hormone and its regulation
• Inhibited release by adrenergic input
mechanism gives away its main action, which is
Actions:
to facilitate fat digestion
• It increases pancreatic secretion and gallbladder • Increases intestinal water and electrolyte
contraction (to release bile) and relaxes the secretion
sphincter of Oddi (to allow for the passage of • Relaxes intestinal smooth muscle and GI tract
pancreatic secretions and bile into the duodenum) sphincters
• It decreases gastric emptying (allowing more time Clinical correlation:
for the pancreatic enzymes to digest fat)
Secretin: • VIPomas are pancreatic tumors that secrete
Definition and source: vasoactive intestinal polypeptide
• From the understanding of the actions of this
A polypeptide hormone release by the S cells in the hormone, one can conclude that patients with this
duodenum. type of tumor will have watery diarrhea and
Regulation: hypokalemia
• Achlorhydria will develop (loss of H+ in
• Increased release by the presence of fatty acids exchange for K+ by the kidneys)
and acidic fluid in the duodenum Nitric oxide:
Action: Clinical correlation:

• Increases the release of bicarbonate to neutralize • This regulatory substance is a very potent smooth
gastric acid in duodenum muscle relaxer
o This is important because pancreatic • Its release stimulates the relaxation of the lower
enzymes cannot work in an acidic esophageal sphincter
environment • Loss of nitric oxide secretion is implicated in the
• Decreases gastric acid secretion pathophysiology of achalasia where there is an
• Increases bile secretion increase in the lower esophageal sphincter tone
Motilin: Ghrelin:
Definition and source: Source:
This polypeptide hormone is released by the stomach.
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Regulation: Pepsin:
Definition and source:
• Increased production in fasting state A digestive enzyme that is released by the chief cells of the
• Decreased production when there is food in the stomach.
stomach Regulation:
Actions: • Its production is increased by vagal stimulation
and presence of acid in the stomach
• Increases appetite
• It’s released in an inactive form known as
Clinical correlation:
pepsinogen
• Decreased production after gastric bypass surgery • Pepsinogen is converted to the active form pepsin
→ decreased appetite and weight loss in the presence of acid (H+)
• Increased production in Prader-Willi syndrome Action:
→ weight gain • Protein digestion
Glucose-Dependent Insulinotropic Peptide:
Definition and source: Bicarbonate:
A peptide hormone released by the K cells in the Definition and source:
duodenum and jejunum. This buffer is secreted by the mucosal cells lining the
Regulation: stomach, duodenum, pancreas and salivary glands. It is
• Increased release by the presence of fatty acids, also released by Brunner glands in the duodenum.
aminoacids and glucose in the lumen of the Regulation:
duodenum and jejunum • Increased release is stimulated by pancreatic and
Actions: biliary secretions, which are stimulated by
• Decreases gastric acid secretion (hence, the other secretin
name gastric inhibitory peptide) Action:
• Increased the release of insulin by the pancreatic • Neutralizes the acid in the lumen of the
beta-cells duodenum which is important for the activation
Clinical correlation: of the pancreatic digestive enzymes
• It has been noted that oral glucose load results in
a higher insulin response than IV glucose Intrinsic Factors:
• This hormone is thought to be responsible for the Definition and source:
higher insulin response of oral glucose load This binding protein is released by the parietal cells of the
compared to IV stomach. Same cells that secrete acid.
Clinical correlation:
Gastrointestinal Secretory Products:
• The absorption of vitamin B12 by the terminal
• These are products that aid in digestion or
ileum requires the binding of vitamin B12 to
absorption.
intrinsic factor
Gastric Acid:
Definition and source: • Autoimmune destruction of parietal cells results
HCl which is released by the parietal cells in the stomach. in chronic atrophic gastritis → loss of intrinsic
Regulation: factor
• Increased production by histamine, vagal • Failure of absorption of vitamin B12 by the
stimulation and gastrin terminal ileum → pernicious anemia
• Decreased production by somatostatin, gastric
acid inhibitor peptide, and prostaglandin Common Oral Pathologies
Cleft Lip/Palate
Actions:
Definition:
• Decreases the pH of the stomach which is
important for the activation of other important A cleft lip deformity is often associated with a cleft palate.
digestive enzymes An occult cleft is the incomplete separation of the lip with
Clinical correlation: distortion but no separation of the vermillion border. An
• Antihistamines, prostaglandin analogs and PPIs incomplete cleft lip is lip separation through the vermillion
work on different targets to decrease acid border with downward displacement of the ala and an
production by the parietal cells and are used in intact nasal sill. A complete cleft lip has complete
the treatment of peptic ulcer disease separation of the lip and nasal sill.
Etiology:

379
 • The nose and lip come from the 1st and 2nd • Nonsmokers
pharyngeal arches • Smokers who quit smoking
• Cleft lips and palates occur due to lack of fusion • Poor oral hygiene
of the medial nasal process of the frontal nasal Triggers:
prominence with the maxillary process during
embryogenesis • Local trauma
Epidemiology: • Emotional or physiologic stress
• Exposure to allergens
• Usually on the left side • Exposure to foods containing cinnamon, cheese,
• 0.1% overall risk citrus or figs
• More common in Asian populations Pathology:
• 29% have associated congenital malformations
Risk factors: • Immune-mediated ulcers by T-cell and neutrophil
dysfunction
• Maternal use of phenytoin, steroids, tobacco, and
alcohol
• Maternal malnourishment

Figure 114: Aphthous ulcer. Source:

https://www.ncbi.nlm.nih.gov/books/NBK431059/

Behcet Disease
Definition:
An oculo-oro-genital syndrome with chronic remitting and
Figure 113: Isolated cleft palate, and cleft lip/palate. relapsing inflammation.
Source: Mayo Clinic
Epidemiology:
Aphthous Stomatitis
• More common in Mediterranean ancestries
Definition:
especially Turkey
Recurrent painful aphthous ulcers known as canker sores • Prevalence in Turkey is as high as 420 per
on the non-keratinized oral mucous membranes. 100,000
• Age of onset is in the second or third decade
Epidemiology: Etiology:
• 20% of the general population • Unknown cause
• More common in females • Autoimmune disease triggered by a dysregulated
• Most often occurs in the second and third decades immune response to HSV, streptococcus or
of life staphylococcus infection
• Can be a manifestation of other systemic diseases • Genetic predisposition in HLA-B51 carriers
such as: Immunologic findings in Behcet disease:
o Behcet disease
o Systemic lupus erythematosus • Autoantibodies against intermediate filaments of
o Reactive arthritis mucous membranes
o Crohn disease • Immune complexes deposition in the involved
Risk factors: sites
• Decreased complement levels
• Iron, vitamin B6 and B12 deficiencies • Immunoglobulin complement deposition within
• Thiamine or zinc deficiency and around small blood vessels (vasculitis)

380
 • Decreased ratio of CD4+/CD8+
Leukocytoclastic vasculitis is pathognomonic of Behcet
disease.
Presentation:

• Multiple aphthous ulcers

• Genital ulcers on the scrotum in males, and vulva
and vagina in females
• Ocular involvement in the form of conjunctivitis,
uveitis, retinal vasculitis, and posterior uveitis →
the latter can lead to blindness
• Non-deforming arthritis of the medium and large
joints which is asymmetric, sterile, and
seronegative
• Deep venous thrombosis, oro-genital ulcers and
eye disease is highly suggestive of Behcet disease
Diagnosis:
Recurrent oral aphthous stomatitis plus two of the
following: Figure 115: Behcet disease clinical presentation. Source:
BMJ Best Practice
• Recurrent painful genital ulcers
• Ocular involvement Herpetic Ulcers:
• Skin lesions such as erythema nodosum, or a • Most cases of primary HSV-1 infection are
positive Pathergy test (a sterile pustule after local asymptomatic
trauma to the skin) • Orolabial herpes is most often due to HSV-1 (few
• Cerebral infarctions or sterile cases have been attributed to HSV-2)
meningoencephalitis • The most common manifestation is aa cold sore
Treatment: or a fever blister
Primary orolabial infection:
• Topical antibiotics and corticosteroids for ulcers
• Topical corticosteroids for ocular disease •Most often asymptomatic
• Colchicine, and NSAIDs for articular disease •Viral prodrome of malaise, fevers, and tender
• Systemic steroids for vascular, or CNS disease lymphadenopathy
• Immunomodulators or immunosuppressive drugs • Painful grouped vesicles on an erythematous base
are reserved for refractory cases • May progress to pustules, erosions and
ulcerations
• Within two to six weeks, lesions crust over, and
symptoms resolve
Recurrent orolabial infection:

•Milder than primary infection

•24-giyr prodrome of tingling and burning
•Classically the vermillion border of the lip is
affected
Treatment:

• Oral valacyclovir two grams twice daily for one

day

381
 • Parotitis, acute salivary gland swelling, orchitis or
oophoritis
• Positive laboratory test result in an asymptomatic
patient
The diagnosis is probable in patients with parotitis or
orchitis lasting two days or more and one of the following:

• Positive IgM antibodies against mumps

• Linkage to another confirmed or probable case in
the patient’s group or community
• An outbreak of mumps
Figure 116: Orolabial herpes. Source: The diagnosis is confirmed in patients with a positive
https://en.wikipedia.org/wiki/Herpes_labialis reverse transcription PCR of mumps and any of the
following:
Leukoplakia and Other Causes of White Tongue
Oral thrush: • Acute parotitis
• Aseptic meningitis
• Caused by candida albicans • Encephalitis
• More common in patients with a CD4+ count less • Orchitis
than 500/mm3
• Oophoritis
• On physical examination, the lesion can be • Mastitis
scrapped off
• Pancreatitis
• Pseudohyphae on microscopy
Leukoplakia:

• A pre-malignant condition
• Oral hairy leukoplakia is caused by EBV in a
patient with HIV
• The white plaque cannot be scrapped off
• More often on the lateral part of the tongue
• Can be classified into two types:
o Homogenous leukoplakia → less likely
to progress to malignancy
o Non-homogenous leukoplakia → high
malignant potential
Figure 118: Parotid gland swelling in an infant with
mumps. Source: Mayo Clinic

Sialolithiasis:
Definition:
Stone formation in a salivary gland duct which results in
obstruction. Can occur in parotid, submandibular or
sublingual glands. A single stone is more commonly seen
in Wharton duct of the submandibular gland.

• Caused by trauma or dehydration

Presentation:

Figure 117: Hairy leukoplakia versus oral candidiasis. • Periprandial pain

Source: https://hellomrdoctor.com/hairy-leukoplakia/ • Swelling of the obstructed gland
Treatment:
Mumps:
Mumps is caused by a viral agent. The diagnosis is • NSAIDs
suspected in patients with one of the following: • Gland massage
• Warm compresses

382
 • Instruct the patient to eat sour candies which •Positive ANA and RF (non-specific)
promote salivary gland flow •Positive SS-A and SS-B (SS-A is specific for
Sialadenitis: Sjogren’s syndrome)
• Gold standard: minor salivary gland biopsy to
• The obstructed salivary gland might become show focal leukocytic sialadenitis
infected Treatment:
• Most often a staph infection
• Antibiotics might be needed • Symptomatic treatment with artificial tears, oral
and vaginal moisturizers

Figure 119: Anatomy of the salivary glands and ducts.

Source: http://medifitbiologicals.com/sialolithiasis/ Figure 120: Schirmer test and slit-lamp exam in Sjogren's
syndrome. Source:
Sjogren’s Syndrome: https://jamanetwork.com/journals/jama/fullarticle/186301

Salivary Glands Neoplasia

Definition:
Definition:
A systemic autoimmune disorder that presents with sicca Salivary gland neoplasms are rare, and they can be benign
symptoms (dryness of the eyes and mouth). or malignant. The pathohistological diagnosis is important
for prognostic and treatment purposes.
Etiology:
The salivary glands can be divided into major salivary
• Genetic predisposition glands and minor salivary glands:
• Epstein-Barr virus infection
Pathology: •The major salivary glands include the parotids
and the submandibular and sublingual glands
• Focal lymphocytic sialadenitis (autoimmune • The minor salivary glands are about 600 to 1000
inflammation of the salivary glands) in number and are found across the oral cavity,
• Predominantly T-lymphocytes palatine tonsils, pharynx and larynx
• Involvement of other exocrine glands including Epidemiology:
the lacrimal glands • 1% of head and neck tumors
• Decreased production of tears and saliva • Incidence is 1.5 per 10,000
Presentation: • 75% are benign – most commonly pleomorphic
adenomas
• Feeling of a foreign body in their eyes and a dry • Tumors arising from the small salivary glands are
mouth more likely to be malignant
• Absence of tears Pathophysiology:
• Keratoconjunctivitis sicca on slit-lamp exam • Radiation exposure, even in low-dosages, might
• Schirmer test help in confirming ocular dryness be a risk factor for pleomorphic adenoma and
• Enlarged parotids or submandibular glands other salivary gland neoplasms
• Polyarthritis, lower extremity purpura, and • Warthin’s tumor appears to be more common in
peripheral neuropathies smokers
Diagnosis: • Epstein-Barr virus appears to be a risk factor for
undifferentiated salivary gland carcinoma
• Schirmer test and slit-lamp exam Pleomorphic Adenoma:

383
 • The most common benign salivary gland tumor
• Most commonly affects the parotid gland
• Variable appearance on histopathology →
pleomorphic
• Well-differentiated tumor with parenchymatous
glands and myoepithelium in a stroma of
chondromyxoid composition
• May undergo malignant transformation

Figure 122: Warthin's tumor. Source:

https://en.wikipedia.org/wiki/Warthin%27s_tumor#/media/
File:Warthin_tumor_(1).jpg

Mucoepidermoid Carcinoma:
• Most common malignancy of the parotid gland
• The second most common malignancy of the
submandibular gland
• Mainly two types of cells: mucous and squamous
cells
Figure 121: Pleomorphic adenoma. Source: • Based on the degree of differentiation, the tumor
https://en.wikipedia.org/wiki/Pleomorphic_adenoma can be classified into low, intermediate and high-
grade
Diagnosis: • Slow-growing tumor that is associated with
cytomegalovirus
• Fine-needle aspiration has excellent sensitivity
(90%)
• US, CT and MRI for staging
Treatment:

• Surgical resection
• The tumor should be handled gently → if rupture
occurs intraoperatively, this can lead to
recurrence
• Potential for malignant transformation → should
be resected if identified
Warthin’s Tumor: Figure 123: Mucoepidermoid carcinoma. Source:
https://en.wikipedia.org/wiki/Mucoepidermoid_carcinoma
• Also known as papillary cystadenoma
#/media/File:Mucoepidermoid_carcinoma_(2)_HE_stain.jp
lymphomatosum
g
• The second most common benign salivary gland
tumor Adenoid Cystic Carcinoma:
• Most commonly affects the parotid gland • Second most common malignancy of the salivary
• More common in older people with history of glands
cigarette smoking • Most common malignancy of the submandibular
• A well-differentiated tumor with germinal gland
centers, cystic spaces, lymphocytosis, and • Distant metastasis to the eyes, lung, brain and
condensed chromatin in the nuclei sinuses are common
• 10% are bilateral and 10% are multifocal • Treatment is surgical resection with or without
• The tumor is slow growing as compared to other radiation
salivary gland tumors • The prognosis is very poor

384
 • The pyloric sphincter separates the two bubbles
from each other
• Air is absent in the distal duodenum

Figure 124: Adenoid cystic carcinoma. Source:

https://en.wikipedia.org/wiki/Adenoid_cystic_carcinoma#/
media/File:Adenoid_cystic_carcinoma_-
_intermed_mag.jpg

Duodenal Atresia
Definition
Duodenal atresia is the congenital absence or closure of the
lumen of the duodenum.
Epidemiology Figure 125: Double-bubble sign on an abdominal
• The estimated incidence is 1 in every 5000 to radiograph of a newborn with duodenal atresia. Source:
10,000 live births https://en.wikipedia.org/wiki/Duodenal_atresia
• Up to 40% of them occur in infants with Down
syndrome • Jejunal and ileal atresia can also occur and are
• 8% of infants with Down syndrome have often caused by ischemic necrosis → segmental
duodenal atresia resorption
Clinical Presentation Treatment:
• During pregnancy, the mother presents with • Stomach aspiration via a nasogastric tube
polyhydramnios • IV fluids because the newborn will be dehydrated
• It is caused by the inability of the fetus to • Duodenoduodenostomy is the definitive treatment
swallow the amniotic fluid and absorb it o Not urgent
• After birth, the newborn presents with upper Hypertrophic Pyloric Stenosis
abdominal distension and bilious vomiting Definition
o Because the most common site of Hypertrophic pyloric stenosis (HPS) is a condition
duodenal atresia is below the insertion affecting infants that is characterized by an abnormally
of the common bile duct, vomiting thickened pyloric portion of the stomach and manifests as
usually has bile obstruction to gastric emptying. Infants present in the first
o In pyloric stenosis, the obstruction is two to twelve weeks of life with forceful projectile
before the common bile duct → non- nonbilious vomiting after feeding.
bilious vomiting
Epidemiology
Complications
• The estimated incidence is 2 to 4 per 1000 live
• The prognosis is very good births
• Complications and prognosis are dependent on • Less common in African and Asian populations
the presence of other congenital anomalies
• Male to female ratio is 4:1
Diagnosis:
• HPS is more common in bottle-fed infants, in
• Radiography is the imaging modality of choice to
rural populations, and in the summer months
confirm the diagnosis of duodenal atresia in a
newborn with bilious vomiting • There is ongoing debate on whether the condition
is acquired or congenital
• The abdominal radiograph shows two large air-
filled spaces which is known as the double- • HPS is the most common cause of gastric outlet
bubble sign obstruction in infants
Possible risk factors:
• The two air-filled spaces are the stomach and
proximal duodenum

385
 • Firstborn child • Ultrasonography reveals a thickened and
• Male gender lengthened pylorus that fails to relax
• Maternal exposure to macrolides
Pathophysiology
• The exact etiology is unknown
• It is hypothesized that the exposure of an
abnormal pyloric tissue to enteric feeding is the
trigger of the condition, and that the pathogenesis
needs two to twelve weeks to cause significant
obstruction
• Deficiency of nerve terminals and peptide-
containing nerve fibers in the pyloric portion of
the stomach
• Decreased production of mRNA for nitric oxide
synthase and a decrease in the interstitial cells of
Figure 127: Ultrasonography in an infant with HPS
Cajal in the muscular layer of the pylorus has
showing a thickened and lengthened pylorus. Source:
been described
https://en.wikipedia.org/wiki/Pyloric_stenosis#/media/File:
• Increased production of insulin-like and platelet- Pyloric-stenosisLocal.jpg
derived growth factors → myocyte hypertrophy
• These pathologies eventually lead to the • Infants develop hypokalemia and metabolic
following: alkalosis due to the loss of stomach acid in
o Impaired relaxation of the pylorus vomiting
muscle • The kidney conserve sodium at the expense of
o Subsequent hypertrophy of the pylorus hydrogen ions → paradoxical aciduria
muscle
• Known as hypokalemic hypochloremic metabolic
Clinical Presentation
alkalosis
• Infants aged 2 to 12 weeks present with forceful
• Barium swallow study reveals a string-sign
projectile nonbilious vomiting
• Palpation reveals a hypertrophic pylorus → often
described as an olive
• The olive sign is present in 99% of the infants
and is diagnostic of HPS
• The child’s hips should be flexed to relax the
abdominal wall
• Figure 1 shows how the olive is palpated in HPS
• Visible peristaltic waves

Figure 128: String-sign in HPS. Source:

https://meddiction.com/knowledgebase/pyloric-stenosis/

Treatment:
• Fluid resuscitation is important to break the cycle
of hypokalemic hypochloremic metabolic
Figure 126: Palpation for the olive sign in an infant with alkalosis and aciduria
HPS. Source: DOI: 10.1053/j.sempedsurg.2006.10.004 • Definitive treatment is pyloromyotomy
Liver Tissue Architecture
Diagnosis: Hepatic Lobules
• Ultrasonography is the imaging modality of A hepatic lobule is the small division of the liver at the
choice with an accuracy of 100% microscopic scale. These are the building blocks of liver

386
parenchyma and they consist of a portal triad, hepatocytes Hepatic stellate cells:
arranged in linear cords in a capillary network, and a
central vein. • Found in the space of Disse
• Store vitamin A
Portal triad: • Produce extracellular matrix when activated
• Responsible for hepatic fibrosis
• The functional unit of the liver
• Figure 3
• Consists of three vessels “interlobular artery,
interlobular vein and a bile duct
• Figure 1

Figure 131: Acinus architecture. Source:

https://www.researchgate.net/figure/The-liver-lobule-and-
acinus-Schematic-representation-of-a-liver-lobule-and-a-
diagram_fig1_318301214

Hepatic Zones:
• Hepatic acini can be divided into different
Figure 129: Portal triad. Source: metabolic zones
https://en.wikipedia.org/wiki/Portal_triad#/media/File:Port • The definition of a zone is the imaginary line
al_triad.JPG connecting two portal triads and extending
towards the two adjacent central veins
Cellular Composition of the Liver: • Figure 4
• The apical surface of the hepatocytes faces bile
canaliculi
• The basolateral surface faces sinusoids
• The functions of the hepatocyte are dependent on
its hepatic zone
Kupffer cells:

• Specialized macrophages
• Located in the sinusoids
• Figure 2

Figure 132: The red diamond-shaped acinus is what we

refer to when we talk about hepatic zones. Zone 1 is
nearest to the portal triads. Zone three is nearest to the
central vein. Source:
https://en.wikipedia.org/wiki/Lobules_of_liver#/media/File
:Liver_scheme1.jpg

Zone I:

• Periportal zone
• Hepatocytes in this zone are mainly concerned
with gluconeogenesis, beta-oxidation of fatty
acids, and cholesterol synthesis
• Most oxygenated part of the acinus
Figure 130: Black arrow points to a Kupffer cell. Source: • First site to be affected by viral hepatitis
https://en.wikipedia.org/wiki/Kupffer_cell#/media/File:Ku • First site to be affected in ingested toxins such as
pffer_cells_high_mag_cropped.jpg cocaine

387
 • This is the affected zone in hemochromatosis • 20% is reabsorbed into the bloodstream
where hemosiderin is deposited o 10% of this will go to the kidneys to be
Zone II: excreted in the urine in the form of
urobilin which gives the urine its
• An intermediate zone characteristic yellow color
• Necrosis of zone II → yellow fever o 90% will enter the enterohepatic
Zone III: circulation to be recycled by the liver
Causes of Jaundice:
• Pericentral vein (centrilobular) zone Definition:
• Least oxygenated zone → first to be affected by
ischemia Jaundice is the yellowish discoloration of the skin, mucous
• Highest concentration of cytochrome P-450 membranes and conjunctiva which occurs when serum
• Responsible for the metabolism of medications bilirubin levels become higher than 3 mg/dL.
and toxins such as ethanol, halothane, rifampin,
and CCl4 • Most cases of acute jaundice are due to
• Most affected site in alcoholic hepatitis intrahepatic pathologies such as acute viral
hepatitis, alcoholic liver disease and drug-induced
liver injury
Note: Bridging fibrosis starts from • 45% of the cases are due to extrahepatic causes
the central vein and progresses to such as gallstone disease, hemolysis, and
the portal triad (zone III before zone malignancy
I). Unconjugated hyperbilirubinemia:
Increased bilirubin production:

Liver Function Tests: • Too much bilirubin is being produced that the
• There are two important enzymes within the conjugation machinery fails to keep up
hepatocytes • Increased red blood cell destruction
• Aspartate transaminase and alanine transaminase • Red blood cell membrane disorders, enzyme
• Destruction of the hepatocyte results in elevation disorders, hemoglobin disorders, or autoimmune
in the blood levels of these two enzymes hemolysis
• Alanine transaminase (ALT) is more specific to o Cold reactive, warm reactive, or drug-
the liver than aspartate transaminase (AST) induced hemolysis
Jaundice: o Sickle cell anemia or thalassemia
Bilirubin Physiology: o G6PD deficiency
o Pyruvate kinase deficiency
• RBCs are destroyed in the reticuloendothelial
o Spherocytosis
system and heme is extracted
o Myeloproliferative neoplasms such as
• Heme is metabolized by heme oxygenase (in
polycythemia vera
macrophages) to biliverdin
• Increased heme metabolism → large amounts of
• Biliverdin is reduced to bilirubin
unconjugated bilirubin → overwhelmed
• Bilirubin at this stage is unconjugated and it is conjugating machinery → clinical jaundice
water insoluble → it needs to be bound to
Impaired bilirubin conjugation:
albumin in the bloodstream
• Unconjugated bilirubin-albumin complex is taken • Normal RBC turnover
up by the liver • Gilbert syndrome is caused by a deficiency in
• UDP-glucuronosyltransferase converts it to UDP-glucuronosyltransferase
conjugated bilirubin which is water soluble o Benign condition with jaundice and
• Direct bilirubin is bilirubin-glucuronate unconjugated hyperbilirubinemia when
• Indirect bilirubin is unconjugated bilirubin fasting or after strenuous exercise
• Conjugated bilirubin enters the gastrointestinal • Crigler-Najjar syndrome is more severe
tract in the bile • Ingestion of UDP inhibitors such as protease
• It gets converted to urobilinogen by the gut inhibitors → clinical jaundice in patients with
bacteria Gilbert syndrome
• 80% of urobilinogen is excreted in the feces as • Physiologic jaundice in newborns
stercobilin → brown color of the stool Conjugated hyperbilirubinemia:

388
Intrahepatic causes: • Peripheral smear, direct antibody tests to exclude
hemolysis
• Viral hepatitis • G6PD enzyme testing
• Alcoholic liver disease (steatosis, hepatitis or • If hemolysis is unlikely, consider Gilbert or
cirrhosis) Crigler Najjar syndrome as the diagnosis
• Nonalcoholic steatohepatitis Further diagnostic workup for conjugated
• Drug-induced liver injury hyperbilirubinemia:
• Sepsis
• Primary biliary cirrhosis • Mainly an elevation in direct bilirubin
• Autoimmune hepatitis • Laboratory testing for viral hepatitis
• Ischemic hepatitis • Ultrasonography
• Wilson disease or hemochromatosis (cirrhosis) • Treat the cause if possible
• Hepatocellular carcinoma or metastatic disease to Achalasia
the liver Definition:
Extrahepatic causes: Achalasia is a neurodegenerative motility disorder of the
esophagus that results in deranged esophageal peristalsis
• Choledocholithiasis and loss of lower esophageal sphincter function. The lower
• Biliary strictures esophageal sphincter fails to relax due to the loss of the
• Biliary atresia myenteric (Auerbach) plexus.
• Cholangitis
Epidemiology:
• Choledochal cysts
• Rare
• Gallbladder carcinoma
• Incidence ranges between 0.5 to 1.2 per 100,000
• Cholangiocarcinoma
per year
• Pancreatic head adenocarcinoma
• Equal frequency in both genders
• CMV or HIV infections
• Possible bimodal peak in incidence in those aged
Pathophysiology
around 30 and 60 years
• Jaundice occurs when there are disruptions in the
• The incidence of achalasia is rising which could
metabolic pathway of unconjugated bilirubin
be due to the increased awareness about the
production, uptake by the liver, conjugation by
condition
the liver, or secretion of conjugated bilirubin
Pathophysiology:
Clinical Presentation
• The exact etiology is unknown
• Enquire about alcohol and drug use
• The end-point pathology regardless of the exact
• Differentiate between intrahepatic causes
trigger is the destruction of the inhibitory
(alcoholic liver disease, viral hepatitis) and
parasympathetic neurons in the myenteric
extrahepatic causes (common bile duct stones or
Auerbach plexus
cholangitis)
Autoimmune diseases and achalasia:
• The physical examination aims to identify the
cause of jaundice • Autoimmune diseases such as systemic lupus
• Examination and history taking can help in the erythematosus and uveitis are found to be more
identification of the cause, but there are no common in patients with achalasia
specific clinical findings to suggest conjugated • In some patients, the myenteric plexus is invaded
over unconjugated hyperbilirubinemia by T-cell infiltrates and there is an increase in the
Diagnosis expression of human leukocyte antigen class II
Initial diagnostic workup of a jaundiced patient: antigens
• Autoantibodies are more often found in patients
• Complete history and physical examination
with achalasia than the general population
• Measure total, direct and indirect bilirubin Infectious agents:
• AST, ALT and ALP
• GGT • Chagas disease can present with achalasia
• Synthetic liver function tests (INR, prothrombin • Varicella zoster virus and Guillain-Barre
time, albumin) syndrome can precede achalasia in some patients
Further diagnostic workup for unconjugated Genetic predisposition:
hyperbilirubinemia:

• Mainly an elevation in indirect bilirubin

389
 • A triad of achalasia, alacrimia and • If surgical intervention is not feasible:
adrenocorticotrophic hormone resistant adrenal o Long-acting nitrates or calcium channel
insufficiency has been described blockers – limited efficacy
Clinical Presentation o Endoscopic injection of botulinum toxin
• Patients present with dysphagia → cardinal to relax the lower esophageal sphincter
symptom of achalasia | solids before liquids → short-term improvement only
• Chest pain Complications
• Nocturnal cough due to the regurgitation of • Aspiration pneumonia
undigested food into the trachea • Megaesophagus
• Weight loss • Increased risk of squamous cell carcinoma:
Diagnosis o Increased levels of nitrosamines
• Esophageal manometry is the gold standard in the produced by bacterial overgrowth due to
diagnosis of achalasia: stasis of food in achalasia
o Aperistalsis and failure of relaxation of • Increased risk of adenocarcinoma when achalasia
the lower esophageal sphincter is treated successfully:
o Successful treatment of achalasia often
leads to GERD
Esophageal Complaints

Introduction:
Esophageal complaints are common. They are usually
benign and do not indicate serious disease. The most
common esophageal symptom is heartburn, however, in this
discussion we will focus on two esophageal-specific
complaints: dysphagia and odynophagia.

Figure 133: Esophageal manometry findings in achalasia. Dysphagia

Source: Definition:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793135/
Difficulty swallowing → food is unable to pass from the
• Endoscopy is important to exclude other causes esophagus to the stomach. Dysphagia is usually caused by
of dysphagia such as carcinoma of the esophagus a structural abnormality of the esophagus, i.e. achalasia for
• Barium esophagogram can show the instance. History and physical examination can correctly
pathognomonic bird’s beak sign in the distal identify the cause in 80 to 85% of the patients.
esophagus with proximal esophageal dilation:
o A late finding in established achalasia Mechanism:
o Its absence does not rule out achalasia • Primary and secondary peristaltic contractions of
the esophagus propel food down to the stomach
• Loss of these contractions result in dysphagia
• Mechanical obstruction of the esophageal lumen
due to an intraluminal mass, i.e. tumor, or
stricture can also result in dysphagia
Causes:

• Mechanical obstruction:
o Benign esophageal strictures
o Webs and rings (associated with iron
deficiency)
Figure 134: Barium esophagogram showing bird's peak o Neoplasms
sign in achalasia. Source: • Motility disorders:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793135/ o Achalasia
o Spastic motility disorders of the
Treatment: esophagus
• Pneumatic balloon dilatation or surgery o Scleroderma

390
 o Chagas disease Diagnosis:
• Other causes:
o Diabetes • Endoscopy
o Alcoholism Esophagitis:
o GERD Definition:
Approach to a patient with dysphagia: Esophagitis is a term that refers to the inflammation of the
esophageal mucosa. It is associated with heartburn, chest
pain, dysphagia and odynophagia. The most common cause
of esophagitis is gastroesophageal reflux disease (GERD).
Here, we focus on the other types of esophagitis that are
not caused by GERD.

Eosinophilic Esophagitis:
• Immune-mediated inflammatory disease
• Eosinophilic infiltration of the esophageal
mucosal layer
• Annual incidence is 7 per 100,000
• The most common symptom is dysphagia for
Diagnosis: solid foods
• Family history of allergies
• Barium swallow Diagnosis:
• Endoscopy
• pH monitoring • Endoscopy demonstrates multiple esophageal
rings that resemble the rings found in the trachea
• Esophageal manometry
• If a biopsy is taken, it would reveal eosinophilic
Odynophagia: infiltration with more than 15 eosinophils in high-
Definition: power-field
Painful swallowing. It can range from a dull retrosternal
ache on swallowing to stabbing pain radiating to the back.
Usually caused by an inflammatory process of the
esophageal mucosa.
Causes:

• Caustic ingestion:
o Acid
o Alkali such as lye
• Pill-induced esophagitis:
o Doxycycline Figure 135: Trachealization of the esophagus as seen on
o Potassium chloride endoscopy in eosinophilic esophagitis. Source:
o Quinidine https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423037/
o Iron sulfate
o Zidovudine Esophagitis in Crohn’s Disease:
o NSAIDs • Crohn’s disease affects the entire GI tract
• Radiation • It is an inflammatory bowel disease
• Infectious: • Up to 3% of patients with Crohn’s disease have
o Candida albicans or HSV in healthy esophagitis
individuals Diagnosis:
o Candida, HSV, CMV, EBV,
tuberculosis, protozoan or idiopathic in • Endoscopy reveals multiple aphthous erosions
HIV patients and ulcerations
• Severe ulcerative esophagitis secondary to GERD • The erosions are far from the esophago-gastric
• Esophageal carcinoma junction
Some of these causes can cause odynophagia and • Fistulae might be found between the esophagus
dysphagia at the same time. and mediastinum, pleural cavity or bronchi

391
 • Biopsy might reveal non-caseating granulomas in o Multiple shallow ulcers in the lower
10% of the cases third of the esophagus
o More common in men
o Can be accompanied by fever
• Candida can also cause esophagitis in
immunocompromised patients
o Endoscopy reveals multiple yellow
plaques covering the entire esophagus
• Bacterial esophagitis is very uncommon.
Staphylococcus aureus, and staphylococcus
epidermidis can cause esophagitis in
immunocompromised patients or in those who
have been receiving long-term H2 blockers or
Figure 136: Aphthous ulcers on endoscopy in a patient PPIs
with esophagitis and Crohn's disease. Source: • Treatment with the appropriate antimicrobial is
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423037/ possible once the etiological diagnosis is made:
o Fluconazole for candida esophagitis
Drug-Induced Esophagitis: o Acyclovir for HSV esophagitis
• Antibiotics such as doxycycline, amoxicillin,
ciprofloxacin, metronidazole and rifaximin
• NSAIDs
• Anti-hypertensives including spironolactone and
furosemide
• Bisphosphonates
• Warfarin
Diagnosis:

• Endoscopy reveals ulcers and erosions of the

middle portion of the esophagus

Figure 138: Candida esophagitis. Source:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC542303/

Caustic Injury Esophagitis:

• Most commonly caused by alkaline liquids
o Colliquative necrosis → destruction of
mucosa within few seconds →
microvascular thrombus formation
within 48 hours
Figure 137: Ulcers in a patient with drug-induced • Acidic substances can also cause esophagitis
esophagitis. Source: o Coagulative necrosis and eschar
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423037/ formation
• Most common alkaline agent is household
Treatment: detergents
• Picosulfate, a laxative, can cause caustic injury
• This type of esophagitis is easily treated with esophagitis
PPIs, antacids and the discontinuation of the o Must be properly dissolved in water
offensive drug before ingestion
Infectious Esophagitis: Other Types of Esophagitis:
• Rare in immunocompetent individuals • Chemotherapeutic agents such as dactinomycin,
• Herpes simplex virus is the most common viral bleomycin, daunorubicin, 5-flourouracil,
agent responsible for esophagitis in methotrexate and vincristine can cause
immunodeficient patients especially those with esophagitis secondary to oropharyngeal mucositis
HIV infection • Thoracic irradiation can cause esophagitis

392
 o Progressive fibrosis and degeneration of • Weight loss
blood vessels, smooth muscle cells, and • Vomiting blood
nerves PPI trial:
Gastroesophageal Reflux Disease
Definition: • Patients with classic GERD symptoms and no
Gastroesophageal reflux disease (GERD) is defined as alarm symptoms can be prescribed a PPI. If
symptoms due to mucosal damage caused by abnormal symptoms resolve → the diagnosis of GERD is
reflux of gastric contents into the esophagus. It can be confirmed
classified into non-erosive and erosive reflux disease. Upper endoscopy:

Epidemiology: • Patients with typical symptoms of GERD who are

• The prevalence can be as high as 20% unresponsive to PPIs should get an upper
• Western countries have higher prevalence of endoscopy
GERD (10 to 20%) than Asian countries (5%) • This will help in the classification of the patient
• These figures are based on the symptomatic into erosive or non-erosive reflux disease
diagnosis of GERD without the confirmation of • Patients with alarm symptoms should receive an
the diagnosis by endoscopy upper endoscopy as first-line diagnostic test
Esophageal pH monitoring:
Pathophysiology:
• Transient decrease in lower-esophageal sphincter • If the patient’s symptoms persist but they are
tone → gastric acid reflux atypical of GERD, esophageal pH monitoring is
• Associated with asthma indicated
Clinical Findings: Barium esophagram:
Typical GERD symptoms:
• GERD patients with dysphagia → to exclude
• Acid regurgitation – water brash peptic strictures
• Heartburn Esophageal manometry:
Atypical GERD symptoms:
• Patients who will receive surgical intervention for
• Epigastric fullness GERD must not have achalasia or scleroderma
• Epigastric pain Treatment:
• Dyspepsia • The treatment approach includes lifestyle
• Nausea modification, medical therapy and surgical
• Bloating therapy
• Belching Lifestyle modifications:
Extraesophageal symptoms:
• Weight loss
• Chronic unexplained cough • Elevation of head of bed
• Bronchospasm • Avoidance of nighttime meals
• Wheezing • Elimination of trigger foods (chocolate, caffeine
• Hoarseness and alcohol)
• Sore throat • Helpful, but rarely enough to control GERD
• Asthma symptoms
• Laryngitis Pharmacological therapy:
• Dental erosions due to acid reflux
• Patients with erosive reflux disease should
Diagnosis: receive a proton pump inhibitor such as
The diagnostic test is dependent on the patient’s omeprazole or lansoprazole
presentation and the presence or absence of alarm • Proton pump inhibitors block the H/K ATPase
symptoms. pump in the gastric parietal cell → acid
suppression
Alarm symptoms:
• H2 blockers such as ranitidine are helpful in non-
• Dysphagia erosive reflux disease
• Odynophagia • PPIs can still be needed on-demand in non-
• Iron deficiency anemia erosive reflux disease

393
 • Antacids such as aluminum hydroxide, • Esophageal adenocarcinoma is more common in
magnesium hydroxide, and calcium carbonate Western countries and affects lower third of the
have limited efficacy in GERD esophagus
Epidemiology:
• 8th most common cancer worldwide
• 6th most common cause of cancer-related deaths
• Incidence of esophageal adenocarcinoma (EAC)
of the distal esophagus is 2.8 per 100,000 in men
• The ratio of esophageal squamous cell carcinoma
of the upper esophagus to EAC of the distal
esophagus is 0.4:1 in the West
• EAC is becoming more common because:
o GERD incidence is increasing
o Obesity incidence has increased
• 5-year survival is 15%
Risk factors:

• Male dominant disease

Figure 139: The main targets of the pharmacological • Male to female ratio is 3:1
treatment of GERD. Source: • EAC is five times more common in Caucasians
https://en.wikipedia.org/wiki/Gastric_acid#/media/File:Det than in any other race
erminants_of_Gastric_Acid_Secretion.svg • Esophageal squamous cell carcinoma is more
common in Chinese and Asian individuals
Surgery:
• A body mass index > 30 is a risk factor for EAC
• Considered in patients who cannot tolerate • GERD → Barrett’s esophagus → EAC
medical therapy, who have medically-refractory • Smoking and alcohol are risk factors for
GERD, or in patients with GERD and a large squamous cell carcinoma of the esophagus
hiatal hernia • HPV infection in esophageal squamous cell
• Traditional fundoplication is an old procedure carcinoma
used in the treatment of medically-refractory • H. pylori infection is protective against EAC
GERD but it has a lot of complications • NSAIDs might be protective against EAC
• LINX Reflux Management System augments the Barrett’s Esophagus:
lower esophageal sphincter by the placement of a • The risk of EAC increases by 60-fold in patients
titanium bracelet with magnetic cores around the with GERD who develop Barrett’s esophagus
LES • Barrett’s esophagus is more common in men
Complications: • Replacement of nonkeratinized stratified
• Erosive esophagitis squamous epithelium with intestinal epithelium
(non-ciliated columnar with goblet cells)
• Peptic stricture
• Barrett’s esophagus
• Esophageal adenocarcinoma in Barrett’s
esophagus
• Pulmonary disease
Esophageal Cancer:
Definition
Esophageal cancer is an aggressive malignancy and a
leading cause of cancer-related death. In the Western
countries, adenocarcinoma is more common than
squamous cell carcinoma.

• Esophageal squamous cell carcinoma is more Figure 140: Barrett's esophagus as seen on endoscopy.
common worldwide and affects upper two-thirds Source:
of the esophagus https://en.wikipedia.org/wiki/Barrett%27s_esophagus#/me
dia/File:Barretts_esophagus.jpg

394
Clinical Findings: • The symptoms are often absent or non-specific
• Patients present with progressive dysphagia such as epigastric discomfort, nausea and
(solids before liquids) vomiting
• Some patients might present with bloody • The inflammation is confined to the mucosa
vomiting • The diagnosis is confirmed by endoscopy and
• Weight loss biopsy
• Clearly, the symptoms are very non-specific → • No place for radiological evaluation
the diagnosis is usually delayed • Microscopic appearance does not correlate with
Diagnosis: the clinical picture
• The symptoms of esophageal cancer are similar to • It is often caused by alcohol, bile reflux, or is
GERD with alarm symptoms drug-induced
• Accordingly, most patients will hopefully receive Severe erosive gastritis:
an upper endoscopy in the early diagnostic
workup • Severe epigastric pain, vomiting and hematemesis
• Once the diagnosis is confirmed by endoscopy, a are often present
biopsy might be taken • CT scan is helpful in confirming the diagnosis
• CT and PET are the next step to determine the • Endoscopy reveals deep ulcerations
local extension of the tumor (CT) and distant
metastasis (PET)
• Endoscopic ultrasound is no longer recommended
Treatment:
• Most patients are diagnosed when they have
dysphagia
o Dysphagia usually occurs in T2 or T3
stage (late presentation)
o Neo-adjuvant chemotherapy or
radiotherapy are indicated
• Surgery is indicated as the following:
Figure 141: Erosive gastritis of the antrum. Source:
o Barrett’s esophagus without EAC:
https://pictures.doccheck.com/com/photo/38008-erosive-
▪ Radiofrequency ablation
gastritis-antrum
o EAC confined to the mucosa:
▪ Endoscopic submucosal
dissection Causes of Acute Gastritis:
o Other Tx stages that are superficial: Reactive acute gastritis:
▪ Minimally invasive
• Caused by NSAIDs and aspirin
esophagectomy
• Most often confined to the greater curvature of
o Locally advanced esophageal cancer:
the stomach
▪ Multimodal treatment with
chemotherapy and debulking • NSAIDs interfere with arachidonic acid pathway
→ reduced prostaglandins which are needed for
surgery
mucosal wall protection
• A stent might be placed if stenosis occurs
Alcohol-induced acute gastritis:
Acute and Chronic Gastritis
General Characteristics of Acute Gastritis: • Heavy drinking can damage the mucosal layer of
Acute gastritis is a non-specific term that refers to different the stomach lining
diseases that cause inflammatory damage to the gastric • This can lead to ulceration
mucosa. Acute gastritis can be classified into: • Additionally, acute bacterial gastritis caused by
• Erosive gastritis which can be superficial, deep or Escherichia coli, Pseudomonas aeruginosa, and
hemorrhagic other bacteria is seen in patients who drink
massive amounts of alcohol → phlegmonous
• Non-erosive gastritis which is caused by
gastritis
Helicobacter pylori – H. pylori most often causes
chronic not acute gastritis Hemorrhagic and ulcero-necrotic acute gastritis:
Superficial acute gastritis: • These types of acute gastritis are seen in critically
ill patients

395
 • Major burns can result in massive water loss → • The final step would be stomach cancer
hypovolemia → decreased perfusion to visceral • Mucosa-associated lymphatic tissue lymphoma is
organs including stomach → ischemic injury and also seen in chronic H. Pylori infection
ulcer formation – Curling ulcer
• Can resemble the ulcers seen in NSAIDs but
involve the fundus of the stomach instead of the
greater curvature
• Traumatic brain injury can also result in
hemorrhagic acute gastritis either by similar
mechanisms or due to severe physical stress:
increased vagal stimulation → increased Ach →
increased H+ production
• This type of ulcer is also known as Cushing’s Figure 142: Chronic gastritis with atrophic gastritis.
ulcer Atrophic gastritis is confirmed by biopsy. Source:
https://www.gastrointestinalatlas.com/english/cronic_gastri
Diagnosis of Acute Gastritis: tis.html
• Endoscopy is the first diagnostic test
o Ulcers Treatment of Chronic Gastritis:
o Hyperemia
• The most important treatment is the eradication of
o Erosions
H. pylori
o A biopsy can be taken
• Triple therapy with amoxicillin, clarithromycin
• Urease breath test is used to screen for H. pylori and omeprazole is an option
infection → can cause non-erosive acute gastritis
Peptic Ulcer Disease:
• IgG and IgM antibodies specific to the suspected Definition:
offending organism Peptic ulcer disease refers to the injury of the stomach or
Treatment of Acute Gastritis: duodenum secondary to acid. In the past, it was
• Misoprostol can be used for the prevention of hypothesized that peptic ulcer disease is caused by a
NSAID-induced gastritis hypersecretory acidic environment. The current
• Antacids understanding of peptic ulcer disease emphasizes that the
• H2 blockers cause is H. pylori infection.
• Proton pump inhibitors
Epidemiology:
• Discontinuation of the offending agent: alcohol,
• Annual incidence is 0.1 to 0.3%
NSAIDs if possible, or other drugs
• Life-time prevalence is 5 to 10%
• Adequate IV fluid replacement in major burns’
• The incidence is decreasing after the introduction
patients
of new therapies for the eradication of H. pylori
Chronic Gastritis and its Types: Pathogenesis:
• Chronic gastritis is non-erosive • H. pylori infection, NSAIDs and aspirin are the
• While H. pylori may cause acute gastritis, it is main risk factors for peptic ulcer disease (PUD)
most often associated with chronic gastritis • Zollinger-Ellison syndrome can cause duodenal
• 90% of chronic gastritis are attributed to H. pylori ulcers
infection • H. pylori secretes different proteins which
• 10% of chronic gastritis are autoimmune → can activate the H+K+/ATPase channel or the
cause pernicious anemia due to intrinsic factor calcitonin-gene related peptide sensory neurons
deficiency → vitamin B12 deficiency • The effects are increased acid production by the
H. pylori chronic gastritis and cancer: gastric parietal cells
• In some cases, hypochlorhydria can develop →
• H. pylori chronic infection results in chronic non-
ulcers are still seen
erosive non-atrophic gastritis in the early stages
• H. pylori also secrete urease which increases the
• Eventually, atrophic gastritis occurs in the
pH of the stomach → more suitable for the
antrum, corpus or both
viability of other bacteria
• Intestinal metaplasia occurs in the atrophic
• NSAIDs can cause peptic ulcer disease by the
regions
following mechanism:
• Dysplasia in the form of intraepithelial neoplasia
occurs

396
 o Reduced prostaglandins → decreased
protective lining of the stomach → ulcer
formation
• Zollinger-Ellison syndrome is characterized by
hypergastrinemia → stimulates gastric parietal
cells to produce more HCl
The following table shows the differences between gastric
and duodenal PUDs.
Duodenal PUD gastric pud
h. pylori 90% - hypertrophy 70%
of Brunner glands
cancer risk Not increased Increased Figure 143: Air under the diaphragm in a patient with a
other causes Zollinger-Ellison NSAIDs perforated PUD. Source:
syndrome https://upload.wikimedia.org/wikipedia/commons/3/3c/Pne
presentation Pain decreases Pain increases umoperitoneum_modification.jpg
with meals with meals
Weight gain Weight loss Diagnosis:
Endoscopy:

Clinical Presentation: • Gold standard for the diagnosis of PUD

• Feeling hungry, and nocturnal abdominal pain in • A biopsy can be taken to confirm the presence of
duodenal ulcers H. pylori
• Postprandial abdominal pain, nausea, vomiting • Rapid urease tests
and weight loss in gastric ulcers
• Asymptomatic in the elderly
Hemorrhage:

• Can occur in gastric and duodenal ulcers

• Posterior duodenal ulcers can cause hemorrhage
more often than anterior duodenal ulcers
• Most common PUD complication
• Gastric ulcers usually erode the left gastric artery
• Duodenal ulcers typically erode the
gastroduodenal artery Figure 144: A PUD on upper endoscopy. Source:
• Can manifest as melena or hematemesis https://emedicine.medscape.com/article/181753-
• Mortality can be as high as 20% workup#c7
Obstruction:
H. pylori non-invasive tests:
• Ulcers in the pyloric channel or duodenum
• Patients present with gastric outlet obstruction • H. pylori is the most common cause of PUD
Perforation: • This led to the development of noninvasive tests
to screen for H. pylori
• More often in anterior duodenal ulcers than • Urea breath test and stool antigen tests are
posterior ulcers available
• An erect abdominal radiograph can reveal free-air Supporting tests:
under the diaphragm
• Irritation of the phrenic nerve → pain can refer to • Barium swallow test – do not order if you suspect
the shoulder a perforation
• Can result in peritonitis → shock → death • Blood gastrin levels – if Zollinger-Ellison
syndrome is suspected
Treatment:
• Offending agents such as NSAIDs, alcohol,
smoking or caffeine need to be stopped
• Triple or quadruple therapy to eradicate H. pylori:

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Triple therapy: o Decreased enterocyte height
o Crypt hyperplasia
• PPI plus amoxicillin plus clarithromycin for two o Villous atrophy
weeks o Increased intraepithelial T lymphocytes
Quadruple therapy: • Dermatitis herpetiformis:
o An inflammatory cutaneous disease
• PPI plus amoxicillin plus clarithromycin plus o Associated with celiac disease
metronidazole for two weeks
o Diffuse, symmetrical polymorphic
Other treatments:
lesions of erythema, urticarial plaques,
• Bismuth can be added to the previous regimens herpetiform vesiculae and blisters
• H2 blockers, misoprostol, and sucralfate are used o Erosions and excoriations
as adjunct treatments o Typically occur in the third decade of
life
• Bismuth and sucralfate increase the production of
Clinical Presentation
HCO3 in the base of the ulcer and provide
physical protection Typical celiac disease symptoms:
Celiac Disease • Chronic diarrhea and steatorrhea
Definition: • Failure to thrive
Celiac disease is a chronic inflammatory autoimmune
• Abdominal distention
disorder of the small intestine due to the ingestion of dietary
• 12 to 18 months of age
gluten products in susceptible people. An abnormal adaptive
Atypical symptoms:
immune response against gluten-containing grains is the
hallmark of the disease. Unlike other inflammatory • Symptoms secondary to malabsorption:
conditions of the GI tract, gluten-induced enteropathy is o Vitamin A, D, E and K deficiency
completely reversible if complete avoidance of gluten is o Vitamin B12 deficiency
possible. o Anemia
o Osteopenia
Epidemiology: • Short stature
• One of the most frequent genetically based • Recurrent abortions
disorders in humans
• Hepatic steatosis
• The estimated prevalence is 1 to 2% in the United
• Recurrent abdominal pain
States
• Dermatitis herpetiformis
• Most cases remain undiagnosed
Complications:
Risk factors for celiac disease: Osteoporosis:

• Family history • Most common complication

• Diabetes mellitus type-1 • Caused by abnormal calcium absorption due to
• Down syndrome defective calcium transport
• Anemia • Vitamin D deficiency (ADEK deficiency)
• Osteoporosis • Can be prevented by avoiding gluten-containing
• Northern European descent products during childhood
Pathology: Enteropathy-associated intestinal T cells lymphoma:
• 90% of patients with celiac disease express HLA-
• A very important complication
DQ2, the remainder express HLA-DQ8
• Complete avoidance of gluten-containing
• History of rotavirus infection in the first year of products might decrease the risk
life appears to increase the risk
Collagenous sprue:
• Gluten is composed of prolamines (gliadins) and
glutenin. • Increased deposition of collagen in the extra-
• An autoimmune response against gliadin appears cellular matrix
to be the pathology: Refractory sprue:
o Elicit T-cell responses
o Induces the production of cytokines • T-lymphocytes express only CD3 and not CD8 –
o Intestinal injury normal T-lymphocytes typically express both
• Histopathology: antigens
Other complications:
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 • Non-Hodgkin lymphoma Crohn’s Disease
• Small bowel adenocarcinoma Definition:
• Ulcerative jejunoileitis → hemorrhage, Crohn disease (CD) is a chronic inflammatory bowel disease
obstruction or perforation characterized by skip lesions and can affect any part of the
gastrointestinal tract from the mouth to the anus. The
Diagnosis:
inflammation is described as transmural.
Serologic tests:

• Antitissue transglutaminase antibodies (anti- Epidemiology:

tTGA) IgA antibodies • Annual incidence ranges from 3 to 20 per
o 97% sensitivity, 96% specificity and 100,000
98* accuracy • More common in the industrialized world
• IgA anti-endomysial has 100% specificity • Slightly higher predominance in women
• Anti-gliadin antibodies are no longer • More common in Ashkenazi Jews
recommended due to low specificity and Risk factors for celiac disease:
sensitivity
• Deamidated gliadin peptides can be used to • Gastrointestinal infections, NSAIDs and
increase certainty of the diagnosis antibiotics can increase the risk of CD by
Histology: changing the gut microbiome
• Salmonella and campylobacter infections appear
• Gold standard to diagnose celiac disease in adults to carry the highest risk of developing CD in the
• Villous atrophy, crypt hyperplasia, decreased next year
enterocyte height, and lymphocytes’ infiltrates of • Cigarette smoking doubles the risk of developing
the small-bowel mucosa CD
• Normal villi with intraepithelial T-lymphocytes • Diets that are high in sugar, omega-6 fatty acids,
can be seen in other conditions: polyunsaturated fatty acids, oil and meat
o Autoimmune enteritis • Family history
o NSAID-induced enteropathy • NOD2 gene polymorphisms
o Helicobacter pylori infection in the Pathology:
stomach
• Can affect any part of the GI tract
• Transmural inflammation:
o Non-stricturing – inflammatory
o Stricturing
o Penetrating
• Cobblestone mucosa, creeping fat, and bowel
wall thickening
• Linear ulcers and fissures
• String-sign on barium swallow
• Histopathology: noncaseating granulomas and
lymphoid aggregates. Th1 mediated
Figure 145: Histopathology in celiac disease. Source: • Malabsorption and increased risk of colorectal
https://en.wikipedia.org/wiki/Coeliac_disease#/media/File: cancer
Coeliac_path.jpg Clinical Presentation:
Location:
Other tests:
• HLA-DQ2 and DQ8 testing → if negative in an • 50% - terminal ileum and colon
asymptomatic patient, celiac disease can be ruled • 30% - small bowel only
out • 20% - isolated colon disease
• In vitro gluten challenge test • Less than 10% of the patients might present with
Treatment isolated perianal complaints, upper GI disease, or
• Life-long gluten-free diet extraintestinal manifestations
• Up to 25% of patients with CD have perianal
disease

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Gastrointestinal symptoms and signs: Diagnosis:
• A clinical diagnosis
• Abdominal pain • Endoscopy is helpful and can reveal the
• Diarrhea following:
• Weight loss o Skip lesions
• Low-grade fever o Varying degrees of inflammation
• Fatigue (erythema, friability, erosions and
• In patients with stricturing disease: ulcers)
o Small bowel obstructions o Luminal strictures
o Lack of fistulas and bowel movements o Fistulae
o Nausea and vomiting • Biopsy:
• In patients with penetrating disease: o Non-caseating granulomas only in 25%
o Fistulas of the patients
▪ Diarrhea in enteroenteric o Lymphocytes, plasma cells,
fistula granulocytes, and distortion of the crypt
▪ Urinary tract infection in architecture are other findings
enterovesicular fistula or o Paneth cell metaplasia → chronicity of
enterouretheral fistula CD
▪ Passage of stool from vagina • Imaging:
in enterovaginal fistula o Computed tomography enterography
▪ Drainage from skin in o Magnetic resonance enterography
enterocutaneous fistula o Small-bowel barium studies
o Abscesses • Serology:
• Bloody stool can be seen in severe colonic CD, o Current recommendation is to not
however this is more common with ulcerative perform serologic testing in CD
colitis o Anti-saccharomyces cerevisiae
Extraintestinal manifestations of CD: antibodies
• Laboratory supporting findings:
• Arthritis: o Elevated ESR and CRP
o 25% of the patients
o Peripheral and axial skeleton Treatment:
o Type I: flares with disease activity | a 5-aminosalicyclic acid:
pauciarticular arthritis involving < 6
• Sulfasalazine, oral mesalamine, and rectal
joints
mesalamine
o Type II: involves more than 6 joints and
is chronic | not related to disease activity • Inhibit cyclooxygenase and lipoxygenase →
o No synovial destruction decreased production of pro-inflammatory
prostaglandins and leukotrienes by the
• Skin manifestations:
arachidonic pathway
o Erythema nodosum – mirrors luminal
disease • Dose-related side effects: headache, epigastric
o Pyoderma gangrenosum – independent pain, nausea, vomiting and rash
of luminal disease • Idiosyncratic side effects: hepatitis, autoimmune
hemolysis, aplastic anemia, agranulocytosis and
• Primary sclerosing cholangitis:
pancreatitis
o More commonly seen in UC
o Not related to luminal disease Corticosteroids:
o Can result in cirrhosis, portal • Induction of remission in CD
hypertension, cholangiocarcinoma and
• Budesonide → lower systemic bioavailability
colon cancer Immunomodulators:
• Uveitis
• Scleritis • Azathioprine
• Osteoporosis and vitamin B12 deficiency • Methotrexate
• Deep vein thrombosis • Infliximab
• Nephrolithiasis • Adalimumab
• Failure to thrive in children

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Antibiotics: o 8% after 20 years
o 30% after 30 years
• Metronidazole o Cancer risk is dependent on the
• Ciprofloxacin disease’s duration and extent
Surgery in stricturing and fistula-forming CD
Clinical Presentation
Ulcerative Colitis Gastrointestinal symptoms and signs:
Definition:
Ulcerative colitis (UC) is a chronic inflammatory bowel • Bloody diarrhea
disease of the colon where there is diffuse friability and • Urgency and tenesmus
superficial erosions of the colonic wall and is often • Abdominal pain
associated with colonic bleeding. • Weight loss
• Fever
Epidemiology Extraintestinal manifestations of UC:
• Annual incidence ranges from 9 to 20 per
100,000 • Episcleritis, scleritis and uveitis
• Has a greater prevalence in adults when • Arthritis:
compared to Crohn’s disease o Peripheral
• Peak incidence in those aged 15 to 30, and those o Type I: flares with disease activity | a
aged between 50 to 70 years pauciarticular arthritis involving < 6
• Appendectomy reduces the risk of ulcerative joints
colitis o Type II: involves the axial skeleton | not
• Cigarette smoking appears to be protective related to disease activity
against ulcerative colitis o No synovial destruction
• Skin manifestations:
Pathology o Erythema nodosum – mirrors luminal
• Defects in colonic mucin and tight-junctions → disease
increased uptake of luminal antigens o Pyoderma gangrenosum – independent
• The lamina propria has an increased number of of luminal disease
activated and mature dendritic cells which • Primary sclerosing cholangitis:
express Toll-like receptors (TLR2 and TLR4) o Not related to luminal disease
• Th2 response o Can result in cirrhosis, portal
• TNF-alpha, interleukin 13, and natural killer T- hypertension, cholangiocarcinoma and
cells also play a role colon cancer
• Continuous involvement of the colon, with o P-ANCA positive
universal involvement of the rectum
Diagnosis:
• Starts from the rectum and moves proximally
• A clinical diagnosis
• Mucosal and submucosal inflammation • Endoscopy is helpful and can reveal the
• Loss of haustra → lead pipe appearance on following:
imaging o Continuous colitis with a friable mucosa
Histopathology: and superficial or deep ulcerations
• Lymphocytes, plasma cells and granulocytes • Biopsy:
infiltrate the mucosa and submucosa o Lymphocytes, plasma cells, and
granulocytes confined to the mucosa
• No skip lesions
and submucosa
• Goblet cell depletion
• Imaging:
• Crypt abscesses
o Double-contrast barium enema → lead
• No granulomas
pipe appearance
• Confined to the colon
• Serology:
Complications:
o P-ANCA positive in patients with PSC
• Fulminant colitis o ASCA antibodies – also found in CD
• Toxic megacolon o Elevated levels of carcinoembryonic
antigen in an active flare
• Perforation
• Supporting laboratory findings:
• Colonic cancer:
o 2% risk after ten years of diagnosis o Elevated ESR and CRP

401
The following table shows the current classification of UC. Acute Appendicitis
Definition:
Extent Endoscopic description Note
stage Acute appendicitis is the acute inflammation of the
E1 Proctitis Symptoms of the disease appendix. The most common etiology is the obstruction of
E2 Left-sided or distal colitis are also graded from S0 the appendix lumen by a fecolith which leads to infection
E3 Pancolitis (remission) to S3 (severe
UC) because of bacterial overgrowth.

Epidemiology
• One of the most common surgical emergencies
and causes of an acute abdomen
• More common in the Western world
• Mainly affects teenagers and young adults
• Lifetime risk is 6%
Pathology
Etiology: from most common to least common

• Fecoliths
• Lymphoid hyperplasia
• Intestinal worms
• Carcinoid tumors
Figure 146: Colonoscopy in UC. Source: Pathology:
https://en.wikipedia.org/wiki/Ulcerative_colitis#/media/Fil
e:UC_granularity.png • The most commonly involved bacterial organisms
are E. coli and B. fragilis
Treatment: • Obstruction of the appendix → continue
5-aminosalicyclic acid: production of mucous → the appendix enlarges
and become infected → inflammation of the
• Sulfasalazine, oral mesalamine, and rectal appendix → the appendix becomes fragile and
mesalamine can rupture
• Inhibit cyclooxygenase and lipoxygenase → • The swelling of the appendix impairs the venous
decreased production of pro-inflammatory drainage and eventually the arterial supply of the
prostaglandins and leukotrienes by the appendix → ischemic injury of the appendix →
arachidonic pathway increased risk of perforation
• Dose-related side effects: headache, epigastric • The afferent fibers supplying the appendix come
pain, nausea, vomiting and rash from the T10 sympathetic level → initially
• Idiosyncratic side effects: hepatitis, autoimmune periumbilical pain
hemolysis, aplastic anemia, agranulocytosis and • Eventually, the swollen appendix irritates the
pancreatitis parietal peritoneum → pain localizes to the right
Corticosteroids: lower abdominal quadrant
Clinical Presentation
• Budesonide → lower systemic bioavailability
Symptoms:
Immunomodulators:

• Azathioprine • Right lower quadrant pain – right iliac fossa pain

• Methotrexate • Nausea
• Vomiting
• Infliximab
• Anorexia
• Adalimumab
Surgery can be curative because the disease is confined to • Constipation – remember the most common cause
the colon. Indications for surgery: is a fecolith which is hardened stool
• Pelvic appendix → urinary frequency, suprapubic
• Failure of medial therapy pain and diarrhea
• Fulminant colitis, toxic megacolon or perforation McBurney’s sign:
• Uncontrollable bleeding
• McBurney’s point is 1/3 the distance from the
• Strictures
right anterior superior iliac spine to umbilicus
• Growth retardation in children

402
 • Deep tenderness in this point is indicative of oThere is no medical management of
acute appendicitis acute appendicitis
Rovsing’s sign: Diverticular Diseases
Definitions:
• Deep palpation of the left iliac fossa causes pain Diverticulum:
in the right iliac fossa
Obturator sign: A blind pouch protruding from the GI tract with
communication with the lumen of the tract. Acquired
• The leg of the patient is flexed and internally diverticula of the esophagus, stomach, and colon are false
rotated diverticula.
• Cause pain in acute appendicitis
Digital rectal examination: True diverticulum:

• Right-side tenderness in the case of a low-lying A diverticulum that has all the three layers of the gut wall.
pelvic appendix Meckel’s diverticulum is an example. They are congenital.
Psoas sign:
False diverticulum:
• The patient is instructed to flex the hip against A diverticulum that only has the mucosa and submucosa
resistance or the hip is extended passively layers of the gut wall. Diverticular diseases of the colon are
• If the position of the appendix is retrocecal → an example of false diverticula.
positive psoas sign
Diagnosis Asymptomatic diverticulosis:
• A clinical diagnosis An incidental finding of colonic diverticula on imaging or
• CT scan can be used to confirm the diagnosis and colonoscopy. They are not treated.
shows edema in the appendix wall and peri-
appendix fluid collections Diverticulitis:
• Other diagnostic studies are indicated to exclude
other possible diagnoses of acute abdomen: An inflammation of a diverticulum. Can be acute or
o β-hCG to rule out ectopic pregnancy chronic. Occurs in 10% of patients with diverticulosis.
o Ultrasound Symptomatic uncomplicated diverticular disease:
o KUB to rule out kidney or ureteric
stones Chronic diverticulosis with chronic abdominal pain but no
• Leukocytosis is often present acute diverticulitis or overt colitis.
Segmental colitis associated with diverticulosis:
Non-specific segmental inflammation in the sigmoid colon
associated with multiple diverticula. Does not need to
involve the diverticula.

Epidemiology:
• Diverticular disease is the 16th most common
cause of death among gastrointestinal diseases
• More than 2.5 million outpatient visits annually
are related to diverticular diseases
Figure 147: Abdominal CT in acute appendicitis revealing • More than 300,000 emergency department visits
peri-appendicular fluid collection and a fecolith. Source: per year are due to acute diverticulitis
https://www.aafp.org/afp/2005/0101/p71.html • Asymptomatic diverticulosis is the most common
finding on colonoscopy, especially in people
Treatment: older than 40 years
• Keep the patient NPO
Pathogenesis:
• Start antibiotics
Weakened colonic wall structure:
• IV fluids
• Laparoscopy appendectomy is the definitive • The diverticula are mucosal and submucosal
treatment herniations in the colonic wall muscle layer

403
 • Through the points of entry of blood vessels (vasa oAn abscess can be felt as a left lower
recta) into the muscularis externa quadrant tender mass and it can result in
• Most of the diverticula are found in the sigmoid high-grade fever
colon o A fistula might result in pneumaturia
• Family history appears to play an important role Segmental colitis associated with diverticulosis:
suggesting the contribution of genetics
• Inflammatory stenosis of the sigmoid colon →
• Age is perhaps the single most important risk
obstruction
factor for diverticular disease
Environmental risk factors: Diagnosis:
Diverticulosis:
• Low dietary fiber intake can result in constipation
and straining • Usually asymptomatic or associated with mild
• This can elevate the intracolonic pressures non-specific symptoms
• It can result in diverticulosis • Accordingly, most cases are incidentally
• The consumption of higher amounts of dietary diagnosed after colonic imaging is performed for
fiber in a patient with established diagnosis of other reasons
diverticulosis decreases the frequency of hospital • CT or colonoscopy
admissions and death
• Obesity appears to be a risk factor. It has been
reported that obese people have shifts in gut
microbiota which might explain the increased risk
of diverticular disease in obese individuals
• Diets high in fat and red meat might increase the
risk of diverticulosis
Pathophysiology of diverticulitis:

• Obstruction of the diverticulum by a fecalith

• Irritation of the mucosa, low-grade inflammation,
venous congestion and further obstruction
• This is known as uncomplication diverticulitis
• Complicated diverticulitis is classified as: Figure 148: CT scan showing diverticulosis of the sigmoid
o Diverticular abscess colon. Source:
o Diverticular fistula https://en.wikipedia.org/wiki/Diverticulosis#/media/File:Di
o Colonic obstruction vertDiseaseMark.png
o Diverticular perforation
Clinical Presentation: Diverticulitis:
Diverticulosis is most often asymptomatic, i.e. an
incidental finding on colon imaging studies. • CBC might reveal leukocytosis
• Anemia in case of hemorrhage
Symptomatic uncomplicated diverticular disease • An abdominal radiograph can reveal air-fluid
(Diverticulosis): levels (obstruction) or free air under the
diaphragm (perforation)
• Fatigue • CT can confirm the diagnosis
• Painless bloody stools • Barium studies are to be avoided → in case of
• Abdominal pain perforation, barium can cause chemical peritonitis
Diverticulitis:

• Left lower quadrant pain

• Fever
• Symptoms related to the complications:
o A perforated diverticulum will result in
severe abdominal pain, guarding and
possibly a high-grade fever

404
 • More common in men
• Extremely rare before the age of 40
Pathology:
Etiology:

•Abnormal physiology and structure of the

cricopharyngeus muscle due to aging →
dehiscence of the muscle during swallowing →
Zenker’s diverticulum
• The Killian triangle between the thyropharyngeal
and cricopharyngeal parts of the inferior
Figure 149: CT scan showing diverticular wall thickening, pharyngeal constrictor is the most commonly
a sign of inflammation, in diverticulitis. Source: affected location
https://en.wikipedia.org/wiki/Diverticulitis#/media/File:Di Pathophysiology:
verticulitis.png
• During swallowing, the intrabolus pressure is
Treatment: increased → elevated hypopharyngeal pressure
Symptomatic diverticulosis: → herniation of the mucosa and submucosa at the
• Increase dietary fiber intake weakened point just above the cricopharyngeus
• Avoid NSAIDs if the patient has past medical muscle | this could be due to esophageal
history of diverticulitis dysmotility
• Vigorous physical activity and weight loss lower • The sac of the diverticulum is lined by stratified
the risk of diverticulitis squamous epithelium
Diverticulitis: • The submucosa is fibrous
• Antibiotics such as metronidazole in selected • Ulcerations might be seen in the diverticulum
cases Clinical Presentation:
• In severe cases, consider keeping the patient NPO • Retention of food particles in the diverticulum:
(bowel rest) o Regurgitation
• IV fluids to prevent dehydration o Halitosis
• Blood transfusions in case of anemia secondary to o Aspiration
hemorrhage o Difficulty swallowing
Surgery: o Recurrent cough
• Usually reserved for patients with a perforated • Long history of dysphagia often precedes the
diverticulum secondary to diverticulitis diverticulum → esophageal dysmotility
• Hartmann’s procedure: • A visible lump might be seen in the neck
o The inflamed area is resected, and a Diagnosis:
stump is formed Barium swallow studies:
o After the inflammation resides (6
weeks), the two parts of the colon are • An outpouching will be seen on the radiograph
re-connected • Diagnostic
Zenker’s Diverticulum
Definition:
A Zenker’s diverticulum (ZD) is a false diverticulum of the
esophagus that develops in the hypopharynx between the
cricopharyngeal muscle and the inferior pharyngeal
constrictor muscle. It involves only the mucosa and
submucosa without the muscular layer of the esophagus. It
can occur in other locations in the esophagus.

Epidemiology: Figure 150: A Zenker's diverticulum as seen on a barium

• Rare swallow study. Source:
• More common in patients aged between 70 and https://en.wikipedia.org/wiki/Zenker%27s_diverticulum#/
90 years media/File:Zenker22015Lateral.JPG

405
Upper endoscopy: o Typically presents within the first two
• Indicated in the presurgical evaluation of the years of life
patient o May have two types of specialized
• Used for the staging of the diverticulum based on epithelia (gastric or pancreatic)
its size • The presence of acid-secreting gastric mucosa
Treatment: can result in GI bleeding and right-lower quadrant
• Asymptomatic diverticula < 2 cm do not require pain secondary to ulceration
any treatment Clinical Presentation:
• Symptomatic diverticula that are small in size and • Typically, asymptomatic, identified at the time of
associated with dysphagia: an appendectomy
o The patient’s symptoms are most likely • May present with hematochezia or melena
secondary to esophageal dysmotility not • Right lower quadrant abdominal pain
the diverticulum • Intussusception
o Botulinum toxin injection might
• Volvulus
decrease the dysphagia
• Small-bowel obstruction
• All other diverticula need to be surgically
removed Diagnosis:
• Meckel radionuclide scan:
Meckel’s Diverticulum: o Technetium-99m is injected
Definition: o It is absorbed by ectopic gastric mucosa
A Meckel’s diverticulum occurs when the o Visualization of the Meckel’s
omphalomesenteric duct in the developing embryo fails to diverticulum
completely obliterate. It is the most common congenital o Co-administration of cimetidine, or
anomaly of the GI tract and it is found in the small intestine. ranitidine increases the uptake of the
Acid secretion from the ectopic gastric mucosa within the radioactive contrast
diverticulum can lead to GI bleeding and abdominal pain. o Pertechnetate can be also used
This is a true diverticulum. • Radioactive tagged RBCs can identify the source
of bleeding in a patient with ongoing lower GI
Epidemiology: bleeding
• Most common congenital anomaly of the GI tract • These tests are rarely needed because the
• Patients with other congenital malformations are diagnosis of a Meckel’s diverticulum is assumed
at increased risk of having a Meckel’s in any child younger than 2 years of age who
diverticulum presents with painless lower GI bleeding
• Estimated prevalence is 2%
Treatment:
• If it becomes symptomatic, most patients present
• IV fluids replacement to prevent shock
in the first decade of life
• Blood transfusion might be needed
Pathology:
• Surgical excision is the treatment of symptomatic
• Incomplete obliteration of the omphalomesenteric
Meckel’s diverticulum
duct:
o This duct connects the yolk sac to the Hirschsprung's Disease
Definition:
gut
Hirschsprung’s disease (HD) is caused by failed migration
o At 7 weeks of gestation, it separates
from the intestine of colonic ganglion cells during gestation which results in a
congenital megacolon.
o If this does not occur, a Meckel’s
diverticulum might occur Epidemiology:
o An omphalomesenteric cyst is cystic • More common in boys
dilation of the incompletely obliterated • Family history of the disease is a very important
vitelline duct risk factor
• The rule of 2’s: • 1 in 5000 live births
o Two-times more common in females • Short-segment disease is the most common form
o Two-times more common to be o Confined to the rectosigmoid region of
symptomatic in males the colon
o Two-inches long • Long-segment disease passes the sigmoid
o Two-feet from the ileocecal valve • Most patients present in infancy
o 2% of the population

406
Pathology: • Absence of soiling
Etiology: • Chronic progressive constipation with onset in
• Polymorphisms or mutations in the RET proto- infancy
oncogene on chromosome 10q11.2 • Failure to thrive
• Associated with MEN type IIA • Fecal impaction
• More common in patients with Down syndrome • Progressive abdominal distention
• Other neurologic conditions linked to Diagnosis:
Hirschsprung disease: • Plain abdominal radiography shows a dilated
o Congenital deafness small or large bowel
o Hydrocephalus • Contrast enema radiographs are diagnostic:
• Can be associated with other congenital o Normal in the first 3 months of life
malformations such as: o Shows dilation of the normal colonic
o Meckel’s diverticulum portion
o Imperforate anus o The aganglionic portion appears normal
o VSDs o A transition zone can be identified
o Renal agenesis • The diagnosis must be confirmed by a rectal
o Cryptorchidism suction biopsy
o Waardenburg’s syndrome Treatment:
o Neuroblastomas • Serial rectal irrigation followed by surgery
o Ondine’s curse
Pathology: Volvulus
• Failure of ganglion cells to migrate Definition:
cephalocaudally through the neural crest within Volvulus occurs when a loop of the intestine (usually the
the 4th to 12th week of gestation colon) twists around itself and the mesentery that supports
• Absence of ganglion cells → colon is unable to it causing a closed-loop obstruction.
relax → proximal portion becomes dilated | a
transition zone Epidemiology:
• The Auerbach and Meissner plexuses are absent • More common in Africa and in people on high-
fiber diets
• The estimated annual incidence in the United
States is 2 to 3 per 100,000
• Most patients are old
• The most commonly affected portion is the
sigmoid colon. Sigmoid volvulus is seen in older
chronically constipated patients
• Cecal volvulus is uncommon and presents with
small-bowel obstruction
• Midgut volvulus is the most common type in
Figure 151: Megacolon in Hirschsprung's disease. Source: infants and is caused by intestinal malrotation
https://www.pinterest.com/rachel491/hirschsprungs- • Segmental volvulus occurs in any age and is due
disease/ to intestinal adhesions
Risk factors:
Clinical Presentation:
Symptoms during infancy: • Intestinal malrotation, Hirschsprung’s disease, or
• Bilious vomiting abdominal adhesions
• Enterocolitis-associated diarrhea • Mega-colon due to other causes
• Failure to pass meconium within the first 24 • Pregnancy
hours of life • High-fiber diet in chronically constipated patients
• Infrequent explosive bowel movements Pathology:
• Jaundice • The most well-studied mechanisms of volvulus
• Progressive abdominal distention are related to chronic constipation and high-fiber
• Tight anal sphincter diet
• Empty rectum • Chronic constipation → dilated sigmoid colon →
Symptoms in older children: more susceptible to torsion

407
 • Repeated attacks of torsion → shortened • Cecal volvulus requires early surgical
mesentery and formation of adhesions intervention
• The sigmoid colon gets twisted and entrapped in • Mortality even after surgical resection can still be
that position → volvulus as high as 15%
• Distension of the affected part → increased Intussusception
compression on mesenteric blood vessels → Definition:
bowel ischemia, acidosis and eventually necrosis Intussusception occurs when part of the intestine folds into
Clinical Presentation: the section next to it. It usually involves the small bowel.
Cecal volvulus: Patients present with abdominal pain that comes and goes,
bloody stools and symptoms and signs suggestive of small
• Nausea bowel obstruction.
• Vomiting
• Lack of flatus Epidemiology:
Sigmoid volvulus: • Usually a disease of infants and young children
• 2000 infants younger than one year develop
• Constipation intussusception each year in the United States
• Abdominal distension due to accumulation of gas • Most cases occur before the age of five months
and fluid • Rare after the age of 18 months
• Patients are usually old, bedridden and debilitated • Intussusception in adults is most often due to a
• Bloody stool neoplasm
• Prolonged volvulus will result in peritonitis and
bleeding per rectum → sigmoid colon Risk factors:
ischemia/necrosis
• Most cases are of unknown cause
Diagnosis:
• Infections
• Abdominal radiograph might reveal a bent inner • Altered motility
tube or a coffee-bean sign
• Meckel’s diverticulum
• A barium enema will reveal a bird’s peak
• Duplication
• CT and endoscopy in selected cases where the
• Polyps
cause of bowel obstruction is suspected to be
colonic cancer • Appendicitis
• Hyperplasia of Peyer’s patches
• Older rotavirus vaccines
Pathology:
• In most cases, the ileum enters the cecum
• Rarely, the ileum or jejunum prolapses into itself
• A peristaltic action of the intestine pulls the
proximal segment into the distal segment → more
prolapse of the proximal intestine into the distal
portion
o The portion of the intestine that
prolapses is known as the
intussusceptum
o The part that receives the prolapse is
known as the intussuscipiens

Figure 152: Coffee-bean sign in sigmoid volvulus. Source:

https://radiopaedia.org/articles/coffee-bean-sign-sigmoid-
colon

Treatment:
• Sigmoidoscopy or a barium enema
o High recurrent rate
o Bowel resection within the next two
days is recommended

408
 o Manually squeezing the telescoped part
might solve the issue
o If not possible, the affected portion of
the bowel might be removed

Figure 153: Telescoping of a proximal bowel segment into

a distal segment. Source: Figure 154: Intussusception on laparoscopy. Source:
https://en.wikipedia.org/wiki/Intussusception_(medical_dis http://sgc2014.kongress-
order) poster.ch/posters/retrograde_intussusception_of_the_roux_
limb_a_rare_complication_after_laparoscopic_rouxeny_ga
• The trapped portion of the small bowel can /
become ischemic
o Sloughing of the gut Other Intestinal Diseases:
o Red currant jelly – occurs in a minority Meconium Ileus:
of the patients Patients with cystic fibrosis due to a delta F508 mutation
Clinical Presentation: are more likely to develop exocrine pancreatic
Early symptoms: insufficiency and meconium ileus during the neonatal
period.
• Periodic “colicky” abdominal pain
• Nausea • The cause of meconium ileus is multifactorial
• Bilious vomiting • Increased absorption of fluid because of the
• Pulling legs to chest to ease the pain abnormal CFTR channel → dehydration of the
Later symptoms: intraluminal intestinal contents → formation of a
meconium plug → obstruction of the intestine
• Rectal bleeding and prevention of stool passage at birth
• Red currant jelly stool Presentation:
• Sausage-shaped mass on physical examination
Very delayed presentation: • Prolonged neonatal jaundice
• Early lung infections
• Bowel ischemia → necrosis → sepsis • Failure to pass stool at birth
• Patients might develop a fever • Other signs suggestive of cystic fibrosis:
Henoch-Schoenlein purpura: o Undescended testicles
o Pancreatic insufficiency
• Severe abdominal pain
The diagnosis can be confirmed by abdominal radiography.
• Other symptoms and signs suggestive of HSP
Diagnosis: Necrotizing Enterocolitis:
• A clinical diagnosis Definition:
• Ultrasound is the diagnostic modality of choice
for intussusception: Life-threatening illness affecting neonates and caused by
o Target sign or doughnut sign bacterial invasion into the intestinal wall.
o 3 cm in diameter
Epidemiology:
• Air enema is used for diagnosis and treatment
Treatment: • Most common life-threatening emergency of the
• Barium, water-soluble or air-contrast enemas are GI tract in neonates
diagnostic and therapeutic • Most cases present in the first second to third
o 80% success rate week of life
o 10% recurrence within the next 24 hours • Prematurity, low-birth weight, and formula
• Surgery: feeding are the main risk factors

409
 • Worldwide incidence is 0.3 to 2.4 per 1000 live • Laboratory findings:
births o Leukopenia
• Mortality ranges from 10 to 50% o Hyponatremia
• Severe cases with perforation and sepsis have a o Low serum bicarbonate
100% mortality rate o Negative blood cultures
Pathology: Treatment:

• Bacterial invasion into the intestinal wall • Stop all enteral feeding → NPO
• Inflammation and cellular destruction of the • Placement of a nasogastric tube to decompress
intestinal wall the bowels
• GI tract immaturity in premature infants play a • Intravenous broad-spectrum antibiotics
role (ampicillin, gentamicin plus “clindamycin or
• Histopathology reveals: metronidazole”)
o Bacteria within the intestinal wall • Parenteral nutrition
o Tissue ischemia and necrosis • Laparotomy in unresponsive cases and resection
o Microperforations → pneumatosis of nonviable bowel
intestinalis “air within the wall of the Imperforate Anus:
intestine” • Patients with trisomy 21 might develop GI tract
Presentation: anomalies:
o Duodenal atresia or stenosis
• Decreased appetite, vomiting, diarrhea and o Annular pancreas
increased abdominal girth o Imperforate anus
• Bloody stools • Imperforate anus is diagnosed in the neonatal
• Systemic signs of sepsis: period
o Respiratory failure • Can be associated with other anomalies:
o Circulatory collapse o Vertebral abnormalities
o Cyanosis o Cardiac defects
o Coma o Tracheal or esophageal fistulas/atresia
• Abdominal distention and tenderness o Renal abnormalities
• Visible intestinal walls o Limb defects
• Erythema of the abdominal wall Colon Cancer:
Diagnosis: Polyps:
Tubular adenomas:
• Abdominal plain radiographs:
o Dilated loops • 80% of neoplastic colonic polyps
o Pneumatosis intestinalis – visualization • Has a stalk and an adenoma or a cap
of small amounts of air within the bowel • Less likely to become cancerous
wall • When seen on colonoscopy, they are usually
o Portal venous air – poor prognostic sign resected and sent for histological examination
o Free air in the abdomen – perforation • May present with occult bleeding
• Caused by chromosomal instability due to
spontaneous mutations in the APC and KRAS
genes

Figure 155: A neonate with necrotizing enterocolitis.

Source: Figure 156: Tubular adenoma histology. Source:
https://en.wikipedia.org/wiki/Colorectal_polyp#/media/File
https://en.wikipedia.org/wiki/Necrotizing_enterocolitis
:Tubular_adenoma_2_high_mag.jpg

410
Villous polyps: Chromosomal instability pathway:

• 20% of neoplastic colonic polyps • 85% of the cases

• Sessile in configuration • Mutations in the APC gene are implicated in the
• Finger like projections adenoma-carcinoma sequence
• More likely to become cancerous • Once an adenoma develops, the chance that it will
become cancerous increases if both KRAS and
APC mutations occur
• The final step in this pathway is the loss of tumor
suppressor genes like p53 → development of an
adenocarcinoma
• The size of the adenoma is predictive of the risk
of progression to cancer (> 4 cm has a 40% risk
of becoming cancerous)
• The degree of dysplasia in an adenoma is also
Figure 157: Villous adenoma histology. Source: predictive of progression to cancer
https://en.wikipedia.org/wiki/Colorectal_polyp#/media/File Genetic Predisposition to Colon Cancer:
:Sessile_serrated_adenoma.jpg Familial adenomatous polyposis:
Familial predisposition to the formation of multiple
Colon Cancer Epidemiology
adenomatous polyps. The colon is riddled with
• Third most common cancer in the United States
adenomatous polyps.
• Most patients are > 50 years of age
• 25% have family history of colon cancer • Autosomal dominant mutation of the APC gene
Risk factors: on chromosome 5q21
• 100% risk of developing colon cancer
• Cigarette smoking
• Thousands of polyps start to arise after puberty
• Inflammatory bowel disease – especially
• Prophylactic colectomy
ulcerative colitis
Gardner syndrome:
• Large villous polyps
• Juvenile polyposis syndrome • Familial adenomatous polyposis plus osseous and
• Genetic predisposition soft tissue tumors (mandibular osteomas)
Molecular Pathways of Colon Cancer: • Congenital hypertrophy of the retinal pigment
Microsatellite instability pathway: epithelium
• Fibromatous abdomen
• 15% of the cases
• Impacted or supernumerary teeth
• Mutations or methylation of mismatch repair Turcot syndrome:
genes
o The DNA needs to be replicated when • Familial adenomatous polyposis plus brain
the cell divides malignant tumors (gliomas or medulloblastomas)
o During the process of replication, Peutz-Jeghers syndrome:
matching of nucleotides is important
o Sometimes, accidents can occur where • Numerous hamartomas throughout the GI tract
there is a mismatch • Hyperpigmented mouth, lips, hands or genitalia
o DNA polymerases checks the newly • Increased risk of breast, colorectal, stomach,
formed DNA strand scanning for small bowel and pancreatic carcinoma
mismatches Hereditary non-polyposis colorectal cancer (HNPCC):
o It cleaves off any mismatches
o When these DNA polymerases are • Lynch syndrome
defective, microsatellite instability • Autosomal dominant mutation of DNA mismatch
occurs repair genes → microsatellite instability
• MLH1 gene mutations • 80% develop colorectal carcinoma
• Cause Lynch syndrome • Proximal colon is always involved
• Serrated “villous” polyps can become • Patients can also develop endometrial, ovarian
carcinogenic via this pathway in sporadic and skin cancers
colorectal carcinoma

411
Clinical Presentation:
• Asymptomatic
• Hematochezia
• A recent change in the characteristics of stool
• Constipation
• Iron deficiency anemia secondary to occult blood
loss

Note: A patient who presents with

incidental iron deficiency anemia Figure 158: Apple-core lesion on barium enema
and is older than 50 years should be radiography in a patient with colon cancer. Source:
presumed to have colon cancer until https://radiopaedia.org/articles/apple-core-sign-colon-1
proven otherwise if a clear cause of
Tumor markers:
the anemia is not easily identifiable.
• CEA tumor marker for monitoring of recurrence
• Not indicated for screening
• Rectosigmoid more often than ascending more Liver Cirrhosis and Portal Hypertension:
often than descending colon Definition:
• Patients are at risk of developing S bovis Liver cirrhosis is characterized by fibrosis and nodule
bacteremia formation of the liver due to chronic hepatic injury. There is
diffuse bridging fibrosis maintained by stellate cells
alternating with regenerative nodules. The normal liver
Note: Ascending colon cancers are architecture is disrupted, and synthetic liver functions are
usually exophytic and the present deranged.
with iron deficiency anemia/weight
Epidemiology:
loss, whereas descending colon
cancers are infiltrating masses that • The estimated prevalence of liver cirrhosis in the
cause partial obstruction and United States is between 0.15 to 0.27%
hematochezia. Etiology:
Fatty liver diseases:

• Alcoholic liver disease

Diagnosis:
• Non-alcoholic fatty liver disease
• Male patients older than 50 years and
Viral:
postmenopausal females with iron deficiency
anemia should be screened for colon cancer • Hepatitis B
Low-risk patients screening: • Hepatitis C
• Colonoscopy at age 50 • Hepatitis D
Autoimmune:
• Alternatives:
o Flexible sigmoidoscopy • Autoimmune hepatitis
o Fecal occult blood testing • Primary biliary cirrhosis
o Fecal immunochemical testing
• Primary sclerosing cholangitis
o CT colonography
• IgG4 cholangiopathy
Patients with a first-degree relative with colon cancer:
Storage diseases:
• Colonoscopy at age 40 or 10 years prior to the
• Hemochromatosis
age of diagnosis of colon cancer in their relative
Diagnosis: • Wilson disease
• Alpha-1-antitrypsin deficiency
• Direct visualization of the lesion on colonoscopy Other causes:
• Confirmed by biopsy
• Recurrent bacterial cholangitis
• An apple core lesion on barium enema
• Bile duct stenosis
• Budd-Chiari syndrome

412
 • Right-heart failure prevent the progression, transform a decompensated patient
• Porphyria to a compensated cirrhotic patient, or to cause regression of
Pathophysiology: the disease. Source:
Main cells involved in hepatic cirrhosis: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583179/

• Hepatocytes Histopathology:
• Hepatic stellate cells
• Sinusoidal endothelial cells • Micronodular cirrhosis:
• Kupffer cells o < 3 mm in dimeter nodules
Fibrosis: o Seen in alcoholic liver disease and
hemochromatosis
• Stellate cells when exposed to pro-inflammatory • Macronodular cirrhosis:
cytokines transform into myofibroblasts o Irregular nodules some > 3 mm in
• They deposit collagen diameter
• Bridging fibrosis occurs o Viral hepatitis and alpha-1-antitrypsin
Role of Kupffer cells: deficiency
• Micronodular cirrhosis can progress to
• Kupffer cells are satellite macrophages macronodular type
• They release pro-inflammatory cytokines in Portal Hypertension:
response to viral hepatitis which activates the Pathophysiology:
stellate cells responsible for bridging fibrosis
• Damaged hepatocytes also release reactive • Chronic fibrosis and abnormal vaso-regulatory
oxygen species and inflammatory mediators that mechanisms of the liver result in an elevation in
activate hepatic stellate cells the portal pressure
Vascular regulation abnormalities in cirrhosis: • Collateral circulation becomes more important
and a hyperdynamic circulation occurs
• Portal hypertension • Nitric oxide and endothelin-1 act on hepatic
• Dysregulation of the systemic and splanchnic stellate cells:
circulation: o They control relaxation (NO) and
o Increased production of NO in the contraction (endothelin-1) of the
systemic and splanchnic circulation → sinusoids
vasodilation → decreased vascular o In liver cirrhosis endothelin-1
resistance production is increased whereas NO
o Activation of the RAAS → increased production is decreased
water and sodium retention → a o This results in increased intrahepatic
hyperdynamic circulation vasoconstriction and resistance
o Increased venous return to the heart by o Portal hypertension occurs
the formation of collaterals o If not treated, vascular remodeling by
Progression of liver cirrhosis: hepatic stellate cells occurs
o Eventually, collateral circulation is
formed
Collateral circulation and portal hypertension:

Figure 159: Hepatic fibrosis can progress to cirrhosis

which can become decompensated and eventually lead to
hepatocellular carcinoma. The goal of treatment is to

413
 o Testicular atrophy and gynecomastia in
men
o Amenorrhea in women
• Portal hypertension:
o Esophageal varices, which may bleed
causing hematemesis
o Gastric varices which can bleed
resulting in melena
o Caput medusae
o Anorectal varices
o Ascites
• Metabolic:
o Hyponatremia
o Hyperbilirubinemia
Typical findings in liver cirrhosis:

• Cutaneous signs of liver disease

• A firm enlarged liver on palpation
• Presence of risk factors for liver disease
Figure 160: The porto-systemic anastomoses in the Spontaneous Bacterial Peritonitis:
esophagus, stomach, spleen, skin, and hemorrhoidal veins. • Common in decompensated hepatic cirrhosis
Source: http://www.mmj.eg.net/article.asp?issn=1110- • Potentially fatal
2098;year=2017;volume=30;issue=1;spage=116;epage=12 • Bacterial infection in patients with cirrhosis and
1;aulast=El ascites
• Presents with fever, abdominal pain, ileus and
Clinical Presentation: worsening encephalopathy
Compensated cirrhosis: • Most often caused by aerobic gram – organisms
such as E. coli or Klebsiella. In rare cases, it can
• Asymptomatic cirrhosis detected by labs,
be caused by streptococcus
physical examination or imaging
• Diagnosed by paracentesis which shows a
• Possible findings on examination are
neutrophil count > 250 cells/mm3
hepatomegaly or splenomegaly
• First-line treatment is a 3rd generation
Decompensated cirrhosis:
cephalosporin such as cefotaxime
• Skin: Diagnosis:
o Jaundice Ultrasonography:
o Spider angiomas
• Inhomogeneity of hepatic tissue
o Palmar erythema
o Purpura and petechiae • Irregular hepatic surface
• Neurologic: • Caudate lobe enlargement and splenomegaly
o Hepatic encephalopathy and asterixis Advanced liver disease:
• Gastrointestinal: • Thrombocytopenia
o Nausea and vomiting • Hypoalbuminemia
o Dull abdominal pain
• Elevated INR
o Fetor hepaticus
• Elevated bilirubin concentration
• Renal:
• ALT and AST will be normal or mildly elevated
o Hepatorenal syndrome
“most hepatocytes are lost”
• Hematologic:
Esophagogastroduodenoscopy:
o Thrombocytopenia
o Anemia • Visualization of esophageal varices
o Coagulation disorders • Assessment of risk of bleeding
o Hypersplenism due to splenomegaly • Should be performed at time of diagnosis before
• Cardiovascular: onset of variceal bleeding
o Cardiomyopathy and peripheral edema
• Reproductive:

414
Biopsy: Pathophysiology of the Components of Liver Function
Tests:
• Contraindicated in most cases, unless the etiology AST:
of liver disease is unclear, and the patient is not in
decompensated cirrhosis • Present in cytosolic and mitochondrial
• Not useful in end-stage liver cirrhosis isoenzymes
Treatment: • Found in the liver, cardiac muscle, skeletal
The goal of management in patients with early liver disease muscle, kidneys, brain, lungs, pancreas,
is to prevent the progression of liver fibrosis to cirrhosis. leucocytes and red blood cells
• Not sensitive or specific for liver disease
• The treatment is based on the etiological ALT:
diagnosis
• Antiviral therapy in cirrhosis due to hepatitis B or • A cytosolic enzyme found mainly in the liver
C • Released after hepatocellular injury, not
• Treatment of iron or copper overload in necessarily cellular death
hemochromatosis and Wilson disease ALP:
respectively
• Abstinence from alcohol to prevent alcoholic • A member of the family of zinc metalloenzymes
cirrhosis • Concentrated in the microvilli of the bile
Liver Function Tests canaliculus, bone and intestines
Introduction: • Non-specific for biliary disease
• The main function of the liver is to detoxify GGT:
toxins and metabolites, synthesize proteins and to
produce other biologically important enzymes • Located on the membranes of cells with high
secretory or absorptive activities (biliary tree)
• The liver plays an important role in lipid and
glucose metabolism • More specific for biliary disease than ALP
Bilirubin:
• Liver function tests are helpful in understanding
the type of liver injury the patient might have and • Lysis of the hemoglobin within the red cells by
the most likely cause the reticuloendothelial system results in the
• The main classification based on the formation of unconjugated bilirubin
abnormalities seen in liver function tests are into • It is transported to the liver while bound to
cholestatic and hepatocellular pathology albumin
Differential Diagnosis in Patients with Abnormal Liver • Bilirubin gests conjugated in the liver to form
Function Tests: bilirubin glucuronide which can be secreted into
Hepatocellular pattern: the bile and gut
• Elevations mainly in alanine transaminase (ALT) • Conjugated bilirubin is water-soluble, i.e. can be
and aspartate transaminase (AST) found in the urine
• Viral hepatitis, vascular causes of liver injury, Synthetic function tests:
autoimmune hepatitis and storage-disease related • Albumin (10 grams are synthesized by the liver
hepatitis result in ALT-predominant pattern per day)
• Alcoholic hepatitis, cirrhosis, and non-hepatic • Prothrombin time which can be elevated in
causes present with AST-predominant elevations cirrhosis
• Non-hepatic causes of elevated AST: • Mainly dependent on factors II, V, VII and X
o Hemolysis which are synthesized by the liver
o Myopathy Clinical Correlation:
o Thyroid disease Alcoholic hepatitis:
o Exercise
Cholestatic pattern: • AST:ALT ratio is 2:1 or more
• Elevated GGT levels increase the certainty of the
• Elevations mainly in alkaline phosphatase (ALP),
diagnosis
gamma-glutamyl transferase (GGT) and bilirubin
Medication-induced hepatitis:

• Very high AST and ALT levels

• Synthetic liver dysfunction

415
Viral hepatitis: Clinical Presentation:
Stage 1:
• Mainly elevations in ALT
• Can be seen in any form of acute hepatitis caused • Persistent vomiting
by hepatitis A, B, C, D, E, EBV or CMV • Lethargy and nightmares
Autoimmune hepatitis: • Confusion
Stage 2:
• Elevated liver function tests without an apparent
cause • Stupor, disorientation and delirium
• Check for the following autoantibodies: • Hyperreflexia
o Anti-smooth muscle antibody • Hyperventilation
o Anti-liver/kidney microsomal antibodies Stage 3:
Non-alcoholic fatty liver disease:
• Coma
• AST:ALT ratio is 1:1, but both are elevated Stage 4:
• Other tests are normal
• Dyslipidemia • Dilated fixed pupils
• Type 2 diabetes mellitus • Deep coma with decerebrate rigidity
Hemochromatosis: Stage 5:

• Elevated ALT levels more than AST • Paralysis

• Elevated serum ferritin level • Seizures
• Transferrin saturation > 45% • Death due to respiratory arrest
Wilson disease: Diagnosis:
Diagnostic criteria:
• Abnormal liver function tests
• Low serum ceruloplasmin level • Acute noninflammatory encephalopathy
• > 100 micrograms of copper per 24 hours in urine documented by:
• Liver biopsy is needed to confirm the diagnosis o An alteration in consciousness and
Reye Syndrome o CSF containing 8 or less
Definition: leukocytes/mm3
Reye syndrome is a rare fatal pediatric illness that is • Liver biopsy only on autopsy to confirm the
characterized by acute noninflammatory encephalopathy diagnosis
and fatty liver failure. • Three-fold or more increase in serum glutamic-
oxaloacetic transaminase or serum glutamic-
Epidemiology: pyruvic transaminase levels
• Rare • Elevated serum ammonia
• Peak age of onset is 5 to 14 years Other diagnostic clues:
• Estimated incidence is 0.11 per 100,000
Pathology: • Elevated AST, ALT and bilirubin
• Most commonly preceded by a viral illness such • Abnormal coagulation studies
as influenza A or B • Elevated lipase and amylase
• More than 80% of those who develop Reye • Hypoglycemia
syndrome have taken aspirin in the preceding Treatment
three weeks • Supportive care and close monitoring
o After the widespread warnings against • Correction of hypoglycemia
aspirin use in viral illness in children, • Treatment of severe acidosis by sodium
the incidence of Reye syndrome has bicarbonate
dropped dramatically • Phenylacetate-sodium benzoate to treat
• Viral illness → mitochondrial injury perpetuated hyperammonemia
by aspirin → inhibition of fatty-acid metabolism • Correction of coagulopathies
• The encephalopathy is due to hyperammonemia Treatment of cerebral edema:
secondary to hepatic failure:
o Hyperammonemia may induce astrocyte • Head elevation to 30 degrees
edema → cerebral edema → elevated • Mannitol or hypertonic saline
ICP • Analgesia or sedation

416
 • Seizure treatment with antiepileptics • Presents very early
Hereditary Hyperbilirubinemias • Patients die within a few years
Bilirubin Physiology • Jaundice, kernicterus, and markedly elevated
unconjugated bilirubin
• Treated with plasmapheresis and phototherapy
• Liver transplantation is curative
Type II:

• Markedly decreased, but not absent, UDP-

glucuronosyltransferase
• Symptomatic unconjugated hyperbilirubinemia
• Responds to phenobarbital which increases the
liver production of UDP-glucuronosyltransferase
Dubin-Johnson Syndrome:
Pathology:

• Defective liver excretion of conjugated bilirubin

Presentation:

• Conjugated hyperbilirubinemia
Figure 161: Genetic disorders affecting bilirubin clearance. • Dark or black liver
Source: https://www.nature.com/articles/pr2015247 • Benign
Rotor Syndrome:
• Hemoglobin is broken down by the Pathology:
reticuloendothelial system into unconjugated
• Impaired intracellular transportation of
bilirubin
conjugated bilirubin
• Unconjugated bilirubin is water-insoluble → it is
• Impaired hepatic uptake of unconjugated bilirubin
bound to albumin
Presentation:
• Hepatocytes take the circulating bilirubin into the
cell for conjugation • Mild symptoms
• UDP-glucuronosyltransferase is responsible for • Normal liver color
the conjugation of bilirubin Wilson Disease:
• Conjugated bilirubin is water soluble and it needs Definition:
to be transported into the lumen of a bile Wilson disease is an autosomal recessive disease that
canaliculus results in excess copper buildup in the body with primary
• Diseases affecting bilirubin uptake, conjugation, involvement of the liver and basal ganglia. It is also known
or intracellular transportation will result in as hepatolenticular degeneration.
hereditary hyperbilirubinemias
Gilbert Syndrome: Epidemiology:
Pathology: • Incidence is 1 in 30,000
• Carrier frequency is 1 in 90
• Mild decrease in UDP-glucuronosyltransferase
• Consanguineous marriages increase the risk
conjugation
• Age at presentation ranges from 4 to 40 years
• Impaired bilirubin uptake
Presentation:
Pathology:
• Common and benign Etiology:
• Patients are often asymptomatic • A mutation in the hepatocellular-copper-
• Mild jaundice only with stress or fasting transporter ATP7B gene on chromosome 13
• Laboratory testing reveals elevated unconjugated • Important for the transportation and excretion of
bilirubin without hemolysis copper into the bile to be excreted in stool
Crigler-Najjar Syndrome: • 95% of copper excretion is by the liver
Type I: Pathophysiology:
• Copper is unable to leave the body →
• Absent UDP-glucuronosyltransferase accumulates in the liver and spills into the

417
 circulation to accumulate into other organ
systems:
o Subthalamus
o Putamen
o Cortex
o Kidneys
o Cornea
• Excess copper increases the formation of toxic
hydroxyl groups → increases oxidative stress:
o Liver damage → liver failure/cirrhosis
o Cortical damage → behavioral
abnormalities Figure 162: Kayser-Fleischer ring in Wilson's disease.
o Basal ganglia damage → movement Source: https://en.wikipedia.org/wiki/Kayser–
disorders Fleischer_ring#/media/File:Kayser-Fleischer_ring.jpg
o Corneal damage → Kayser-Fleischer Diagnosis:
rings Ceruloplasmin level:
• ATP7B is important because it links copper to • Less than 20 mg/dL
ceruloplasmin to be released into the bloodstream Confirmation of the diagnosis:
and removing the excess of copper by secreting it • Kayser-Fleischer rings, and
into bile • Urinary copper levels > 100 micrograms per dL,
• When defective, ceruloplasmin is secreted and
without being bound to copper → rapidly • Serum ceruloplasmin level < 20 mg/dL
degraded in the bloodstream • If in doubt, order a liver biopsy
• Damage of the lenticular nucleus and the liver →
hepatolenticular degeneration Treatment:
• Chelation therapy with penicillamine or trientine
Clinical Presentation: • Oral zinc supplementation
• Positive family history in some patients
• Abdominal pain Hemochromatosis:
• Jaundice Definition:
• Weakness Hereditary hemochromatosis is an autosomal recessive
• Personality changes disorder that affects the body’s regulation of iron. It is the
• Migraines most common genetic disease in whites. Iron overload in
• Seizures men is 24 times more common as compared to women with
• Movement disorders hemochromatosis.
• Hemiballismus
Physical examination: Epidemiology:
• Stigmata of chronic liver disease • The estimated prevalence in whites is 0.64 to
2.06%
• Kayser-Fleischer rings (also seen in primary
biliary cirrhosis) – due to copper deposition in • The estimated prevalence in other ethnic groups
Descemet membrane of cornea is from 0 to 0.1%
• Muscle rigidity and spasticity due to basal ganglia • 6% of those who develop cirrhosis secondary to
involvement hemochromatosis develop hepatocellular
carcinoma
• Bluish discoloration of the base of fingernails
• The risk of hepatocellular carcinoma is 20 times
higher in patients with hemochromatosis
o Most important cause of death
Pathology:
Iron physiology:

• Iron is important for normal cellular functions

and metabolism
• It is part of hemoglobin, myoglobin and the
cytochrome P450 system
• Total body iron levels are precisely regulated
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 • When disrupted, toxic levels of iron accumulate • Hepatocellular carcinoma
in different body organs
Etiology:
Note: Most patients are older than
• Abnormal expression of the HFE protein 40 years and become symptomatic
responsible for regulating hepcidin (important for only when total body iron > 20 g
iron regulation) – chromosome 6
o A missense mutation at aminoacids
position 282
o Production of C282Y Diagnosis:
o Decreased hepcidin expression in Who should be screened?
response to elevated iron levels
• Symptomatic patients
o Unregulated control of iron levels
o 90% of the patients have this mutation • Asymptomatic patients with abnormal iron study
results
Pathology:
• Patients with a first-degree relative diagnosed
• Excess iron deposition in the heart causes with hereditary hemochromatosis
restrictive cardiomyopathy, diastolic dysfunction, Serum ferritin and transferrin saturation:
dysrhythmias and conduction defects → AV
block and bradyarrhythmias can be seen • Transferrin saturation > 45%
o Reversible if recognized and treated • Serum ferritin levels are elevated
before onset of overt HF Confirmation:
• Excess iron deposition in hepatocytes → • HFE gene testing focusing on C282Y mutation
hepatocyte toxicity → fibrosis → cirrhosis Liver transaminase levels:
o 20-fold increased risk of hepatocellular
carcinoma compared to the general • When elevated, combined with the above
population findings, a liver biopsy might be indicated if
o Prognosis is largely dependent on the serum ferritin > 1000 ng/mL
presence of cirrhosis • Prussian blue stain is used in liver biopsy
• Deposition of iron in the pancreas → bronze
diabetes triad:
o Cirrhosis
o Diabetes
o Bronze skin pigmentation
• Impaired iron sensing → increased intestinal
absorption of iron despite elevated levels →
increased ferritin and total body iron and
decreased TIBC → elevated transferrin saturation
Clinical Presentation:
• Abdominal pain
• Amenorrhea
• Ascites
• Arthralgias due to calcium pyrophosphate
deposition in metacarpophalangeal joints
• Cardiomyopathy
• Cirrhosis
• CHF Figure 163: Liver biopsy in hemochromatosis. Source:
• Spider nevi, palmar erythema and bronze skin https://en.wikipedia.org/wiki/Iron_overload#/media/File:H
pigmentation emosiderosis_high_mag.jpg
• Diabetes mellitus
• Hypogonadism, hypothyroidism and other Monitoring:
endocrine dysfunctions
• Regular evaluation of liver, heart, and endocrine
• Splenomegaly and hepatomegaly
function
• Weakness
• Screening hepatic ultrasonography
• Weight loss
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Iron study results in hemochromatosis: • Early in the disease, the changes are mainly seen
in the portal tracts
iro ferrit transferri tib transfer hemoglo • The inflammatory infiltrate includes
n in n% c rin bin lymphocytes, plasma cells and neutrophils
Hig High High Lo Low Normal
• The ongoing inflammation results in periportal
h w
fibrosis, loss of bile ducts, and disorganized
ductular proliferation → eventually cirrhosis
Risk of cirrhosis in hereditary hemochromatosis: • Increased risk of biliary tree malignancy
o Not related to disease duration or
• Normal serum ferritin level → risk of cirrhosis is severity of biliary fibrosis
0 • More often with ulcerative colitis
• Elevated serum ferritin, but normal ALT/AST,
platelet count and no excessive alcohol use → Clinical Presentation:
45% • Liver specific symptoms such as itch, jaundice
• Elevated serum ferritin, ALT or AST, and and pain
thrombocytopenia but no excessive alcohol use • Non-specific symptoms such as fatigue
→ 80% • Most patients have history of inflammatory bowel
• Elevated serum ferritin, ALT or AST, disease
thrombocytopenia, and excessive alcohol use → • Most patients are identified by imaging and
> 80% biochemical testing
Treatment:
Treatment goals: Diagnosis:
Cholestatic pattern on liver function tests:
• Maintain serum ferritin between 50 to 150 ng/mL • AST and ALT might be elevated
(complete eradication of the risk of cirrhosis!) • ALP and GGT are markedly elevated
• Maintain hemoglobin level > 12.5 g/dL • Conjugated hyperbilirubinemia
Treatments: Supporting laboratory tests:
• A positive p-ANCA
• Repeated phlebotomy to maintain normal serum • Elevated IgM level
ferritin levels Imaging:
• Chelation therapy with deferasirox, deferoxamine • MRI cholangiography is the gold standard
or oral deferiprone diagnostic modality nowadays
Primary Sclerosing Cholangitis o Most cases are diagnosed early
Definition: nowadays before the classical picture of
Primary sclerosing cholangitis (PSC) is characterized by generalized beading of the biliary tree
chronic bile duct destruction that leads to end-stage liver and stenosis can be seen on
disease. Up to 80% of the cases are associated with cholangiography
inflammatory bowel disease.
• Endoscopic cholangiography is used for
intervention
Epidemiology:
o Alternating strictures and dilation with
• Estimated incidence in high-prevalence areas beading of the intra and extrahepatic
such as northern Europe is 1.3 per 100,000 bile ducts
• Estimated prevalence is 16.2 per 100,000 Liver biopsy:
• 60% of the patients are men • If endoscopic cholangiography is normal and you
• Median age at onset is 30 to 40 years still suspect PSC, a liver biopsy can help in
• Associated with inflammatory bowel disease confirming the diagnosis
• Most patients are non-smokers Colonoscopy:
• Full colonoscopy is indicated in any patient with
Pathology: PSC with no prior history of inflammatory bowel
• Progressive chronic injury of the small, medium disease
and large bile ducts • If the diagnosis of inflammatory bowel disease
• Inflammatory and obliterative concentric fibrosis has been established, colonoscopy should be
known as onion-skinning → biliary strictures performed every year after the diagnosis of PSC

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 o Presence of PSC in a patient with • Ethnic variability:
inflammatory bowel disease increases o Most common in native Americans
the risk of colon cancer o Extremely rare in Asians
Treatment: Risk factors:
Biliary interventions:
• Antibiotic prophylaxis during endoscopic • Female gender during reproductive years
retrograde cholangiography is mandatory • Use of estrogen containing contraceptives or
o Typically, ciprofloxacin hormonal replacement therapy
• Long-term antibiotics only in patients with • Obesity, especially in women:
recurrent cholangitis o Increased activity of HMG CoA
o Alternate between amoxicillin- reductase → increased biliary secretion
clavulanic acid, ciprofloxacin and co- of cholesterol → increased risk of
trimoxazole gallstones
• Endoscopic interventions are indicated for • Rapid weight loss → increased hepatic secretion
dominant biliary strictures and for the early of cholesterol into bile → gallbladder bile sludge
diagnosis of malignancy and formation of gallstones
o Increased risk of cholangiocarcinoma • Increased intake of fat and refined carbohydrates
and gallbladder cancer combined with decreased intake fiber appears to
Liver transplantation: be a risk factor for gallstones
• Indications: • Sedentary lifestyle
o Decompensated cirrhosis • Drugs:
o Intractable cholangitis o Fibric acid derivatives such as clofibrate
o Biliary obstruction o PPIs
o Hepatocellular carcinoma o Ceftriaxone
• Recurrence rate after transplantation is 20% • Diabetes:
within 5 years o Elevated levels of triglycerides increase
the risk of gallstones
Gallstones: Pathology:
Outline: • Gallstones form when the bile is oversaturated
• Definition with cholesterol or when there is an increased
• Epidemiology production of bilirubin
• Pathology • Gallbladder stasis is an important factor
• Clinical Presentation Cholesterol stones:
• Diagnosis
• 80% of all gallstones
• Treatment
Definition: • Up to 20% are radiopaque due to calcification
Gallstones, also known as cholelithiasis, are hardened Pigmented stones:
deposits composed of bile that form within the gallbladder. • Increased production of bilirubin
Epidemiology: • Seen in hemolytic diseases
• Gallbladder stones are more common in middle- • Associated with Crohn’s disease, chronic
aged and older individuals hemolysis, alcoholic cirrhosis, biliary infections
o The most common type is cholesterol and total parenteral nutrition
stones • Black on gross examination
o Biliary cholesterol saturation increases • Most of them are radiopaque
with age o Brown gallstones are due to infection
o As people age, the activity of and are radiolucent
cholesterol 7α hydroxylase decreases → Complications:
increased risk of cholesterol gallstones
• Women during fertile years are twice as common • Larger stones can obstruct the gallbladder →
to develop gallstones than men cholecystitis
o Estrogen increases cholesterol • Smaller stones can be dislodged and obstruct the
saturation in the bile and decreases common bile duct → cholangitis; or the
gallbladder movement → cholestasis → pancreatic exocrine duct → acute pancreatitis
formation of gallstones Biliary colic:

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 • Increased production of CCK after a fatty meal → • Provide functional information about gallbladder
contraction of the gallbladder → stone impaction contraction → helpful in acalculous cholecystitis
into cystic duct → right upper quadrant pain, Other diagnostic tests:
nausea and vomiting • A complete blood count might reveal
Clinical Presentation: leukocytosis
• Most patients are asymptomatic – silent stones → • Elevated bilirubin and ALP or GGT in patients
require no treatment in most cases with obstructive jaundice
• Recurrent episodes of right upper quadrant or Treatment:
epigastric pain → biliary colic Elective cholecystectomy:
• Biliary colic characteristics:
o Intermittent impaction of a stone in the • Patients with recurrent episodes of biliary colic
cystic duct should undergo elective cholecystectomy
o Right upper quadrant pain that increases • Children with asymptomatic gallstones should
in intensity over 30 minutes to few undergo elective cholecystectomy:
hours o Almost all of them will eventually
o Possible pain referral to the shoulder become symptomatic
blades or below the right shoulder • Asymptomatic gallstone disease in patients with
(Boas’ sign) sickle cell disease
o Attacks occur after a fatty meal and • During surgery for morbid obesity
always at night • Laparoscopic cholecystectomy is the treatment of
Acute cholecystitis as a presentation of gallstones: choice
Choledocholithiasis
• Most commonly caused by E. coli and Definition:
bacteroides species Choledocholithiasis is the presence of a stone, or stones,
• Severe right upper quadrant pain, nausea, within the common bile duct. It is the indication of
vomiting, fever and leukocytosis cholecystectomy in up to 22% of the patients.
• May progress to gangrene and perforation in
some patients Pathology:
Choledocholithiasis: • Gallstones can be classified into cholesterol
stones, mixed, or pigmented stones
• The stone might lodge in the common bile duct • Primary choledocholithiasis is the formation of a
• Obstructive jaundice biliary stone within the biliary tree without the
• May be painless in some patients presence of gallstones
Other presentations: • Secondary choledocholithiasis occurs when
gallstones are ejected from the gallbladder to be
• A fistula between the gallbladder and duodenum
later lodged within the common bile duct
might form
• Primary choledocholithiasis is most often due to
• Gallstones can be dislodged directly into the
brown stones (infectious etiology)
duodenum → obstruction of the duodenum →
Complications:
Bouveret’s syndrome
Diagnosis: • Acute pancreatitis
• History of biliary colic or a presentation of acute • Cholangitis
cholecystitis or choledocholithiasis are suggestive
of gallstones disease Clinical Presentation:
Ultrasonography: Charcot’s triad: in acute cholangitis
• Most often tool used in the diagnosis of • Right upper quadrant pain
gallstones disease and cholecystitis • Jaundice
• Specificity and sensitivity of 90 to 95% • Fever
• Can demonstrate the presence of common-bile- Biliary pancreatitis:
duct stones, bile-duct dilatation, and show • Acute pancreatitis with marked elevation in
thickening of the gallbladder wall serum amylase and lipase levels
Nuclear studies:
Note: In most patients, history of
• Technetium-99 m
established gallstone disease is
• Hepatic iminodiacetic acid (HIDA) or disopropyl
present.
iminodiacetic acid (DISIDA)

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Diagnosis: • Multiorgan dysfunction
Findings highly suggestive of choledocholithiasis: • Necrotizing pancreatitis
• Charcot’s triad Pathology:
• A common bile duct stone on transabdominal Anatomy and physiology:
ultrasound
• Serum bilirubin > 4 mg/dL • The pancreas has endocrine and exocrine
Liver function tests: functions
• Early elevation in AST and ALT • It releases digestive enzymes into the duodenum
• In persistent biliary obstruction → marked • A pancreatic duct runs from the pancreatic tail to
elevation in ALP and bilirubin enter the duodenum
Imaging: • In some cases, the pancreatic duct is joined by the
• Transabdominal ultrasonography common bile duct before entering the duodenum
• MR cholangiopancreatography o This anatomical variation means that a
• Endoscopic retrograde cholangiopancreatography gallstone might pass from the common
shows multiple filling defects in the common bile bile duct to the pancreatic duct,
duct – gold standard for the diagnosis of obstructing the latter
choledocholithiasis Pathophysiology:
Supporting tests: • Premature activation of exocrine digestive
• CBC can show leukocytosis in patients with acute enzymes in the pancreas → acute reversible
cholangitis inflammation
Treatment: • The most common causes are gallstones and
Goals of treatment: alcohol
• Removal of the biliary stone • Other less common causes include:
• Early recognition and treatment of complications: o Trauma
o Obstructive jaundice o Steroids
o Acute pancreatitis o Mumps
o Acute cholangitis o Autoimmune disease
Endoscopy: o Scorpion sting
• Capable of treating 90% of the cases o Hypertriglyceridemia
• Endoscopic sphincterotomy (sphincter of Oddi) o Hypercalcemia
and endoscopic papillary balloon dilation → o ERCP – as a complication
stone extraction o Sulfa-containing drugs, and protease
Surgery: inhibitors
• Laparoscopic common bile duct exploration or Complications:
laparoscopic-assisted trans-gastric endoscopic • Acute renal failure
retrograde cholangiopancreatography (LA-ERCP) • Acute respiratory distress syndrome
• Ascites
Acute Pancreatitis • Disseminated intravascular coagulation
Definition
• Ileus
Acute pancreatitis is characterized by premature activation
• Pancreatic necrosis
of the exocrine enzymes of the pancreas which results in
inflammation. • Pseudocyst formation
• Mesenteric venous or splenic venous thrombosis
Epidemiology: • Sepsis
• Approximately, 50,000 persons are admitted • Peritonitis
every year for acute pancreatitis • Fistula formation
• 40% are caused by choledocholithiasis Clinical Presentation:
• 35% are caused by chronic alcohol use or abuse Pain:
• 4% are caused by ERCP • Sudden onset left upper quadrant abdominal pain
• Mortality rate in mild acute pancreatitis is less • Periumbilical, epigastric or pain radiation to the
than 1% back have been described
• Mortality rate in severe acute pancreatitis is 30% • Painless in some patients
Bad prognostic features: • The pain worsens after eating fatty foods and
eventually becomes constant
• Hemorrhagic pancreatitis Other symptoms and signs:
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 • Nausea and vomiting Urinary trypsinogen activation peptide (TAP) has
• Clay-colored stools → obstructive prognostic value
choledocholithiasis
Treatment:
• Decreased urine output → multiorgan
dysfunction • Bowel rest
Examination: • IV fluid therapy:
• Fever o Potassium or dextrose might be needed
in addition to normal saline
• Hypotension
• Tachypnea and tachycardia • Analgesia:
o Acute pancreatitis can be quite painful
• Diaphoresis
to the patient
• Severe abdominal tenderness and guarding
• Nasogastric tube suction
• Jaundice
• Antibiotics:
Cullen sign:
o Need to include metronidazole
• Ecchymosis and edema in the subcutaneous tissue
• Surgery in necrotic pancreatitis or in the
around the umbilicus
management of pancreatitis complications
Grey Turner sign:
Pancreatic pseudocysts:
• Ecchymosis of the flank
• Has no true epithelial cell lining
Diagnosis:
• Formed by an inflammatory process → scarring
Initial workup:
and entrapment of pancreatic juices in the cyst
• A complete blood count → leukocytosis • Diagnosed by the finding of an elevated amylase
• Lipid profile level after the resolution of acute pancreatitis
• Lipase level → specific for pancreatic injury – 3 • Cysts larger than 5 cm or those that persist for
times the upper normal limit more than 6 weeks should be aspirated or
• Amylase level is elevated, but is not specific for surgically excised
pancreatic injury Acute Cholecystitis:
• Hypocalcemia Definition:
Etiological diagnosis: Acute cholecystitis is the acute inflammation of the
gallbladder wall secondary to cystic duct obstruction by an
• Contrast-enhanced computed tomography → impacted gallstone.
confirms the diagnosis
Epidemiology:
• Ultrasonography → gallstones
Further testing after establishing the cause: • The most frequent complication of gallstone
disease
• ALP, bilirubin level, MRCP and ERCP if the • One third of all surgical emergency hospital
cause is gallstone admissions
Prognostic labs: • 18.5% of all intra-abdominal source of infection
• Biliary stones are the main etiology
• Arterial blood gas • The risk of acute cholecystitis in patients with
• Calcium level gallstones disease is 1% per year
• CRP • The risk of acute cholecystitis in symptomatic
• Interleukin-6 and 8 gallstone disease is 20% per year → the rationale
• LDH level behind elective cholecystectomy in symptomatic
• Urinalysis gallstone disease
Pathology:
Pathophysiology:
Note: Lipase or amylase levels need
to be three times the upper normal • A gallbladder stone is impacted at the
limit for the diagnosis of acute infundibulum or the cystic duct → obstruction →
pancreatitis. A lipase to amylase continued mucin production and gallbladder
ratio of more than 4 is suggestive of distention → increased intraluminal pressure in
an alcoholic cause of pancreatitis. the gallbladder → impaired micro and
microcirculation perfusion of the gallbladder

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 • This results in serosa edema, mucosal sloughing, • Cholescintigraphy – not readily available but has
venous congestion and ischemic changes in the excellent accuracy
gallbladder wall o The gallbladder is not visible in acute
• This environment is optimum for bacterial cholecystitis
overgrowth, most often E. coli and bacteroides
species
• Necrosis of the gallbladder wall might result in
gangrene and perforation, two feared
complications of acute cholecystitis
Complications:

• Gallbladder perforation → peritonitis and sepsis

• Emphysematous cholecystitis
• Gangrene of the gallbladder wall
Clinical Presentation:
Pain: Figure 164: Abdominal ultrasound findings in acute
cholecystitis. Source:
• Right upper quadrant pain https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5442405/
• Positive Murphy’s sign
o Inspiratory arrest on RUQ palpation Treatment:
because of pain • Keep the patient NPO
• Pain may radiate to the shoulder plates or under • IV fluids
the right shoulder region • Analgesia
Other symptoms and signs: • Antibiotics
• Urgent cholecystectomy is recommended over
• The patient should not be jaundiced, unless there
delayed cholecystectomy
is concomitant obstruction of the common bile
o Laparoscopic approach is superior to
duct
open approach
Diagnosis:
Acute Acalculous Cholecystitis:
Initial workup:
• Bile stasis in the gallbladder, or hypoperfusion to
• Leukocytosis the gallbladder wall
• Elevated CRP level • Seen in critically ill patients
Scoring: • Confirmed by the presence of cholecystitis on
HIDA scan or ultrasonography without the
• The goal of scoring is to predict who is going to presence of gallstones
develop gangrenous cholecystitis Chronic Pancreatitis:
• The following five parameters are the main risk Definition
factors for gangrenous cholecystitis: Chronic pancreatitis is a progressive fibrotic inflammatory
o Age > 45 years disease of the exocrine pancreas which eventually results in
o Heart rate > 90 per minute the destruction of the pancreas and adversely affects the
o Gallbladder thickness on ultrasound > endocrine pancreas. Chronic pancreatitis is a possible
4.5 mm complication of recurrent acute pancreatitis or can be
o Leukocytosis primary and insidious in onset.
o Male gender
Imaging: Epidemiology:
• Estimated incidence is 4 per 100,000 per year
• No role for plain radiography • Prevalence is 41.67 per 100,000
• Abdominal ultrasound is the first-line imaging in • Men are more likely to develop chronic
acute cholecystitis pancreatitis
o Presence of gallstones • African Americans have a higher frequency of
o Increased gallbladder wall thickness chronic pancreatitis than whites
o Positive Murphy’s sign on abdominal Risk factors:
ultrasound
• CT is useful in confirming the diagnosis of • Alcohol is the single most important risk
emphysematous or gangrenous cholecystitis factor/cause of chronic pancreatitis and is

425
 responsible for 50% of the cases alone, and an • Serum lipase and amylase – normal or elevated
additional 40% of the cases combined with other Imaging:
risk factors
• Smoking • Abdominal CT scan shows pancreatic atrophy
• Family history and calcifications
• Ductal obstruction by inflammatory strictures,
benign tumors or malignancies
Pathology:
Etiology:

• Calcific pancreatitis:
o Alcohol, alone or with other risk factors
(90%)
o Smoking
o Genetic – cystic fibrosis Figure 165: Abdominal CT showing pancreatic
• Obstructive pancreatitis: calcification, atrophy and a dilated pancreatic duct. Source:
o Trauma http://dx.doi.org/10.1016/S0140-6736(16)00097-0
o Tumors
o Recurrent acute pancreatitis due to any
cause
Note: The diagnosis in most cases of
• Autoimmune
chronic pancreatitis is obvious, i.e.
• Idiopathic recurrent episodes of acute
Pathophysiology: pancreatitis and alcoholism. Imaging
• Increased viscosity of the interlobular and can confirm the diagnosis.
intralobular secretions secondary to a failure in
ductal bicarbonate secretion → formation of
protein-rich plugs Treatment:
• Ductal obstruction by the formed protein plugs → • Patients with chronic pancreatitis often have
inflammation → pancreatic parenchymal fibrosis intractable pain
• Ductal obstruction increases the pancreatic ductal o Opioids are often needed
intraluminal pressure → hypoperfusion to the o Celiac ganglion block
acinar cells → ischemic injury to the pancreas • Exocrine pancreatic replacement therapy:
• Eventually, the exocrine and endocrine pancreas o Trypsin and lipase
are destroyed → pancreatic exocrine and • Diet containing medium chain fatty acids:
endocrine deficiency o Their digestion is not dependent on
Complications: pancreatic enzymes
• Treatment of complications such as diabetes and
• Diabetes mellitus
pseudocysts
• Fat-soluble vitamin deficiency (A, D, E and K)
• Referral of the patient to an alcohol abstinence
• Pseudocysts program if possible:
• Steatorrhea – when 90% of the exocrine pancreas o Continued alcohol intake → increased
is lost risk of pancreatic cancer → very poor
Clinical Presentation: prognosis
• Recurrent acute pancreatitis Pancreatic Cancer
• Steatorrhea Definition:
• Weight loss Pancreatic cancer is an adenocarcinoma arising from the
• Type 3C diabetes mellitus due to the destruction pancreatic ductal system.
of beta-cells (similar to type 1 in that there is
absolute insulin deficiency) Epidemiology:
• Anorexia • Fourth leading cause of cancer death in the
Diagnosis: United States
Initial workup: • 5-year survival is 5 to 15%
• Is responsible for more than 300,000 deaths per
• Fecal elastase 1 – low specificity and sensitivity year in the United States

426
 • Highest incidence of pancreatic cancer is in those • Anorexia
older than 70 years • A palpable, non-tender distended gallbladder
• 90% of the patients are older than 55 years (Courvoisier sign)
Risk factors: • Acholic stools and dark urine → obstruction of
the CBD
• Alcohol • Recurrent DVT → pancreatic cancer creates a
• Physical inactivity hypercoagulable state
• High consumption of red meat • Migratory thrombophlebitis (Trousseau
• Cigarette smoking syndrome)
Pathology: Diagnosis:
Etiology: Initial workup:
• Smoking is responsible for 20% of pancreatic • Elevated ALP, conjugated bilirubin, and liver
cancers and is the most important risk factor function test abnormalities
• Diabetes • Elevated amylase and lipase levels
• Obesity • Elevated CA 19-9 and CEA levels (CEA is less
• Chronic pancreatitis specific)
• Occupational exposures Imaging:
• Genetic predisposition:
o Family history • Multidetector computed tomography is the
o Lynch syndrome imaging modality of choice to diagnose and
o Peutz-Jeghers syndrome evaluate pancreatic cancer
o Von Hipaul Lindau syndrome • PET CT to look for metastasis, which are often
o MEN1 present at time of diagnosis
Pathology:

• Most often it is an adenocarcinoma

• Can also be serous, sero-mucinous or mucinous
• 90% are duct cell adenocarcinomas (disorganized
glandular structure with cellular infiltration)
• Two thirds arise in the pancreatic head
• Associated with tumor markers CEA and CA 19-
9

Figure 167: Abdominal CT showing an adenocarcinoma of

the head of the pancreas. Source:
https://en.wikipedia.org/wiki/Pancreatic_cancer#/media/Fil
e:MBq_cystic-carcinoma-pancreas.jpg

Treatment:
Figure 166: Histopathology in pancreatic adenocarcinoma • Whipple procedure for tumors located in the head
showing disorganized glandular structure with cellular of the pancreas
infiltrates. Source: o Pancreaticoduodenectomy
https://en.wikipedia.org/wiki/Pancreatic_cancer#/media/Fil • Postoperative chemotherapy with 5-florouracil
e:Pancreas_adenocarcinoma_(4)_Case_01.jpg and gemcitabine
• Postoperative radiotherapy
Clinical Presentation: • Involvement of the hepatic artery renders the
• Painless jaundice (70%) cancer unresectable
• Weight loss • Average survival after diagnosis is 1 year
• Abdominal pain o Extremely bad prognosis
• Weakness
• Pruritus

427
Small Bowel Obstruction • Increased intraluminal pressure → increases
Definition: peristalsis above and below the obstruction →
Small bowel obstruction (SBO) is defined as any luminal early diarrhea and flatus
obstruction from the duodenum to the terminal ileum. • Proximal SBO → vomiting
• Prolonged SBO → increased intraluminal
hydrostatic pressure → increased pressure in
capillary beds → third-spacing of fluid,
electrolytes and protein into the intestinal lumen
→ dehydration
• Severe dehydration in SBO is the main
determinant of morbidity and mortality
• Continued distention of the small bowel leads to
twisting on the mesenteric pedicle → strangulated
SBO → arterial occlusion, ischemia and necrosis
→ if untreated, perforation, peritonitis and death
Clinical Presentation:
• Nausea and vomiting, typically bilious
Figure 168: Adhesions are the most common cause of
• Constipation or obstipation → a late finding
SBO. Source: http://www.clearpassage.com/avoid-
surgery/avoid-surgery-for-small-bowel-obstruction/ • Abdominal distention with visible peristalsis
• Fever and tachycardia are seen in patients with
Epidemiology: strangulated SBO
• 15% of hospital admissions for abdominal pain • Intermittent abdominal pain which may progress
are due to SBO to become constant
• Approximately, 300,000 hospital admission • Presence of signs of peritoneal irritation such as
annually rebound tenderness or guarding → bowel
• 75% are caused by postoperative adhesions ischemia
• Malignancy, Crohn disease, and hernias account Diagnosis:
for the remainder of the cases in the Western Laboratory workup:
world • Serum electrolytes which can be impaired in
• In the developing world, the most common cause patients with third-space fluid loss and
is hernia followed by adhesions, tuberculosis and dehydration
least common are malignancy, Crohn disease and • Elevated BUN and creatinine levels in dehydrated
parasitic infections patients
Pathology: • Serum lactate levels which may be elevated in
Etiology: ischemic bowel injury
• CBC which may show leukocytosis in prolonged
• Intraabdominal adhesions postoperatively → SBO secondary to bacterial overgrowth and
typically 4 weeks post-surgery infection
• Malignancy (10%) Imaging:
• Incarcerated groin hernias (10%)
• Inflammatory bowel disease, volvulus and • Upright plain abdominal radiography which
miscellaneous causes account for the remainder might show air-fluid levels or absence of gas in
of the cases the small bowel
• Pediatric causes of small bowel obstruction: • Multi-slice CT has excellent sensitivity in
o Congenital atresia diagnosing SBO
o Pyloric stenosis o Helpful in detecting complications of
o Intussusception SBO such as ischemia, perforation, and
Pathology: mesenteric edema
• Ultrasonography, which as a specificity of 100%
• An SBO leads to proximal dilation of the (good for exclusion of SBO)
intestine • Barium studies should be cautiously used:
o Accumulation of GI secretions and air o Barium is very irritating/toxic to the
o Stimulation of cell secretory activity peritoneum in case of perforation

428
 Pathology:
Etiology:
Mesenteric arterial occlusion:

• Embolism in patients with atrial fibrillation or

arterial embolic disease
• Congestive heart failure
• Digitalis therapy
• Hypercoagulable state
• Hypovolemic shock
Venous thrombosis:

• Portal hypertension
• Trauma
Figure 169: Multiple air-fluid levels on a plain radiograph • Hypercoagulable state
indicative of SBO. Source: Wikiradiography • Chronic renal failure
Treatment: • Intra-abdominal inflammation
Pathology:

• Atherosclerotic vascular disease → atheroma

Note: The etiological diagnosis is formation → plaque rupture and thrombosis →
important because treatment is blockage of the lumen of the artery
usually tailored to the cause of SBO. • Embolism from another source such as a mural
thrombus in atrial fibrillation → occlusion of the
superior mesenteric artery
• Hypercoagulable states:
Initial treatment: o Factor V Leiden
• IV fluids to replace third-space loss o Antithrombin III deficiency
Nonoperative treatment: o Protein C deficiency
Inflammatory bowel disease associated SBO: • Ischemic injury to the affected part of the bowel
• High-dose steroids → small bowel necrosis → sloughing of the
• Bowel rest mucosa presents as currant jelly stools
Malignancy: Clinical Presentation:
• Usually a metastatic tumor • Postprandial pain
Operative treatment: • Abdominal pain out of proportion to findings
• Strangulated SBO → surgical emergency • Nausea and vomiting
• Obstipation → complete SBO → early surgical • Hemodynamic instability
intervention • Established diagnosis of other comorbidities
• Laparoscopy is superior to open laparotomy Complications:
Prevention:
• The most common cause of SBO is postoperative • Sepsis
adhesions • Septic shock
• Limiting laparotomy by utilizing minimally • Necrosis and perforation of part of gut
invasive techniques and laparoscopy has been • Death – remember these patients have other
proven to decrease the incidence of SBO comorbidities
Diagnosis:
Acute Mesenteric Ischemia Laboratory workup:
Definition:
Acute mesenteric ischemia can only occur in patients with • CBC: leukocytosis
preexisting comorbidities. It can be classified into 4 types: • Elevated lactate levels
acute superior mesenteric artery thromboembolic occlusion, • Elevated serum amylase and LDH levels
mesenteric arterial thrombosis, mesenteric venous CT angiography confirms the diagnosis
thrombosis and nonocclusive mesenteric ischemia.

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Treatment: Pathology:
Classical signs of mesenteric ischemia on history and CT Pathology:
in an unstable patient:
• Autoimmune reaction which might be triggered
• Transfer the patient to the OR immediately or to by recurrent E. coli infections
endovascular therapy • Lymphocytic infiltrate and granuloma formation
Stable patients with classical signs of mesenteric ischemia: in the biliary ductal system → destruction of
lobular bile ducts
• IV fluids • Associated with other autoimmune disorders
• Antibiotics Clinical Presentation:
• Anticoagulants • Fatigue is present in most patients:
• Early endovascular intervention o Could be caused by elevated
Insidious onset or vague symptoms: inflammatory cytokines and excessive
manganese deposits in the globus
• Anticoagulation pallidum
• IV fluids • Pruritus:
• Bowel rest o Caused by cholestasis
• Repeat CT • Jaundice
• Treatment of the possible causes • Xanthomas
• Exploratory laparotomy in unresponsive cases • Osteoporosis
Primary Biliary Cirrhosis • Dyslipidemia:
Outline: o Reduction in biliary secretion of
• Definition cholesterol
• Epidemiology o Hypercholesterolemia and
• Pathology hyperlipidemia
• Clinical Presentation
• Diagnosis
• Treatment Note: Prognostic models such as the
Mayo Risk Score take into account
the patient’s age, bilirubin, and
Definition: edema severity in determining
Primary biliary cirrhosis (PBC) is an autoimmune which patients should be considered
progressive cholestatic liver disease characterized by for a liver transplantation.
cholestasis, circulating anti-mitochondrial antibodies and Fortunately, most patients nowadays
nonsuppurative destructive cholangitis and interlobular bile do not need a liver transplantation.
duct destruction.

Epidemiology:
• More common in women Diagnosis:
• Median age of diagnosis is 50 years Diagnostic criteria: Two of the following are needed
• Estimated prevalence in the United States is 400 • Anti-mitochondrial titer > 1:40
per million
• ALP > 1.5 times the upper limit of normal for >
• Much less common in Africa or Asia with an 24 weeks (cholestatic liver disease)
estimated prevalence of 20 per million
• Nonsuppurative destructive cholangitis and
Risk factors: interlobular bile duct destruction on liver
• Recurrent urinary tract infections histology
• Cigarette smoking Stages of PBC on histology:
• Alcohol consumption could be protective! 1. Portal inflammation
• Family history 2. Increased size of periportal lesions with interface
• Presence of other autoimmune diseases such as hepatitis
Raynaud syndrome or Sjogren syndrome 3. Distortion of hepatic architecture with fibrous
• HLA-DR7 and DR8 septa
• HLA-DR11 and DR13 are protective 4. Cirrhosis

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Inflammation in PBC: Pathology:
Etiology:
• Mainly lymphocytes
• Some mononuclear cells • Strong association with chronic HBV and HCV
• Near the basal membrane of the cholangiocytes infection
(which undergo necrosis and destruction) • Associated with other causes of cirrhosis such as
• Granuloma formation due to lymphohistiocytic excessive alcohol consumption and coinfection
cells with HDV
• Cigarette smoking increases the risk
• Environmental exposure to aflatoxin
• Treatments that prevent hepatic cirrhosis in at-
risk patients decrease the risk of hepatocellular
carcinoma
Pathology:

• Chromosomal instability or single nucleotide

polymorphism in a patient with chronic liver
disease predispose him/her to tumorigenesis
Figure 170: Lymphocytic infiltrates around the small bile • Mainly signaling pathways JAK/STAT, WntB-
ducts in a patient with early PBC. Source: catenin, and mTOR
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419097/ • Hepatocellular carcinoma displays significant
genomic heterogeneity → failure to develop
Treatment: targeted therapy
UDCA therapy: • Presence of gene mutations in the tumor
suppressor gene p53 is associated with poor
• Ursodeoxycholic acid prognosis
• Protection of cholangiocytes • Can resemble fibrolamellar hepatic tumors:
• Stimulation of biliary secretions of bile acids o More common in the young
• Can cause diarrhea o Not associated with chronic hepatitis
Corticosteroids: o Normal alpha-fetoprotein levels
o Mostly resectable
• Useful in patients with interface hepatitis
Clinical Presentation:
Hepatocellular Carcinoma:
• Initially asymptomatic or symptoms and signs of
Definition:
chronic liver disease
Hepatocellular carcinoma is a primary liver cancer that is
increasing in frequency in parallel to the increasing • Upper abdominal discomfort and distention
incidence of chronic liver disease and cirrhosis. • Weight loss
• Fever
Epidemiology: • Anorexia
• Fifth most common cancer • Early satiety
• Second cause of cancer-related death • Diarrhea
• Most of the cases are due to chronic viral B and C
hepatitis
• Estimated incidence in men is 11.5 per 100,000 Note: Acute liver decompensation in
• Estimated incidence in women is 3.9 per 100,000 a patient with compensated cirrhosis
• Male to female ratio 3:1 = suspicion of a hepatocellular
• Most common present in the elderly carcinoma.
• HCV is the most common cause in the United
States
Paraneoplastic syndromes:
Note: Most common cause of liver • Hypoglycemia
malignancy is metastatic disease • Erythrocytosis
from other sources. • Hypercalcemia
• Severe watery diarrhea

431
Diagnosis: these three features (for example, does the hernia have a
Assessment of the severity of liver disease: narrow long neck as in femoral hernia or a wide short
neck?).
• Synthetic liver function tests such as albumin and
prothrombin time The most commonly seen hernial contents are fat and
• Bilirubin levels bowel, however any abdominal structure or organ can
• AST and ALT herniate.
Diagnosis in high-risk patients:
Incarcerated hernia:
• MRI or CT
Non-reducible hernia that fails to be reduced back to the
• An increased alpha-fetoprotein level abdomen or pelvis after applying pressure.
• Biopsy is not required if the MRI shows
characteristic findings on T2 imaging Strangulated hernia:
Diagnosis in low-risk patients:
A hernia that has its neck compressed → compromised
• MRI, CT or ultrasound venous return and congestion → compromised arterial
• If a hepatic tumor/nodule is identified, biopsy supply → ischemia → necrosis
must be taken
• The diagnosis can be confirmed only by biopsy • Tenderness
• Erythema
• Fever
Epidemiology:
• The lifetime risk of a spontaneous abdominal
hernia is 5%
• Hernia repair procedures are the second most
common abdominopelvic operation in the United
States
A B
• More than one million repairs per year
Figure 171: A. Histopathology examination of a liver • Inguinal hernias are way more common in males
biopsy showing a hepatocellular carcinoma. B. CT than in females
showing a hepatocellular carcinoma. Source: o 10% are bilateral
https://en.wikipedia.org/wiki/Liver_cancer#/media/File:CT o 70% of all abdominal wall hernias
_cholangioca.jpg • Femoral hernias are more common in females;
however, inguinal hernias remain more common
Treatment: in females than femoral hernias
• Surgical resection if possible (20% of the o 15% of abdominal wall hernias
patients) • The remainder of the abdominal wall hernias can
• Chemotherapy and radiotherapy be classified as umbilical, epigastric and
• Liver transplantation incisional types
Liver Adenoma: • Strangulation, a possible complication, is more
• Most common in middle-aged women common in internal hernias such as
• More common in pregnant women or those taking diaphragmatic hernias
estrogen-containing oral contraceptives Pathology:
• The diagnosis is confirmed by ultrasonography • Increased intraabdominal pressure is the main
which reveals a mass with well-defined borders predisposing factor for the development of an
• Some patients might have elevations in AST/ALT abdominal hernia in adults. It can be caused by:
or GGT o Obesity
• Most people are asymptomatic o Chronic cough
• Symptomatic treatment is indicated which may be o Bladder outlet obstruction
hormonal therapy or resection o Ascites
Hernias: • The second important predisposing factor is a
Definition: weakened abdominal musculature which can be
A hernia is a protrusion of a part or a structure through caused by:
tissues that normally contain it. A hernia has a sack, a neck o Previous surgery
and contents. The complications of hernias are related to o Trauma

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 o Aging • Lateral to the inferior epigastric vessels
o Impaired wound healing • Covered by all 3 layers of spermatic fascia
• The typical presentation of an uncomplicated • Follows the path of descent of the testicles
abdominal hernia is: Etiology:
o A lump that appears and increases in
size with coughing, standing or straining • Failure of closure of the processus vaginalis
o The lump reduces spontaneously or with This type of hernia is more common in males and can be
manual manipulation by the patient or diagnosed in infants or in adults.
the surgeon
Inguinal Hernias: Direct inguinal hernia:
Anatomy of the inguinal canal: Definition:
• The deep internal ring is found in the The hernia protrudes through the parietal peritoneum
transversalis fascia, lateral to the inferior directly (inguinal or Hesselbach triangle).
epigastric vessels
• The spermatic cord gets its internal spermatic Anatomical landmarks:
fascia from the transversalis fascia
• Another opening is found in the transversus • Medial to the inferior epigastric vessels
abdominis muscle • Lateral to the rectus abdominis muscle
• The spermatic cord pierces the transversus • Only covered by the external spermatic fascia
abdominis muscle and the internal oblique muscle • Only passes through the external inguinal ring
• It drags with it a layer of the internal oblique → • Hesselbach triangle:
cremasteric muscle and fascia o Inferior epigastric vessels laterally
• Finally, it passes through the external inguinal o Lateral border of rectus abdominis
ring found in the aponeurosis of the external medially
oblique muscle → forms the external spermatic o Inguinal ligament inferiorly
fascia Etiology:

• More common in older men

• Caused by weakened abdominal muscles and
transversalis fascia
Femoral Hernia:
Definition:
A hernia that protrudes below the inguinal ligament
through the femoral canal.
Anatomy landmarks:

• Below and lateral to the pubic tubercle

• Below the inguinal ligament
• Medial to the femoral vessels
Clinical significance:
Figure 172: Anatomy of the inguinal canal. 1. Indirect
inguinal hernia. 2. Direct inguinal hernia. 3. Femoral • More common in females
hernia. 4. Spigelian hernia. Source: • More likely to be incarcerated or strangulated
https://www.researchgate.net/figure/Diagram-of-the- than inguinal hernias because of their narrow and
inguinal-canal-IC-and-its-contents-The-deep-inguinal-ring- long neck
is-formed-by_fig1_318615287 Diaphragmatic Hernias:
The previously discussed hernias were defined as
Indirect inguinal hernia: protrusions through the abdominal wall. Diaphragmatic
hernias are internal hernias.
Definition:
A hernia that goes through the internal inguinal ring,
external inguinal ring, and into the scrotum.
Anatomical landmarks:
433
Definition:
Abdominal structures enter the thorax via a congenital
defect of the pleuroperitoneal membrane or from a trauma.
It is more common on the left side.

Figure 173: Congenital diaphragmatic hernia. The left-lung

is often hypoplastic. Source:
https://www.nejm.org/doi/full/10.1056/NEJMicm1701321

Hiatal hernia:

• The stomach herniates upward through the

esophageal hiatus of the diaphragm
• Can result in acid reflux
Sliding hiatal hernia:

• The gastroesophageal junction is displaced

upward
• The gastric cardia slides into hiatus
• Known as hourglass stomach
• Most common type
• Can result in gastroesophageal reflux disease
Paraoesophageal hiatal hernia:

• The gastroesophageal junction is normal in

position
• The fundus protrudes through the hiatus into the
thorax
• More likely to strangulate

Figure 174: An illustration of the two hiatal hernias.

Source:
https://en.wikipedia.org/wiki/Hiatal_hernia#/media/File:Hi
atus_hernia.svg

434
 Chapter 10:

Hematology and oncology

435
Blood Cellular Components • They form niche “nests” in different sites
Hematopoiesis depending on the stage of hematopoiesis, i.e. yolk
Hematopoiesis is defined as the formation of blood cellular sac early, bone marrow in adult life
components which occurs during embryonic development • The definitive HSC cells give rise to a common
and throughout adulthood to produce and replenish the myeloid progenitor and a lymphoid progenitor
blood cellular components. Common myeloid progenitor pathway:

Primitive Hematopoiesis • Gives rise to erythrocytes, platelets and

Hematopoiesis occurs in two distinct waves. A primitive monocytes
wave before the gestational age of two weeks and a • Monocytes further mature into myeloid dendritic
definitive wave that starts after the age of 17 gestational cells, neutrophils, eosinophils, macrophages and
days and continues during adulthood. This is different from basophils
what is commonly referred to embryonic versus mature Lymphoid progenitor pathway:
hematopoiesis which refers to the site of hematopoiesis.
• Give rise to B-cells which mature in the bone
• Primitive and definitive hematopoiesis starts from marrow in adults → hence the letter “B”
pluripotent hematopoietic stem cells of mesoderm • T-cells which migrate to the thymus to mature
origin there → hence the letter “T”
• Mesoderm expressing bmp2b, bmp7, tbx16 and • T-cells further divide into CD4+ and CD8+ T-
cdx4 transforms into a hemangioblast cells
• These hemangioblasts further differentiate into
angioblasts which are responsible for primitive
angiogenesis and primitive hematopoietic-stem-
cell-like which gives rise to common myeloid
progenitor
• It is important to note that the number of
expressed genes related to pluripotency decrease
as we move forward to more differentiated cells
• The common myeloid progenitor cell gives rise to
erythroid progenitor and myeloid progenitor cells
Figure 176: Definitive hematopoiesis
• Erythroid progenitor cells give rise to
erythrocytes, whereas myeloid progenitor cells
Embryonic Hematopoiesis
give rise to monocytes which are primitive
Age 17 to 21 gestational days:
leukocytes
• Yolk sac
Age 21 gestational days to 27 days:

• Development of early blood circulation

• Hematopoiesis now shifts to the developing liver
• 27 to 30 days, hematopoiesis shifts to the aorta-
gonad-mesonephros
Age 30 days to 10.5 weeks:

• Hematopoiesis is back to the liver

Figure 175: Primitive hematopoiesis. Source: DOI: • Complete colonization of the bone marrow and
10.1242/dev.083147 thymus by 10.5 weeks
• Finally, hematopoiesis shifts to the bone marrow
Definitive Hematopoiesis and thymus after 10.5 weeks
• Starts at the age of 17 gestational days Fetal erythropoiesis:
• Same cell types seen in adult blood
• Hemogenic endothelium is derived from • Follows a pattern slightly similar to the steps
mesoderm mentioned for embryonic hematopoiesis
• Definitive HSC cells are derived from the • From the yolk sac from 3 to 8 weeks
hemogenic endothelium • Liver starts producing erythrocytes at 6 weeks
and continue until birth

436
 • The spleen produces erythrocytes from 10 to 28 • One-third of platelet pool is stored in the spleen
weeks of gestation
• The bone marrow is capable of producing mature
erythrocytes starting at 18 weeks of gestation
Erythrocytes:
Characteristics:

• Anuclear cells that lack organelles

• Biconcave in shape
• Large surface area to volume ratio for allowing
rapid gas exchange
• Life span 120 days
• Incapable of aerobic metabolism → cannot use
Figure 178: Platelets (small blue dots/fragments). Source:
the oxygen its hemoglobin is carrying
https://en.wikipedia.org/wiki/File:Platelets2.JPG
• Energy production is dependent on glycolysis
• The membrane contains Cl/HCO3 antiporter Main functions:
which allows RBCs to export HCO3 and transport
CO2 from the peripheral tissues to the lungs for •
Primary hemostasis
elimination •
Activated by endothelial injury → aggregate with
other platelets → interact with fibrinogen to form
a platelet plug
• vWF receptor is glycoprotein Ib
• fibrinogen receptor is glycoprotein IIb/IIIa
• Megakaryocyte proliferation is stimulated by
thrombopoietin
Abnormalities:

• Thrombocytopenia or decreased platelet function

Figure 177: Red blood cells. Source: → petechiae
https://www.fi.edu/heart/red-blood-cells • Thrombocytosis is a non-specific marker of
inflammation – similar to ESR and CRP
Main functions:
Monocytes:
• Carry oxygen from the lungs to the tissues Characteristics:
• Transport CO2 from the peripheral tissues to the
• Cells that contain a single nucleus
lungs for elimination
• They differentiate into macrophages in peripheral
Abnormalities:
tissues
• Erythrocytosis or polycythemia is an elevated • They are found mainly in the blood
RBC count → hematocrit is increased • Large kidney-shaped nucleus with extensive
• Anisocytosis is a condition where RBCs have frosted-glass cytoplasm
varying sizes
• Poikilocytosis is a condition where RBCs have
varying shapes
• Reticulocytosis are immature RBCs that have
nuclear remnants → increased in hemolysis
o Polychromasia on Wright-Giemsa stain
due to residual ribosomal RNA
Thrombocytes:
Characteristics:

• Small cytoplasmic fragments derived from Figure 179: Monocytes. Source:

megakaryocytes https://en.wikipedia.org/wiki/Monocyte#/media/File:Mono
• Life span is 8 to 10 days cytes,_a_type_of_white_blood_cell_(Giemsa_stained).jpg
• Contain dense granules (ADP and calcium)
• Alpha-granules (vWF, fibrinogen and fibronectin)

437
Leukocytes: • Can present antigens to lymphocytes because
Normal ranges: they express MHC-II
Functions:
• Neutrophils 60%
• Lymphocytes 30% • Phagocytosis of bacteria, cellular debris and
• Monocytes 6% senescent erythrocytes
• Eosinophils 3% • Activated by interferon-gamma
• Basophils 1% • Granuloma formation in tuberculosis and
Neutrophils: sarcoidosis
Abnormalities:
Characteristics:
• Implicated in the pathophysiology of septic shock
• Phagocytic cells where bacterial lipopolysaccharides bind to CD14
• They have a multilobed nucleus receptors on macrophages
• They have specific granules with leukocyte Eosinophils:
alkaline phosphatase (LAP)
• They express collagenase, lysozyme, and Characteristics:
lactoferrin which are important for their function
• Bilobate nucleus
• Azurophilic granules are lysosomes that contain
• Have large eosinophilic granules of uniform size
proteinases, acid phosphatase, myeloperoxidase
and beta-glucuronidase • Produce histaminase, major basic protein,
eosinophil peroxidase, cationic protein, and
derived neurotoxins

Figure 180: Neutrophils. Source:

https://en.wikipedia.org/wiki/Neutrophil#/media/File:Neutr
ophils.jpg Figure 181: An eosinophil. Source:
https://en.wikipedia.org/wiki/Eosinophil#/media/File:Eosin
Functions: ophil_blood_smear.JPG

• Acute inflammatory response Functions:

• Important in bacterial infections
• Defend against helminthic infections (major basic
• Chemotactic agents recruit them: C5a, IL8,
protein)
kallikrein and platelet-activating factor
Abnormalities: • Phagocytosis of antigen-antibody complexes
(involved in allergic conditions)
• Vitamin B12/folate deficiency → Hypersegmented Abnormalities:
neutrophils with 6 or more lobes
• Eosinophilia is seen in parasitic infections,
• Increased band cells → immature neutrophils →
asthma, Churg-Strauss syndrome,
seen in bacterial infections and in CML
myeloproliferative disorders, chronic adrenal
Macrophages:
insufficiency, and Hodgkin lymphoma
Characteristics: Basophils:

• Long life in peripheral tissues Characteristics:

• Differentiated from circulating monocytes • Densely basophilic granules that contain heparin
• Known as Kupffer cells in liver, histiocytes in (an anticoagulant) and histamine (a vasodilator)
connective tissue, Langerhans cells in skin,
• Can synthesize leukotrienes
osteoclasts in bone, and microglial cells in brain

438
 Lymphocytes:
• They mediate adaptive immunity
• Include B and T cells
• Natural killer cells are lymphocytes but part of
the innate immune response
• They have a round dense nucleus with small
amount of pale cytoplasm

Figure 182: Basophil. Source:

https://en.wikipedia.org/wiki/Basophil#/media/File:Basoph
ile-9.JPG

Functions:

• Mediate allergic reactions Figure 184: Lymphocyte. Source:

• Hyperemia secondary to decreased viscosity of https://en.wikipedia.org/wiki/Lymphocyte#/media/File:Ly
blood (heparin) and vasodilation (histamine) mphocyte2.jpg
release by basophils
Mast cells: B-lymphocytes:
• Originate from a common precursor with •Originate from stem cells in the bone marrow
basophils •Mature in the bone marrow
• Mediate local allergic reactions •Finally, they migrate to peripheral lymphoid
• Can bind to Fc portion of IgE to its membrane tissues such as lymph nodes (follicles), white
o IgE crosslinking by antigen → pulp of the spleen and in unencapsulated
degranulation of its basophilic granules lymphoid tissues
→ release of histamine, heparin, and o These are the main sites that will most
tryptase → allergy likely encounter new foreign antigens
• Involved in type I hypersensitivity reactions where antibodies are needed to be
• Cromolyn sodium, used in the treatment of formed against to sustain an adaptive
asthma, prevents mast cell degranulation immune response
Myeloid dendritic cells: • When they encounter an antigen, they
• Highly phagocytic antigen-presenting cells differentiate into B-memory cells and plasma
• Link the innate and adaptive immune systems by cells
presenting antigens to the adaptive immune • Plasma cells produce antibodies specific to the
system antigen that activated them
• They express MHC-II and Fc receptors on their • B-memory cells are also specific for the antigen
surface which are important for antigen- that caused their formation
presentation • B-lymphocytes can also present antigens to other
• They are called Langerhans cells in the skin immune cells including T-lymphocytes
Plasma cells:

• Antibodies are produced by activated plasma

cells
• They originate from B-lymphocytes that were
exposed to an antigen
• They have a clock-face chromatin, and an
eccentric nucleus
• The rough endoplasmic reticulum and Golgi
Figure 183: Myeloid dendritic cell. Source: apparatus are well-developed and abundant →
https://www.researchgate.net/figure/Morphology-of- important for the rapid production of large
monocyte-derived-dendritic-cells-cultured-in-Department- amounts of antibodies
of-Clinical_fig1_5847585 • They do not circulate in the peripheral blood →
remain in the bone marrow

439
 • Multiple myeloma is a malignancy of plasma
cells

Figure 186: Normal results in adults and newborns. A:

HbA, F: HbF, and A2: HbA2. Source:
http://www.labpedia.net/test/80
Figure 185: Plasma cell. Source: Example hemoglobinopathies:
https://en.wikipedia.org/wiki/Plasma_cell#/media/File:Plas
macell.jpg • There are two possible abnormalities to be seen
• A difference in the range of HbA and HbF which
T-lymphocytes: is seen in thalassemia for example
• Or the presence of HbS (sickle cell anemia) or
• They mediate cellular immune response HbC
• Part of the adaptive immune response • Presence of HbS and HbA → sickle cell trait
• They originate from bone marrow stem cells but • HbS migrates faster than HbC because the single
migrate to the thymus to mature aminoacids substitution in HbS is valine (neutral)
• They differentiate into cytotoxic CD8+ T cells in place of glutamic acid (-). In HbC, lysine
(recognize MHC-I), helper CD4+ T cells which is positively charged replaces glutamic
(recognize MHC-II) and regularity cells acid → negative charge of HbA stronger > HbS >
• CD28 costimulatory signal is needed for T-cell HbC
activation
• 80% of circulating lymphocytes are T-cells
• HIV targets CD4+ T cells
Hemoglobin Electrophoresis
Definition: Figure 187: HbS in sickle cell disease/trait. Source: Source:
Hemoglobin electrophoresis is a screening tool used in the http://www.labpedia.net/test/80
evaluation of hemoglobinopathies. An alkaline or a citrate
agar gel is used. Different types of hemoglobin migrate at a
different rate from the cathode to the anode in the gel based
on their negative charge.

Indications:
• Patients with unexplained hemolytic anemia
• Patients with microcytic anemia not explained by
iron deficiency, chronic disease or lead toxicity
• Patients with target or sickle cells on a peripheral
blood film Figure 188: Normal, sickle cell trait, sickle cell disease,
• Patients with positive family history of HbC disease and HbSC disease. Source:
hemoglobinopathy https://www.nairaland.com/2681121/genotype-
Interpretation: compatibilities-sc-ac-what
Normal results:
Erythrocyte Morphology
• 95% HbA1 Normal Erythrocyte Morphology
• 1.5 to 3.5% HbA2 • Biconcave
• HbF < 2% but is variable and dependent on age • Volume is 90 femtoliters
• HbC and HbS absent • Anuclear
• Without organelles
Acanthocytes
• Also known as spur cells
• The cells have spikes

440
 • They are seen in people with liver disease, and • Associated with G6PD deficiency
dyslipidemia (abetalipoproteinemia)

Figure 192: Degmacytes. Source:

Figure 189: Acanthocytosis in a patient with http://natechertack.com/medicine/hemeonc/images/degmac
abetalipoproteinemia. Source: yte.png
https://en.wikipedia.org/wiki/Acanthocyte#/media/File:Aca
nthocytosis.jpg Burr Cells:
• Also known as echinocytes
Basophilic Stippling • The cells have uniform smaller and wider spikes
• Seen on peripheral blood smears not like in acanthocytosis
• Due to aggregation of residual ribosomes • Seen in end-stage renal disease, liver disease and
• Associated with sideroblastic anemias due to lead pyruvate kinase deficiency
poisoning or myelodysplasia
• Also seen in thalassemia

Figure 193: Burr cells. Source:

https://p5759554.vo.llnwd.net/e1/courses/imgs/599-
154883.jpg
Figure 190: Basophilic stippling. Source:
https://library.med.utah.edu/WebPath/HEMEHTML/HEM Elliptocytes:
E012.html • As the name implies, the cells are elliptical in
shape
Dacrocytes • Seen in hereditary elliptocytosis
• Also known as teardrop cells • Caused by a mutation in Spectrin which is a
• RBCs look like they are shedding tears membrane protein in the RBC
• This happens because they are mechanically • Usually asymptomatic
squeezed out of a crowded bone marrow
• Occurs in bone marrow infiltrative disorders such
as myelofibrosis
• Also associated with thalassemia

Figure 194: Elliptocytes. Source:

https://p5759554.vo.llnwd.net/e1/courses/imgs/15115-
326763.jpg
Figure 191: Dacrocytes. Source:
https://en.wikipedia.org/wiki/Dacrocyte#/media/File:Teard Macro-ovalocytes:
rop_Cells_smear_2009-09-22.JPG • The cells are enlarged in size and can be slightly
oval in shape
Degmacytes: • Seen in megaloblastic anemia
• Also known as bite cells • Patients with megaloblastic anemia also have
• The cells are literally bitten out Hypersegmented polymorphonuclear cells

441
 Figure 195: Macro-ovalocytes. Source: Figure 198: Ringed sideroblasts. Source:
http://media.mssm.edu/blood/morphology_tutorial_sciglian https://upload.wikimedia.org/wikipedia/commons/6/62/Sid
o/images/985.jpg eroblast.png

Sickle-cells: Schistocytes:
• The cells are crescent shaped • Also known as helmet cells
• Sickling – the change in the cell’s shape – occurs • They are fragmented RBCs
when the patient is dehydrated or under • Seen in patients with microangiopathic hemolytic
physiologic stress anemias such as disseminated intravascular
• Seen in sickle cell disease coagulopathy, thrombotic thrombocytopenic
purpura, hemolytic uremic syndrome, mechanical
hemolysis secondary to prosthetic heart valves,
and HELLP syndrome

Figure 196: Sickle cells. Source:

https://www.microscopyu.com/assets/gallery-
images/pathology_sicklecellanemia40x02.jpg
Figure 199: Schistocyte. Source:
Spherocytes: https://i.pinimg.com/originals/da/92/fa/da92fabf597aebe5f
• The RBCs are small and spherical (lose their 069dd0ee4663369.jpg
biconcave shape)
• They do not have central pallor Target Cells:
• Seen in patients with hereditary spherocytosis • The cells have a target appearance
• Also associated with drug and infection induced • Associated with HbC disease, asplenia, liver
hemolytic anemias disease and thalassemia

Figure 197: Spherocytes. Source:

https://jwilliamcupp.name/Things/Blood/spherocytes_nw.j Figure 200: Target cells. Source:
pg https://p5759554.vo.llnwd.net/e1/courses/imgs/599-
359107.jpg
Ringed Sideroblasts:
• Only seen in the bone marrow, i.e. not in Heinz Bodies:
circulating blood • Oxidative damage to hemoglobin results in small
• Prussian blue stain is used to visualize them precipitations
• Seen in patients with sideroblastic anemia

442
 • These precipitations can damage the RBC’s B12 deficiency or orotic aciduria; or defective
membrane DNA repair as in Fanconi anemia
• Phagocytes recognize them, and bite the enclosed • Non-megaloblastic causes of macrocytosis
part of the RBC → results in bite cells include Diamond-Blackfan anemia, liver disease
• Associated with G6PD deficiency and alcoholism
Red Blood Cells
Introduction:
• Before studying anemias and other RBC
abnormalities, it is important to understand the
normal structure, production, function and life
cycle of the RBC
• Human adults have about 5 liters of blood
• The main functions of the blood can be
summarized as carrying oxygen and nutrients to
Figure 201: Heinz bodies. Source: living cells and clearance of waste products from
https://img.tfd.com/MosbyMD/thumb/heinz-bodies.jpg peripheral tissues
• In addition to RBCs, the blood also has immune
Howell-Jolly Bodies: cells which fight infections, and platelets which
• Basophilic nuclear remnants in RBCs are important for primary hemostasis
• They are normally removed by splenic • The blood also has many noncellular components
macrophages (proteins, carriers, complement factors,
electrolytes, etc.) which are important for the
• Accordingly, they can be seen in patients with
body’s homeostasis and physiologic functioning
functional hyposplenia or asplenia
• Blood is so important in the United States that it
has been called the red gold! More than 30
million units of blood components are transfused
to patients annually in the United States
Structure:
• Also known as erythrocytes
• Most common type of cell found in the blood
• 4 to 6 million RBCs per mm3 of blood
• Diameter is 6 µm
o Small enough to squeeze through the
smallest blood vessels
Figure 202: Howell-Jolly body. Source: • Mature RBCs lack a nucleus
https://upload.wikimedia.org/wikipedia/commons/thumb/f/ o RBCs have more room to store
ff/Howell-Jolly_body.png/220px-Howell-Jolly_body.png hemoglobin
o Increases their capacity to carry and
Erythrocyte size abnormalities: transport oxygen to peripheral tissues
Microcytic RBCs: • Biconcave in shape
o Increases their surface area
• The RBC volume < 80 fL
o More rapid diffusion of oxygen and CO2
• Seen in patients with defective heme synthesis
across their surfaces
(iron deficiency anemia, lead poisoning,
sideroblastic anemia and anemia of chronic • RBCs are red because they contain hemoglobin
o Anemic patients appear pale because of
disease)
low hemoglobin
• Also associated with defective hemoglobin chain
synthesis as in thalassemia • Hemoglobin is needed for the transportation of
oxygen from the lungs to the peripheral tissues
Macrocytic RBCs:
• Spectrin is an important RBC membrane protein
• The RBC volume > 100 fL • RBC membrane is composed of a bi-layered
• Generally classified into megaloblastic and non- membrane of cholesterol and phospholipids
megaloblastic anemias Complete blood count with a focus on RBCs:
• Megaloblastic anemia may be caused by
defective DNA synthesis as in folate or vitamin

443
 • A complete blood count measures different • They perform anaerobic respiration for energy
important features of the cellular components of production by converting glucose to pyruvate
the blood • Pyruvate is converted to lactate → 2ATPs are
• It can give invaluable information about anemias, released → Na+/K+-ATPase pump uses the ATP
infections and other common diseases produced to maintain electroneutrality
• The normal range for RBCs is: Lifecycle:
o 4.3 to 5.9 million/mm3 in males • RBCs have a life span of 120 days
o 3.5 to 5.5 million/mm3 in females • RBCs’ membranes get weakened after 120 days
• The normal range for hemoglobin is: • Specialized macrophages in the spleen, liver and
o 13.5 to 17.5 g/dL in males bone marrow recognized senile RBCs and
o 12.0 to 16.0 g/dL in females phagocytose them
• The normal range for hematocrit is: percentage of o This is known as the reticuloendothelial
RBCs to total blood volume system
o 41 to 53% in males • The inner core membrane of the RBC contains
o 36 to 46% in females phosphatidyl serine. Macrophages recognize
• The normal range for the RBC volume is: RBCs that have this molecule exposed “because
o 80 to 100 fL they are old” and they destroy such RBCs
Production: • When an RBC is destroyed by macrophages, the
• RBCs are made in the bone marrow of long bones following metabolites form:
• 2 to 3 million RBCs are produced by the bone o Iron is released where it binds to
marrow every second transferrin in the blood stream
• Stem cells give rise to a hematocytoblast which o Bilirubin is released in an unconjugated
gives rise to a proerythroblast form “water insoluble” and it binds to
• Proerythroblasts are committed stem cells albumin
meaning they can only mature into RBCs o If an RBC undergoes hemolysis,
• Proerythroblasts give rise to an erythroblast hemoglobin gets converted into
which gives rise to a normoblast haptoglobin
• Normoblasts eject their nuclei giving rise to a Hemostasis
reticulocyte Definition:
• Reticulocytes mature into erythrocytes which lack Whenever there is a cut wound in the body, a complicated
nuclei, organelles, RNA, and ribosomes process of hemostasis that involves the coagulation cascade
• This process is known as erythropoiesis gets activated which results in stopping of bleeding and
• Erythropoietin is the main drive for this process eventually healing. This happens because when there is a
and it is produced by the kidneys cut, the small blood vessels get injured exposing
• Testosterone enhances the effects of subendothelial components to the circulating platelets which
erythropoietin initiates the process of coagulation.
Hemoglobin:
Relevant Microvascular Anatomy
• Hemoglobin consists of heme (iron-containing
ring) and globin (two alpha and two beta chains)
• Each heme group contains a single iron atom
which can bind one molecule of oxygen
• Hemoglobin contains four globin chains → have
four hemes → can carry four molecules of
oxygen
• RBCs are red because of the heme group
(porphyrin and Fe2+)
• Histidine holds the iron atom in the center of the
heme group
• Each RBC can carry 270 million molecules of
hemoglobin
Function: Figure 203: Microvascular anatomy and primary
hemostasis. Source:
• RBCs carry oxygen to peripheral tissues, but they
https://vet.uga.edu/ivcvm/courses/VPAT5200/01_circulati
cannot utilize it because they lack mitochondria
on/hemostasis/hemostasis03.html

444
 • This is a longitudinal cut in a small blood vessel o Thromboxane A2 is also released, which
• The blood vessel is lined by endothelium which is again important for platelet activation
releases prostacyclin and nitric oxide Platelet activation:
• These two mediators prevent platelet adhesion
and the formation of clots in a normal intact • ADP binds to P2Y12 receptor to induce the
blood vessel expression of Gp2b/3a at platelet’s surface
Platelet aggregation:
• The first step to initiate hemostasis is for a cut to
occur that disrupts the integrity of the • Fibrinogen binds to the induced Gp2b/3a
endothelium layer receptors to connect platelets
• Subendothelial collagen is exposed to the • At this stage, a temporary platelet plug has
circulating platelets formed
• Platelets adhere to the exposed collagen and they • This plug stops the bleeding, but it is unstable and
get activated can easily dislodge
• They release more platelet factors, attract more • Accordingly, secondary hemostasis which is best
platelets, platelet aggregation starts, and fibrin explained by the coagulation cascade model
gets released needs to occur to stabilize the initial platelet plug
• An initial platelet plug is formed Hemostasis is about balance and not uncontrolled platelet
Primary Hemostasis: plug formation:
• Also known as platelet plug formation
Endothelial injury: • Hemostasis is well-controlled, otherwise the
platelet plug will grow indefinitely to occlude any
• The integrity of the endothelial layer needs to be blood vessel regardless of whether bleeding has
impaired in order for subendothelial collagen to stopped or not
be exposed to circulating platelets • Pro-aggregation factors include thromboxane A2,
• The damaged endothelium releases endothelin and decreased blood flow by vasoconstriction →
• Neural stimulation results in vasoconstriction increased platelet aggregation
o Transient effect • Anti-aggregation factors include prostacyclin and
o Decreases/stops bleeding to give time nitric oxide which are released by endothelial
for platelets to adhere and get activated cells. Prostacyclin inhibits platelet aggregation,
Exposure: and nitric oxide is a potent vasodilator →
increased blood flow and decreased platelet
• Circulating von Willebrand Factor (vWF) gets aggregation
released from Weibel-Palade bodies of
endothelial cells and alpha-granules of circulating
platelets
• It binds to the exposed subendothelial collagen at
the site of injury
Platelet adhesion:

• It is essential to understand that platelets cannot

bind to exposed collagen directly
• vWF needs to act like a bridge between Gp1b on
the platelet’s surface and the exposed collagen
• When vWF binds to its Gp1b receptor on the Figure 204: Primary hemostasis. 1. Subendothelial
platelet → platelets undergo conformational collagen is exposed. 2. vWF binds to subendothelial
change collagen. 3. Platelets adhere to the vWF-collagen complex
o ADP and calcium are released from via Gp1b receptor. 4. Platelets are activated by ADP which
adhering platelets binds to P2y12 receptors. 5. Platelet aggregation is mediated
o ADP is necessary for the activation of via fibrinogen which binds platelets together via Gp2b/3a
platelets receptors. Source: First Aid 2018
o ADP also helps platelets better adhere to
the endothelium Clinical relevance:
o Calcium is necessary for coagulation
cascade • Aspirin irreversibly inhibits cyclooxygenase →
inhibits thromboxane A2 synthesis → impaired
platelet aggregation
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 • Clopidogrel, prasugrel and ticlopidine inhibit impaired coagulation and elevated
P2Y12 receptors → inhibit ADP-induced PT and PTT.
expression of Gp2b/3a → inhibition of platelet
activation and subsequently aggregation
• Monoclonal antibodies abciximab and
Coagulation Cascade:
eptifibatide inhibit Gp2b/3A directly → inhibition
• This model explains how coagulation factors act
of platelet aggregation
on each other in a cascade
• Deficiency in vWF or Gp1b → impaired platelet
adherence • It takes into account the coagulation factors
without the cellular components of coagulation
o Ristocetin activates vWF to bind to
Gp1b → initiation of platelet • A mixed model takes into account the primary
aggregation in vitro hemostasis as the cellular component of
o Failure of platelet aggregation with coagulation and secondary hemostasis as the
ristocetin → von Willebrand disease coagulation cascade
(vWF deficiency) or Bernard-Soulier • It has been historically divided into intrinsic,
syndrome (Gp1b deficiency) extrinsic and common pathways
Intrinsic pathway:
Coagulation Factors:
No Name Function
I Fibrinogen Fibrinogen gets converted to
fibrin
II Prothrombin Converts fibrinogen to fibrin
III Thromboplastin Receptor for activated VII
V Proaccelerin Receptor for activated X
VII Proconvertin Important for the extrinsic
pathway
VIII Antihemophilic factor Receptor for activated IX
IX Christmas factor Activates factor X
X Stuart factor Activates prothrombin and
factor VII
XI Plasma thromboplastic Activates factor IX
antecedent
XII Hagen factor Activates factor XI
XIII Fibrin stabilizing factor Creates fibrin polymers →
water insoluble

Figure 205: Intrinsic pathway of the coagulation cascade.

Classification of coagulation factors: Source:
https://en.wikipedia.org/wiki/Coagulation#/media/File:Clas
Fibrinogen group: sical_blood_coagulation_pathway.png

•These include factors I (fibrinogen), V • The intrinsic pathway is activated by HMWK:

(proaccelerin), VIII (antihemophilic factor) and o The kinin cascade is activated by blood
XIII (fibrin stabilizing factor) trauma to the endothelium
• They are consumed during clot formation process o HMWK is needed to activate the kinin
• Will be decreased in disseminated intravascular cascade and the intrinsic cascade
coagulation for example o Kallikrein converts HMWK to
Prothrombin group: bradykinin which results in
vasodilation, increased permeability and
• These factors are vitamin K dependent (need induces pain fibers
vitamin K to be activated by the liver) o HMWK also activates factor XII to XIIa
• They include factors II (prothrombin), VII resulting in the initiation of the intrinsic
(vWF), IX (Christmas factor), and X (Stuart pathway
factor) • Factor XIIa activates XI → Xia which activate IX
→ IXa which in the presence of VIIIa activates
factor X to Xa
Note: All coagulation factors are
• At this stage we start the common pathway
produced by the liver, except factor
Extrinsic pathway:
VIII. Liver disease results in

446
 • Thrombin also activates factor XIII which in the
presence of calcium converts fibrin monomers
into fibrin polymers
• A fibrin stable mesh is formed, and secondary
hemostasis is finished
Remodeling of the secondary hemostatic plug:

• Again, if left unchecked, this secondary plug can

result in problems
• The fibrinolytic pathway is now active
• Plasminogen is converted by tissue plasminogen
activator (tPA) into plasmin
• Plasmin degrades fibrin polymer → fibrin
degradation products (elevated in DIC)
Figure 206: The extrinsic and intrinsic pathways both Clinical relevance:
activate factor X to Xa. Source:
Anticoagulants that inhibit factor Xa:
https://en.wikipedia.org/wiki/Coagulation#/media/File:Clas
sical_blood_coagulation_pathway.png • Targeting factor Xa is a smart move
• It would inhibit the initiation of the common
• When peripheral tissues are injured, tissue factor pathway without worrying whether the intrinsic
is exposed or extrinsic pathway was the culprit
• VII in the presence of calcium is converted to • Low-molecular weight heparin, heparin and
VIIa which in the presence of tissue factor direct Xa inhibitors such as apixaban, and
activates factor X into Xa rivaroxaban inhibit factor Xa
• The common pathway is initiated • Fondaparinux inhibits factor Xa
The common pathway: Anticoagulants that inhibit thrombin:

• Thrombin is important for the activation of

factors VIII, V, and the conversion of fibrinogen
into fibrin
• Again, inhibiting thrombin would be a smart
move for anticoagulation
• Heparin, low-molecular weight heparin and direct
thrombin inhibitors such as argatroban,
bivalirudin and dabigatran inhibit thrombin
Thrombolysis:

• Instead of inhibiting coagulation, one might want

to dissolve a currently formed thrombus
• tPAs such as alteplase, reteplase, streptokinase
and tenecteplase fall in this category
Figure 207: The intrinsic, extrinsic and common • Aminocaproic acid is a tPA inhibitor
coagulation pathways. Source: Vitamin K:
https://en.wikipedia.org/wiki/Coagulation#/media/File:Clas
sical_blood_coagulation_pathway.png • Vitamin K is produced by enteric bacteria in an
oxidized inactive form
• Regardless of whether coagulation started via the • It gets reduced by epoxide reductase (which is the
intrinsic or extrinsic pathway, factor X is now target of warfarin)
activated (Xa) • Reduced vitamin K acts as a cofactor for gamma-
• Factor V is activated into Va which in the glutamyl-carboxylase
presence of Xa activates prothrombin into • Gamma-glutamyl-carboxylase activates factors
thrombin (2, 7, 9 and 10) which are important for the
• Thrombin converts fibrinogen into fibrin extrinsic, intrinsic and common pathway
monomers • Accordingly, warfarin is the anticoagulant that
has an effect on the extrinsic pathway, not to

447
 forget its effect on the intrinsic and common • Elevated when on heparin or in hemophilia
pathways Anemia Basics
• Warfarin elevates the INR and PT Definition:
• Vitamin K also activates protein C and S which Anemia is a condition in which the number of RBCs or
are anticoagulant: their oxygen-carrying capacity (hemoglobin concentration)
o The half-life of protein C and S is are insufficient to meet the physiological needs of the
significantly shorter than clotting factors body.
2, 7, 9 and 10
o Warfarin, if given without heparin, can Accordingly, anemia is a decrease in hematocrit (RBC
inhibit protein C and S before inhibiting percent to total blood volume) or hemoglobin.
clotting factors
o Paradoxical effect of warfarin is seen When dealing with anemia, two important questions need
(skin necrolysis and accelerated to be answered:
coagulation)
• What is the cause of anemia
• Neonates lack enteric bacteria and are incapable
of producing vitamin K: • What is the urgency of correction of anemia (is a
blood transfusion needed?)
o Early administration of vitamin K
Classification:
prevents neonatal coagulopathy
Different classifications systems exist based on the RBC
• The antidote for warfarin is vitamin K
size, chromia and morphology; or underlying mechanism.
administration (slow) or fresh frozen plasma
(immediate) RBC size, chromia and morphology:
Physiologic Anticoagulation
• Protein C is activated into activated protein C. In • Hypochromic microcytic
the presence of protein S, factors Va and VIIIa • Macrocytic normochromic
are cleaved and inactivated • Normochromic normocytic
• tPA activates plasminogen into plasmin which Underlying mechanism:
results in fibrinolysis
• Antithrombin inhibits factors IIa, VIIa, IXa, Xa, • Decreased bone marrow production of RBCs:
XIa, and XIIa (extrinsic, intrinsic and common o Bone marrow aplasia or infiltrative
pathway factors) disease
o Factors IIa (thrombin) and Xa are the o Ineffective hematopoiesis as in
main targets of antithrombin myelodysplastic syndromes or
• Heparin enhances the activity of antithrombin megaloblastic anemia
• Factor V Leiden mutation produces a factor V o Substrate deficiency as in iron
that is resistant to protein C → pro-coagulopathy deficiency anemia
o Erythropoietin deficiency as in chronic
• Protein C and S are not used clinically as
kidney disease
anticoagulants, but tPA is used as a thrombolytic
• Peripheral loss:
Coagulation Profile o Bleeding
PT: o Sequestration
• Prothrombin time • Peripheral destruction:
• Function of common and extrinsic pathways o Intravascular hemolysis
o Extravascular hemolysis
• Mainly factors I, II, V, VII, and X
History:
INR:
Symptoms related to anemia:
• International normalized ratio
• Patient PT/Control PT • Increased tiredness
• 1 is normal • Dyspnea
• > 1 → on anticoagulation or have coagulopathy • Decreased effort tolerance
• Test used for monitoring of warfarin History taking approach to identify the type/cause of
PTT: anemia:
• Partial thromboplastin time
• Function of common and intrinsic pathways • It is essential to ask about the duration of
• Tests all factors except factors VII (extrinsic) and symptoms and determine the acuity of the
XIII condition

448
 • Inquire about transfusion history, in case the • Paresthesia, peripheral neuropathy, ataxia, and
patient needs one loss of vibration and proprioception in vitamin
• Inquire about dietary history B12 deficiency
o Pica which is craving for unusual food
items is seen in iron deficiency anemia Laboratory Testing:
• Inquire about travel history to exclude malaria or Complete blood count:
other infectious causes of anemia
• Inquire about a change in bowel habit to exclude • Initial test when you suspect anemia
colonic cancer, a serious cause of chronic blood • Hemoglobin < 13 g/dL in males or 12 g/dL in
loss and anemia females is diagnostic of anemia
• Inquire about hematemesis, blood in stool, o Hemoglobin < 7 g/dL is an indication of
melena, and blood in urine blood transfusion (2 packed RBC units)
• Inquire about medications history to exclude o Old patients with cardiopulmonary
causes of hemorrhage (anticoagulants) or causes compromise and a hemoglobin level <
of bone marrow suppression (anticonvulsants or 10 g/dL should be given packed RBCs
chemotherapeutic agents) o One unit of packed RBCs elevated
• Inquire about symptoms and signs of chronic hemoglobin level by 1 g/dL and
disease hematocrit by 3%
• Inquire about surgical history to exclude small • A reticulocyte count is important as it gives an
bowel surgery or gastrectomy → malabsorptive indication about the bone marrow status
problems
• Inquire about family history of anemia in children
Note: Patients with volume
to exclude hereditary causes
contraction secondary to
Clinical Examination:
hemorrhage can have a normal
Skin and mucous membranes:
hemoglobin level at first. Once IV
• Pallor fluid resuscitation is commenced,
• Angular stomatitis → iron deficiency anemia they will have dilutional anemia.
• Glossitis → nutritional deficiencies The decision to treat this as anemia
• Koilonychia which are spoon-shaped nails → iron or not is based on the volume status
deficiency anemia of the patient. If the patient is
• Premature greying hypervolemic, pseudo-anemia is
• Scleral ictus → hemolysis concluded and treatment of the
cause of hypervolemia takes
Cardiovascular: precedence.
• Hyperdynamic circulation:
o Increased HR
o Increased CO
o Increased SV Bone marrow examination:
o Increased extraction of oxygen by • Indicated when bone marrow infiltration, failure
peripheral tissues or myelodysplasia are suspected
In anemic patients, the hemoglobin-dissociation graph shifts Further testing is indicated based on the suspected etiology.
to the right because 2,3-diphosphoglycerate decreases the
affinity of hemoglobin to oxygen resulting in more delivery Blood Smear Microscopy Approach:
of oxygen to peripheral tissues. Morphology Possible causes Further testing
Oval macrocytes - Vitamin B12 - Serum vitamin
- Folate deficiency B12 and folate
• Cardiac failure levels
Hypochromia - Iron deficiency - Serum ferritin
Neuromuscular: anemia - Transferrin
• Muscle weakness - Iron levels
• Headache, drowsiness and lack of concentration Sickle-cells - Sickle cell disease - Hb
electrophoresis
which might be seen in anemic patients in general Spherocytes - Hereditary - Red cell
and in megaloblastic anemia due to vitamin B12 spherocytosis membrane
deficiency in particular analysis
- Selected
membrane protein
abnormalities

449
 Autoagglutination - Autoimmune - Coombs test evidence of anemia is defined as a hemoglobin level two
hemolytic anemia
Red cell - Microangiopathic - Platelet count to standard deviations below normal for age and gender.
fragmentation anemia differentiate
- Macroangiopathic micro (decreased Reference range of MCV and hemoglobin:
anemia platelets) from
macroangiopathic
anemia • MCV in adult women and men is in average 90
- Exclude DIC and fL
HUS
• Cut-line for the diagnosis of anemia in men is
Reticulocyte Count Approach: hemoglobin < 13.0 g/dL
Increased reticulocyte count (> 2%): • Cut-line for the diagnosis of anemia in women is
Bleeding: hemoglobin < 12.2 g/dL
• Locate the source of bleeding • Most iron-deficient anemic patients have an
Hypersplenism: MCV < 80 fL, however the cut-line has been set
at 95 fL in order to emphasize that the most
• Could be caused by spherocytosis
common cause of all anemias is iron deficiency
Hemolysis:
anemia
• Elevated LDH
Causes:
• Elevated haptoglobin Causes can be classified into:
• Elevated indirect bilirubin
Decreased reticulocyte count: “inappropriate bone marrow • Inadequate iron intake – self-explanatory
response to anemia” • Decreased iron absorption
• Increased iron loss
Bone marrow failure is suspected: • Increased iron demand
• Bone marrow aspirate and trephine biopsy are Decreased iron absorption:
indicated when MCV or normal or elevated and
vitamin B12 and folate levels are normal • Celiac disease
Based on MCV: • Intestinal resection
Microcytic (< 70 fL): • Bacterial overgrowth
• Iron deficiency anemia (measure serum ferritin, Increased iron loss:
transferrin, and iron levels)
• Thalassemia (Hb electrophoresis) if normal iron • Bleeding:
studies o Abnormal uterine bleeding
• Anemia of chronic disease (inability to utilize o Long-term use of NSAIDs
iron) o Colonic carcinoma – occult bleeding
• Lead poisoning ▪ Any male with iron deficiency
• Sideroblastic anemia anemia who is above 40 years
Normocytic (80 to 99 fL): of age should be evaluated for
• Aplastic anemia the possibility of colonic
cancer
• Bone marrow fibrosis
o Angiodysplasia
• Malignancy
o Blood donation
• Anemia of chronic disease o Gastric carcinoma
• Chronic kidney disease o Esophagitis
Macrocytic (> 100 fL): o Esophageal carcinoma
• Vitamin B12 or folate deficiency o Peptic ulcer disease
• Liver disease Increased iron demand:
Iron Deficiency Anemia
Definition: • Pregnancy
Iron deficiency anemia is defined as decreased red blood Clinical Presentation:
cell production because of decreased iron stores in the • Fatigue
body. Iron deficiency anemia is the most common cause of • Conjunctival pallor
nutritional deficiency worldwide and the most common • Pica – consumption of unusual products in place
microcytic anemia. of food
The diagnosis of iron deficiency anemia requires • Spoon nails – koilonychia
laboratory confirmed evidence of anemia in addition to • Orthostatic hypotension
evidence of low iron stores. Laboratory-confirmed • Exertional dyspnea

450
 • Hypotension and tachycardia in acute hemorrhage • Microcytic hypochromic RBCs with increased
central pallor

Figure 208: Conjunctival pallor in an anemic patient.

Source: https://www.researchgate.net/figure/Conjunctiva- Figure 209: Hypochromic RBCs on peripheral blood
that-appears-pale-in-color-compared-with-a-pink-hue- smear.
indicates-iron_fig5_274401959
Etiological workup in iron deficiency anemia:
Specific for iron deficiency anemia:
• After the confirmation of the diagnosis of iron
• Glossitis deficiency anemia, the next step is to identify the
• Cheilosis cause
• Plummer-Vinson syndrome: Premenopausal women:
o Iron deficiency anemia
o Esophageal webs • Inquire about abnormal uterine bleeding → if yes,
o Dysphagia evaluate the patient accordingly
Diagnosis: • If no, give a trial of iron therapy, if no response
Confirmation of the diagnosis of iron deficiency anemia: → evaluate the patient for GI blood loss
Men and postmenopausal women:
Initial tests:
• Perform upper endoscopy, colonoscopy and
• MCV < 80 fL consider celiac disease workup in younger
• Hemoglobin < 13.0 g/dL in men and 12.2 g/dL in patients
premenopausal women o If a source of bleeding is identified, treat
Ferritin: it
• In case no evidence of a source of GI bleeding,
• Ferritin < 30 ng/mL → confirmed diagnosis of give a trial of iron therapy:
iron deficiency anemia o If no response, perform capsule
• Ferritin 31 to 99 ng/mL: endoscopy
o Elevated total iron-binding capacity Treatment:
(TIBC), low serum iron level and low Initial treatment:
transferrin saturation → confirmed
diagnosis of iron deficiency anemia • Treat the cause whenever possible
o Does not meet the above criteria but • Start oral ferrous sulfate supplements:
have an increased level of soluble o Some patients cannot tolerate oral iron
transferrin receptor → confirmed o Can cause nausea, constipation and
diagnosis of iron deficiency anemia dyspepsia
o All the above tests are normal, but iron o If not tolerated → give parenteral IV
deficiency anemia is still suspected: iron therapy
▪ Low bone marrow iron level Further treatment:
on biopsy → iron deficiency
anemia • Repeat CBC and check if hematocrit, RBC count,
• Ferritin > 100 ng/mL → exclusion of iron and MCV are improving after one month
deficiency anemia, consider other causes of • If yes, continue treatment for three more months
microcytic anemia after meeting the following goals:
Peripheral blood smear: o Normal hematocrit
o Normal ferritin level

451
 o Keep monitoring the patient periodically • Deficient or absent synthesis of alpha globin
with repeat CBC chains
• Patients who do not respond to iron therapy after • Excess beta globin chains
one month: • Alpha globin chains expression is controlled by
o Reevaluate the etiology two genes on each chromosome 16
o Initiate intravenous iron therapy • Deletion of one or more of these genes result in
o Consider packed RBC transfusion if the different types of alpha thalassemia
symptomatic (hypotensive and o Single gene deletion → alpha
tachycardic) thalassemia silent carrier
Oral iron therapy: o Two-gene deletion → alpha thalassemia
trait (minor)
• Ferrous sulfate o Three gene deletion → alpha
• Ferrous fumarate thalassemia intermedia or HbH disease
• Ferrous gluconate (four beta chains)
Intravenous iron therapy: o Four gene deletion → alpha thalassemia
major (hemoglobin Bart’s which has
• Sodium ferric gluconate
four gamma chains)
• Iron dextran Beta thalassemia:
• Iron sucrose • Deficient or absent synthesis of beta globin
Thalassemias chains
Definition
• Excess alpha globin chains
Thalassemias are a group of inherited autosomal recessive
• Beta globin chains expression is controlled by
disorders that result in hemolytic anemia due to decreased
one gene on each chromosome 11
or absent synthesis of a globin chain. The imbalance
between the ratios of the different globin chains results in • Most commonly point mutations in this gene, or
hemolysis. rarely a deletion, cause beta thalassemia
o One gene defect → beta thalassemia
Epidemiology minor
o Two gene defects → beta thalassemia
• 1.7% of the population has alpha or beta
major
thalassemia trait
▪ Never symptomatic at birth
• Thalassemias affect 4.4 people every 10,000 live
because 80% of hemoglobin is
births
HbF (two alpha and two
• Alpha thalassemias are more common in Africans gamma)
and Southeast Asians
• Beta thalassemias are more common in people of
Mediterranean, African and Southeast Asian
descent
• Beta thalassemia minor is the most common type

Pathophysiology
Normal hemoglobin:
• Normal adult hemoglobin has four globin chains
(two alpha and two beta) and an iron-containing
heme ring
o Fetal hemoglobin has two alpha and two
gamma chains
o Hemoglobin A2 has two alpha and two
delta chains
o Fetal hemoglobin accounts for 80% of
hemoglobin at birth
o By six months of age, infants will have
mainly hemoglobin A (two alpha and
two beta chains)
Alpha thalassemia:

452
 • Fatal

Beta Thalassemias
Beta thalassemia trait:
• One gene of two is defective
• Asymptomatic patients
• Mild microcytic hypochromic anemia
Beta thalassemia intermedia:
• Two genes are affected by mild mutations
• An intermediate picture between beta thalassemia
trait and beta thalassemia major
Beta thalassemia major:
• Two genes are defective
• Severe decrease in beta globin synthesis
• Abdominal swelling
• Growth retardation
• Irritability
• Jaundice
• Pallor
• Skeletal abnormalities
o Bone marrow expansion
o Rugged-appearance bone
• Splenomegaly
• Fatal if not treated within the first year of life
• Blood transfusion dependent patients

Figure 210: Normal hemoglobin variants (HbF, HbA and

HbA2), alpha thalassemia intermedia and alpha
thalassemia major. Source:
https://www.aafp.org/afp/2009/0815/p339.pdf

Alpha Thalassemias Figure 211: Frontal bossing secondary to bone marrow

Alpha thalassemia silent carrier: expansion in a child with beta thalassemia major. Source:
• One of four genes deletion https://en.wikipedia.org/wiki/Skull_bossing#/media/File:Fr
• Patients are asymptomatic ontal_bossing-in_a_child.jpg
Alpha thalassemia trait:
• Two of four genes are deleted Thalassemias and Hemoglobinopathies
• Patients are asymptomatic • Some patients have a defect in one of the globin
• Mild microcytic hypochromic anemia chains that result in a decrease in production
Alpha thalassemia intermedia: (thalassemia) and another defect that results in an
• Three of four genes are deleted abnormal globin chain (sickle cell for instance)
• Reduced output of alpha globin • This results in a heterogenous genetic defect
• Development of HbH disease which results in combined disease
• Moderate to severe hemolytic anemia Comparison Between Thalassemias and Iron Deficiency
Anemia
• Mild ineffective erythropoiesis
• Splenomegaly
• Bony changes suggestive of thalassemia Alpha Beta Iron
thalassemia thalassemia deficiency
• HbH on electrophoresis mcv Decreased Decreased Decreased
Alpha thalassemia major: rdw Normal Normal or Increased
• Four genes are deleted increased
ferritin Normal Normal Decreased
• Nonimmune hydrops fetalis
453
 gel HbH or Hb Increased Normal • Patients should receive the pneumococcal
electrophoresis Bart’s HbA2, reduced
HbA and polysaccharide vaccine before splenectomy
increased HbF • Pneumococcal conjugate vaccine is indicated in
children
RDW and Thalassemias: • Penicillin 250 mg twice daily for two years post-
• Red blood cell distribution width (RDW) is useful splenectomy
in differentiating iron deficiency anemia from Pregnancy:
thalassemia • Preconception genetic counseling is indicated
• 90% of patients with iron deficiency anemia have
an elevated RDW
• Only 50% of patients with thalassemias have an
elevated RDW
• Accordingly, when a patient has microcytic
hypochromic anemia (MCV < 80 fL), the first
test to order would be RDW
• If the RDW is elevated (> 15 fL), ferritin studies Figure 212: Genetic counseling in beta thalassemia trait.
are indicated Source:
o If ferritin is low, consider iron https://www.aafp.org/afp/2009/0815/afp20090815p339-
deficiency anemia s1.pdf
o If ferritin is normal (> 100 ng/mL), Lead Poisoning
consider thalassemia Definition
• Normal RDW → consider thalassemia Lead is a neurotoxin that interferes with neurotransmission,
cellular migration, and synaptic plasticity in addition to
Treatment: causing microcytic anemia.
Who does not require treatment?
• Patients with alpha thalassemia silent carrier Pathophysiology
• Alpha thalassemia trait Understanding the possible sources of childhood exposure
• Beta thalassemia minor to lead makes it easier to understand who needs screening.
• Beta thalassemia intermedia early in the disease
Sources of childhood lead exposure:
Blood transfusion:
• In beta thalassemia major, aim for a Hb > 9.5 • Lead-based pain:
g/dL o Houses built before 1978
o Can need transfusions as early as six o Deteriorating paint
months of age • Lead in soil is an important exposing risk for
o Episodic and frequent transfusions those living near industrial plants or highways
• In alpha thalassemia intermedia or HbH disease, • Lead containing toys
transfusions are occasionally needed depending • Lead from old pipes can contaminate drinking
on the patient’s clinical situation water
• Patients start iron chelation between age five to • Food can be contaminated by lead when it is put
eight years with deferoxamine in crystal glassware
o Deferasirox is an alternative • Jewelry
o Less side effects than deferoxamine
Pathophysiology:
because the later has been associated
with agranulocytosis • Aminolaevulinic acid (ALA) is converted to
Bone marrow transplant: porphobilinogen by the action of ALA
• Curative in beta thalassemia major if done in dehydratase in the cytoplasm
childhood • Protoporphyrin is converted to heme by the action
• Patients should have no hepatomegaly, no portal of ferrochelatase in the mitochondria
fibrosis on liver biopsy, and not to be on regular • These two enzymes are inhibited by lead
iron chelation therapy poisoning
Hypersplenism: • This results in microcytic anemia
• Splenectomy decreased transfusion requirements • Accordingly, patients with lead poisoning will
• Usually performed at the age of four years have elevated levels of ALA and protoporphyrin

454
 • In addition to microcytic anemia, patients with
lead poisoning also have central nervous system
pathology due to impaired neurotransmission and
plasticity
• Patients also develop gastrointestinal and kidney
disease
• Long-term lead poisoning in children is
associated with low IQ
• Long-term lead poisoning in adults is associated
with mild cognitive impairment, headache and
Figure 213: Basophilic stippling on peripheral blood
demyelination
smear. Source:
Clinical Presentation
https://library.med.utah.edu/WebPath/HEMEHTML/HEM
• Symptoms and signs of anemia such as pallor,
E012.html
fatigue and dyspnea
Rourke Baby criteria:
• On bone marrow examination, ringed
• Child lives in a house that was build before 1950 sideroblasts:
for last six months o Prussian blue stain is used to visualize
• Child lives in a house that is undergoing them
renovations
• Patients can have family history of lead poisoning
• A young child might have history of eating pain
chips or chewing on toys
Clinical findings in lead poisoning not related to anemia:

• Memory loss
• Headache
• Polyneuropathy Figure 214: A sideroblast on bone marrow biopsy. Source:
• Unexplained new-onset neurological deficits https://en.wikipedia.org/wiki/Sideroblastic_anemia
• Mental deterioration in children
• Decreased academic performance in adolescents • Elevated protoporphyrin and ALA levels
Diagnosis Treatment
Anemic children who meet Rourke baby criteria or who • Repeat blood lead level test to confirm the
have other neurologic symptoms not explained by anemia diagnosis
should be screened for lead poisoning: • Confirm exposure history
• Prevent further exposure immediately
• Blood lead level is the diagnostic test of choice
• If the patient also has iron deficiency anemia,
for screening and confirming the diagnosis of
commence iron therapy
lead poisoning
o > 10 µg/dL • Calcium and zinc supplementation are indicated
• Chelation therapy is indicated only when blood
• Remember! Most common cause of microcytic
anemia is iron deficiency! Always order iron lead level is > 45 µg/dL
studies to exclude iron deficiency as the cause. o Discontinuation of lead exposure is
Serum ferritin would suffice here usually sufficient to normalize lead
Lead poisoning specific findings: levels in most patients, however this
takes long
• On peripheral blood smear, basophilic stippling is Sideroblastic Anemias
seen: Definition
o Aggregation of residual ribosomes Sideroblastic anemias are either acquired or inherited
disorders of abnormal heme synthesis that are characterized
by anemia and the presence of ringed sideroblasts in the
bone marrow. Sideroblasts are erythroblasts with iron-
loaded mitochondria and they can be visualized by Prussian
blue staining.

455
Pathophysiology • On bone marrow examination, ringed
Inherited sideroblastic anemias: sideroblasts:
o Prussian blue stain is used to visualize
• Mutations in different genes involved with heme them
synthesis steps result in sideroblastic anemias
• Such mutations can be autosomal recessive or x-
linked (ALA synthase)
Acquired sideroblastic anemias:

• Ethanol-induced sideroblastic anemia

• Drug-induced sideroblastic anemia such as
isoniazid or chloramphenicol
• Vitamin B6 is required as a co-factor for ALA-
synthase → vitamin B6 deficiency may result in Figure 216: A sideroblast on bone marrow biopsy.
sideroblastic anemia Source:
• Hyperglycemia and hemin are inhibitors of ALA- https://en.wikipedia.org/wiki/Sideroblastic_anemia
synthase → can cause sideroblastic anemia
• Lead poisoning inhibits ALA dehydrase and Treatment
ferrochelatase → sideroblastic anemia • Identify the cause and treat it:
• Acquired myelodysplastic syndromes o Avoid alcohol
What are ringed sideroblasts? o Discontinue offending drugs
o Treat lead poisoning, vitamin B6
• Iron cannot be incorporated into heme because of deficiency, copper deficiency, or
impaired heme synthesis acquired myelodysplastic syndromes
• Iron overloads the mitochondria which are found Vitamin B6 supplementation (pyridoxine)
in a ring configuration around the nucleus of the Macrocytic Anemia and Folate Deficiency
erythroblast Definition
• Prussian blue stain shows this ring configuration, Anemia is defined as a hemoglobin level < 13.0 g/dL in
hence the name ringed sideroblasts men and 12 g/dL in premenopausal nonpregnant women.
Clinical Presentation Macrocytic anemia is anemia that has a mean corpuscular
• Symptoms and signs of anemia such as pallor, volume (MCV) > 100 fL. MCV is calculated as follows:
fatigue and dyspnea MCV = hematocrit (%) x 10 / RBC count.
Diagnosis
• Macrocytic anemia is becoming less common
• Patients present with microcytic anemia nowadays
• Iron studies reveal: • 28% of macrocytic anemia cases in the elderly
o Elevated serum iron level are caused by vitamin B12 or folate deficiency
o Normal total iron binding capacity Pathophysiology
o Elevated serum ferritin level
• Folic acid is available in green vegetables and
• Peripheral blood smear reveals basophilic animal products such as liver
stippling:
• The recommended daily allowance of folic acid
for adults is 240 µg
o Daily allowance for pregnant or
lactating women is 400 µg
• Folic acid is absorbed in the upper jejunum by
passive diffusion and active uptake
• Folic acid deficiency is most commonly caused
by nutritional deficiency as in poor diet or
alcoholism
Figure 215: Basophilic stippling on peripheral blood • Malabsorption as in patients with celiac disease
smear. Source: or Crohn’s disease can cause folic acid deficiency
https://library.med.utah.edu/WebPath/HEMEHTML/H • Pregnant and lactating women in addition to
EME012.html patients with chronic hemolysis require larger
amounts of folic acid which can result in folic
acid deficiency

456
 • Medications like methotrexate, trimethoprim and • 20% with macrocytic anemic patients have
phenytoin can cause folic acid deficiency vitamin B12 deficiency
• The active form of folic acid requires vitamin • Vitamin B12 deficiency is more common in the
B12 → accordingly, vitamin B12 deficiency is elderly
often associated with folic acid deficiency • Pernicious anemia, a possible etiology of vitamin
• Folic acid stores in the liver last for B12 deficiency, is more common in people of
approximately three months Northern European descent
Pathophysiology: Pathophysiology
Etiology:
• Folate derivatives participate in the synthesis of
purines and pyrimidines Autoimmune:
• Accordingly, folate deficiency will result in
impaired DNA synthesis • Pernicious anemia is an autoimmune condition
o Nucleus maturation of precursor cells in • Autoantibodies against intrinsic factor or the
bone marrow is delayed → cells are parietal cells which produce intrinsic factor are
stuck at G2 phase formed
o Megaloblastic anemia and macrocytosis • These autoantibodies bind to the intrinsic factor,
o Hypersegmented neutrophils inhibiting its ability to bind to vitamin B12 and
• Folic acid is also important for the clearance of this impairs vitamin B12 absorption in the
homocysteine → folic acid deficiency results in terminal ileum
elevated levels of homocysteine Malabsorption:
• Folic acid deficiency during pregnancy is
• Patients who undergo gastric bypass surgery:
associated with neural tube defects
o Parietal cells synthesize and release
Clinical Presentation
intrinsic factor
• Symptoms and signs of anemia o Loss of the parietal cells in gastric
• Glossitis bypass surgery → inability to absorb
• Stomatitis vitamin B12 due to lack of intrinsic
• No neurologic symptoms in contrast to vitamin factor
B12 deficiency • Damage to the terminal ileum as in Crohn or
Diagnosis: Celiac disease
Evidence of macrocytic anemia confirmed by MCV > 100 • Tapeworm Diphyllobothrium latum infection
fL plus: Dietary insufficiency:
• Low RBC folic acid level • Liver stores of vitamin B12 can last for up to 3
• Low or normal vitamin B12 level years
• RBC macrocytosis on peripheral blood smear • Patients on a strict vegan diet for three years or
• Hypersegmented neutrophils on peripheral blood more can develop vitamin B12 deficiency
smear Important enzymes related to vitamin B12:
• Elevated homocysteine levels
• Normal methylmalonic acid levels • Methylmalonic acid mutase is activated by
Treatment: vitamin B12 and it is important for succinyl-CoA-
• Oral folic acid supplementation myelin synthesis from methylmalonyl-CoA →
Macrocytic Anemia and Vitamin B12 Deficiency vitamin B12 deficiency will result in elevated
Definition level of methylmalonic acid (MMA) and
Vitamin B12 or cobalamin is a water-soluble vitamin that is impaired myelination
derived from animal products including red meat, dairy and • The activation of folic acid into tetrahydrofolate
eggs. Vitamin B12 acts as a cofactor for enzymes involved is dependent on vitamin B12 → vitamin B12
in the synthesis of DNA, fatty acids and myelin. deficiency will be often associated with folic acid
Accordingly, vitamin B12 deficiency results in deficiency
megaloblastic anemia (MCV > 100 fL) and neurologic • Folic and vitamin B12 deficiency will result in
abnormalities due to myelin loss. elevated levels of homocysteine
• Folic acid derivatives are important for the
Epidemiology synthesis of thymine → vitamin B12 and folic
• 1 to 2% of anemic patients have vitamin B12 acid deficiency will result in defective DNA
deficiency synthesis → macrocytic megaloblastic anemia

457
Clinical Presentation: • If the marker is not seen in urine →
Symptoms and signs of anemia: malabsorption of vitamin B12 or pernicious
anemia
• Fatigue • If the marker is seen in urine after the
• Pallor administration of intrinsic factor → pernicious
• Exertional dyspnea anemia is the etiology
• Jaundice may be seen due to increased hemolysis Treatment:
in patients with vitamin B12 deficiency Patients with vitamin B12 deficiency due to nutritional
Symptoms and signs more specific for vitamin B12 deficiency:
deficiency:
• Oral vitamin B12 supplementation
• Glossitis Patients with pernicious anemia or malabsorption:
• Diarrhea
• Autoimmune disease history • Monthly intramuscular vitamin B12 dose of 1000
• History of gastric bypass surgery µg
• History suggestive of inflammatory bowel disease Normocytic Anemia: Anemia of Chronic Disease
• Neurologic abnormalities Definition
Neurologic abnormalities in vitamin B12 deficiency: Anemia of chronic disease is found in patients who have an
illness that elicits an active immune inflammatory response
• Not related to anemia, but related to the loss of that reduces iron uptake at varying sites. This definition
myelin excludes anemic patients who have anemia secondary to
• Dementia the chronic use of a medication or those who have an
• Peripheral neuropathy anemia secondary to a hematologic neoplastic disorder
• Ataxia (does not exclude patients with solid malignancies).
• Loss of proprioception Anemia of chronic disease (ACD) is a nonhemolytic
• Neuropsychiatric disturbances normocytic anemia (MCV 80 – 100 fL).
• Subacute combined degeneration of the spinal Epidemiology
cord:
• ACD is the most common cause of anemia in
o Damage to myelin admitted patients
o Affects the dorsal columns, lateral
• Second most common cause of anemia in the
corticospinal tracts, and spinocerebellar
general population after iron deficiency anemia
tracts
o Believed to be the cause of the • Up to 77% of the elderly have ACD
neurologic abnormalities seen in • It is usually mild to moderate
vitamin B12 deficiency Pathophysiology
Diagnosis: Etiology: from most common to least common cause of
Initial tests: ACD

• CBC reveals anemia with MCV > 100 fL • Infection

• Peripheral blood smear reveals RBC • Autoimmune diseases including rheumatoid
macrocytosis and Hypersegmented neutrophils arthritis, systemic lupus erythematosus, vasculitis,
Confirmatory tests: and sarcoidosis
• Chronic rejection after solid-organ transplantation
• Serum vitamin B12 level below 100 pg/mL • Chronic kidney disease
• MMA and homocysteine levels are elevated Pathophysiology:
• Always measure folic acid levels in patients with
vitamin B12 deficiency • Chronic illness activates CD3 T lymphocytes
Schilling test: which release:
o Interferon gamma
• A historical exam that is no longer performed in o TNF-alpha
clinical practice o IL1
• The patient orally ingests radiolabeled vitamin o IL6 (from monocytes)
B12 • Increased production of hepcidin by the liver
• If the marker is found in urine → normal vitamin which inhibits iron absorption from the
B12 absorption duodenum and iron release from bone marrow
macrophages

458
Effects of inflammatory cytokines on iron metabolism and soluble tr. receptor High Normal
hepcidin Normal High
erythropoiesis:
• Serum hepcidin is considered as the most
TNF-alpha: accurate test for the confirmation of the diagnosis
of ACD
• Stimulation of ferritin synthesis → elevated Treatment
ferritin • Treatment of the underlying cause is the best
• Direct inhibition of erythropoiesis by decreasing therapeutic approach for ACD
the response to erythropoietin Iron therapy:
• Inhibition of erythropoietin production by the
kidneys •
Ineffective but might be needed in patients with
Interferon-gamma: combined ACD and iron deficiency anemia
Erythropoiesis-stimulating agents:
• Increased intracellular iron in macrophages
• Impaired release of iron from macrophages in the •
Erythropoietin or agents that work on bone
bone marrow morphogenetic protein (BMP-SMAD)
Effects of hepcidin: • Only approved for patients with anemia and solid
cancers and chronic kidney disease
• Binds to ferroportin on intestinal mucosal cells Packed RBC transfusion:
and macrophages
• Inhibition of iron transport •Reserved for patients with severe anemia (Hb <
• Decreased release of iron from macrophages of 6.5 g/dL) that is associated with cardiac
the bone marrow decompensation
o Associated with increased mortality →
• Decreased absorption of iron from the gut
use cautiously in ACD
o Eventually, can lead to combined ACD
and iron deficiency anemia Normocytic Anemia: Aplastic Anemia
o Patients would then have microcytic Definition
anemia Aplastic anemia is a syndrome of chronic primary
Clinical Presentation hematopoietic failure due to injury to the bone marrow
• Symptoms and signs of chronic illness such as which results in diminished or absent hematopoietic
arthritis, skin nodules and morning stiffness in precursors in the bone marrow and is associated with
rheumatoid arthritis pancytopenia.
• Symptoms and signs of anemia such as pallor, Epidemiology
fatigue and exertional dyspnea • Rare
• Microcytic anemia not responding to iron • Annual incidence is estimated to be from 0.6 to
supplementation 6.1 cases per million
Diagnosis
• Seen in children and in young adults (aged 20 to
Initial tests:
25 years)
• Hemoglobin is generally from 8 to 9.5 g/dL Pathophysiology
• When hemoglobin is < 6 g/dL, look for other Etiology:
causes of severe anemia before attributing it to • Infection (sepsis, CMV, EBV, HHV-6, HIV and
chronic illness VZV)
• Reduced reticulocyte count • Autoimmune diseases including eosinophilic
• Thrombocytosis fasciitis, graft versus host disease and systemic
Peripheral blood smear: lupus erythematosus
• Normochromic normocytic anemia initially • Benzene, lindane (an insecticide), inorganic
arsenicals, pentachlorophenol (wood
• Hypochromic microcytic anemia eventually
preservative) and toluene (glue) toxicity
• Toxic granules in neutrophils in septic patients
• Dose-dependent effect seen in alkalyting
Iron studies in ACD versus iron deficiency anemia:
chemotherapeutic recipients, patients on certain
serum iron deficiency anemia of chronic antibiotics (chloramphenicol and sulfonamides),
anemia disease methotrexate, radiation and ticlopidine
iron Low Low
transferrin High Low or normal • Idiosyncratic reaction to antiepileptics
transferrin saturation Low Low (carbamazepine), anti-thyroid drugs, gold salts,
ferritin Low High

459
 indomethacin, organic arsenicals and
penicillamine
• Hereditary as in Fanconi anemia (DNA repair
defect) and Shwachman-Diamond-Oski syndrome
• Anorexia nervosa
• Thymoma
• Seronegative hepatitis
Pathophysiology:

• Damaged hematopoietic stem cells mature into

self-reactive T-helper cells: Figure 217: Bone marrow findings in aplastic anemia.
o Release interferons and TNF-alpha Source:
o Becomes cytotoxic to other https://library.med.utah.edu/WebPath/HEMEHTML/HEM
hematopoietic stem cells E052.html
• Hematopoietic stem cells lose their ability to
proliferate and differentiate is seen in patients Treatment
with Fanconi anemia • Withdrawal of the offending agent
• Shortened telomeres are present in the cells of • Immunosuppressive therapy when the etiology is
half of the patients with aplastic anemia linking autoimmune:
telomeres’ defects with the disorder o Avoid methotrexate because it can
• In summary, patients have bone marrow failure cause aplastic anemia by itself
and destruction of myeloid stem cells o Use antithymocyte globulin or
Histopathology: cyclosporine
• Bone marrow allograft transplantation → curative
• Markedly hypocellular bone marrow • Bone marrow stimulation therapy with GM-CSF
• Fat cells and fibrotic stroma replace normal bone • Packed RBC and platelets transfusion
marrow tissue Normocytic Anemia: Intrinsic Hemolysis: Spherocytosis
• Abundance of stray lymphocytes and plasma cells Definition
→ emphasizing the autoimmunity of the disease Hereditary spherocytosis refers to a group of heterogenous
Clinical Presentation inherited anemias that result in a spherical erythrocyte on
• Symptoms and signs of anemia including fatigue, the peripheral blood smear. It is classified under intrinsic
dyspnea and pallor hemolytic anemia – extravascular hemolysis and is caused
• Symptoms and signs of pancytopenia: by a genetic mutation in proteins interacting with the RBC
o Thrombocytopenia → petechiae, membrane skeleton and plasma membrane.
purpura and mucosal bleeding
o Neutropenia → recurrent bacterial Epidemiology
infections • Most common cause of inherited chronic
o Increased risk of acute leukemia hemolysis
Diagnosis • Affects one person in 2000 people
• Pancytopenia • Less common in African American people
• Decreased reticulocyte count • Often mild and subclinical
• Elevated erythropoietin level Pathophysiology
• Normochromic normocytic anemia Etiology:
• Bone marrow biopsy is indicated which reveals
hypocellularity and a decrease in the population • Mutations in membrane proteins ankyrin, band 3,
of myeloid precursors beta-spectrin, alpha-spectrin or protein 4.2
• Autosomal dominant in 75% of the cases

460
 Diagnosis
• Anemia with normal or decreased MCV
• Normocytic or microcytic erythrocytic
spherocytes on peripheral blood smear
• Elevated LDH
• Elevated reticulocyte counts → appropriate bone
marrow response to anemia
• Elevated indirect (unconjugated) bilirubin level
• Elevated MCHC
• Positive in vitro osmotic fragility test
Treatment
Based on the severity of the anemia.
Parameter Mild Moderate Severe
hemoglobin Normal 6 – 8 g/dL < 6 g/dL
level
retic count < 6% > 10% > 10%
Peripheral Few Only Micro-
smear spherocytes spherocytes spherocytes
osmotic Normal Increased Increased
Figure 218: The membrane supporting proteins circled here fragility
are the ones found to be defective in HS. Source: DOI: treatment Not needed Splenectomy at Splenectomy at
10.1016/S0140-6736(08)61588-3 age 5y age 3y
• Splenectomy is curative
Pathophysiological effects of hereditary spherocytosis: • Patients often require folate supplementation
Normocytic Anemia: Intrinsic Hemolysis: G6PD
Deficiency
Definition
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme
found in the cytoplasm of all cells in the body including
erythrocytes. It is a housekeeping enzyme that prevents
cellular damage from reactive oxygen species. G6PD
deficiency results in intrinsic intravascular hemolysis when
there is excessive oxidative stress on the RBCs.

Epidemiology
• Most common human enzyme defect
Figure 219: Pathophysiology in hereditary spherocytosis. • More than 400 million people are affected
Source: DOI: 10.1016/S0140-6736(08)61588-3 worldwide
• Because it is caused by a mutation in an X-linked
• Spherocytes have reduced cellular deformability gene, it is more common in men
• In the spleen, they get trapped → erythrostasis • Most prevalent in tropical and subtropical areas
• Because of this, they have enough time to be in • Protective against uncomplicated malaria
contact with splenic macrophages which results • More common in people of African,
in extravascular hemolysis Mediterranean and Asian descent
• RBCs that do not get destroyed undergo splenic Pathophysiology
conditioning where there is further loss of the Etiology:
plasma membrane
• X-linked recessive mode of inheritance
• The pathological RBCs have osmotic fragility in
vitro • Gd gene encodes G6PD
Clinical Presentation • Mutations result in structural changes in the
enzyme reducing its activity
• Symptoms and signs of anemia
• Splenomegaly • In some patients, there is a reduction in the
amount of G6PD
• Jaundice from hemolysis or from biliary
obstruction because of the increased risk of • Complete inactivation of G6PD is lethal to the
embryo → does not occur in live births with
pigment stones
G6PD deficiency
• Hemolytic, aplastic and megaloblastic crises
461
Pathophysiology: • Hemolytic anemia results in pallor, fatigue,
exertional dyspnea and tachycardia
• G6PD is the rate-limiting first step in the pentose • Evidence of recent drug exposure or increased
phosphate pathway oxidative stress as in infection or myocardial
• Glucose-6-phosphate is used to convert NADP infarction
into its reduced form NADPH • Splenomegaly in patients with red blood cell
• NADPH is used by erythrocytes to prevent sequestration
oxidative damage • Jaundice
• NADPH is used as a substrate for glutathione • Dark urine
reductase which produces reduced glutathione • Back pain
• Reduced glutathione converts hydrogen peroxide Diagnosis
to water → preventing cellular damage Newborns:
• RBCs that have a qualitative or quantative defect
in G6PD have reduced amounts of reduced • Assessment of jaundice
glutathione • Measurement of total serum bilirubin
Triggers of hemolysis: • Screening for G6PD is available but is only
recommended in patients with severe jaundice
• Patients with G6PD often do not have chronic resistant to phototherapy
hemolysis o Rapid fluorescent spot test detects the
• Rather, they have recurrent episodes of hemolysis generation of NADPH from NADP
that are triggered by oxidative stressors Adults:
• Oxidative stressors include fava beans (favism),
infections, and drugs • History taking is essential to identify the most
• Common medications that can cause hemolysis in likely cause of hemolysis (the oxidative trigger)
G6PD deficient patients include: • A complete blood count
o Acetaminophen • Bilirubin level is elevated
o Chloramphenicol • Reticulocyte counts are elevated
o Antimalarials • LDH is elevated
o Colchicine Peripheral blood smear:
o Isoniazid
o Nitrofurantoin • Bite cells
o Sulfa-containing drugs • Heinz bodies
o Trimethoprim Treatment
o Vitamin K Neonates:

• Treatment of jaundice
Note: While G6PD is often • Prevention of kernicterus
associated with intravascular • Exchange transfusion in severe cases
hemolysis, splenic sequestration and Adults:
extravascular hemolysis is also
commonly seen in hemolytic crises. • Less severe presentations are managed with
supportive care and avoidance of the stressor
• Treatment of triggers such as infections
• Severe cases may require packed RBC
Clinical Presentation
transfusion
Newborns:
• Splenectomy in patients with RBC splenic
• Neonatal hyperbilirubinemia sequestration
• Kernicterus which has the following symptoms: Normocytic Anemia: Intrinsic Hemolysis: Pyruvate Kinase
o Lethargy Deficiency
o Extreme sleepiness Definition
o Poor muscle tone Red blood cell pyruvate kinase (PK) deficiency is a rare
• Rare, but can be associated with significant congenital hemolytic anemia caused by a glycolytic defect.
morbidity It occurs secondary to a mutation in the PKLR gene located
Adults: on chromosome 1q21.

462
Epidemiology • Patients develop hemolytic anemia and often
• Prevalence of heterozygous carriers is from 1 to require frequent blood transfusions
3% • Jaundice
• Prevalence of PK deficiency is 1 per 20,000 • Endocrine dysfunction
• More common in Pennsylvania Amish • Splenomegaly and hepatomegaly
community due to a founder effect Diagnosis
• Equal frequency in males and females • Hemolytic anemia in a newborn is most often
• Age at diagnosis is 5 months in average secondary to pyruvate kinase deficiency
• Gallstones are present in half of the cases • No clear guidelines for the diagnosis
• Splenectomy is required in half of the cases • Hemoglobin is often < 7g/dL
• More than 90% of the cases occur in white people • Indirect hyperbilirubinemia in 100% of the cases
Pathophysiology Genetic testing:
Etiology:
• Missense mutations involving both PKLR genes
• Autosomal recessive pyruvate kinase mutation → most likely to respond to splenectomy
• Presumed infections are the most common trigger • Non-missense mutations involving both PKLR
of hemolysis in infants and children genes → least likely to respond to splenectomy
Pathophysiology: • One missense and one non-missense mutation
involving each copy of the PKLR gene
• PK catalyzes the conversion of Peripheral blood smear:
phosphoenolpyruvate to pyruvate → release of
ATP • Burr cells which are erythrocytes with uniform
• PK deficiency results in a reduction in the small spikes
production of ATP → shortened reticulocyte and
erythrocyte lifespan because the cell cannot
maintain electrochemical gradient and membrane
integrity
• The damaged RBCs are recognized by the
macrophages of the spleen to be cleared from the
blood stream
• RBCs that are PK deficient have an increased
level of 2,3-BPG which decreases the hemoglobin Treatment
affinity for oxygen Neonates:
Clinical Presentation:
Prenatal: • Treatment of jaundice
• Prevention of kernicterus
• Preterm birth occurs in half of the patients
• Exchange transfusion in severe cases
• Severe prenatal anemia requiring in-utero
Post-natal:
transfusions occur in half of the cases
• Intrauterine growth retardation • Recurrent blood transfusions
Neonates: • Partial response to splenectomy in 22% of the
cases
• Most patients who present during the neonatal
o Splenectomy is usually at the age of 4
period develop indirect hyperbilirubinemia
years
secondary to hemolysis
• Most patients by the age of 14 years have a
• Rarely, patients can develop severe hepatic
cholecystectomy due to recurrent gallstone
disease which can progress to liver failure disease
Post-natal, children and adults: Normocytic Anemia: Intrinsic Hemolysis: PNH
• Most patients are diagnosed in the neonatal Definition:
period Paroxysmal nocturnal hemoglobinuria (PNH) occurs
• Those with milder disease can have a delayed secondary to a nonmalignant clonal expansion of
presentation during infancy hematopoietic stem cells that have acquired a somatic
• Aplastic crisis and extramedullary hematopoiesis mutation of PIGA. PIGA encodes a glycoprotein important
can be seen for the protection of RBCs from complement activation and
cytolysis.

463
 • Pancytopenia (bone marrow failure can occur in
Pathophysiology: some patients)
Etiology: • Venous thrombosis
Treatment:
• Acquired somatic mutation of PIGA Conventional therapy:
• Nonmalignant clonal expansion of the abnormal
hematopoietic stem cells • Corticosteroids for chronic and acute hemolysis
Pathophysiology: • Iron therapy
Complement inhibitors:
• RBCs are deficient in glycosyl
phosphatidylinositol-anchored proteins (GPI- • Eculizumab is a C5 inhibitor
APs) • Symptomatic improvement and marked
• The most important GPI-APs in PNH are CD55 improvement in quality-of-life
and CD59 • It is believed to alter the natural history of PNH
• Absence of CD55 which is a decay-accelerating Normocytic Anemia: Intrinsic Hemolysis: Sickle Cell
factor results in: Disease
o Activation of the alternative pathway of Definition:
complement Sickle cell disease (SCD) is a multisystem disease
o Occurs at night because people tend to associated with progressive organ damage in patients with
hypoventilate → acidemia characteristic sickle-shaped erythrocytes on peripheral
• Absence of CD59 which blocks the formation of blood smear. Sickle-cell disease can be caused by different
the cytolytic membrane attack complex → genotypes, however sickle-cell anemia which is the most
cytolysis common form of the disease refers to a homozygous
• This results in intravascular hemolysis mutation in the beta-allele.
• Increased risk of acute leukemias
Clinical Presentation: Epidemiology:
• Symptoms and signs of hemolytic anemia • Sickle cell disease and sickle cell carriers are
• Hemoglobinuria and intermittent dark urine most commonly African
• Thromboembolic disease due to thrombophilia • One in 12 Africans carry a single sickle-cell allele
• Dysphagia and odynophagia • Sickle cell disease is also common in people of
• Abdominal pain Italian, Greek and Arab descent
Diagnosis: • The prognosis is largely dependent on the
Who should be screened? frequency of vaso-occlusive crises:
o Patients with three crises per year in
• All patients with PNH report gross average have an estimated life
hemoglobinuria expectancy of 35 years
• Such patients need to be screened for the Pathophysiology:
possibility of PNH Etiology:
• Patients with venous thrombosis involving
unusual sites such as Budd-Chiari syndrome or • An autosomal recessive mutation in the beta-
mesenteric veins globin chain
• Patients with episodic dysphagia and • Classified under hemoglobinopathies
intravascular hemolysis • The 6th aminoacids in the beta-globin chain has
Minimal tests for the confirmation of the diagnosis of valine instead of glutamic acid
PNH: • Homozygous mutation involving both alleles is
required for the disease to manifest
• Flow cytometric analysis of peripheral RBCs to • People with a single allele mutation are sickle cell
confirm GPI-APs deficiency carriers
• Supporting evidence of intravascular hemolysis: Pathophysiology:
o Elevated LDH
o Elevated indirect bilirubin • Oxygenated HbS has a normal configuration
o Urine hemosiderin • When HbS gets deoxygenated, HbS polymerizes
Triad in PNH: o This happens in patients with increased
peripheral oxygen demand as in
• Negative Coombs hemolytic anemia

464
 infections, decreased oxygen saturation, o Spleen autoinfarction → increased risk
or acidosis of infections caused by encapsulated
• When the erythrocytes are dehydrated and bacteria such as streptococcus
deoxygenated, the polymerized HbS clumps to pneumoniae, Neisseria meningitidis,
one side of the erythrocyte → sickled erythrocyte Haemophilus influenzae, Klebsiella
• These sickle-shaped erythrocytes lack spp., and osteomyelitis secondary to
deformability → they can occlude small blood salmonella
vessels → end-organ infarction → vaso-occlusive • End-organ infarction:
attacks: o High-output heart failure due to loss of
o Acute chest syndrome cardiac myocytes
o Acute pain in other body areas o Bone infarction most commonly
o Splenic autoinfarction affected the tibia and femur. Presents as
o Osteonecrosis an extremely painful crisis that lasts two
o Nephropathy to seven days and resolves
• Neutrophils and other immune cells and platelets spontaneously
are attracted to the area → release of o Hand-foot disease
inflammatory mediators, VCAM-1, adhesion o Avascular necrosis of the metacarpals
molecules and hypercoagulable state: and metatarsals
o Worsening of vaso-occlusive attack o Acute chest syndrome
• The abnormal sickle-shaped erythrocytes also get o Hypo-splenism
hemolyzed → hemolytic anemia o Avascular necrosis of large joints →
• Hemolyzed erythrocytes release free hemoglobin joint deformity
in the blood → inactivation of nitric oxide and o Cerebrovascular accidents which can
generation of reactive oxygen species → occur in children
Vasculopathy and endothelial dysfunction: o Retinopathy which can lead to blindness
o Pulmonary hypertension o Chronic nonhealing leg ulcers
o Priapism • Delayed puberty and failure to thrive in children
o Leg ulcers Diagnosis:
o Cerebrovascular disease • Evidence of hemolytic anemia such as elevated
indirect bilirubin, anemia, elevated LDH, and
increased reticulocyte count
• Sickle-shaped erythrocytes with normal
erythrocytes (mosaicism) on peripheral blood
smear
• Hemoglobin electrophoresis can confirm the
diagnosis by providing evidence for the presence
of HbS
Treatment:
Preventive treatment to avoid crises:

• Avoidance of high-altitudes due to low oxygen

tension
• Good oral hydration
• Adequate treatment of infections
• Vaccination against encapsulated organisms
Figure 220: Pathophysiology of sickle-cell disease crises. especially after the age of 4 years (most common
Source: DOI:10.1016/S0140-6736(10)61029-X age where splenic autoinfarction is evident)
• Penicillin prophylaxis therapy
Clinical Presentation: • Folate supplements
• Symptoms and signs of hemolytic anemia: Treatment of painful crises:
o Jaundice
o Pallor • From the basic understanding of the pathology of
o Gallstones disease painful crises, it becomes evident that hydration
• Increased risk of infectious disease: is key for the successful management
o Parvovirus B19 → aplastic anemia • Opioids like morphine are often needed

465
 • High-flow oxygen is indicated because decreased RBCs in the reticuloendothelial system and
oxygen tension results in sickling hemolysis
Treatment of complications: • Insects, snakes or other poisonous animals’
venom can result in extravascular or intravascular
• Avascular necrosis of the femoral head is treated hemolysis by an autoimmune mediated
with core decompression and autologous bone mechanism
marrow grafting Autoimmune Hemolytic Anemia
• Proliferative retinopathy is unresponsive to laser • Autoantibody-mediated destruction of RBCs
photocoagulation, however intravitreal • Positive direct-antiglobulin-test (DAT)
bevacizumab might have some benefits • Binding temperature of the autoantibodies
• Sickle hepatopathy is treated with liver classify autoimmune hemolytic anemia into cold
transplantation and warm agglutinins
• Priapism is prevented by adrenergic agonists • Most often idiopathic, but can be associated with:
Indications for blood transfusion: o Viral and bacterial infections
o Autoimmune disease
• Exchange transfusion therapy in early acute chest
o Connective tissue diseases
syndrome
o Lymphoproliferative malignancies
• Urgent transfusion in stroke o Blood transfusions
• Acute exacerbation of anemia which is often o Transplantation
linked to parvovirus B19 infection Warm AIHA:
Normocytic Anemia: Extrinsic Hemolysis:
Definition: • More common than cold AIHA
Hemolytic anemia is defined as the premature destruction • IgG antibodies to the Rh complex
of red blood cells before their normal 120-day lifespan. • React with RBCs at normal body temperature
Hemolytic anemia can be acute, chronic, compensated or • IgG-coated RBCs are removed by the
life-threatening. reticuloendothelial macrophages (extravascular
hemolysis)
Pathophysiology:
• Can result in splenomegaly
Antibody-mediated hemolysis results in the destruction of
RBCs by phagocytosis or complement-mediated • Treatment includes glucocorticoids, management
of the underlying cause and possibly blood
hemolysis. It can occur intravascularly or extravascularly.
transfusion
Extrinsic intravascular hemolysis: Cold AIHA:

• Alloimmune reaction which can occur as a • IgM antibodies known as cold agglutinins
transfusion reaction or in hemolytic disease of the • React with polysaccharide antigens on RBC at
fetus and newborn low temperatures
o Direct destruction by the activation of • Causes hemolysis on rewarming by complement
the complement attack complex plays a fixation (intravascular hemolysis)
role • Mycoplasma pneumoniae and mononucleosis are
• Autoimmune hemolytic anemia two common etiologies of cold AIHA
o Warm or cold autoimmune hemolytic • Treatment includes supportive measures,
anemia avoidance of triggers (hypothermia), and
o Can be intravascular or extravascular management of the underlying cause
• Microangiopathic hemolytic anemia results in Drug-Induced Immune Hemolytic Anemia:
mechanical fragmentation of RBCs Transfusion reactions:
• Freshwater drowning results in osmotic lysis of
RBCs • Alloantibodies react with incompatible RBCs
• Trauma to the red blood cells by artificial • Hemolysis can be acute or delayed
metallic heart valves or burns can result in • It can be life-threatening
hemolysis Drug-induced hemolysis:
Extrinsic extravascular hemolysis:
Immune-mediated:
• Systemic illnesses such as malignant • Rare
hypertension, autoimmune disease and other
• Drug-induced autoantibodies
diseases can result in extravascular trapping of

466
 • Positive DAT • If the patient has a skin rash → Rickettsia, human
• Methyldopa and penicillin are the classic causes immunodeficiency virus or malaria infection
• Cefotetan, ceftriaxone, piperacillin, and NSAIDs • If the patient does not have a skin rash:
are the most common causes nowadays o Pregnant → abnormal liver function
Thrombotic microangiopathic-mediated: tests → HELLP syndrome
o Diarrhea → positive stool culture or
• Occurs when a drug causes platelet-mediated shiga toxin → hemolytic uremic
microthrombi syndrome
• Results in microangiopathic hemolytic anemia o New drug → drug-induced thrombotic
• Quinine, cyclosporine, and tacrolimus can cause microangiopathy
thrombotic-microangiopathic anemia Normal RBCs’ morphology:
• It is important to discontinue the offending agent,
provide supportive care, and consider plasma • Drug-induced immune hemolytic anemia
exchange therapy Spherocytes:
Oxidative-injury-mediated:
• DAT negative → hereditary spherocytosis
• This is an extrinsic cause of hemolysis in a • DAT positive:
patient with an intrinsic predisposition to o Recent drug exposure → drug-induced
hemolysis, i.e. G6PD deficiency immune hemolytic anemia
• The topic is covered in detail in the article about o No recent drug exposure → AIHA:
G6PD deficiency ▪ Binding to RBCs at body
Diagnostic Approach temperature → warm AIHA
Presentation: (IgG)
▪ Binding to RBCs at a lower
• Fatigue temperature → cold AIHA
• Pallor (IgM)
• Shortness of breath
• Jaundice
• Laboratory evidence of anemia
Initial laboratory workup:
Test Finding in Cause
hemolysis
Lactate Increased - Released from the
dehydrrogenase destroyed RBCs
Haptoglobin Decreased - Binds free Figure 221: Direct antiglobulin test (direct Coombs),
hemoglobin demonstrating the presence of autoantibodies (shown here)
Reticulocyte count Increased - Normal response
of bone marrow or complement on the surface of the red blood cell.
to anemia Patient’s blood is mixed with Coombs reagent in DAT.
Indirect bilirubin Increased - Increased
hemoglobin
breakdown Indirect Coombs test:
Urinalysis Positive • Patient’s serum is added to donor blood
urobilinogen
• Autoantibodies in the patient’s serum coat donor
Peripheral blood smear: RBCs
• Patients who meet the above diagnostic findings • Coombs reagent is added → agglutination
on their initial laboratory testing are likely to (indirect Coombs positive)
have hemolysis
• A peripheral blood smear is important in
identifying the most likely cause and choosing the
right next diagnostic test
Schistocytes:

• Fragmented RBCs due to mechanical trauma to

RBCs
• Can be caused by microangiopathic hemolytic
anemia

467
Figure 222: Indirect Coombs test. Source:
https://en.wikipedia.org/wiki/Coombs_test#/media/File:Co
ombs_test_schematic.pngHeme Synthesis and Porphyrias
Pathway of Heme Synthesis:
• Eight sequential steps
• Delta aminolaevulinic acid (ALA) is synthesized
from Succinyl CoA and glycine by ALA synthase
o ALA synthase deficiency occurs in X-
linked protoporphyria
• ALA is converted to porphobilinogen by ALA
dehydratase
• Porphobilinogen is converted to Figure 223: Heme synthesis pathway. Source:
hydroxymethylbilane by porphobilinogen 10.1056/NEJMra1608634
deaminase → deficiency in this enzyme results in
acute intermittent porphyria Acute Intermittent Porphyria:
• Hydroxymethylbilane is converted to Definition:
uroporphyrinogen III by uroporphyrinogen
synthase Acute intermittent porphyria (AIP) is caused by a partial
• Uroporphyrinogen III is converted to deficiency in porphobilinogen deaminase. It is an
coproporphyrinogen III by uroporphyrinogen autosomal dominant condition.
decarboxylase → deficiency in this enzyme
• Estimated prevalence is 1 per 2000
results in porphyria cutanea tarda
• Penetrance (acute attacks) is in less than 10% of
• Coproporphyrinogen III is converted to
protoporphyrinogen IX by coproporphyrinogen the carriers
oxidase Presentation:
• Protoporphyrinogen IX is converted to • Most patients are females
protoporphyrin IX by protoporphyrinogen • They complain of several days of fatigue and
oxidase → deficient enzyme in protoporphyria inability to concentrate (CNS symptoms)
• Finally, protoporphyrin IX is converted to heme • This is followed by abdominal pain, nausea and
by ferrochelatase vomiting
• Finally, patients develop transient weakness,
dysesthesia and/or altered affect
• Patients usually self-medicate with analgesia but
notice no relief
• These episodes are often recurrent
• History of recurrent visits to the emergency
department without a definite diagnosis
• Seizures are reported in 20% of patients
5 P’s of AIP:

• Painful abdomen
• Polyneuropathy (more of multiple neurologic
defects rather than neuropathy)
• Psychological abnormalities (decreased affect)
• Paranoia

468
 • Port-wine (dark amber) urine that turns pink • HIV infection
when left in light • Iron overload (acquired or congenital as in
Diagnosis: hemochromatosis)
• Use of alcohol
Findings during the attack:
• Use of estrogen
• Normal or dark amber urine Diagnosis:
• Very high levels of porphobilinogen and Findings in active disease:
uroporphyrin in the urine (usually 10 times higher
than the upper normal limit) • Brown or reddish-brown urine
Findings while asymptomatic: • Normal porphobilinogen level in urine
• Markedly elevated uroporphyrin level in urine
• Normal uroporphyrin level in urine (20 times upper normal limit)
• Mildly elevated (up to 10 times upper normal Findings while asymptomatic:
limit) porphobilinogen level in urine
Barbiturates in AIP: • Normal porphobilinogen level in urine
• Elevated uroporphyrin level in urine (10 times
• Barbiturates activate the cytochrome P450 system
upper normal limit)
in the liver
Treatment:
• From Figure-1, it is evident that heme breakdown
can occur via this pathway • Iron chelating therapy in iron overload
• Heme has a negative-feedback effect on its • Beta-carotene
synthesis pathway Approach to Bleeding Disorders:
• Loss of heme → increased activity of the heme
synthesis pathway → increased levels of Review of Normal Hemostasis:
precursors before the deficient enzyme → • Blood vessel injury results in the activation of the
increased abdominal pain sympathetic nervous system and vasoconstriction
Porphyria Cutanea Tarda: • Platelet recruitment, adhesion, activation, and
Definition: aggregation follows to form the primary
hemostatic clot
Porphyria cutanea tarda (PTC) is the most common type of
the porphyrias and it is due to the inhibition of • Finally, the coagulation cascade is activated to
uroporphyrinogen decarboxylase, the fifth enzyme in the form the secondary hemostatic clot
heme synthesis pathway. • The secondary hemostatic (fibrin) clot undergoes
remodeling and eventually resolves by the
• Estimated prevalence is 5 to 10 per 100,000 activation of fibrinolysis and other inhibitors of
Pathogenesis: coagulation

• Excessive iron as in hemochromatosis inhibits

uroporphyrinogen decarboxylase
• Mutations in uroporphyrinogen decarboxylase are
uncommon and are usually not associated with
PTC (PTC is an acquired disease)
• The circulating porphyrins are light-sensitive →
photosensitivity is a hallmark of PTC
Presentation:

• Slow onset of painless blisters

• Fragile skin
• Scars
• Hypertrichosis on sun-exposed skin Figure 224: Summary of normal hemostasis. Source:
• Male predominance in patients older than 40 PMCID: PMC3410146
years (AIP is more common in females aged 18 to
40 years) Clinical Assessment:
Associated conditions: Mixed model of coagulation:
• Hepatitis C infection

469
 • The mixed model of coagulation recognizes that Laboratory Assessment:
normal hemostasis is dependent on cellular Complete blood count:
(platelet) and acellular (coagulation factors)
components •
Exclude abnormalities in platelet count
• A functional abnormality of platelets or a •
Peripheral blood smear examination might reveal
deficiency in platelets or coagulation factors can abnormalities in platelet morphology
result in a bleeding disorder • Exclude other hematologic abnormalities such as
Symptoms and signs more commonly seen in platelet pancytopenia
disorders: PT and APTT:

• Petechiae •The intrinsic pathway is assessed by APTT:

• Purpura o Normal range is 25 to 38 seconds
• Ecchymosis o Increased in coagulation disorders that
• Gingival bleeding affect the intrinsic pathway factors such
as hemophilia A and B
• Easy bruising
• The extrinsic and common pathways are assessed
• Epistaxis
by PT:
• Menorrhagia
o Normal range is 10 to 14 seconds
• Hematuria o Highly variable between laboratories →
hence the development of INR
o Prolonged in factor VII deficiency and
early oral anticoagulation therapy
• Thrombin time (TT) assesses the generation of
fibrin (normal range is 15 to 19 seconds)
Bleeding time and PFA:

• Normal bleeding time is 3 to 9 minutes

Figure 225: 2A. Petechiae. 2B. Purpura. 2C. Ecchymosis. o Very inaccurate and not reliable
Source: PMCID: PMC3410146 • PFA-100 is a recently developed test of platelet
function
Symptoms and signs more commonly seen in coagulation o Excellent sensitivity and specifity for
factor defects: platelet dysfunction especially in
patients taking aspirin
• Bleeding into deep tissues such as muscle
• Hemoarthrosis Examples of Common Bleeding Disorders
• Body cavity hematomas Platelet disorders:
• CNS bleeds Thrombocytopenia Normal platelet count
Platelet count < 150 x 109 per liter 150 – 400 x 109 per liter
Possible - Congenital: - Inherited: Glanzmann
causes Wiscott-Aldrich thrombasthenia,
syndrome with Bernard Soulier
eczema and syndrome and vW
impaired disease
immunity - Acquired: aspirin,
- Impaired bone uremia and
marrow myeloproliferative
production as in disorders
aplastic anemia
- Increased platelet
destruction as in
Figure 226: Hemoarthrosis. Source: PMCID: ITP, DIC, SLE
PMC3410146 and TTP
PT and PTT Normal Normal (elevated PTT in
vW disease)
Symptoms and signs suggestive of an inherited bleeding Bleeding time Increased Increased
disorder: and PFA
Coagulation cascade disorders:
• Easy bruising
Congenital causes Acquired causes
• Excessive bleeding post minor trauma Prolonged PT - Factor VII - Early oral
• Hemoarthrosis deficiency anticoagulation
• Presence of symptoms since early childhood

470
 Prolonged APTT - Factors VIII, IX, - Lupus anticoagulant • Easy bruising
XI or XII
deficiency • Mucosal bleeding which can lead to anemia
- Von Willebrand • Moderate post-traumatic bleeding
disease
Prolonged PT - Factors V, X, - Oral anticoagulation • Retroperitoneal, intraperitoneal or bleeding into
and APTT and II deficiency - Vitamin K any other body’s cavity can occur
deficiency
- Liver disease
• CNS bleeding can occur, and it can be
Prolonged PT, - Fibrinogen - DIC catastrophic → aggressive treatment is often
APTT and TT deficiency - Liver disease required
- Heparin
Hemophilia
Definition:
Hemophilia:
Hemophilia A and B are congenital bleeding disorders
caused by a partial deficiency or a complete absence of
coagulation factors VIII and IX. They are X-linked
disorders. They are difficult to distinguish clinically.
Hemophilia A: Figure 227: Hemoarthrosis in a patient with hemophilia.
Hemophilia A is characterized by the deficiency or absence Source:
of coagulation factor VIII. http://www.healthcaretip.com/2017/02/Hemarthrosis-ICD-
Hemophilia B: 10-Definition-Symptoms-Causes-Treatment.html
Hemophilia B is characterized by the deficiency or absence
of coagulation factor IX. Diagnosis
• PTT is elevated
Epidemiology • It is important to measure factor VIII and IX
• Hemophilia A occurs in one per 5000 males levels to determine the type of hemophilia the
• Hemophilia B occurs in one per 50,000 males patient has
• No racial predilection • Patients with low factor VIII levels should get
• Two-thirds of persons with hemophilia live in the their vWF level checked to exclude vWF disease
developing world → remember factor VIII is stabilized by vWF

Pathophysiology Treatment
• After the formation of the primary platelet clot, Common treatments:
the secondary clot starts to form via the intrinsic • Patients with hemoarthrosis can have pain
and/or extrinsic coagulation pathways • Treat with acetaminophen + codeine
• From the basic understanding of the coagulation • Avoid NSAIDs and aspirin because they inhibit
cascade model, we know that the sequential platelet functioning
activation of different coagulation factors is key • Immobilize affected joints
for the activation of factor X which is where the • Apply ice packs on affected joints
common pathway starts to act on prothrombin Hemophilia A:
• Factor IX when activated and in the presence of • Factor VIII concentrate
factor VIIIa which is stabilized by vWF results in • Desmopressin → increases the production of
the activation of factor X factor VIII and vWF
• Accordingly, a deficiency in either factor IX or • Gene therapy is promising
VIII would result in a very similar pathology Hemophilia B:
(inability to activate factor X via the intrinsic • Factor IX concentrate
pathway) • No role for desmopressin
• This will result in a bleeding disorder Approach to Thrombocytopenia
Definition
Clinical Presentation Thrombocytopenia can be defined numerically as a platelet
• The clinical presentation of hemophilia A and B count less than 150 x 109/L. Platelet count of 100 to 150 x
is similar 109/L is a hazy range which can be normal or pathological.
• Mild or moderate joint and muscle bleeds are
often seen • Clinically significant spontaneous bleeding
• Severe hemoarthrosis (bleeding into large joints) occurs when platelet count < 10 to 20 x 109/L
can occur

471
Pathophysiology • Pregnant women might have thrombocytopenia
Decreased production of platelets: secondary to:
o ITP
• Bone marrow failure: o HELLP syndrome
o Aplastic anemia o Preeclampsia
o Fanconi’s anemia o Abruptio placenta
o Congenital rubella Diagnosis
• Infiltrative disorders of bone marrow: Step 1: Complete Blood Count:
o Tumors
o Myelodysplastic syndromes • Isolated thrombocytopenia:
• Bone marrow injury: o ITP
o Chemotherapy o DITP
o Gold-induced o HIV
o Benzene o HCV
o Insecticides o H. pylori
• Radiation o HIT
Increased destruction/consumption of platelets: o DIC
• Lymphocytosis or neutrophilia:
• Disseminated intravascular coagulation o Infectious cause of thrombocytopenia
• Thrombotic microangiopathies o Seen in critically ill patients
• Immune-mediated destruction of platelets: • Associated with anemia:
o ITP o Aplastic anemia
o HIT (heparin induced o Bone marrow failure
thrombocytopenia) o Hemolytic anemia → consider DAT
Other mechanisms: Step 2: Peripheral Blood Smear:
• Platelet sequestration in congestive splenomegaly • When assessing a peripheral blood smear in a
due to portal hypertension critically ill patient, you want to answer the
• Hemodilution is seen in patients receiving following questions:
massive fluid therapy after significant o Does your patient have a thrombotic
hemorrhagic shock microangiopathy? → fragmented RBCs
Clinical Assessment on peripheral blood smear in addition to
Symptoms and signs of a platelet disorder: thrombocytopenia
o Does the patient have a malignant cause
• Petechiae – small of thrombocytopenia? → blasts on
• Purpura – larger than petechiae peripheral blood smear is suggestive of
• Ecchymosis acute leukemia
• Mucosal surface bleeding • In other clinical scenarios, all three cell lineages:
• Easy bruising RBCs, WBCs and platelets need to be examined
• Epistaxis to narrow down the most likely cause of
• Menorrhagia thrombocytopenia
• Hematuria Step 3: Further Investigations:
• Hemoarthrosis and hematomas are rarely seen in
platelet disorders • Based on the results of the peripheral blood
Symptoms and signs giving clues about the cause: smear, the following tests can help narrowing
down the differential diagnoses:
• Outpatients who present with petechiae can have Presence of schistocytes: Diagnostic workup for
ITP consumptive coagulopathy secondary to thrombotic
• Inpatients are more likely to have multisystemic microangiopathy is indicated:
illness as the cause of their thrombocytopenia:
• LDH
o Infections
o TTP and HUS • Bilirubin level
o DIC • PT and aPTT
o HIT • D-dimers
o Bone marrow disorders • Fibrinogen

472
Presence of blasts: Diagnostic workup to exclude o Thrombosis
malignancy: o Thrombocytopenia unlikely to be
secondary to other causes
• Bone marrow aspiration and biopsy DIC:
Microspherocytes and RBC agglutination: Diagnostic
workup for autoimmune hemolytic anemia: • Thrombocytopenia
• Elevated fibrin degradation products
• Reticulocyte count • Prolonged PT
• LDH • Decreased fibrinogen level
• Bilirubin level • Platelet count < 50 x 109/L, strongly increased
• DAT fibrin degradation products level, and a PT > 6 s
Peripheral Blood Smear of the upper limit of normal range → overt DIC
Clearly, the peripheral blood smear provides important with high mortality
information about the most likely cause of Disseminated Intravascular Coagulation
thrombocytopenia. The following findings in the three cell
Definition
lineages when associated with thrombocytopenia can give
The International Society on Thrombosis and Hemostasis
a clue about the most likely cause:
(ISTH) defines DIC as follows:
Platelet abnormalities on peripheral blood smear:
• Disseminated intravascular coagulation is an
• Platelet clumping is seen in 1 person per 1000 acquired syndrome characterized by the
and is normal activation of intravascular coagulation with loss
• Large platelets suggest hereditary of localization. It can be caused by several
macrothrombocytopenia etiologies and can result in end-organ damage
• Large platelets and normal platelets suggest From this definition, it is important to note the following:
consumptive coagulopathy • DIC is an acquired disorder
White blood cell abnormalities on peripheral blood smear:
• DIC is a consumptive coagulopathy where
• Blasts and other leukemic cells → malignant platelets and coagulation factors are consumed
hematological disorders such as acute leukemias • DIC cannot be localized to a single site (DVT for
• Leukocyte inclusions and neutrophilia → sepsis example is a thrombus in the deep venous system
of the legs and it is localizable)
• Atypical lymphocytes → viral infection
• Hypo-lobulated neutrophils → myelodysplastic • DIC is always a secondary phenomenon not a
syndromes primary disease
Red blood cell abnormalities on peripheral blood smear: • DIC does not always cause end-organ damage
Pathophysiology
• Schistocytes or fragmented RBCs → thrombotic Etiology:
microangiopathy such as TTP or HUS, or DIC
• Dacrocytes → myelofibrosis When we discuss the diagnostic criteria of DIC later, it will
• Nucleated RBCs → hemolytic anemia or become evident that a diagnosis of DIC cannot be made
infiltrative disorders of the bone marrow without an apparent cause that is known to be associated
Examples of Thrombocytopenic Disorders: with DIC.
Heparin-induced thrombocytopenia:
• Etiologies of DIC can either result in a systemic
• Up to 5% of patients receiving heparin inflammatory response or increase the release of
• Type 1 occurs in the first 48 hours after the pro-coagulant material
initiation of heparin • Activation of cytokines is seen for example in
o There is typically history of heparin use patients with sepsis and polytrauma
in the last three months • Release of pro-coagulant material is more
o Due to the formation of antibodies relevant to DIC associated with malignancies and
against a heparin fragment obstetrical causes
• Type 2 occurs 3 to 12 days after starting heparin Infections:
o Heparin should be stopped
• The 4Ts of HIT: • Bacterial infections and septicemia are major
causes of DIC
o Thrombocytopenia
o Temporal relation to heparin

473
 • Cell membrane components of the offending • In some patients, plasminogen activator inhibitor
organism or bacterial exotoxins are the main levels are not elevated → increased fibrinolytic
trigger of DIC activity → DIC with bleeding manifestations
• Gram-negative bacilli and gram-positive cocci Natural anticoagulants and DIC:
can cause sepsis and DIC
• CMV, HIV, hepatitis and dengue fever have been • The increased generation of thrombin, (a pro-
associated with DIC coagulant), is driven by tissue factor in DIC →
• Invasive pulmonary aspergillosis may cause DIC extrinsic pathway
Obstetrical causes: • Anti-thrombin III is the most important inhibitor
of thrombin in the coagulation cascade
• Abruptio placentae, amniotic fluid embolism, • Markedly decreased concentrations of anti-
intrauterine fetal demise and pre-eclampsia can thrombin III are seen in patients with sepsis →
cause DIC DIC
• Abruptio placentae releases thromboplastin-like • The activation of the cytokines’ cascade down-
material which is the cause of DIC in such regulates thrombomodulin expression →
patients decreased activation of protein C which is another
Malignancy: important anti-coagulant

• DIC caused by malignancies is often less

fulminant than DIC associated with sepsis or
polytrauma
• Tumors can produce pro-coagulant factors such
as tissue factor and a cysteine protease that is
capable of activating factor X → thrombosis and
DIC
• Acute promyelocytic leukemia and solid tumors
such as prostatic cancer are the most common
malignancies associated with DIC
SIRS:

• Anything that can result in a systemic

inflammatory response syndrome might cause
DIC
• Causes that fall under this category include
polytrauma, crush injuries, massive burns, severe
hypo or hyperthermia, severe pancreatitis and
gunshot brain injury
• In severe trauma, in addition to the activation of
the cytokine cascade, the release of phospholipids Figure 228: Summary of the pathology in DIC. Source:
and fat from major fractures into the blood stream DOI: 10.4103/0019-5049.144666
results in hemolysis, endothelial damage and the
Microangiopathic Hemolytic Anemia (MAHA):
activation of the coagulation cascade
Exogenous toxins: • Mimics DIC but it is not DIC
• Viper snake bites • Patients have a similar clinical picture to DIC
Pathogenesis: • Normal PT and aPTT, in DIC they are usually
elevated
• Increased thrombin production and impaired anti- Clinical Presentation
coagulant systems are the hallmarks of DIC • Patients with DIC are usually critically ill, except
• Increased fibrin generation and deposition in the DIC associated with malignancies which can be
vascular system gradual and less fulminant
• In early DIC, plasmin activity increases in an • Most patients with DIC are already admitted at
attempt to control micro-thrombi formation the intensive care unit for the treatment of other
• This response fails eventually because of an serious illnesses such as sepsis or polytrauma
elevated concentration of plasminogen activator • Patients develop petechiae, purpura and
inhibitor which inhibits fibrinolysis ecchymosis
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 • Bleeding from IV catheters, urinary catheter, GI Fibrinogen:
tract and other places
• Multiorgan failure such as acute kidney failure • Fibrinogen is an acute phase reactant
• Intracranial hemorrhage which can be fatal • It will remain elevated in most patients with DIC
• Symptoms and signs suggestive of the etiology despite the consumptive coagulopathy
• In severe DIC, fibrinogen will be decreased
Diagnosis How to increase the accuracy of the individual tests:
ISTH diagnostic algorithm of DIC: important because it
takes into account the pathogenesis of DIC, but is not • Clearly, none of these tests is specific and
mandatory for USMLE Step 1 sensitive enough for DIC when taken individually
• The incorporation of these tests into a scoring
This is a five-step diagnostic algorithm that has excellent system such as the ISTH increased the specificity
sensitivity and specificity for the diagnosis of DIC: and sensitivity for DIC significantly
1. Does the patient have a known cause of DIC? • Another approach is to order serial tests:
Proceed only if yes o A trend of declining platelet counts,
2. Order the following tests: increasing d-dimer concentration,
a. PT increasing PT duration and decreasing
b. Platelet count fibrinogen level (despite being > 1 g/L)
c. Fibrinogen is highly suggestive of DIC
d. A fibrin related marker such as d-dimer Differential diagnosis of DIC:
3. Score your results as follows:
• Thrombotic microangiopathy:
a. Platelet count: > 100 → 0; < 100 → 1
o Schistocytes
point; < 50 → 2 points
o Fever
b. PT: > upper normal limit by 1 to 2
o Neurologic symptoms
seconds → 0; more than 3 seconds → 1
point; more than 6 seconds → 2 points o PT and aPTT are normal
c. Fibrinogen level: > 1 g/L → 0; < 1 g/L • Heparin-induced thrombocytopenia:
→ 1 point o Temporal relation to use of heparin
d. D-dimer: no increase → 0; moderate o Rebound of platelets after the
increase → 2 points; strong increase → discontinuation of heparin
3 points o Normal PT
4. Add the points together to get a total score o Prolonged aPTT
5. Analyze your total score: • Vitamin K deficiency:
a. > 5 points → overt DIC: repeat score o Prolonged PT and aPTT
daily to predict mortality o Normal platelet count
b. < 5 points → non-overt DIC: repeat Treatment
score after two days Proper treatment of the underlying cause:
Thrombocytopenia in DIC:
• Treatment of the underlying cause can revert or
• Seen in almost all patients with DIC prevent the development of DIC
• < 50 x 109/L in half of the cases • The diagnosis of DIC cannot be made without an
• Not specific for DIC when taken independently apparent cause that is known to be associated
Fibrin degradation products: with DIC
Platelet transfusion therapy:
• D-dimer is the most commonly used one in
clinical practice • DIC patients with platelet counts < 50 x 109/L
• In addition to DIC, d-dimer can be also elevated with active bleeding or undergoing surgery
in trauma, recent surgery and venous • DIC patients with platelet counts < 20 x 109/L
thromboembolism even if not actively bleeding
PT and aPTT: Fresh frozen plasma:

• Both are usually elevated in half of the cases of • Correction of coagulation defects
DIC • Severe hypofibrinogenemia despite fresh frozen
• Attributed to consumptive coagulopathy plasma → administer purified fibrinogen
• Half of the patients of DIC have normal PT and concentrate or cryoprecipitate
aPTT → does not exclude DIC

475
 • Aim to bring PT and aPTT to < 1.5 times the • Annual incidence in adults is 1.6 cases per
normal 100,000
Heparin: • Slightly higher incidence in female adults than
males
• Used in DIC due to metastasized malignancies, • Common in the elderly
purpura fulminans and major vascular • Most often a secondary disease
abnormalities
• Low-molecular weight heparin is indicated for Pathophysiology
the prevention of DVT in ICU patients even if • The factors that initiate autoantibody production
they have DIC in ITP are unknown
Promising new treatments: • Antibodies against platelet surface glycoproteins
are formed
• Based on the recent understanding of the • Most often, antibodies against glycoprotein
pathogenesis of DIC IIb/IIIa are found
• Recombinant human soluble thrombomodulin is • Antibodies coat platelets which are then
promising presented to macrophages
• Anti-thrombin concentrate • Macrophages phagocytose coated platelets and
• Activated protein C concentrate degrade them
• Tranexamic acid in DIC patients with severe • Antigen-presenting cells degrade glycoprotein
bleeding IIb/IIIa
Immune Thrombocytopenia • Activated macrophages present glycoprotein
Definition IIb/IIIa to CD4 T cells which result in the
Primary immune thrombocytopenia: activation of an autoimmune T-cell colony and
the activation of B-cells
An autoimmune disorder characterized by isolated • Massive amounts of autoantibodies against
thrombocytopenia in the absence of other causes that can glycoprotein IIb/IIIa are formed → ITP develops
cause thrombocytopenia. It is a diagnosis of exclusion. • Antibodies belong to IgG family
Secondary immune thrombocytopenia:
All forms of immune-mediated thrombocytopenia where
an identifiable cause is apparent including SLE-associated
ITP and drug-induced ITP.
ITP phases:
Newly diagnosed ITP:
First three months after diagnosis.
Persistent ITP: Figure 229: Pathophysiology of ITP. A vicious cycle
develops that results in the production of massive
3 to 12 months after diagnosis without reaching full autoantibodies against platelet surface glycoproteins.
remission. Source: DOI: 10.1016/j.hoc.2013.03.001
Chronic ITP:
Clinical Presentation
ITP lasting for more than 12 months. Bleeding:
Severe ITP: • Most common clinical manifestation of ITP
• Mucocutaneous bleeding presenting as petechiae,
ITP presenting with bleeding symptoms that require purpura, ecchymosis, epistaxis, gingival and
treatment. gastrointestinal bleeding
Epidemiology • Menorrhagia
• Prevalence is estimated to be around 5 cases per • Intracranial hemorrhage can be catastrophic:
100,000 children o 0.2% of children with ITP develop
• Highest prevalence is seen in children aged intracranial hemorrhage
between 1 and 5 years

476
 o Almost always occurs at platelet counts • Platelet-associated IgG has excellent sensitivity
< 10 x 109/L but very poor specificity
• Specific platelet glycoprotein antibodies have
excellent specificity and below-average
sensitivity (good positive predictive value)
Treatment
Children:

• Spontaneous recovery in 80%

• Usually resolves within 6 months and is most
often post-infection
Figure 230: Petechiae on the leg of a patient with ITP. • Those with severe thrombocytopenia or bleeding
Source: https://www.mayoclinic.org/diseases- complications might require a short course of
conditions/idiopathic-thrombocytopenic- corticosteroids, IVIg, or anti-D in Rh-positive
purpura/symptoms-causes/syc-20352325 individuals
• The unlucky 20% develop persistent ITP which is
Fatigue: treated with rituximab or romiplostim
Adults:
• Present in one quarter of the cases
• Might be related to ITP or its treatment (a side • Most cases evolve into chronic ITP
effect of steroids) • The goal is to achieve a platelet count of 20 to 30
• Patients with ITP have elevated levels of IL-2 and x 109/L or more
interferon-gamma which can explain why they • Treatment is complex but can be summarized as
are fatigued follows
Thrombosis: First-line:

• Paradoxical development of thrombosis in a • Corticosteroids such as prednisolone or

thrombocytopenic patient has been reported dexamethasone
• Most likely caused by the emergence of • IVIg
antiphospholipid antibodies which are associated • Anti-D in Rh-positive patients
with ITP o They coat Rh-positive RBCs
Diagnosis o Coated RBCs are recognized by the
spleen and removed
• Isolated thrombocytopenia in primary ITP
o This causes a mild anemia
o Platelets count < 100 x 109/L
o The spleen is too busy dealing with
o Platelets count from 20 to 100 x 109/L
coated RBCs and it ignores coated
→ increased risk of bleeding
platelets
complications
o Antibody-coated platelets are left free to
o Platelets count < 20 x 109/L →
roam the circulation
increased risk of major bleeding
Second-line in unresponsive cases:
complications
o Platelets count < 10 x 109/L → • Rituximab
increased risk of fatal intracranial • Romiplostim
hemorrhage
• Splenectomy
• Normal size platelets or slightly increased size Refractory ITP:
• Peripheral blood smear examination excludes
other causes of thrombocytopenia such as • Combination chemotherapy
thrombotic microangiopathy (fragmented RBCs • Combination of first-line and second line
in addition to thrombocytopenia) therapies
Bone marrow biopsy: • Hematopoietic stem cell transplantation
Thrombotic Thrombocytopenic Purpura
• Increased numbers of megakaryocytes
Definition
• Increased numbers of immature large
The definition of thrombotic thrombocytopenic purpura
megakaryocytes
Serologic tests: (TTP) has been recently updated into the following criteria:

477
 1. Multiorgan ischemic symptoms (thrombosis)
mainly targeting the brain
2. Microangiopathic hemolytic anemia
3. Severe thrombocytopenia
4. Severe deficiency of ADAMTS13
Epidemiology
• Most cases of TTP are acquired and occur in
adults
• One third of the cases of TTP in children are
inherited (ADAMTS13 mutations)
Risk factors:

• Female gender
• Black ethnicity Figure 231: Pathophysiology in TTP. Source: DOI:
• HLA-DRB1*11 10.1182/blood-2016-10-709857
• Obesity
Pathophysiology Clinical Presentation
TTP is a consumptive thrombotic disease: TTP pentad which is seen in 10% of the cases:

• Platelets are circulating normally in the peripheral • Fever

blood stream • Thrombocytopenia
• Von Willebrand factor (vWF) multimers are also • Microangiopathic hemolytic anemia (MAHA)
found in the peripheral blood stream • Neurologic symptoms
• When vWF production is increased as in • Renal insufficiency
infections, inflammation or pregnancy; ultra-large Most common presentation:
vWF multimers are formed
• Severe thrombocytopenia (platelet count < 30 x
• In the presence of ADAMTS13, these ultra-large
109/L)
vWF multimers are cleaved and thrombi do not
• MAHA
form
• Skin and mucosal hemorrhage such as petechiae,
• When ADAMTS13 is absent, ultra-large vWF
purpura (non-blanching) and ecchymosis
multimers adhere to the vascular walls and
Neurologic symptoms in TTP are seen in 60% of the cases:
platelets recognize them
• Platelets adhere to the ultra-large vWF multimers • Headache
to form microthrombi (thrombocytopenia • Confusion
develops) • Stroke
Causes of ADAMTS13 severe deficiency:
• Coma
• Autoantibodies form against ADAMTS13 • Seizures
• This can be idiopathic, of unknown cause, or Other ischemic complications:
associated with other conditions:
• Heart ischemia in 25% of the cases
o Autoimmune disease such as SLE
• Mesenteric ischemia in 35% of the cases
o HIV
o Malignancy • Acute kidney failure in 10% of the cases
o Pregnancy Associated conditions:
• Genetic mutations account for a minority of the • SLE
cases that are hereditary • Antiphospholipid syndrome
Microangiopathic hemolytic anemia in TTP:
• Pregnancy
• The microthrombi are mechanical barriers to the • Drugs (clopidogrel, ticlopidine, and quinine)
circulating RBCs • Pancreatitis
• RBCs get fragmented to form schistocytes • HIV infection
• Tissue ischemia develops • Cancers
• Organ transplantation
Diagnosis
• Patients with severe thrombocytopenia, MAHA
(schistocytes on peripheral blood smear) and
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 symptoms and signs suggestive of TTP should • Equal frequency between males and females
undergo ADAMTS13 activity assessment
• If ADAMTS13 activity is < 10% the diagnosis of • Acquired vWD represents 5% of all cases of
TTP is confirmed vWD
• The next step is to order anti-ADAMTS13 IgG Risk factors for acquired vWD:
essay which if positive confirms the diagnosis of
autoimmune TTP • Use of ECMO
• If anti-ADAMTS13 IgG is negative, it is essential
to monitor ADAMTS13 activity during treatment: • Metallic cardiac valves
o If ADAMTS13 activity becomes > 10%
• Malignancies
during remission → acquired TTP of
unknown mechanism is diagnosed Pathophysiology
o If ADAMTS13 activity remains < 10% Etiology:
despite treatment → order ADAMTS13
genetic testing looking for mutations • vWF is synthesized by megakaryocytes and
Coagulation profile in TTP: endothelial cells

• Normal PT and aPTT → differentiate TTP from • vWD can be inherited or acquired
DIC
• Inherited vWD has three distinct phenotypes
• Elevated bleeding time
Treatment: Type 1:
Standard treatment:
• Autosomal dominant disease
• Daily therapeutic plasma exchange therapy with
or without corticosteroids until in remission • 60% penetrance
• Add rituximab if a TTP exacerbation develops or • Partial quantitative deficiency of vWF
the patient has unresponsive TTP
• Splenectomy in severe unresponsive TTP Type 2:
Responsive TTP:
• Autosomal dominant disease
Full clinical recovery AND a sustained platelet count > 150
x 109/L for two days or more. • It is caused by a qualitative defect of vWF

Unresponsive TTP: Type 3:

Platelet count fails to rise to double the baseline despite • Autosomal recessive disease
four days of plasma exchange therapy with steroids. • Complete quantitative deficiency of vWF
TTP exacerbation: • Most severe type of vWD
Worsening clinical manifestations or worsening Acquired causes of vWD:
thrombocytopenia despite treatment.
• Lung cancer, gastric cancer, Wilm's tumor, hairy
Von Willebrand Disease cell leukemia, CLL, multiple myeloma, and
Definition myeloproliferative neoplasms are associated with
Von Willebrand disease (vWD) is a qualitative or quantitative defects of vWD and increased
quantitative deficiency of pro-von Willebrand factor which bleeding tendency
results in increased bleeding tendency.
• vWF is a large multimeric glycoprotein which
Epidemiology renders it susceptible to shear stress in high flow
• Approximately, 1% of the general population states (i.e. acquired vWF deficiency in patients
have vWD with metallic cardiac valves)
• Clinically significant vWD has a prevalence of Pathophysiology:
125 per million
• Type 1 vWD is characterized by a mild decrease
• Severe vWD affects five per million in vWF

479
 • This results in a mild decrease in vWF activity • Desmopressin is helpful in minor bleeding
and VIII levels episodes such as epistaxis and increased
menstrual bleeding
• vWF provides stability for factor VIII
vWF replacement therapy:
• Type 2 vWD is further classified into type 2A and
type 2B. Both are characterized by a decrease in • Indicated in patients with vWD type 3 and severe
vWF and VIII concentrations, vWF activity, and type 1
absence of large vWF multimers. Type 2B is
hypersensitive to ristocetin-induced platelets • Can be co-administered with factor VIII
aggregation (RIPA)
Drugs to avoid:
Clinical Presentation
• Cryoprecipitate is not indicated, and it carries an
• Most patients with type 1 vWD are asymptomatic
increased risk of viral transmission
• Symptomatic patients present with:
• NSAIDs should be avoided as they inhibit
• Recurrent and excessive bruising thromboxane A2 and can worsen platelet
dysfunction in vWD
• Prolonged bleeding after minor trauma
Hodgkin's Lymphoma
• Epistaxis Definition
Hodgkin's lymphoma is a rare monoclonal lymphoid
• Menorrhea neoplasm with high cure rates. It is classified into classical
and nodular lymphocyte-predominant Hodgkin lymphoma.
• Petechiae
• Hematomas Epidemiology
• Rare malignancy
• Severe type 2 vWD can present with soft tissues • Annual incidence is estimated to be around 2.6
and joints bleeding cases per 100,000
• Bimodal distribution with one peak in patients
Diagnosis aged between 20 to 40 years and another peak in
• Patients with symptoms and signs suggestive of a those older than 55 years
bleeding disorder typically undergo the following • More common in males in the pediatric
initial laboratory tests: population
• A complete blood count → normal platelet
levels in vWD Pathophysiology
Etiology:
• Prolonged aPTT (due to factor VIII • Unknown cause
instability) but normal PT • Increased risk in patients with Epstein-Barr virus
infection
• Decreased vWF antigen level in quantitative • Familial predisposition plays a role
defects of vWD such as in types 1 and 3 • Autoimmune disorders and immunosuppressed
patients are more likely to develop Hodgkin's
• Decreased vWF activity especially in vWD lymphoma
type 2B Pathophysiology:
Treatment • Reed-Sternberg cells are large multinucleated
Type 1 and type 2B: cells with two mirror-image nuclei that resemble
owl eyes in a reactive cellular background
• Desmopressin • Reed-Sternberg cells are pathognomonic for
classical Hodgkin's lymphoma
• Desmopressin shows no response in vWD types • These cells originate from B cells with mutations
2B and 3 in IgH-variable region segment
Types:
• Desmopressin works by increasing the release of
• Nodular sclerosis classical HL is seen in 70% of
vWF from endothelial cells
the cases of classical HL
• Mixed cellularity classical HL in 20%

480
 • Lymphocyte-rich classical HL in 5%
• Lymphocyte-depleted classical HL in < 1%
• Nodular lymphocyte-predominant HL in 4%

Clinical Presentation
Most common presentation:
• Painless supra-diaphragmatic lymphadenopathy
in one to two lymph node areas
• B-symptoms including severe weight loss, high
fevers, and severe night sweats
Other presentations:
• Pain in affected lymph nodes after the Figure 232: Reed-Sternberg cells are characteristic of HL.
consumption of alcohol Source:
• Chronic pruritus https://en.wikipedia.org/wiki/Hodgkin%27s_lymphoma#/
• Chest pain and shortness of breath in mediastinal media/File:Reed-Sternberg_lymphocyte_nci-vol-7172-
lymphadenopathy 300.jpg
Nodular sclerosis classical HL specific clinical findings: Staging:
• Young adults • Stage 1: Single lymph node involvement
• Diagnosed before the development of B- • Stage 2: Involvement of two or more lymph
symptoms nodes on the same side of the body but above the
Mixed cellularity classical HL: diaphragm
• Children and the elderly • Stage 3: Involvement of lymph nodes below and
• Patients usually present with advanced disease above the diaphragm
Lymphocyte-depleted HL: • Stage 4: Wide-spread disease or extra-nodal
• Severe extra-nodal disease disease
• Usually affects the elderly
• Associated with AIDs infection Treatment:
Nodular lymphocyte-predominant HL: Stages 1 and 2:
• Neck lymphadenopathy • Short-course chemotherapy with (doxorubicin,
• Spares the mediastinum bleomycin, vinblastine and dacarbazine)
• Indolent course • Followed by restricted involved-field radiation
• Increased risk of late relapses therapy (IFRT)
Stages 3 and 4:
Diagnosis • Chemotherapy with the same combination as
• A biopsy is needed to confirm the diagnosis of above but without radiotherapy
HL Response rate and relapse:
• Excisional biopsy is superior to fine-needle • 90% cure rate
aspiration due to the high false-negative rate of • 30% relapse rate
the latter
• Reed-Sternberg cells Non-Hodgkin’s Lymphoma
• Mixed cellularity types show Reed-Sternberg
Definition
cells, eosinophils, plasma cells, and B-cells
Non-Hodgkin lymphomas (NHL) are malignant neoplasms
• Computed tomography is indicated for disease
of B, T and natural killer cells that infiltrate the lymphoid
staging
and hematopoietic tissues and can extend to other organs.
• Laboratory testing reveals leukocytosis,
eosinophilia and an elevated ESR Epidemiology
• More than 70,000 new cases of NHL are
diagnosed per year in the United States
• Constitutes 5% of all cancers
• Responsible for approximately 19,000 deaths per
year
• 5-year survival rates are from 63 to 73%
Pathophysiology
• The cause of NHL is still largely unknown

481
 • Epstein-Barr virus infection is a major risk factor • Age > 60 years
for B-cell lymphomas including Burkitt • Elevated LDH level
lymphoma • ECOG (Eastern Cooperative Oncology Group)
• HIV is associated with an increased risk of performance score > 2
lymphomas including HL and NHL • Ann Arbor stage III or IV
• Human T-lymphotropic virus type 1 infection is • More than one extra-nodal disease site
associated with lymphomas and leukemias Epidemiology:
• Helicobacter pylori is associated with mucosa-
associated lymphoid tissue lymphoma (MALT) • One-third of all NHL
• Hepatitis C virus infection is associated with • Most common histologic subtype
splenic marginal zone lymphoma • 80% are B-cell tumors
• Previous exposure to radiation or chemotherapy • 20% are T-cell tumors
in patients with HL puts them at an increased risk • Occurs in older adults
of NHL • 20% of the cases occur in children
Comparison Between HL and NHL Treatment:
hl nhl
Involved sites - Single group of - Involvement of • Aggressive but curable
lymph nodes multiple nodal
- Contiguous areas • CHOP chemotherapy (cyclophosphamide,
spread to other - Extra-nodal hydroxydaunorubicin, oncovin “vincristine” and
nodal areas involvement more
- Better prognosis common
prednisone) with or without radiotherapy
than NHL - Noncontiguous • 3-year survival rate ranges from 60 to 91%
spread Follicular Lymphoma
characteristic cells - Reed-Sternberg - B-cell in origin
cells - Less commonly, T- Characteristics:
cell
age distribution - Bimodal (young - Children and adults • Centroblasts are seen on microscopy and their
adults and men number determines the grade of follicular
older than 55
years) lymphoma
associations - Epstein-Barr - HIV and • Most patients present with advanced disease and
virus autoimmune
diseases
bone marrow involvement
• 2% per year transform to aggressive disease
• Many patients survive more than ten years after
Diffuse Large B-Cell Lymphoma
the diagnosis
Characteristics:
• B-cell tumor characterized by small lymphocytic
• Diffuse proliferation of large malignant lymphoid lymphoma
cells
• High mitotic rate
• Activated B-cells, GCB, and Myc gene
rearrangements with Bcl-2 or Bcl-6

Figure 234: Follicular lymphoma with characteristic small

B-cells. Source:
Figure 233: Diffuse large B-cell lymphoma. Source: https://en.wikipedia.org/wiki/Follicular_lymphoma#/media
https://en.wikipedia.org/wiki/Diffuse_large_B- /File:Follicular_lymphoma_--_low_mag.jpg
cell_lymphoma#/media/File:Diffuse_large_B_cell_lympho
ma_-_cytology_low_mag.jpg Prognostic index:

Prognostic index: • Age > 60 years

• Elevated LDH
The presence of the following risk factors is associated • Hemoglobin < 12 g/dL
with a reduced survival rate:
482
 • Ann Arbor stage III or IV • 7% of all lymphomas
• Involvement of more than 4 nodal areas • Male predominance
Epidemiology: • Involvement of the bone marrow and
gastrointestinal tract is common
• Second most common lymphoma in the United • Median survival after diagnosis is 5 years
States Clinical features:
• Constitutes approximately 20% of all lymphomas
• Occurs in older adults • Lymphadenopathy
• Associated with CLL • B-cell symptoms
CD20 and follicular lymphoma: • Hepatosplenomegaly
• Abdominal pain and early satiety
• CD20 positive B-cells are characteristic of • Recurrent infections
follicular lymphoma (small cleaved cell)
• Anemia
• The cells have a 14:18 translocation with
• Thrombocytopenia and bleeding tendency
overexpression of Bcl2
• Superior vena cava obstruction is a possible
• Bcl2 inhibits apoptosis making B-cells immortal
complication
• Anti-CD20 therapy is important in follicular Diagnosis:
lymphoma and one example is rituximab
Burkitt’s Lymphoma • Lymph node biopsy is indicated when lymph
Characteristics: nodes grow more than 1 cm in diameter over 4
weeks
• B-cell tumor
• Chest radiography and CT scan of the chest,
• Small non-cleaved cells abdomen and pelvis
• Occurs in children • Serum LDH and beta-2 microglobulin are
• 8:14 translocation (c-myc and heavy-chain Ig) elevated
• Epstein-Barr virus infection is a major risk factor • ALP is elevated
• Occurs in adults with AIDs • AST, ALT and bilirubin are elevated
• Affects the abdomen in the sporadic form. • Bone marrow biopsy is indicated to evaluate bone
Affects the jaw in endemic form in Africa marrow involvement
• Starry sky appearance with sheets of lymphocytes Treatment:
with interspersed macrophages
• Chemotherapy followed by radiotherapy
CHOP regimen (cyclophosphamide, hydroxydaunorubicin,
oncovin and prednisone)
Multiple Myeloma
Definition:
Multiple myeloma (MM) is a clonal plasma cell
proliferative disorder characterized by increased abnormal
A. B. monoclonal paraproteins and end-organ damage.
Monoclonal gammopathy is a spectrum of disorders that are
Figure 235: A. Macrophages in sheets of lymphocytes in
characterized by monoclonal paraprotein elevation. MM is
Burkitt's lymphoma. B. Jaw lesion in Burkitt's lymphoma.
on this spectrum. Monoclonal gammopathy of undetermined
Source:
significance (MGUS) is a monoclonal gammopathy without
https://www.pathpedia.com/education/eatlas/histopatholog
end-organ damage. Smoldering multiple myeloma is
y/lymph_node/burkitt_lymphoma.aspx and
between MGUS and MM on the spectrum.
https://www.merckmanuals.com/professional/hematology-
and-oncology/lymphomas/burkitt-lymphoma
Epidemiology
Mantle Cell Lymphoma • MM represents 1.8% of all new cancer cases in
Characteristics: the United States
• Occurs predominantly in the geriatric population
• Lymphoma with 11:14 translocation which • Median age at diagnosis is 70 years
results in the overexpression of cyclin D1 • Male to female ratio is 3:2
• Cells express CD5 and overexpress SOX11 • More common among African Americans
o Overexpression of SOX11 is associated
with poor prognosis
483
Pathophysiology • A biopsy is mandatory for the diagnosis of MM
Etiology: • The percentage of abnormal malignant plasma
cells must be recorded
• The exact cause is unknown • Plasma cells in MM can be mature, immature
• Genetic abnormalities involving CMYC, NRAS (low nuclear-cytoplasmic ratio, also known as a
and KRAS play a role plasmoblast), or bizarre multinucleated plasma
• Alcoholism, obesity, environmental exposure to cells
insecticides, and radiation are risk factors for MM • Flame cells with fiery red cytoplasm or Mott cells
Pathophysiology: which have multiple cytoplasmic droplets are also
seen
• MM arises from a pre-malignant asymptomatic
stage of clonal plasma cell growth known as • Plasma cells are normally found in the bone
MGUS marrow. When they are found in the peripheral
blood stream of a patient with MM, the term
• MGUS is present in 3% of those above the age of
plasma cell leukemia is used
50 years
• Myeloma cells are CD56, CD38, CD138 and
• 1% of those with MGUS progress to MM per
CD319 positive | CD19 and CD45 negative
year
Clinical Presentation
Fundamental steps in MM pathogenesis:
Bone pain:
• Establishment of MGUS:
• Osteolytic lesions due to overexpression of
o Cytogenetic abnormalities generated
RANK L protein → stimulation of osteoclasts
during an abnormal response to an
unknown antigen • Hypercalcemia
o Monoclonal immunoglobulin • Chest and rib pain
production • Localized pain secondary to a pathologic fracture
• Progression from MGUS to MM: Kidney disease:
o Follows the second hit hypothesis
• Hypercalcemia → tubular damage from light
o The accumulation of additional chain proteins → Bence Jones proteins leak into
cytogenetic lesions in the original
urine → acute tubular necrosis
plasma cell clone due to genetic
• Predisposition to amyloidosis
instability or abnormalities in the
hematopoietic microenvironment • Pyelonephritis
o The malignant plasma cells are highly Pancytopenia:
sensitive to interleukin-6 for their • Anemia: pallor, fatigue, and dyspnea
growth and survival
• Leukopenia: recurrent infections
Consequences of excess monoclonal immunoglobulin
o Pneumonia caused by streptococcus
production: pneumoniae, staphylococcus aureus,
• Hyperviscosity and Klebsiella pneumoniae
o Urinary tract infections caused by E.
• Platelet dysfunction
coli
• Renal tubular damage and the development of
MM nephropathy • Thrombocytopenia: bleeding tendency | patients
are also at an increased risk of thromboembolic
• Neurologic abnormalities secondary to
disease due to hyperviscosity
thrombophilia
• Increased bleeding tendency Diagnosis:
• Renal failure Old MM diagnostic criteria:
MM and the bone:
• CRAB criteria
• The bone marrow is occupied by malignant • Hypercalcemia, renal failure, anemia and bone
plasma cells → anemia, thrombocytopenia and lesions → signifying end-organ damage
leukopenia Current diagnostic criteria:
• The malignant myeloma cells change the bone
• Bone marrow clonal (single plasma cell origin)
microenvironment → activation of osteoclasts
and suppression of osteoblasts → bone loss and equal to 10% or presence of a bony or
extramedullary plasmacytoma
increased risk of pathologic fractures
Histopathology: • One or more of the following:

484
 o Hypercalcemia
o Renal insufficiency
o Anemia
o One or more osteolytic lesions on
skeletal radiography, CT or PET-CT

Note: The skull radiograph in MM

shows punched-out, round
radiolucent lesions known as pepper Figure 238: Rouleaux formation of RBCs on peripheral
pot skull, see Figure 1. blood smear. Source:
https://en.wikipedia.org/wiki/Rouleaux

Treatment:
Initial therapy:

• Patients should be evaluated for the possibility of

a bone marrow transplant
• Those eligible should receive induction therapy
for few months followed by peripheral blood
stem cell mobilization and finally autologous
transplant
Figure 236: Pepper pot appearance of a skull of a patient • Lenalidomide, dexamethasone, and bortezomib
with MM. Source: https://radiopaedia.org/articles/multiple- are used in those who are ineligible for a
myeloma-1 transplant
• Prognosis is generally bad (median survival is 4
Paraproteins in MM: to 5 years)
Treatment of MM complications:
• Serum protein electrophoresis shows a
monoclonal M protein spike (IgG), see Figure 2 • Symptomatic anemia is treated with blood
• Total protein in serum is elevated transfusion
• High levels of Bence-Jones proteins in urine (Ig • Hyperviscosity is treated with plasmapheresis
light chains) • Renal failure due to hypercalcemia is treated with
• Tamm Horsfall protein (IgG like chains) hydration, glucocorticoids and bisphosphonates
• Prophylactic antibiotics to avoid infections
• Bone pain is treated with opioids
• Spinal cord compression due to vertebral fracture
or a plasmacytoma is a medical emergency:
o Managed aggressively with
radiotherapy
o Early orthopedic consultation
CML and CLL
Chronic Myeloid Leukemia
Figure 237: M-spike on serum protein plasmapheresis. Definition:
Source: Chronic myeloid leukemia (CML) is a myeloproliferative
https://en.wikipedia.org/wiki/Myeloma_protein#/media/Fil neoplasm caused by the fusion of Abelson murine
e:Monoclonal_gammopathy_Multiple_Myeloma.png leukemia (ABL1) gene on chromosome 9 with breakpoint
cluster region (BCR) gene on chromosome 22. This results
Other supporting laboratory findings:
in the expression of the oncogene BCR-ABL1.
• Elevated ESR
• Incidence is 1 to 2 cases per 100,000 adults
• Rouleaux formation of RBCs on peripheral blood
• Accounts for 15% of leukemias in adults
smear, see Figure 3
• Age of onset is 40 years in average
• Plasma cell FISH showing characteristic
translocations such as t(11:14) • Myeloid stem cell lines are affected

485
 • Leukocytes, erythrocytes and platelets are • Left shift to granulocytes, small blast cells,
affected myelocytes and metamyelocytes (Figure 1)
Pathogenesis: • Eosinophils
• BCR-ABL1 is an active tyrosine kinase • Low LAP
• It promotes cellular growth and replication by
RAS, RAF, JUN and MYC downstream signaling
• Leukemogenesis becomes cytokine-independent
• 9:22 translocation is known as Philadelphia
chromosome
Clinical Findings:
• Half of the patients are asymptomatic and
diagnosed by routine physical examination and
blood tests
• CML is classified into three phases: CML chronic Figure 239: Blast crisis in a patient with CML. Source:
phase (CP), acute phase (AP) and blast phase http://www.freestockphotos.biz/stockphoto/15271
(BP)
CML-CP: Treatment:
• BCR-ABL tyrosine kinase inhibitors such as
• 95% of the cases present in this phase imatinib and Dasatinib are first-line therapies
• Anemia and splenomegaly • Average survival after diagnosis is 3 years
• Fatigue Chronic Lymphocytic Leukemia:
• Weight loss Definition:
• Left upper quadrant fullness and early satiety Chronic lymphocytic leukemia is characterized by the
• Thrombocytopenia (rare) clonal proliferation and accumulation of mature CD5-
• Gouty arthritis due to elevated uric acid levels positive B cells within the blood, bone marrow, lymph
• Priapism nodes and spleen. Leukemogenic transformation from
• Gastrointestinal ulceration and bleeding CML to CLL is possible.
• White blood cell counts usually exceed 100 x
• Incidence is 4 cases per 100,000 adults
109/L
• Most common leukemia and accounts for 4500
CML-AP:
deaths per year
• Insidious or present with worsening anemia, • Age of onset is 67 to 72 years in average
splenomegaly and multiorgan infiltration • Multiple genomic abnormalities have been
CML-BP: reported including 13q deletion, 11q deletion and
trisomy 12
• Presents as an acute leukemia Pathogenesis:
• Most often present as acute myeloid leukemia • The most common pathology is the deletion of
(60%) 13q14 segment
• Worsening in constitutional symptoms such as • This deletion results in a benign course
fever • Within this region, miRNAs such as miR-15a and
• Infections 16-1 are located
Diagnosis: • The deletion of these specific miRNAs results in
The documentation of the presence of the Philadelphia CLL suggesting their role as tumor suppressors
chromosome t(9:22) in the setting of persistent unexplained • B-cells in CLL are almost always CD5+ (CD-5 is
leukocytosis is enough for the diagnosis of CML. Up to a T-cell surface antigen) and are mature B-cells
100% of patients with CML have the Philadelphia that express B-cell surface antigens CD20+ and
chromosome. CD23+
Clinical Findings:
• Bone marrow aspiration is mandatory in all cases
• Most patients are asymptomatic
• The confirmation of the diagnosis is based on
• Can present with painless lymphadenopathy and
cytogenetic analysis of bone marrow aspirate
splenomegaly
Supporting laboratory findings:
• Predisposition to recurrent infections
• Leukocytosis usually 50 to 200 x 109/L • Anemia and thrombocytopenia

486
The treatment of CLL is based on the presence of Treatment:
symptoms. Symptomatic CLL is defined as one of the • CLL can transform to diffuse large B-cell
following: lymphoma in what is known as Richter
transformation
• Progressive bone marrow failure • Purine analogs such as fludarabine and
• Massive and progressive splenomegaly pentostatin are used as monotherapy
• Massive and painful lymphadenopathy • Monoclonal antibodies against B-cell surface
• Progressive lymphocytosis antigens are also used in treatment of CLL and
• Lymphocyte doubling time (duration needed for they include rituximab, ofatumumab, and
lymphocyte count to be doubled) < 6 months Blinatumomab
• Autoimmune anemia AML and ALL
• Weight loss Acute Myeloid Leukemia
• Fever Definition:
• Night sweats Acute myeloid leukemia (AML) is a heterogenous disorder
Diagnosis: characterized by clonal expansion of myeloid blasts in the
The diagnosis of CLL uses the iwCLL guidelines: bone marrow and peripheral blood. The condition has a
40% cure rate in patients younger than 60 years of age.
• B-cell count > 5000 cells/µL • Most common acute leukemia in adults
• Persistence of an elevated B-cell count for more • Incidence is 3 to 5 cases per 100,000
than 3 months • The incidence increases with age
• Confirmation of the clonality of the circulating B • The prognosis is still grim in the elderly (75% of
lymphocytes by flow cytometry patients diagnosed with AML older than 65 years
• Leukemia cells in the blood smear are small, will die within 1 year of diagnosis)
mature lymphocytes with a narrow border of Pathogenesis:
cytoplasm and a dense nucleus without nucleoli
• A series of recurrent hematopoietic stem cell
• Peripheral blood smear also shows atypical, genetic alterations accumulate with age
cleaved, or polymorphic cells • Common genetic alterations include t(8;21) in
• Cell debris and smudge cells are other core-binding factor AML and t(15;17) in acute
characteristic features found on peripheral blood promyelocytic leukemia (APL)
smear • APL is characterized by the formation of
• CD5 is a T-cell antigen which B-cells in CLL co- chimeric proteins PML-RARA which impact the
express with B-cell surface antigens CD20 and maturation of myeloid precursor cells
CD23 • Molecular genetic mutations without
Supporting laboratory findings: chromosomal re-arrangements can also cause
• Lymphocytosis AML
• Infiltrating leukemic cells on bone marrow biopsy • The leukemic cells in AML have Auer rods and
myeloperoxidase positive cytoplasmic inclusions
(particularly in APL)
• Risk factors include exposure to alkylating
chemotherapy, radiation, history of
myeloproliferative disorders, and Down
syndrome
• DIC is a possible complication of AML
Clinical Findings:
• Leukocytosis and signs of bone marrow failure
such as anemia and thrombocytopenia
• Fatigue, anorexia, and weight loss are common
manifestations
Figure 240: B-cells on peripheral blood smear in CLL. • Lymphadenopathy and organomegaly are not
Source: https://commons.wikimedia.org/wiki/File:B- typical of AML
cell_chronic_lymphocytic_leukemia_(B-CLL).jpg • Death occurs within few months if left untreated
• Most common causes of death are infection and
bleeding

487
Diagnosis: breakdown syndrome increase the risk of ALL in
• The diagnosis is confirmed by the presence of children
20% or more blasts in the bone marrow or • Exposure to ionizing radiation, pesticides, EBV
peripheral blood smear and HIV can also increase the risk of ALL in
• These blasts have myeloperoxidase activity children and adults
confirming their myeloid origin • Most cases of ALL occur de novo
• Immunophenotyping reveals Auer rods which are • Genetic alterations accumulate in lymphoid
azurophilic needle-shaped cytoplasmic inclusions progenitor cells which include t(12;21), t(1;19)
most commonly seen in APL and t(9;22) “BCR-ABL1”. The last
• The confirmation of t(8;21) or t(15;17) regardless rearrangement is known as Philadelphia
of the percentage of blasts is enough for chromosome and is also seen in patients with
establishing the diagnosis of AML CML
• Patients with t(12;21) have better prognosis
Clinical Findings:
• Nonspecific constitutional symptoms and signs of
bone marrow failure
• Anemia, thrombocytopenia and leukopenia occur
• B-symptoms such as fever, weight loss and night
sweats are common
• Easy bruising and bleeding
• Recurrent infections
Figure 241: Auer rods in AML. Source: • Lymphadenopathy and organomegaly are
https://en.wikipedia.org/wiki/Auer_rod#/media/File:Myelo common
blast_with_Auer_rod_smear_2010-01-27.JPG • CNS involvement most commonly as cranial
nerve deficits occurs in 8% of patients
Treatment: Diagnosis:
• Intensive anthracycline and cytarabine regimen • The diagnosis of ALL is established by the
following the (7+3) regimen for induction therapy presence of 20% or more lymphoblasts on bone
is indicated in most patients (an anthracycline for marrow or peripheral blood smear
first three days with seven days of cytarabine) • Immunophenotyping and cytogenetic testing are
• This must be followed with consolidation therapy helpful in confirming the diagnosis
• Patients with APL should be treated with all-trans • LP and CSF analysis are mandatory to exclude
retinoic acid (ATRA) CNS involvement
• ATRA decreases the risk of DIC and improves • If CNS involvement is suspected, brain MRI is
the outcome of APL indicated
• ATRA induces the differentiation of • Patients are at an increased risk of tumor lysis
promyelocytes syndrome → baseline uric acid, calcium,
phosphate and LDH should be checked
Acute Lymphoblastic Leukemia:
Definition:
Acute lymphoblastic leukemia (ALL) is a malignancy of
lymphoid progenitor cells in the bone marrow, blood and
extramedullary sites. 80% of ALL cases occur in children.
When ALL occurs in adults, it is a devastating disease.
• Estimated incidence is 1.6 per 100,000
• Two peaks in incidence, one in children and
another in those aged 50 years
• Poor prognosis when it occurs in adults
Pathogenesis: Figure 242: Lymphoblasts on bone marrow aspirate in a
• Abnormal proliferation and differentiation of a patient with ALL. Source:
clonal population of lymphoid cells https://en.wikipedia.org/wiki/Acute_lymphoblastic_leukem
• Down syndrome, Fanconi anemia, Bloom ia#/media/File:Acute_leukemia-ALL.jpg
syndrome, ataxia telangiectasia and Nijmegen
Supporting laboratory findings:

488
 • TdT+ which is a marker of pre-T and pre-B cells • Plasma cells in multiple myeloma are highly
• CD10+ which is a marker of pre-B cells differentiated and express CD138. Malignant
Treatment: plasma cells in WM express CD20 (B-cell
• Intensive chemotherapy marker)
• ALL is the most responsive to chemotherapy Factors associated with poor prognosis:
among the different leukemias
• Age > 65 years
• Hemoglobin < 11.5 g/dL
Waldenström Macroglobulinemia
• Platelet count < 100,000/mm3
Definition: • Monoclonal IgM > 7 mg/dL
Waldenström macroglobulinemia (WM) is defined as a
Treatment:
lymphoplasmacytic lymphoma associated with a
Hyperviscosity syndrome:
monoclonal immunoglobulin M (IgM) protein.
Hepatomegaly, splenomegaly, lymphadenopathy, fatigue • Patients present with epistaxis, gingival bleeding,
and normochromic normocytic anemia are common and retinal hemorrhages
presentations. • Normal serum viscosity is 1.8. Hyperviscosity
syndrome is diagnosed when serum viscosity
Epidemiology: exceeds 4
• Estimated incidence is 3.8 per million persons per • Treatment is plasma exchange until systemic
year therapy works
• Incidence increases with age Systemic chemotherapy to reduce tumor mass:
• Male to female ratio is 2:1
• WM is more common in whites than in blacks • The goal of treatment in WM is to reduce the
• 10-year survival nowadays is 66% plasma cell mass that is producing IgM
Pathophysiology: • Rituximab is the drug of choice when used in
• The malignant cells in WM express B-cell surface combination therapy
markers (CD19 and CD20) • Chlorambucil and cladribine when used as single-
• The most common genetic alteration is 6q agent chemotherapies are superior to rituximab
deletion and it is associated with an adverse Langerhans Cell Histiocytosis
prognosis Definition
• The malignant plasma cells which originate from Langerhans cell histiocytosis (LCH) is an idiopathic
B-cells produce large amounts of monoclonal disease characterized by the clonal expansion of abnormal
IgM Langerhans cells which are antigen-presenting immune
• This can result in hyperviscosity syndrome cells. The initial presentation can be a rash. The disease
among other complications related to can involve the bone marrow, lungs, liver, spleen and
macroglobulinemia lymph nodes.
Clinical Findings: Epidemiology
• Oronasal bleeding secondary to • LCH is a rare disease
thrombocytopenia and hyperviscosity syndrome
• Occurs in 1 to 2 newborns per million per year
• Lymphadenopathy
• The annual incidence in children is 4 to 5 cases
• Microcytic hypochromic anemia and its related per million
symptoms and signs
• The annual incidence in adults is 1 to 2 cases per
• Organomegaly million
Diagnosis: Pathophysiology
• IgM level is above 5 mg/dL Etiology:
• Bence Jones proteins are found in the urine of
10% of patients • The exact cause of LCH is unknown
• Elevated ESR • It is believed to be a reactive or neoplastic
Differentiating IgM multiple myeloma from WM: process of Langerhans cells
Pathophysiology
• MYD88 gene is typically mutated in WM but not
multiple myeloma • Langerhans cells are dendritic antigen-presenting
• Lytic bone lesions are not seen in WM cells
• t(11;14) is seen in multiple myeloma but not WM

489
 • Langerhans cells in LCH have increased
capability to proliferate but decreased ability to
present antigens
• The lesions in LCH contain inflammatory cells,
T-lymphocytes, eosinophils, neutrophils and
macrophages in addition to Langerhans cells
• The abnormal proliferation of Langerhans cells
into different tissues result in the loss of the
function of that tissue (involvement of the bone Figure 243: Biopsy of LCH lesion. Source:
marrow results in decreased blood cell https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosi
production) s#/media/File:Langerhans_cell_histiocytosis_-
Histopathology _very_high_mag.jpg

• The lesions in LCH are granulomatous with • Once the diagnosis is confirmed, workup for
eosinophils, macrophages, T-cells and systemic involvement should be started:
multinucleated cells o Skeletal survey
• Birbeck granules are characteristic of LCH o Abdominal ultrasound
Clinical Findings o Complete blood count
• The symptoms and signs of LCH depend on o Evaluation for diabetes insipidus
which organs are involved
• Rash is the most common presentation
o It can range from a single lesion to
widespread involvement
o The lesions are described as scaly
papules, nodules or plaques
o Can be misdiagnosed as seborrheic
dermatitis
o LCH lesions can be differentiated from
seborrheic dermatitis by the presence of
petechiae, or bloody crusting
• Bony involvement occurs in about 78% of Figure 244: CT scan showing LCH infiltration of peri-
patients orbital tissue. Source:
o Lesions involve the skull, hip, pelvis, https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosi
femur and ribs s#/media/File:CT_of_periorbital_Langerhans_cell_histiocy
o Can be painful tosis.jpg
• Pulmonary involvement presents with pulmonary
symptoms and lymphadenopathy Treatment
• Involvement of the pituitary gland can cause • Isolated lesions might not need treatment
diabetes insipidus • Topical steroids, oral methotrexate or thalidomide
o The initial presentation of LCH can be can be used for isolated lesions
polyuria, polydipsia, dilute urine and Chemotherapy and radiation are used for systemic disease.
hypernatremia
Diagnosis Hematology-Pharmacology
• The diagnosis is confirmed by biopsy of the Heparin:
involved sites • Heparin is a mixture of sulfated polysaccharides
o Lesions stain positive for S-100 and • Administered parenterally (intravenously or
CD-1a subcutaneously)
• Short half-life, however, Low-molecular-weight
(LMW) heparins (e.g., enoxaparin) have potential
advantage of longer half-lives, less
thrombocytopenia, and possibly enhanced activity
against factor Xa.

490
MOA:
• Heparin is an activator of antithrombin III
• Heparin catalyzes the binding of antithrombin III
(a serine protease inhibitor) to factors IIa, IXa, MOA
Xa, XIa, and XIIa, resulting in their rapid • ↓ Hepatic synthesis of vitamin K–dependent
inactivation factors II, VII, IX, X
• coumarins prevent g-carboxylation by inhibiting
Clinical Uses: vitamin K epoxide reductase
• Rapid anticoagulation (intensive)
• Prophylaxis as well as treatment of venous Clinical Uses:
thrombosis and pulmonary embolism • Longer-term anticoagulation (controlled) for
• Adjuvant therapy for unstable angina, MI, and thromboses, emboli, post-MI, heart valve
stroke unstable angina damage, atrial arrhythmias
• Disseminated intravascular coagulation (DIC), • Clinical effects are monitored by following the
PT and INR.
• Open-heart surgery
Side Effects:
• Administered for anticoagulation during
pregnancy because it does not cross the placenta • Bleeding, however, reversed immediately with
administration of fresh-frozen plasma and, within
Side Effects: a few hours, with vitamin K infusion.
• Bleeding, thrombocytopenia, and heparin-induced
Contraindications include:
thrombocytopenia (HIT).
• History of bleeding disorders and active
• Toxicity are reversed by protamine sulfate and
pregnancy (cross placenta)
are followed by measuring the PTT.

Contraindications include:
• Active bleeding, bleeding disorders, history of
HIT, and aortic dissection.
• Patients on heparin therapy should be monitored
using partial thromboplastin time (HIPTT =
heparin, intrinsic PTT).

Warfarin (Coumadin)
• Small molecule, lipid-soluble derivatives of
vitamin K
• Administered Orally
• Half-life +30 hours

491
 Streptokinase
• Acts on both bound and free plasminogen (not
clot specific), depleting circulating plasminogen
and factors V and VIII
• antigenic (foreign protein derived from β-
hemolytic streptococci); may cause a problem if
recent past use or infection—strep antibodies may
↓ activity

Direct thrombin inhibitors Alteplase (tPA)

Examples: • Clot specific, acting mainly on fibrin-bound
• Lepirudin plasminogen, the natural activator, so no allergy
• Bivaluridin problems
MOA:
• Directly inhibit thrombin and do not require Side effects:
antithrombin III • Complications include bleeding, possible
Clinical Uses: intracerebral haemorrhage
• administered IV) for patients with a history of • Contraindicated in patients with active bleeding,
HIT or heparin allergy history of intracranial bleeding, recent surgery,
• Used with aspirin in unstable angina when known bleeding diatheses, or severe
undergoing percutaneous transluminal coronary hypertension.
angioplasty (PTCA) • Streptokinase may cause hypersensitivity
Side effects: reactions and hypotension
• Bleeding • Nonspecific reversal with antifibrinolytics (eg,
aminocaproic acid, tranexamic acid)
Direct factor Xa inhibitors
• Factor Xa inhibitor, does not require monitoring ADP receptor inhibitors
of PT or INR Examples: Clopidogrel, prasugrel, ticagrelor (reversible),
• Used to prevent DVTs after knee/hip surgery; ticlopidine.
prevention of stroke and systemic embolism in
non-valvular atrial fibrillation
• Examples: Rivaroxaban and Other “-xabans
• Side effects: Bleeding- irreversible

Thrombolytics
• Called fibrinolytics, thrombolytics lyse thrombi
by catalyzing the formation of the endogenous
fibrinolytic plasmin (a serine protease) from its
MOA
precursor, plasminogen.
• Irreversibly inhibiting the binding of ADP to its
• Clinical Uses: used intravenously for short-term receptor on platelets, thereby reducing platelet
emergency management of coronary thromboses aggregation.
in myocardial infarction (MI), deep venous
Clinical Uses:
thrombosis, pulmonary embolism, and ischemic
stroke (tPA).
492
 • Used with aspirin to decrease ischemic events in
patients with a previous history of stroke,
coronary artery disease, and peripheral arterial
disease.
• It is also used to reduce thrombosis following
cardiac stent placement or in patients who cannot
tolerate aspirin therapy
Side effects:
• Bleeding
• Severe neutropenia,
• TTP
• Rashes
• Dyspepsia

Abciximab, eptifibatide, and tirofiban

Clinical Uses:
• Antagonists that bind to glycoprotein IIb/IIIa
receptors →↓ aggregation by preventing the
cross-linking reaction
• Used mainly in acute coronary syndromes and
postangioplasty
Side effects:
• bleeding (GI bleed)
Thrombocytopenia

493
 Chapter 11:

Musculoskeletal and Dermatology

494
Rotator Cuff Muscles
Definition:
The rotator cuff muscles are a group of small muscles of
the shoulder that add stability to the glenohumeral joint and
help in abduction, lateral rotation, and medial rotation of
the arm.
Supraspinatus:
Origin:
The supraspinous fossa of the scapula
Insertion:
The greater tubercle of the humerus in the superior facet
Blood supply: Figure 246: Posterior view showing the infraspinatus
The suprascapular artery muscle. Source:
Innervation: http://anatomyzone.com/3d_atlas/musculoskeletal/upper-
The suprascapular nerve which has C4 to C6 nerve roots limb/rotator-cuff/
Action:
• Initiation of arm abduction Subscapularis:
Origin:
• Stabilization of the glenohumeral joint
The subscapular fossa of the scapula
Insertion:
The lesser tubercle of the humerus
Blood supply:
The subscapular artery
Innervation:
The upper and lower subscapular nerves with roots C5 to
C7
Action:
• Medial rotation of the arm
Figure 245: The supraspinatus muscle highlighted in • Adduction of the arm
brighter shade. Source: • Stabilization of the glenohumeral joint
http://anatomyzone.com/3d_atlas/musculoskeletal/upper-
limb/rotator-cuff/

Infraspinatus:
Origin:
The posterior surface of the scapula below the spine of the
scapula
Insertion:
The greater tubercle of the humerus in the middle facet Figure 247: Subscapularis muscle. Source:
Blood supply: http://anatomyzone.com/3d_atlas/musculoskeletal/upper-
The suprascapular and circumflex scapular arteries limb/rotator-cuff/
Innervation: Teres Minor:
The suprascapular nerve Origin:
Action: The superolateral portion of the scapular border
• Lateral rotation of the humerus Insertion:
• Stabilization of the glenohumeral joint The inferior facet of the greater tubercle of the humerus
Blood supply:
The subscapular and circumflex scapular
arteries
Innervation:
The axillary nerve with roots C5 and C6
Action:
• Lateral rotation of the arm – assists the
infraspinatus muscle
• Stabilization of the glenohumeral joint

495
Figure 248: Posterior view showing the teres minor muscle
which is below and behind the infraspinatus. Source:
http://anatomyzone.com/3d_atlas/musculoskeletal/upper-
limb/rotator-cuff/
Figure 249: Contraction of a muscle cell is initiated when
Skeletal Muscle Contraction the cell gets depolarized and calcium gets released from the
Setting the scene sarcoplasmic reticulum. Source:
• While flexing or extending your arm or leg might https://opentextbc.ca/anatomyandphysiology/chapter/10-3-
sound a very simple thing, the molecular bases of muscle-fiber-contraction-and-relaxation/
voluntary skeletal muscle contraction are quite • Relaxation of the skeletal muscle can be thought
complicated of as the default state
• The events of skeletal muscle contraction are • Meaning, once Ach release ceases and the action
initiated when an action potential arrives at the potential stops, repolarization of the skeletal
neuromuscular junction muscle cell occurs
• When a muscle contracts, the individual muscular • The repolarization of the T-tubules and the
cells are shortened sarcoplasmic reticulum results in shielding of the
• Therefore, skeletal muscle contraction is due to binding sites on the actin filament because
an intracellular mechanism that involves calcium, calcium is reabsorbed
ATP, thin, and thick filaments • This process is not passive because ATP is still
required for calcium resorption by the
Depolarization of the skeletal muscle: sarcoplasmic reticulum
• For the skeletal muscle to contract, an action
potential needs to be transmitted by the
innervating nerve of the muscle which results in
the release of acetylcholine (Ach) at the
neuromuscular junction
• The depolarization of the nerve axon opens the
presynaptic voltage-gated Ca2+ channels for
calcium influx into the axon
• This induces Ach release from Ach vesicles
• Ach binds to postsynaptic receptors in the
neuromuscular junction which induces muscle
cell depolarization at the motor end plate
• Sodium channels are opened in the muscle cell Figure 250: Relaxation of the skeletal muscle cell. Source:
membrane → depolarization of the entire muscle https://opentextbc.ca/anatomyandphysiology/chapter/10-3-
cell muscle-fiber-contraction-and-relaxation/
• The action potential travels through T-tubules to Molecular basis of muscle contraction:
depolarize the sarcoplasmic reticulum → release • It is clear that the process of skeletal muscle
of calcium from the sarcoplasmic reticulum contraction is dependent on cross-bridging
• Calcium initiates the contraction of the muscular between the myosin thick filaments, and actin
cell and ATP sustains the contraction thin filaments; calcium; ATP; and troponin C and
other important molecular targets
• This mechanism of muscle fiber shortening
occurs in the sarcomeres
• The muscle fiber shortens because myosin heads
pull on the actin filaments

496
 • A myofibril is composed of many sarcomeres ATP and skeletal muscle contraction:
• Muscle cells have multiple myofibrils • So far, it must be obvious that ATP is very
• Accordingly, the shortening (contraction) of a important for muscle contraction
muscle cell occurs when the sarcomeres contract • There are three important sources of ATP for the
Role of calcium: muscle
• It was mentioned earlier that the whole process of Creatine:
sarcomere’s contraction is initiated when calcium • When the muscle is active, creatine phosphate
gets released from the sarcoplasmic reticulum and ADP are metabolized by creatine kinase into
which occurs secondary to depolarization of the creatine and ATP (ATP is used as the energy
entirety of the muscle cell source for muscle contraction)
• The actin filaments when in resting state have the • When the muscle is resting, ATP and creatine are
myosin-head binding sites shielded by metabolized into ADP and creatine phosphate
tropomyosin
• The actin filaments have troponin C which is the
binding site of the released calcium. Binding of
calcium to troponin C results in shifting of
tropomyosin to expose myosin-binding sites
• The myosin head binds strongly to actin forming
a cross-bridge
Pulling of actin (thin filament) by myosin (thick filament)
in the sarcomere:
• When the myosin head binds to actin forming a Figure 252: Creatine and ATP production in the skeletal
crossbridge, this releases Pi which initiates a muscle. Source:
power stroke https://opentextbc.ca/anatomyandphysiology/chapter/10-3-
• Force is produced when myosin pulls on the thin muscle-fiber-contraction-and-relaxation/
filament over the thick filament Anaerobic glycolysis:
• The H and I bands of the sarcomere as well as the • The second source of ATP for the muscle is
distance between the Z-lines are shortened, glycolysis
whereas the A band remains constant (more about • Glucose is metabolized into pyruvate and two
this when the sliding filament model of ATP molecules are produced to be used for
contraction is discussed) energy production
• ADP is released at the end of the power stroke Aerobic mechanisms:
but now the myosin head needs to get detached • The slow-twitch red muscle fibers have abundant
from actin filament in order for it to pull actin mitochondria
again (further shorten the sarcomere) • When oxygen is present, glucose, pyruvate and
• For this to happen, a new ATP molecule binds to fatty acids get metabolized to produce large
the myosin head → detachment from actin → amounts of ATP
ATP hydrolysis into ADP and Pi → myosin head • 95% of resting and moderately active muscles
is back in high-energy (cocked) position to bind have their ATP from aerobic respiration
to actin again if the myosin-binding sites are still
unshielded (calcium is still available and bound to The sliding filament model of contraction
troponin C) • It has been mentioned that myosin heads pull
actin filaments
• How exactly this leads to a shorten sarcomere can
be understood from the sliding filament model
• The sarcomere is linearly configured

Figure 251: The molecular basis of sarcomere contraction.

Source: First Aid 2018

497
 Origin:
Occiput, medial margin of the ligamentum nuchae and the
spinous processes of the vertebra C7 to T12
Insertion:
The lateral third of the clavicle, acromion process of the
scapula and the spine of the scapula
Blood supply:
Transverse cervical artery
Figure 253: Sarcomere configuration in a relaxed state. Innervation:
Source: Accessory nerve and cervical nerves C3 and C4
https://www.unm.edu/~lkravitz/Exercise%20Phys/muscles Action:
arcomere.html • The fibers of the muscle are classified into three
functional groups
• Clearly, form this configuration, you would • The upper fibers elevate the scapula and rotates it
expect H zone, I band and distance between Z- during arm abduction
lines to be shortened when actin is pulled towards • The middle fibers retract the scapula
the M-line • The lower fibers depress the scapula downwards
• You would also expect the A-band to remain • The whole muscle extends the neck
constant

Deltoid:

Figure 254: The sliding filament model explains how a

sarcomere is shortened in muscle contraction. Source:
https://opentextbc.ca/anatomyandphysiology/chapter/10-3-
muscle-fiber-contraction-and-relaxation/

• Finally, when the sarcomere is in full contraction, Origin:

the thin filaments (actin) can overlap The clavicle, acromion process and spine of the scapula
Insertion:
Upper Extremity Muscles The deltoid tuberosity on the humerus
Shoulder Blood supply:
The main muscles in the shoulder area are the trapezius, The deltoid branch of the thoraco-acromial artery
deltoid, levator scapulae, rhomboid minor and rhomboid Innervation:
major. The rotator cuff muscles are discussed in the lecture The axillary nerve from roots C5 and C6
titled Rotator Cuff Action:
• The anterior fibers flex the arm
Trapezius:
• The middle fibers abduct the arm
• The posterior fibers extend the arm

Levator scapulae

498
Origin:
The transverse processes of vertebrae C1 to C4
Insertion:
The superomedial border of the scapula
Blood supply:
The dorsal scapula artery
Innervation:
The dorsal scapula nerve from roots C4 and C5. The
cervical nerves C3 and C4
Origin:
Action:
• Elevation of the scapula, as the name implies • Two heads
• The short head originates from the coracoid
Rhomboid minor process
• The long head originates from the supraglenoid
tubercle
Insertion:
Radial tuberosity
Blood supply and innervation:
All muscle of the anterior compartment of the arm are
supplied by the brachial artery and innervated by the
musculocutaneous nerve
Origin: Action:
Spinous processes of vertebrae C7 and T1 • Flexion of the elbow
Insertion: • Supination of the forearm
The superomedial scapula, at the root of the spine of the
scapula Brachialis:
Blood supply:
Same as levator scapulae
Innervation:
Dorsal scapular nerve
Action:
• Elevation and retraction of the scapula

Rhomboid major

Origin:
Distal half of the anterior portion of the humerus
Insertion:
Origin: Ulnar tuberosity
Spinous processes of vertebrae T2 to T5 Action:
Insertion: • Elbow flexion
Medial portion of the scapula from the root of the scapular
spine to the inferior angle of the scapula Coracobrachialis:
Blood supply:
Same as rhomboid minor
Innervation:
Same as rhomboid minor
Action:
Same as rhomboid minor

Anterior compartment of the arm:

Biceps brachii

499
Origin: Pisiform bone, hook of hamate bone, and 5th metacarpal
Coracoid process base
Insertion: Blood supply:
Medial midshaft of the humerus All muscles of the superficial layer of the anterior
Action: compartment of the forearm are suppled by the ulnar artery
• Arm flexion Innervation:
Ulnar nerve with roots from C7 and C8
Posterior compartment of the arm: Action:
Triceps brachii: • Wrist flexion
• Wrist adduction

Flexor carpi radialis

Origin:
• Has three heads, as the name implies
• The long head originates from the infraglenoid
tubercle of the scapula
• The medial head originates from the distal half of
the posterior humerus
• The lateral head originates from the proximal half
of the posterior humerus Origin:
Insertion: Medial epicondyle of the humerus
All three heads insert into the olecranon process of the ulna Insertion:
Blood supply: 2nd and 3rd metacarpal base
Brachial artery Innervation:
Innervation: Median nerve from roots C6 and C7. Palmaris longus and
Radial nerve which has nerve roots from C7 and C8 pronator teres are also supplied by the median nerve.
Action: Action:
• Elbow extension • Wrist flexion
• Shoulder extension • Wrist abduction
Pronator teres
Anterior compartment of the forearm:
Superficial layer
Flexor carpi ulnaris

Origin:
• Two heads
• The humeral head originates from the medial
Origin: epicondyle of the humerus
• Two heads • The ulnar head originates from the coronoid
• The humeral head originates from the medial process
epicondyle of the humerus Insertion:
• The ulnar head originates from the olecranon and In the middle of the lateral surface of the radius
posterior border of the ulna Action:
Insertion:
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 • Forearm pronation
• A weak flexor of the elbow Deep layer
Palmaris longus Flexor digitorum profundus

Origin: Origin:
Medial epicondyle of the humerus The medial and anterior portions of the ulna in addition to
Insertion: the interosseous membrane
Distal half of the flexor retinaculum and palmar Insertion:
aponeurosis • It has four tendons which attach into the palmar
Action: surface of the distal phalanges of fingers 2 to 5
• Wrist flexion • To reach their insertion, the tendons pierce the
• Tightening of the palmar aponeurosis insertions of the flexor digitorum superficialis in
a sling like fashion
Intermediate layer: Blood supply:
Flexor digitorum superficialis • All the muscles of the deep layer of the anterior
compartment of the forearm are supplied by the
anterior interosseous artery.
• The flexor digitorum profundus is additionally
supplied by the ulnar artery
Innervation:
• Receives dual nerve supply
• The lateral half of the muscle is innervated by the
anterior osseous nerve, which is a branch of the
Origin:
median nerve (same nerve that supplies flexor
• Two heads
pollicis longus and pronator quadratus)
• The humero-ulnar head originates from the
• The medial half of the muscle is innervated by the
medial epicondyle of the humerus, ulnar
ulnar nerve
collateral ligament, and coronoid process of the
Action:
ulna
• Flexion of the distal interphalangeal joints of
• The radial head originates from the proximal half
digits 2 to 5 in addition to their
of the radius
metacarpophalangeal joints
Insertion:
• Wrist flexion
• Has four insertion tendons
• They insert into the palmar surface of the middle Flexor pollicis longus
phalanges of fingers 2 to 5
Blood supply:
Ulnar artery
Innervation:
Median nerve with roots C7 to T1
Action:
• Because of their unique insertion, they flex both
the proximal interphalangeal joints of digits 2 to 5
and the metacarpophalangeal joints of same digits
• Wrist flexion
Origin:
• Two heads

501
 • First head originates from the anterior surface of
the radius
• Second head originates from the radial half of the
interosseous membrane
Insertion:
• Palmar surface of the base of the distal phalanx of
the thumb
Action:
• Interphalangeal joint of the thumb flexion
Origin:
A small square-shaped muscle that originates from the
Pronator quadratus:
distal anterior surface of the ulna
Insertion:
Inserts into the distal anterior surface of the radius
Action:
• Forearm pronation

Posterior compartment of the forearm:

Superficial layer:
ORIGIN INSERTION BLOOD INNERVATION ACTION IMAGE
SUPPLY
BRACHIORADIALIS Lateral Lateral surface of Radial recurrent Radial nerve Elbow flexion
supracondylar distal radius when forearm is
ridge of the pronated
humerus

EXTENSOR CARPI Lateral Base of 2nd Radial Radial nerve Wrist extension
RADIALIS LONGUS supracondylar metacarpal and abduction
ridge of the
humerus

EXTENSOR CARPI Lateral Base of 3rd Radial Radial nerve Wrist extension
RADIALIS BREVIS epicondyle of the metacarpal and abduction
humerus

ANCONEUS Lateral Olecranon and Deep brachial Radial nerve Elbow extension
epicondyle of the proximal ulna and recurrent and abduction of
humerus interosseous the ulna when
pronated

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 EXTENSOR Lateral 4 tendons insert on Recurrent and Posterior Extension of
DIGITORUM epicondyle of the the four medial posterior interosseous digits 2 to 5 and
humerus digits interosseous nerve wrist

EXTENSOR DIGITI Lateral Extensor expansion Recurrent Posterior Extension of 5th

MINIMI epicondyle of the of the 5th interosseous interosseous digit
humerus metacarpophalangeal nerve
and interphalangeal
joints

EXTENSOR CARPI Two heads: Base of 5th Ulnar Posterior Extension and
ULNARIS - Lateral metacarpal interosseous adduction of
epicondyle nerve wrist
of the
humerus
- Posterior
ulna

Deep layer Abductor pollicis longus

Supinator

Origin:
Origin: Posterior surfaces of the ulna and radius in addition to the
• Multiple origins interosseous membrane
• Lateral epicondyle of humerus Insertion:
• Radial collateral ligament Base of the 1st metacarpal bone
• Annular ligament Action:
• Supinator crest of the ulna • As the name implies, abduction of the thumb. It
Insertion: also extends the thumb at the carpometacarpal
Lateral, posterior and anterior surfaces of the proximal one joint
third of the radius
Blood supply and innervation: Extensor pollicis longus
All muscles of the deep layer of the posterior forearm
compartment are supplied by the posterior interosseous
artery and innervated by the posterior interosseous nerve
Action:
• As the name implies, forearm supination

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 Hand
The anatomy of the hand is quite complicated.
Accordingly, only clinically relevant anatomy is provided
in this section.

Overview of the muscles of the hand

Muscle supplied by the ulnar nerve:
Superficial branch of the ulnar nerve:
• Palmaris brevis → improves grip
Origin: Deep branch of the ulnar nerve:
Posterior surface of the middle one third of the ulna and the • Dorsal interossei → abducts digits from axial line
interosseous membrane at the metacarpophalangeal joints
Insertion: • Flexor digiti minimi brevis → flexion of proximal
Base of the distal phalanx of the thumb phalanx of the little finger
Action: • Abductor digiti minimi → abducts little finger
• As the name implies, it extends the distal phalanx • Opponens digiti minimi → opposition of little
of the thumb at the interphalangeal joint and it finger with thumb (works on the little finger)
extends the thumb at the carpometacarpal joint • Medial two lumbricals → flexion of the
metacarpophalangeal joints and extension of the
Extensor pollicis brevis interphalangeal joints
• Adductor pollicis → thumb adduction
• Palmar interossei → adducts digits toward axial
line at the metacarpophalangeal joints
Muscles supplied by the median nerve: affected by carpal
tunnel syndrome
• Lateral two lumbricals
• Opponens pollicis → opposition of the thumb
Origin: with the little finger (works on the thumb)
The posterior surface of the radius and the interosseous • Abductor pollicis brevis → thumb abduction
membrane • Flexor pollicis brevis → thumb flexion
Insertion: Thenar muscles: thenar atrophy in median nerve injury
The base of the proximal phalanx of the thumb – remember • Opponens pollicis
the thumb has two phalanges not three like the other digits • Abductor pollicis brevis
Action: • Flexor pollicis brevis
• Extension of the proximal phalanx of the thumb Hypothenar muscles: hypothenar atrophy in ulnar nerve
at the carpometacarpal joint injury
• Opponens digiti minimi
Extensor indicis
• Abductor digiti minimi
• Flexor digiti minimi brevis

Palmar muscles of the hand

Origin:
The posterior surface of the ulna and interosseous
membrane
Insertion:
The extensor expansion of the 2nd digit
Action:
• As the name implies, extension of the 2nd digit

504
 o Can be entrapped in meralgia causing
pain and paresthesia in the outer thigh
area
• The pudendal nerve arises from S2 and S3 roots
o Exits through the greater sciatic
foramen below the piriformis to enter
the lesser sciatic foramen
o Innervates the perineum through the
pudendal canal.
• The superior gluteal nerve arises from L5 and S1
o Goes through the greater sciatic
foramen above the piriformis
o Innervates the hip abductors, tensor
Dorsal muscles of the hand fasciata lata, gluteus minimus, gluteus
medius and stabilizes the pelvis during
gait
o The Trendelenburg gate occurs when
the superior gluteal nerve is injured. The
patient shifts the body weight to the
weak side to swing the limb underneath
o When the patient stands on one leg, the
pelvis might drop on one side. The
Lumbosacral Plexus and Lower Limb Nerves injured nerve is on the contralateral side
The anatomy of the lumbosacral plexus of the pelvic drop
Definition: • The inferior gluteal nerve arises from S1 and S2
The lumbosacral plexus is formed by the fusion, division, o Goes through the greater sciatic
and branching of the ventral roots L1 to S3. They foramen below the piriformis
contribute to the nerves of the lower limbs. o Innervates the gluteus maximus which
is responsible for hip extension and
Roots: lateral rotation
• The nerve to piriformis innervates the piriformis
• The lumbar plexus is formed by the ventral rami muscle which is a lateral hip rotator
of L1 to L3 and part of L4 • The nerve to the obturator internus innervates the
• The sacral plexus is formed by the lumbosacral obturator internus. It goes through the lesser
trunk from L4 and L5, the ventral ramus of S1, sciatic foramen and the muscle is a lateral hip
and a part of the ventral rami of S2 and S3 rotator
The early branches of the lumbosacral plexus • The posterior femoral cutaneous nerve arises
• The iliohypogastric nerve has roots from L1 and from S1 to S3 and it provides sensation to the
T12 posterior thigh. It goes through the greater sciatic
• The ilioinguinal nerve is mainly from L1 roots foramen below the piriformis
o Travels through the inguinal canal The terminal branches of the lumbosacral plexus
o Provides sensation to the scrotum in • The lumbar plexus has one terminal ventral
males and labia majora in females branch (the femoral nerve) and one terminal
• The genitofemoral nerve has fibers from L1 and dorsal branch (the obturator nerve)
L2 o The femoral nerve passes beneath the
o The genital branch travels through the inguinal ligament
inguinal canal to contribute to sensation o Through the femoral triangle
in the scrotum and labia majora o Innervates the anterior thigh muscles
o The femoral branch provides sensation which are the hip flexors and knee
to a small area on the proximal anterior extensors.
thigh ▪ The iliopsoas which includes
• The lateral femoral cutaneous nerve arises from the psoas major and iliacus. It
roots L2 and L3 also supplies the pectineus and
o Sensation to the anterolateral thigh sartorius muscles. The

505
 iliopsoas also laterally rotates
the hip
▪ The knee extensors include the
quadriceps
o The femoral nerve continuous as the
saphenous and vastus medialis
branches. The saphenous nerve is the
longest sensory nerve in the body
o The obturator nerve innervates the
sartorius, pectineus, and gracilis
muscles
o The obturator nerve passes through the
obturator canal
▪ It innervates the medial thigh
muscles which are hip
adductors and lateral hip
rotators
• The sacral plexus has one terminal dorsal branch
(the sciatic nerve) and one ventral branch (the
tibial nerve)
o The sciatic nerve is the largest nerve in
the body in diameter
o The sciatic nerve supplies the knee Figure 255: The anatomy of the roots, divisions, and
flexors and hip extensors branches of the lumbosacral plexus. Source:
o Posterior hip dislocation can damage the https://accessanesthesiology.mhmedical.com/content.aspx?
sciatic nerve causing avascular necrosis bookid=572&sectionid=42543728
→ adducted, flexed, internally rotated
shortened leg Hip and Gluteal Muscles
o The tibial nerve passes through the Gluteal
popliteal fossa to innervate the posterior Deep layer:
leg muscles
• The lumbosacral trunk (L4 and L5) becomes part
of the sciatic nerve which also has roots from S1
and S2

Piriformis:

• Innervated by the piriformis nerve

• Originates from the anterior portion of the lateral
process of the sacrum and inserts at the superior
border of the greater trochanter
• Lateral rotation of the hip
Superior gemellus:

• Innervated by the nerve to the obturator internus

• Originates from the ischial spine to insert onto the
medial surface of the greater trochanter
• Lateral rotation of the hip
Obturator internus:

• Innervated by the nerve to the obturator internus

506
 • Originates from the internal surface of the
obturator membrane to insert onto the medial
surface of the greater trochanter of the femur
• Lateral rotation of the hip
Inferior gemellus:

• Innervated by the nerve to the quadratus femoris

• Originates from the posterior ischial tuberosity to
insert onto the medial surface of the greater
trochanter
• Laterally rotates the hip Iliopsoas muscle:
Quadratus femoris:
• Innervated by direct L1 to L3 branches “psoas
• Innervated by the nerve to the quadratus femoris major muscle” and the muscular branch of the
• Originates from the lateral margin of the femoral nerve “iliacus muscle”
obturator ring to insert onto the quadrate • The psoas major originates from the transverse
membrane and the intertrochanteric crest in the processes of L1 to L5 and the iliacus originates
proximal posterior region of the femur from the upper two-thirds of the iliac fossa and
• Laterally rotates the hip the anterior sacroiliac ligament
Superficial layer: • Both muscles insert onto the lesser trochanter of
the femur
• They are the main flexors of the hip
Knee extensors:

• The rectus femoris, vastus intermedius, vastus

medialis, and vastus lateralis are the main
extensors of the knee
• They are innervated by the muscular branches of
the femoral nerve
Gluteus medius and minimus: • The rectus femoris originates from the anterior
inferior iliac spine and a groove above the
• These muscles are innervated by the superior acetabulum
gluteal nerve • The other three muscles originate from the
• They are mainly hip abductors and medial superior half of the anterior surfaces of the femur
rotators • They insert into the patella and the patella
• They provide stability to the gait during walking ligament to eventually attach in the tibial
or standing on one leg tuberosity
Gluteus maximus: Medial Thigh
• This is the most superficial muscle of the gluteus
muscles
• It is a hip extensor that also provides lateral
rotation and abduction
• It is innervated by the inferior gluteal nerve
Tensor fasciae latae:

• Innervated by the superior gluteal nerve

Hip adductors:
• It forms the iliotibial band which runs to the
superolateral aspect of the tibia • The adductor brevis, longus and magnus are the
• It is a hip abductor, medial rotator and flexor main adductors of the hip. They also laterally
• It stabilizes the hip and knee joints rotate the hip
Anterior Thigh • They originate from the pubic ramus
• The adductor brevis inserts on the pectineal line,
the adductor longus inserts onto the middle third

507
 of linea aspera and the adductor magnus inserts
onto the adductor tubercle
• They are innervated by the obturator nerve
• The gracilis muscle is thin long muscle that
originates from the lower margin of the pubic
bone, inserts onto the superomedial shaft of the
tibia, and is innervated by the obturator nerve
o Hip adduction
o Knee flexion
o Medial rotation of the knee when flexed
• The obturator externus is also innervated by the
obturator nerve • The tibialis anterior, extensor hallucis longus,
extensor digitorum longus and fibularis are
Posterior Thigh dorsiflexors of the foot
• They are all innervated by the deep fibular nerve
• The tibialis anterior is also responsible for foot
inversion and support of the medial foot arch
• The extensor hallucis longus is responsible for
great toe extension
• The extensor digitorum longus is also the main
extensor of the lateral four toes
• The fibularis is also the main muscle concerned
Biceps femoris: with foot eversion
Posterior Compartment
• Innervated by two nerves: The long head is
innervated by the tibial nerve whereas the short
head is innervated by the common peroneal nerve
• Originates from the ischial tuberosity (long head)
and the linea asparta and lateral supracondylar
ridge of the femur (short head)
• Inserts onto the fibular head and the lateral tibial
condyle
• Flexes the knee, laterally rotates the tibia, and
extends the hip
Semitendinosus:

• Innervated by the tibial nerve Superficial layer:

• Originates from the ischial tuberosity to insert
onto the superomedial tibial shaft • All these muscles are innervated by the tibial
• Knee flexion, hip extension, and medial rotation nerve
of the tibia when the knee is flexed • They are the main plantar flexors of the foot
Semimembranosus: • They also flex the knee
• They all insert into the calcaneal tendon which is
• Innervated by the tibial nerve attached to the posterior surface of the calcaneus
• Originates from the ischial tuberosity to insert Soleus:
onto the posterior portion of the medial tibial
condyle • Originates from the soleal line and middle third
• Same action as semitendinosus of the posterior tibia
Plantaris:
Leg Muscles
• Originates from the inferior aspect of the lateral
Anterior compartment:
supracondylar line of the distal femur
Gastrocnemius:

• The medial head originates from the posterior

medial femoral condyle

508
 • The lateral head originates from the posterior • Inability to synthesize melanin
lateral femoral condyle • The proliferation of melanocytes is intact
Deep layer: Pathology:
• These muscles also support the medial arch of the OCA1:
foot
• They flex the great toe (flexor hallucis longus), • Autosomal recessive mutation
the other four toes (flexor digitorum longus) or • TYR gene which encodes tyrosinase
invert and plantar flex the foot (tibialis posterior) • L-tyrosine is hydroxylated to L-DOPA which is
• The popliteus unlocks the knee joint by laterally oxidized to DOPAquinone
rotating the femur on a fixed tibia • This is the rate-limiting step in melanin synthesis
• All these muscles are innervated by the tibial OCA2:
nerve
• Autosomal recessive mutation
Lateral Compartment: • OCA2 gene which encodes a protein of unknown
function
• Patients present with impaired melanin synthesis
of an unknown cause
OCA3:

• Autosomal recessive mutation

• TYRP Gene which encodes tyrosinase-related
protein 1
• This protein stabilizes and modulates tyrosinase
OCA4:
• Fibularis longus and brevis
• Innervated by the superficial fibular nerve • Autosomal recessive mutation
• They support the arches of the foot and are • SLC45A2 gene which encodes a protein that is
responsible for foot eversion important for melanin synthesis
Histopathology:
Albinism
Definition • Hematoxylin and eosin staining reveal normal
Albinism refers to a group of heritable conditions that are skin
characterized by decreased or absent melanin in ectoderm- • Melanin staining is normal because melanocytes
derived tissues. Patients have a characteristic pallor. are normally present
• Not useful or needed for the confirmation of
Oculocutaneous albinism (OCA) is a group of genetic diagnosis
disorders that have a similar phenotype with involvement
of the eyes and skin caused by errors in melanin synthesis. Clinical Presentation
Epidemiology The classical picture of albinism is that of OCA type 1.
Patients have complete lack of melanin and have white
• Estimated annual incidence is 1 per 17,000 to
hair, eyelashes, skin and pink eyes.
20,000
• OCA1 prevalence in the United States is 1 in Ocular findings:
40,000 and represents 70% of the cases
• OCA2 is more common in African Americans • Photophobia
and Sub-Saharan Africa • Refractive errors
• OCA3 is seen Pakistani, German, Indian and • Foveal hypoplasia
Japanese populations • Involuntary pulsatile horizontal nystagmus
• Other types of OCA are very rare • Strabismus
• Angelman syndrome Prader-Willi syndrome can • Reduced iris pigmentation which can be pink
also present with albinism (transparent), or light blue
• Yellow retina due to hypomelanosis of retinal
Pathophysiology epithelium
Etiology:

• A hereditable mutation in melanocytes

509
 Figure 258: Bacillary angiomatosis. Source:
https://www.merckmanuals.com/professional/infectious-
Figure 256: Skin and hair features in albinism. Source: diseases/gram-negative-bacilli/bacillary-angiomatosis
https://upload.wikimedia.org/wikipedia/commons/d/de/Alb
ino_baby_by_Felipe_Fernandes_03.jpg Cherry Hemangioma
• Benign capillary hemangioma
Diagnosis • Seen in the elderly
• Clinical diagnosis • Does not regress
• Skin biopsy is indicated to exclude skin
malignancy
Treatment
• Patients should be instructed to avoid direct sun
exposure and ultraviolet light protection
• No cure

Vascular Skin Tumors

Angiosarcoma Figure 259: Cherry hemangioma. Source: First Aid 2018
• Rare blood vessel malignancy
• Typically affects the head, neck and breast skin Strawberry Hemangioma
• More common in the elderly • Benign capillary hemangiomas in infancy
• Associated with radiation therapy and chronic • Typically appears within the first few weeks of
postmastectomy lymphedema life
• Very aggressive malignancy • Grows rapidly
• Diagnosis is delayed in most cases • Regresses spontaneously by age five to eight
years

Figure 257: Angiosarcoma of the face. Source: Figure 260: Strawberry hemangioma. Source: Source:
https://jamanetwork.com/journals/jamadermatology/fullarti https://commons.wikimedia.org/wiki/File:Capillary_haema
cle/2436318 ngioma.jpg

Bacillary Angiomatosis Cystic Hygroma

• Benign capillary skin papules • A cavernous lymphangioma of the neck
• Found in AIDS patients • Often associated with Turner syndrome
• Caused by Bartonella infection
• Neutrophilic infiltrate on histology exam

510
 Figure 261: Cystic hygroma. Source:
https://en.wikipedia.org/wiki/Cystic_hygroma#/media/File:
Newborn_infant_with_a_cystic_hygroma_(cropped).jpg Figure 263: Pyogenic granuloma. Source:
https://commons.wikimedia.org/wiki/File:Pyogenic_Granu
Glomus Tumor loma_Elbow_(1).jpg
• A benign painful red-blue tumor under the
fingernails Lymphangiosarcoma
• Modified smooth muscle cells on histopathology • Lymphatic vessels malignancy
• Smooth muscle cells arise from the • Associated with persistent lymphedema
thermoregulatory glomus body in the skin postmastectomy
Kaposi Sarcoma
• An endothelial malignancy of the skin and
mucous membranes
• Associated with HHV-8 infection in HIV positive
patients
• Lymphocytic infiltrate on histopathology
(remember, neutrophilic infiltrate on
histopathology in bacillary angiomatosis)

Figure 264: Lymphangiosarcoma occurs in the ipsilateral

limb in a mastectomy patient with chronic limb
lymphedema. Source:
http://www.pathologyoutlines.com/topic/softtissuelymphan
giosarcoma.html

Sturge-Webber Disease
• Affects the ophthalmic and maxillary
distributions of the trigeminal nerve
Figure 262: Kaposi sarcoma. Source: • Affects capillary-sized blood vessels
https://en.wikipedia.org/wiki/Kaposi%27s_sarcoma • Presents with a port-wine stain on the face (nevus
Flammeus)
Pyogenic Granuloma • Ipsilateral leptomeningeal angiomatosis which
• A polypoid lobulated capillary hemangioma can cause seizures in the patient
• The tumors can ulcerate and bleed • Increased risk of glaucoma
• Often preceded by trauma or pregnancy

511
 • Caused by the production of exfoliative toxin A
by staphylococcus aureus which causes loss of
cell adhesion in the epidermis
• The bullae contain a yellow fluid which
eventually turns dark brown
• No erythematous base or surrounding edema
• Systemic features such as fever are more common
Diagnosis:

• A clinical diagnosis
Figure 265: Port-wine stain of the face and ipsilateral Treatment:
leptomeningeal angiomatosis. Sources: Non-bullous impetigo:
https://step1.medbullets.com/neurology/113095/sturge-
weber-syndrome and https://en.wikipedia.org/wiki/Sturge– • Topical mupirocin or fusidic acid
Weber_syndrome Bullous impetigo:

Skin Infections and Infestations • Systemic antibiotics are indicated

Impetigo • Cephalexin
Definition:
A skin infection that is confined to the epidermis layer. It is
highly contagious and is often caused by gram-positive
bacteria.
Etiology:

• Represents 10% of skin complaints in children A B

• Non-bullous impetigo is caused by Figure 266: A. Non-bullous impetigo. B. Bullous impetigo.
staphylococcus aureus and represents 80% of the Source: https://en.wikipedia.org/wiki/Impetigo
cases
o It can be also caused by group A beta- Erysipelas
hemolytic streptococcus and MRSA Definition:
• Bullous impetigo is exclusively caused by
staphylococcus aureus and is seen in infants A skin infection that involves the dermis layer of the skin
Pathophysiology: and can extend to the superficial cutaneous lymphatics. It
has a well-demarcated, raised configuration. Cellulitis on
Primary impetigo: the other hand has ill-defined borders.
• Previously normal skin → direct invasion by Etiology:
bacteria of the epidermis
Secondary impetigo: • Streptococcus
• Facial erysipelas is often caused by group A
• Impetigo forming at the site of a previous skin streptococcus, whereas, lower extremity
wound infections are caused by non-group A
Clinical presentation: streptococcus
• More common in young children and the elderly
Non-bullous impetigo:
Pathophysiology:
• Multiple vesicles which coalesce and rupture
• A skin break → direct invasion of the skin’s
• Purulent exudate dermis and superficial lymphatics → erysipelas
• A honey-colored crust • The skin’s integrity might be broken by insect
• Erythematous base bites, stasis ulceration or surgical incisions
• Multiple lesions on the face and extremities Clinical presentation:
• No systemic features
Bullous impetigo: • Systemic symptoms of fever, malaise and chills
occur 48 hours before the onset of the skin lesions
• Small vesicles become a flaccid bulla

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 • The lesion is erythematous, sharply demarcated • A clinical diagnosis
with raised edges • A CBC might show leukocytosis
• Burning, tenderness and itchiness • Elevated ESR and CRP
• When it occurs near a swollen joint, the more Treatment:
serious diagnosis of septic arthritis must be
excluded • Intravenous antibiotics
Diagnosis: • Broad-spectrum antibiotics such as vancomycin
might be needed
• A clinical diagnosis • Vancomycin plus ceftriaxone is a common
Treatment: combination for orbital cellulitis
• Penicillin

Figure 268: Cellulitis. Source:

Figure 267: Erysipelas. Source: https://en.wikipedia.org/wiki/Cellulitis#/media/File:Cellulit
https://en.wikipedia.org/wiki/Erysipelas is3.jpg
Cellulitis Abscess
Definition: Definition:
An acute painful spreading infection of the deeper dermis A collection of pus within the deeper layers of the skin that
and subcutaneous tissues. Slower in progression than is walled-off.
erysipelas and has ill-defined borders. More likely to be
associated with systemic features. Etiology:

Etiology: • Most commonly staphylococcus aureus

Clinical presentation:
• Streptococcus pyogenes and staphylococcus
aureus • A superficial skin swelling
Pathophysiology: • Warm, tender and erythematous
• The lesion is deep
• A skin break → direct invasion of the skin’s • It can be tense due to elevated pressure within the
dermis and subcutaneous tissues → cellulitis abscess
• Direct hematogenous spread in patients with • Systemic features such as fever
bacteremia Diagnosis:
• Direct spread from an infection joint as in septic
arthritis • CBC can show leukocytosis
• Specific types such as orbital cellulitis must be • Ultrasonography confirms the swelling is fluid-
properly diagnosed and managed filled
Clinical presentation: • Aspiration and culture
Treatment:
• Patients tend to be sicker than those with
erysipelas • Often, it needs to be incised and drained
• The lesions are described as erythematous, warm • IV antibiotics might be needed afterwards
to touch and with ill-defined borders
• The lesions are often not raised
Diagnosis:

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 Figure 269: An abscess. Source: Figure 270: Folliculitis, furuncle and carbuncle. Source:
http://pimplesandzits.blogspot.com/2018/04/top-5-abscess- https://www.derm-hokudai.jp/shimizu-
pus-boil-on-fingers.html dermatology/pdf/24-02.pdf
Folliculitis: Staph Scalded Skin Syndrome:
Definition: Definition:
A localized bacterial infection in a single hair follicle. A Also known as Ritter disease, it is characterized by
pustule forms and is associated with erythema. It may denudation of the skin and is caused by exotoxin
progress to a furuncle or a carbuncle. production by staphylococcus species. Typically occurs in
Etiology: the first 48 hours of life and is rare in children older than
six years.
• Staphylococcus aureus or staphylococcus
Etiology:
epidermidis
Pathophysiology: •Staphylococcus species that produces the
epidermolytic exotoxin
• Minor trauma, obstruction and scratching around
a hair follicle → invasion of the hair follicle by • A localized, distant infection of the upper
the bacterial pathogen → inflammation of the respiratory tract, ears, or umbilicus
involved follicle • In most patients, the source of the infection is not
Clinical presentation: identifiable
Pathophysiology:
• Erythema and a pustule occur at the hair follicle.
The lesion forms a crust in few days and heals • Toxin-producing staphylococcus species produce
without scarring. an exotoxin that targets desmoglein 1 complex in
• Acne vulgaris is multiple facial folliculitis the zona granulosa of the epidermis → skin
exfoliation
Diagnosis:
• Can be mild and localized, or can involve whole
• A clinical diagnosis of body
Treatment: Clinical presentation:

• Heals spontaneously •Irritability, fever and malaise for 24 to 48 hours

• Topical or oral antibiotics might be needed in •A very tender rash starts to occur on the face and
complicated cases flexures such as the groin, axillae and neck
Furuncle and Carbuncle: • The rash is erythematous and has fissures
• Large thin blisters or bullae form which can be
• A furuncle is an advanced folliculitis where a filled with clear fluid or yellow pus
pustular plug forms at the center of the lesion and • The disease often involves the entirety of the
there is a purulent swelling and it involves a body
single hair follicle Diagnosis:
• When more than one hair follicle are involved,
the term carbuncle is used • CBC and urinalysis to exclude sepsis
• Treated with incision and drainage followed by • Blood cultures and blister fluid cultures
oral antibiotics • Skin biopsy in critically ill patients

514
Treatment: • Anemia
• Hyponatremia
• Nafcillin or oxacillin for methicillin-sensitive • Hyperglycemia
staphylococcus aureus
• Elevated creatinine
• Vancomycin for MRSA Treatment:

• Immediately transfer the patient to the critically

intensive care unit
• Most patients are septic → aggressive IV fluids
replacement therapy and inotropes are indicated
• Linezolid, piperacillin/tazobactam, and
clindamycin are often combined and given
systemically
• Surgical debridement → antibiotic treatment
alone is absolutely not acceptable

Figure 271: Staphylococcal scalded skin syndrome.

Source:
https://www.ncbi.nlm.nih.gov/books/NBK448135/#article-
29451.s9

Necrotizing Fasciitis:
Definition:
An aggressive skin and soft tissue infection that causes Figure 272: Necrotizing fasciitis. Source:
necrosis of the muscle fascia and subcutaneous tissues. https://en.wikipedia.org/wiki/Necrotizing_fasciitis
Etiology: Pediculosis:
• Staphylococcus aureus and streptococci Definition:
infections Lice infestation of the human head, or other parts of the
Pathophysiology: body. Pediculosis of the head causes pediculosis capitis.
• A break in the skin’s integrity → bacteria invade Etiology:
the deeper layers of the skin
• Necrosis of the muscle fascia and subcutaneous • Pediculus humanus var capitis
tissues → the skin first appears normal despite Clinical presentation:
severe tenderness → eventually it will become
reddish-purple to bluish-gray hue • Scalp pruritis and itchiness
• Skin breakdown starts in three to five days → • Posterior cervical lymphadenopathy
bullae and cutaneous gangrene • Adult lice or eggs (nits) are found
• Pain subsides in the affected area because of • They are not movable along the hair shafts
damage to the peripheral nerves and • More common in children
microvascular thrombosis Treatment:
Clinical presentation:
• OTC 1% permethrin lotion
• Pain out of proportion to clinical findings • Topical ivermectin
• Crepitus due to the formation of methane and • Malathion
CO2 • Physical removal with comb of the eggs, vacuum
• Bullae and purple color skin and washing all clothes and bed linens/pillows
• Also known as flesh-eating bacteria
Diagnosis:

• Mainly a clinical diagnosis → it is a surgical

emergency
• Elevated CRP, leukocytosis, and ESR
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 Etiology:

• Cimex lectularius
Clinical presentation:

• Edematous papules all over the body

Treatment:

• Spontaneously resolve within one or two weeks

• Topical anti-itch creams can help with the itch
• It is important to clean everything in the
bedroom. An exterminator might be needed

Figure 273: Pediculosis. Source: SlideShare

Scabies:
Definition:
A highly contagious skin infestation by the mite sarcoptes
scabiei.
Clinical presentation:

• Itchiness and red pimple-like rash

• Tiny burrows can be seen under magnification Figure 275: Cimex lectularius. Source:
• The burrows are linear markings which occur due https://en.wikipedia.org/wiki/Bed_bug
to the movement of the mites
Viral Skin Infections
• The lesions are most often seen on finger webs,
Chickenpox
umbilicus, breasts, and genitalia
• Chickenpox and shingles are caused by the same
• More common in people living in crowded places
viral agent
such as prisons
Diagnosis: • Primary infection with the varicella zoster virus
results in chickenpox
• Skin scraping and microscopic examination to • Patients develop diffuse vesicles with
check for the mites, eggs, or the feces of the mite erythematous base
Treatment: • The vesicles are of various stages of healing and
can cover most of the body’s surface
• 5% permethrin cream (apply on all of the body), • The diagnosis is confirmed by polymerase chain
oral ivermectin reaction, or culture
• It is important to wash and vacuum everything • Direct fluorescent antibody can be also used to
the patient uses confirm the diagnosis

Figure 274: Scabies. The skin lesions are found on the

finger webs.

Bed Bugs: Figure 276: Chickenpox skin eruption. Source:

Definition: https://en.wikipedia.org/wiki/Chickenpox

A human parasite that feeds on human blood and is found Shingles

in bedding and are active at night.

516
 • Reactivation of latent varicella zoster virus results
in shingles
• The vesicular rash is confined to a single
dermatome
• Shingles can be recurrent, however, chickenpox
occurs only once
• The diagnosis can be confirmed by PCR or
Tzanck prep
• Viral culture can be used to confirm the
diagnosis, however this is rarely needed
• Acyclovir or valacyclovir can be used to reduce Figure 278: HSV1 recurrent eruption on the vermillion
the duration of the symptoms border of the lip. Source:
https://en.wikipedia.org/wiki/Herpes_labialis

Verruca Vulgaris
• This is the common wart
• It presents as a raised exophytic papule with a
rough surface
• More common on the hands, but can occur in any
part of the body especially after trauma
• More common in children and young adults
• They are caused by the human papillomavirus
Figure 277: Shingles of the C8 and T1 dermatomes. which infects the basal layer of the keratinocytes
Source: of the skin
https://en.wikipedia.org/wiki/Shingles#/media/File:Shingle • HPV has many types. The exact type the patient
s.JPG has determines the malignancy potential and the
morphology of the wart
Herpes Simplex • Verruca planae are flat warts which are pink
• The most common types are herpes simplex virus colored and have a smooth surface
type 1 (orolabial disease) and herpes simplex • Palmoplantar verruca are thick endophytic
virus type 2 (genital disease) papules
• The anatomical distinction between HSV1 and • Warts usually resolve on their own, however this
HSV2 is becoming blurred might take several years
• HSV1 eruptions are recurrent activation of the • Cryotherapy, salicylic acid or other destructive
virus and they occur on the vermillion border of treatments can be used if the warts cause
the lip significant discomfort to the patient
• The rash is intensely painful and is vesicular
• The vesicles contain clear fluid. If secondary
bacterial infection occurs, pustules might occur
• More likely to present with recurrences than VZV
• In most cases, the diagnosis is not needed to be
confirmed, but if necessary PCR or Tzanck prep
can be used
• Acyclovir can be used to treat a current episode
or for prophylaxis when more than 10 eruptions
per year
• A herpetic whitlow is a herpetic eruption on the
finger Figure 279: Common warts on the finger.

Genital Warts:
• These are sexually transmitted disease and they
are caused by HPV as well
• They can occur on the external genitalia,
perineum, perianal, or inguinal region

517
 • They are verrucous sessile exophytic papules in is a fungistatic or with allylamines which are
configuration fungicidal
• Extensive disease in HIV positive patients or o Patients’ education about frequent
immunocompromised patients changing of socks and use of foot
• HPV types 6 and 11 cause genital warts. Types powder for dryness is essential
16 and 18 are associated with high grade • Onychomycosis requires oral antifungals,
intraepithelial neoplasia typically terbinafine
o A vaccine (Gardasil) against HPV types • Chronic or recurrent tinea pedis infection → skin
6, 11, 16 and 18 is available breaks and fissures → entry of bacteria into the
• Cryotherapy, electrocautery, laser, or surgery are deeper layers of the skin → cellulitis
used in the treatment of genital warts
• Imiquimod is a TLR7/8 agonist that stimulates
the immune system. It is used in the treatment of
genital warts
Molluscum Contagiosum:
• This is a viral infection that involves the skin and
mucous membranes
• Numerous small flesh-colored smooth papules
with central umbilication
• Can be found on the face, trunk, extremities or
genitals
• They are caused by poxvirus Figure 281: Tinea pedis.
• Cryotherapy can be used in extensive cases;
Tinea corporis:
however, they tend to resolve on their own in few
months • Also known as ringworm
• Affects the trunk and limbs – corporis = body
• Presents with ring-shaped lesions with central
clearing that are itchy
• Uncomplicated cases are treated with topical
antifungals. Severe cases require oral terbinafine
• Tinea cruris affects the groin

Figure 280: Molluscum contagiosum. Notice the central

umbilication of the lesion. Source:
https://www.dermnetnz.org/topics/molluscum-
contagiosum-images/

Fungal Skin Infections

Dermatophytes Figure 282: Tinea corporis.
Tinea pedis:
Tinea capitis
• Athlete’s foot
• Prolonged wearing of shoes creates a moist • Affects the scalp and hair
environment where the fungus can grow • More common in children
• Patients present with scaling and redness of the • Patients present with black dots on the scalp,
affected toe seborrheic spots, kerion with is an abscess and
• Interdigital, vesiculobullous or moccasin broken hairs → balding
• When the nails are involved, the term • History of contact with animals
onychomycosis is used
• Uncomplicated tinea pedis infections are treated
with topical antifungals such as imidazole which

518
 o While scaling responds quickly, the re-
pigmentation of the skin takes longer

Figure 285: Tinea versicolor.

Figure 283: Tinea capitis.
Candidal Intertrigo
Examples of dermatophytes: • This is a burning red rash of the large skin folds
such as the groin, armpits, under breasts, buttocks
• T rubrum, Epidermophyton and Trichophyton
or abdominal folds
mentagrophytes cause tinea pedis
• More common in obese people
• Trichophyton, microsporum and Epidermophyton
cause tinea corporis and capitis • They are more common in hot and humid weather
• They can be identified by KOH preparation • Topical antifungals are usually successful in
treating the rash

Figure 286: Candidal intertrigo.

Figure 284: KOH preparation - dermatophytes. Diaper Candidiasis

• Presents in infants wearing diapers with red
Tinea Versicolor erosions in the diaper area and satellite lesions
• Dermatomycosis furfuracea or tinea flava • Involves skin folds
• Presents with macules and patches on the skin of • Candida is normally found in the feces. Urine in
multiple colors that can be hyperpigmented or the diaper contains urea which is broken down by
hypopigmented urease into ammonia → ammonia irritates the
• Mainly affects the trunk skin and makes small breaks in its integrity →
• The lesions are not scaly, but they can feel scaly candida enters the superficial layers →
to touch candidiasis
• Better appreciated in summer season when skin is • Nystatin creams or imidazole are used in the
tanned treatment
• They are caused by Malassezia yeast
• KOH preparation confirms the diagnosis where
short hyphae are seen. Dermatophytes have long
hyphae
• Responds to shampoos containing antidandruff
agents (ketoconazole, selenium sulfide or
pyrithione zing) or fluconazole cream

519
 • The distended follicles rupture and
proinflammatory mediators get released which
results in inflammation of the pilosebaceous unit
Epidemiology

• Onset in adolescence and persists through the

early thirties
• More common in males
• 20% of those with acne vulgaris develop severe
acne with scarring
• Acne is more severe in Asians and Africans
Clinical presentation
Grade 1:
Figure 287: Diaper candidiasis.
• Comedones which an be open or closed. Closed
Irritant dermatitis: comedones occur due to keratin and sebum
plugging of the pilosebaceous orifice below the
• Does not have satellite lesions skin surface.
• Does not involve skin folds • Open comedones occur due to plugging of the
• Improves with barrier creams – does not need pilosebaceous orifice by sebum on the skin
antifungals surface
• KOH preparation is negative Grade 2:

Inflammatory Skin Conditions • Small inflammatory papules with erythema

Acne vulgaris Grade 3:
Definition
• Pustules form
Acne vulgaris is an inflammatory condition of the Grade 4:
pilosebaceous unit. It’s a chronic disorder that is self-
limiting and is triggered by Cutibacterium acnes. • Multiple pustules coalesce into nodules and cysts
Healing of acne:
Etiology and pathophysiology
• Severe acne can result in depressed, hypertrophic
• DHEAS, a normal circulating androgen should or keloidal scars
have no effect on the pilosebaceous units of the Associated symptoms and signs:
skin
• Cutibacterium acnes increases the sensitivity to • Women with hyperandrogenism, i.e. PCOS,
this androgen, which results in acne vulgaris might have hirsutism, acanthosis nigricans,
• Acne vulgaris can be also seen in patients taking irregular menstrual periods and weight gain
certain medications such as lithium, Diagnosis
corticosteroids or anticonvulsants • Acne vulgaris is a clinical diagnosis
• Endocrine disorders like polycystic ovarian
syndrome are associated with an increased level
of androgens which can lead to acne vulgaris
Pathophysiology

• Puberty increases sebum production by the

pilosebaceous unit. This occurs because 5-alpha
reductase converts more testosterone to DHT
• DHT increases sebum production by causing
hyperproliferation of follicular epidermis →
retention of sebum
• These effects are enhanced when cutibacterium
acnes is present

520
 • More common in females (F:M is 3:1)
• Onset in young adulthood
Clinical presentation
The severity of the disease, which is assessed by Sartorius
staging system, is important in predicting the prognosis.
Elements of Sartorius staging system:

• The number of skin lesions classified by type of

lesion (abscesses, nodules, sinuses, and scars)
• The distance between the lesions in the same
region
Figure 288: Acne vulgaris. Source: • The presence of normal skin between the lesions
https://www.ncbi.nlm.nih.gov/books/NBK459173/ • The number of anatomic regions involved (axilla,
groin, gluteal, and other regions)
Treatment:
Topical treatments:

• Retinoids like retinoic acid, adapalene, or

tretinoin
• Clindamycin or azithromycin gels and lotions
• Benzoyl peroxide
Systemic treatments:

• Doxycycline
• Minocycline – superior to doxycycline in that it
needs one dose per day Figure 289: Hidradenitis suppurativa of the axilla. Source:
• Isotretinoin https://en.wikipedia.org/wiki/Hidradenitis_suppurativa
Teratogenicity of retinoids:
Diagnosis:
• Retinoids should be used cautiously in women of
childbearing age • Hidradenitis suppurativa is a clinical diagnosis
Treatment:
• They are highly teratogenic
Hidradenitis suppurativa •Oral rifampicin + clindamycin for three months
Definition •Intralesional steroids in localized disease
Also known as acne inversa, is a chronic skin disease that •Antiandrogen therapy in diffuse disease
is characterized by inflamed and swollen lumps that are •Weekly doses of TNF inhibitors such as
painful and can easily break to release pus or fluid. They adalimumab are useful in severe disease
are most common underarms, under the breasts, and in the • Topical retinoids are ineffective
groin area. Severe hidradenitis suppurativa:

Etiology and pathophysiology: • Patients with severe hidradenitis suppurativa with

multiple undiagnosed and untreated sinuses can
• Unknown etiology develop squamous cell carcinoma
• Most likely multifactorial with genetic and • Amyloidosis, arthropathy and anemia are also
environmental factors possible complications of severe fistulous
• Excessive sweating, androgen dysfunction, hidradenitis suppurative
obesity, and plugged pilosebaceous units are Rosacea
possible risk factors Definition:
• Autosomal dominant inheritance has been
suggested Rosacea is a chronic skin disease that affects the face and
Epidemiology presents with redness, pimples, swelling and small
superficial dilated blood vessels.
• 1 to 4% of the general population
Etiology and pathophysiology:
521
 • The exact cause is unknown
• An inflammatory condition of an unknown
trigger
• Patients have elevated levels of the antimicrobial
peptide cathelicidin and stratum comeum tryptic
enzymes (SCTEs)
• Antibiotics decrease the level of SCTEs which
might explain why they work in rosacea
• Demodex folliculorum mites can cause rosacea
by introducing the bacterial pathogen bacillus
oleronius
• Another theory of the pathophysiology of rosacea
is that there is small intestinal bacterial
overgrowth → increased levels of SCTEs and Figure 290: Rosacea of the nose. Source:
cathelicidin → development of rosacea https://en.wikipedia.org/wiki/Rosacea#/media/File:Acne_r
Epidemiology: osacea.jpg
• 5% of the general population Diagnosis:
• Onset in thirties to fifties years old
• Family history is important • Rosacea is a clinical diagnosis
• More common in patients taking steroids Treatment:
• More common in white women
Clinical presentation: • Avoiding triggers of flushing
• Ivermectin and azelaic acid creams
Erythrotelangiectatic rosacea: • Oral doxycycline and isotretinoin

• Also known as vascular rosacea Pityriasis alba

• History of prolonged flushing of the face in Definition:
reaction to emotional stress, hot drinks, spicy
foods or cold and hot weather A benign skin disorder that affects children and
• Permanent redness, small widened blood vessels adolescents and presents with fine hypopigmented scales.
visible under the skin, burning, stinging, and More common in patients with history of atopy.
itching
Etiology and pathophysiology:
• The skin becomes very dry and flaky
Glandular rosacea: •
Unknown cause
•
Might be a minor manifestation of atopic
• More common in men
dermatitis
• Edematous papules and large pustules with
• Decreased melanin production in the affected
nodulocystic lesions
areas
Phymatous rosacea:
o Normal number of melanocytes
• Can present with rhinophyma, an enlargement of • Associated with iron-deficiency anemia and low
the nose levels of serum copper
• The skin is thickened with irregular surface Epidemiology:
nodularity
• Most common in children aged three to 16 years
• 5% of children in the United States have the
condition
• More common in Egypt and Mali
• Slight male predominance
• Normal skin pigmentation returns spontaneously
within a year
Clinical presentation:

• An initial stage of erythematous skin lesions

522
 • Followed by hypopigmented scales mainly on the Histopathology:
face
• History of atopy in the patient or the family • Perifollicular and perivascular lymphohistiocytic
• Often, it is an incidental finding on examination inflammatory infiltrate
• The hypopigmentation is more prominent in the • Some patients might have dermal epithelioid
summer (surrounding normal skin becomes granulomas
darker) • Absence of follicular spongiosis in contrast to
• The scaling is more prominent in winter because other dermatitis conditions
of dry air inhouse Epidemiology:

• Young adult females aged between 20 to 45 years

• Equal frequency between genders in children
Clinical presentation:

• Erythematous-grouped papules on both sides of

the mouth, eyes or nose
• Scaling, vesicles and pustules are also common
• Sparing of the vermillion borders of the lip
• Burning sensation in the affected areas
• Absence of systemic manifestations
Figure 291: Pityriasis alba. Source:
https://www.ncbi.nlm.nih.gov/books/NBK431061/

Diagnosis:

• Pityriasis alba is a clinical diagnosis

Treatment:

• Assurance that the condition is benign

• Patients should be aware that resolution might
take several months, up to a year
• Topical 1% hydrocortisone might accelerate re- Figure 292: Perioral dermatitis. Source: Medscape
pigmentation
Diagnosis
Allergic Skin Conditions and Dermatitis
Perioral dermatitis • Clinical diagnosis
Definition • Consider biopsy in atypical presentations
Treatment
Perioral dermatitis is a benign eruption in young female
adults that is characterized by small inflammatory papules, • Metronidazole cream or gel
pustules, and pink scaly patches around the mouth. • Clindamycin lotion or gel
• Topical calcineurin inhibitors such as tacrolimus
Etiology and pathophysiology: ointment
Atopic dermatitis
• Unknown cause but multiple known risk factors: Definition:
o Topical corticosteroid use
o Candida albicans and fusiform bacteria Atopic dermatitis, eczema, is a specific type of dermatitis
overgrowth → both related to topical that is associated with other atopic diseases and is the most
corticosteroid use common type of dermatitis.
o Fluorinated toothpaste
o Dental fillings Etiology and pathophysiology:
o Some cosmetic products
Atopic triad:
o Oral contraceptive pills are protective
• The main pathology is perifollicular and • Atopic dermatitis
perivascular inflammation • Allergic rhinoconjunctivitis
• Asthma

523
Etiology: • Acute lesions are edematous, erythematous
papules, plaques, and vesicles
• Defective barrier of the skin, upper respiratory • Subacute lesions are erythematous, scaly and can
and lower respiratory tract → atopic triad have crusting
• History of atopy in the individual or his/her • Chronic lesions are thick plaques with
family increases the risk of atopic dermatitis lichenification and scaling
significantly Diagnosis:
• Genetic alterations in filaggrin can result in atopic
dermatitis • A clinical diagnosis
• Food hypersensitivity can cause or exacerbate • A biopsy will reveal an eczematous pattern
atopic dermatitis • IgE antibodies against specific allergens might be
Pathophysiology: detected
Treatment:
• Defective skin barrier → xerosis → exposure to
allergens → inflammation and pruritus → atopic • Avoidance of known triggers
dermatitis • Daily skin care with application of emollients
• Defective skin barrier can be caused by a twice day
decreased level of ceramides • Anti-inflammatory therapy with topical steroids
• Allergens and irritants are more likely to • Systemic immune modulators such as
penetrate a defective skin rather than normal azathioprine or methotrexate
intact skin barrier • Novel anti-inflammatory therapies such as
• Inflammation is mediated by a Th2 response in dupilumab which blocks IL-4 receptor
acute lesions (IL-4, and 5) and Th1 response in
chronic disease (interferon-gamma and IL-12)
• Scratching of the lesions → increased production
of pro-inflammatory cytokines by keratinocytes
(TNF-alpha, IL-1 and IL-6) → worsening of
atopic dermatitis
• Broken skin is more likely to be infected with
staphylococcus aureus
Epidemiology:
Figure 293: Atopic dermatitis of the face an infant and of
• Up to 30% of children the antecubital fossa in a child. Source:
• 10% of adults https://commons.wikimedia.org/wiki/File:Atopic_dermatiti
• Early-onset atopic dermatitis occurs at birth up to s_child_1.jpg and
two years of age and is the most common type of http://www.tabletsmanual.com/wiki/read/atopic_dermatitis
atopic dermatitis
o 60% resolve by 12 years old Contact dermatitis
• Late-onset atopic dermatitis begins after puberty Definition:
• Senile-onset atopic dermatitis occurs in patients
Contact dermatitis is an inflammatory eczematous skin
older than sixty years old and is rare
disease that is triggered by the exposure to an irritant or an
Clinical presentation:
allergen.
Infants:
Irritant contact dermatitis is a nonspecific non-T-cell
• Edematous papules and plaques mediated skin response to direct chemical damage and
• Scalp, face and extensor extremities release of pro-inflammatory mediators from epidermal
• Lesions might have vesicles or crust cells.
Children: Allergic contact dermatitis is a delayed type 4
• Patches and plaques on antecubital and popliteal hypersensitivity reaction to contact antigens and is T-cell
fossae mediated.
Adults:

• Chronic lichenoid lesions on the hands

Classification of lesions:

524
Etiology and pathophysiology: • In the subacute please, patients develop crusts,
scales and hyperpigmentation
Irritant contact dermatitis: • In the chronic phase, patients develop
• Physical irritants such as friction, abrasions, lichenification and possibly hypopigmentation
occlusion and sodium lauryl sulfate • The most commonly affected sites are the hands
• Chemical irritants include any substance that can and wrists
damage the epidermis
• The quantity, concentration, duration and
frequency of exposure determines the severity of
contact dermatitis
• Damaged, very dry skin is more likely to develop
irritant contact dermatitis
• Damage to keratinocytes → release of pro-
inflammatory cytokines → skin barrier disruption
Allergic contact dermatitis:

• Common allergens include nickel, balsam of Figure 294: Allergic contact dermatitis. Source:
Peru, chromium, neomycin, formaldehyde, https://www.dermnetnz.org/topics/allergic-contact-
fragrance mix, parthenium, cobalt and thiomersal dermatitis/
• The condition has two phases and is T-cell
mediated Diagnosis:
• Phase 1: sensitization:
Patch testing is the gold standard in diagnosing contact
o Antigens penetrate the skin and are
allergic dermatitis. Chemicals found in metals, rubber,
drained by lymphatic vessels to lymph
leather, fragrance, and other common products are found in
nodes
the patch test. The results of the patch test are as follows:
o Cutaneous dendritic cells migrate from
the skin to the lymph node and present • Negative
the antigen to specific effector T-cells • Irritant reaction (not allergic)
o The T-cells are activated • Uncertain
• Phase 2: elicitation: • Weak positive
o The activated T-cells produce various
• Strong positive
chemical mediators
• Extreme positive
o Antigen-specific inflammation
Treatment:
Histopathology:
• Avoidance of the irritant/allergen
• In irritant contact dermatitis, there is mild
spongiosis, epidermal cell necrosis and • Topical corticosteroids
neutrophilic infiltration of the epidermis • Antihistamines decrease pruritus
• In allergic contact dermatitis, the infiltrate is • Immunomodulators are used in severe resistant
mainly by lymphocytes and mononuclear cells cases
Epidemiology:
Seborrheic dermatitis:
• Previous history of atopy increases the risk of Definition:
irritant contact dermatitis
Seborrheic dermatitis is a chronic skin disorder that
• Most cases of irritant contact dermatitis are
presents with red, scaly, greasy, itchy lesions in the scalp,
occupational dermatitis
face and chest.
• Allergic dermatitis is more common in people
with other allergies and atopic dermatitis Etiology and pathophysiology:
Clinical presentation:
• Might be related to proliferation of the yeast
• The skin manifestations of contact dermatitis Malassezia
occur at the site of contact with the chemical or • Mainly Malassezia globosa and Malassezia furfur
allergen agent • The yeast might produce irritant substances
• In the acute stage, there is erythema, edema, which cause skin inflammation
crusting, tenderness, vesicles and pustules Pathophysiology:

525
Malassezia hydrolyze sebum → production of saturated Etiology and pathophysiology:
and unsaturated fatty acids → the fungus takes up saturated
fatty acids and leaves behind unsaturated fatty acids → • Unknown
unsaturated fatty acids penetrate the skin → inflammation Epidemiology:
and development of dandruff and seborrhoeic dermatitis
• Estimated prevalence is 2 per 1000
Epidemiology: • It is a disease of adulthood
Clinical presentation:
• 40% of babies
• 2% of adults • Round or oval red plaques on the trunk, limbs,
• Risk factors: stress, winter, Parkinson disease, face and hands
epilepsy and Down syndrome • Chronic, relapsing and itchy
Clinical presentation:

• Gradual onset. First, flaky skin and scalp

• The flakes can be yellow, white or grayish
• Yellowish to reddish scaly pimples can occur

Figure 296: Nummular dermatitis.

Diagnosis:

• A clinical diagnosis
• Patch testing is indicated to exclude allergic and
irritant contact dermatitis
Treatment:
Figure 295: Seborrheic dermatitis of the nose and mouth.
Source: • Creams and bath oils to keep the skin moisturized
https://en.wikipedia.org/wiki/Seborrhoeic_dermatitis • Oral antihistamines help with the itch
• Ultraviolet light treatment
Seborrheic dermatitis in infants:
• Vitamin D supplementation in winter when there
• Known as cradle cap is less sun
• Thick, oily yellowish crust around the hairline
and on the scalp Asteatotic dermatitis
Definition:
• The condition resolves within few days without
treatment Also known as xerotic eczema. It is characterized by a very
Diagnosis: dry, red, itchy and cracked skin.
• Clinical diagnosis Clinical presentation:
Treatment:
• More common in winter and in dry conditions
• Topical antifungals in shampoos such as • More common on the lower legs and underarm
ketoconazole and ciclopirox area
Nummular dermatitis • Dry, red, itchy and cracked skin
Definition: • Most are elderly people
Also known as discoid dermatitis is one form of dermatitis • Some patients might have red, pimple-like rash
that has round or oval shaped itchy lesions that look like a
coin.

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 Treatment:

• Topical corticosteroids
• Compression stockings
• Intermittent pneumatic compression pumps

Dyshidrotic eczema
Definition:
Dyshidrotic eczema is a type of dermatitis that presents
with itchy blisters on the palms of the hands and bottoms
Figure 297: Asteatotic eczema. Source: Medscape of the feet.

Treatment: Etiology and pathophysiology:

• It is essential to rehydrate the skin with a • Unknown cause but may be trigged by an allergic
humidifier reaction to house dust might
• Moisturizing soaps can prevent further skin • Food allergies might trigger dyshidrotic eczema
irritation Epidemiology:
• Inflamed cracked skin lesions require topical
steroids • Estimated prevalence is 1 in 2000
• Equal frequency in males and females
Stasis dermatitis Clinical presentation:
Definition:
• Itchiness of the palms or soles followed by the
Stasis dermatitis are skin changes that occur in the leg development of very itchy small blisters on the
because of blood pooling from insufficient venous return. fingers, palms or feet
• The blisters disappear in few weeks
Etiology and pathophysiology: • The eruptions do not occur elsewhere on the body
• Recurrent
• Insufficient venous return → increased
hydrostatic pressure in the capillaries → leakage
of fluid and red blood cells from the capillaries →
breakdown of RBCs → deposition of
hemosiderin → stasis dermatitis
Clinical presentation:

• Thin, brown tissue-like skin with macules and

patches that are erythematous
• Ulcers – known as venous or stasis ulcers Figure 299: Dyshidrotic dermatitis. Source:
• Most often in the legs and ankles which might be https://en.wikipedia.org/wiki/Dyshidrosis
swollen
Diagnosis:
• Itching
• Increased risk of secondary bacterial infection • A clinical diagnosis
and cellulitis Treatment:

• Barrier creams and wearing gloves

• Topical steroids only for short-term use
• Potassium permanganate – must be diluted
• Dapsone
• Alitretinoin

Figure 298: Stasis dermatitis. Source:

https://en.wikipedia.org/wiki/Stasis_dermatitis

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Urticaria • Similar etiologies to urticaria
Definition: • The swelling occurs in deeper layers of the skin
Clinical presentation:
Urticaria or hives are a skin rash that has red, raised, itchy
bumps. They can burn, or sting and the rash seems to move • Can affect the face, extremities, tongue, pharynx,
around. Typically, they last few days. larynx and bowels
• Affecting the larynx can result in hoarseness,
Etiology and pathophysiology:
dyspnea and compromised airway
• Infection or allergic reaction to medication, • Affecting the GI tract can result in obstruction
insects or food → activation of mast cells → • Can be a presentation of anaphylaxis
release of histamine → histamine binds to H2
receptors → increased vascular permeability →
swelling
• Previous exposure to the allergen results in a
faster response because of the presence of IgE
antibodies bound to mast cells
• Physical non-allergic triggers of urticaria include
pressure, temperature, water and sun
• Chronic urticaria is caused by autoimmune IgG
mediated reaction Figure 301: Angioedema of the face and eyes in a child.
Clinical presentation: Source:
https://en.wikipedia.org/wiki/Angioedema#/media/File:An
• Raised wheal lesions surrounded by red halo and
gioedema2010.JPG
flare. Very itchy
• Swelling of the dermis Treatment:
• Dermatographia is a subtype of chronic urticaria
that occurs seconds after physical trauma • Epinephrine, high-flow oxygen and IV fluids
Drug Induced Hypersensitivity Syndrome
• Drug reaction with eosinophilia and systemic
symptoms
• Patients develop rash, fever, inflammation of
internal organs, and lymphadenopathy
• Involvement of the kidneys, heart and liver can
occur
• Does not involve mucous membranes
• Symptoms may persist for weeks after drug
Figure 300: Urticaria. Source: discontinuation
https://en.wikipedia.org/wiki/Hives#/media/File:EMminor • Most commonly caused by allopurinol, sulfa-
2010.JPG containing antibiotics, penicillin, antiepileptics
and NSAIDs
Treatment: • Treated by removing the offending drug, topical
steroids and antihistamines
• Old-generation antihistamines (H1 receptor
blockers) for symptoms at night time • Systemic steroids might be needed in more severe
o Diphenhydramine cases
o Hydroxyzine
• Non-sedating antihistamines for symptoms during
the day:
o Loratadine
o Cetirizine
Angioedema
Definition:
Angioedema is the rapid swelling of the dermis, Figure 302: Facial erythema and swelling in a patient with
subcutaneous, mucosal and submucosal tissues. DIHS secondary to minocycline. The patient also has

528
 lymphadenopathy. Source: Autoimmune Skin Conditions
doi:10.1001/archdermatol.2008.521 Psoriasis
Definition
SJS
Definition Psoriasis is a chronic inflammatory and proliferative
condition of the skin. Characterized by erythematous
Stevens-Johnson syndrome and toxic epidermal necrolysis plaques cover with silvery scales over the extensor
are two diseases on a spectrum. They are life-threatening surfaces, scalp, and lumbosacral region.
skin emergencies which occur as an adverse reaction to
drugs. The epidermis detaches from the dermis. Etiology

SJS involves less than 10% of body surface area. TEN • The exact etiology is unknown
involves more than 30% of body surface area. • An autoimmune disease that is T-cell mediated
• Familial predisposition
Etiology • Can be caused/worsened by chloroquine, lithium,
beta-blockers, and NSAIDs
• Sulfa-containing antibiotics, allopurinol, Pathophysiology
tetracyclines, anticonvulsants and NSAIDs
Clinical presentation • Infiltration of the skin by activated T-cells →
stimulation of proliferation of keratinocytes →
• Symmetric and over the face, trunk and proximal dysregulation in keratinocyte turnover →
extremities formation of thick skin plaques
• Quick spread • Epidermal hyperplasia and parakeratosis
• Red irregular, bloody macules that coalesce and • Failure of epidermal cells to secrete lipids →
form blisters flaky and scaly skin
• Skin detachment Epidemiology
• Involvement of the mucous membranes
• Systemic features such as headaches, myalgias • 2% of the population in the United States are
and fever affected
• High mortality due to multiorgan failure and • The disease has not been reported in aboriginal
sepsis Australians and Indians from South America
• Bimodal age of onset. First peak in those aged 15
to 20 years. Second peak in those aged 55 to 60
years
Clinical presentation:

• Well-defined erythematous plaques covered with

silvery scales
• Involvement of the scalp, extensor surfaces over
the knees and elbows, and lumbosacral region
Type 1 psoriasis:

• Positive family history

Figure 303: Stevens-Johnson syndrome. Source:
https://en.wikipedia.org/wiki/Stevens– • Onset before age 40 years
Johnson_syndrome#/media/File:Stevens-johnson- • HLA-Cw6 association
syndrome.jpg Type 2 psoriasis:

• No family history
Complications:
• Onset after age 40 years and not associated with a
• Corneal damage specific HLA type
• Fluid and electrolyte abnormalities Skin manifestations and lesions in psoriasis:
• Secondary bacterial infection → sepsis
• Plaque
Treatment:
o The classical presentation described
• Withdraw the causative drug above
• Supportive care • Guttate

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 o Eruptive psoriasis seen in children after o Micro-abscesses
an upper respiratory tract infection o Elongation of ridges in the form of
caused by streptococcus. Multiple camel foot appearance
raindrop-shaped lesions over the trunk o Spongiform pustules of Kogoj
and back o Dilated and tortuous capillaries in the
o Excellent prognosis dermal papilla
• Erythrodermic Treatment:
o Wide-spread inflammation, erythema
and exfoliation of the skin > 90% of • Topical emollients, moisturizers and
BSA corticosteroids for mild to moderate disease
o Can result in multiorgan failure • Phototherapy
secondary to electrolytes’ disturbances • Systemic methotrexate, retinoids, cyclosporine, or
and sepsis fumarates for severe psoriasis
• Pustular • Infliximab, adalimumab, and interleukin
o Small noninfectious pus-filled pustules antagonists for severe refractory psoriasis
o Generalized pustular psoriasis is Vitiligo
associated with hypocalcemia and can Definition:
involve the whole body
Vitiligo is an acquired skin disease characterized by well-
• Inverse
defined depigmented macules and patches secondary to
o Flexural psoriasis that affects the groins,
melanocyte dysfunction and loss.
armpits, intergluteal region and under
the breasts Pathology:
• Psoriatic arthritis
o 30% of patients with psoriasis develop • Multifactorial
arthritis • Environmental trigger in a genetically
o Painful inflammation of the joints and predisposed individual
surrounding connective tissues • An autoimmune process that impairs
o Leads to sausage-shaped swelling of the melanocyte’s function and results in melanocyte
fingers and toes known as dactylitis adhesion deficits → loss of melanocytes
• Ocular features: Clinical presentation:
o Trichiasis
o Ectropion Non-segmental vitiligo:
o Conjunctivitis
o Corneal dryness → ulceration • 85% of the cases
o Blepharitis
o Anterior uveitis

Figure 305: Non-segmental vitiligo. Notice that the

affected areas do not follow a dermatomal distribution.
This presentation is often associated with other
autoimmune diseases. Source:
https://www.researchgate.net/publication/44666092_Vitilig
o_Pathogenetic_Hypoth
Figure 304: Skin lesions and types of psoriasis. Source:
http://www.kayakalpglobal.com/type-of-psoriasis.php Segmental vitiligo:
Diagnosis: • 15% of the cases
• The lesions are linear and follow a dermatomal
• Often a clinical diagnosis
distribution
• If a skin biopsy is taken, the following features
are characteristic of psoriasis:
o Parakeratosis
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 • Involvement of mucous membranes
• Flaccid blisters which may coalesce
• Eventually, these blisters rupture and cause
painful erosions
Nikolsky’s signs:

• Direct Nikolsky’s sign is positive when applying

pressure to a blister results in extension into
surrounding normal skin
Figure 306: Segmental vitiligo. Notice the dermatomal • Indirect Nikolsky’s sign is positive when rubbing
distribution (V2). normal skin causes shearing
Patients can also have nail dystrophy, paronychia, or
subungual hematomas.
Note: The diagnosis of vitiligo is a
clinical one.

Treatment:
Medical therapies:

• Topical tacrolimus or mometasone

• Systemic therapy with methotrexate, minocycline
or dexamethasone Figure 307: Skin lesions in pemphigus vulgaris. Source:
• Ultraviolet light therapy https://www.merckmanuals.com/en-
• Monochromatic excimer light laser therapy ca/professional/dermatologic-disorders/bullous-
• Combination therapy diseases/pemphigus-vulgaris
Procedures:
Diagnosis
• CO2 laser therapy with ultraviolet light therapy
• Cellular transplantation of non-cultured • Clinical findings suggestive of the disease
epidermal cell suspension • Light microscopy findings of:
• Transplantation of melanocyte-keratinocyte o A single layer of basal keratinocytes
combination attached to the dermoepidermal
basement membrane (tomb-stone
Pemphigus vulgaris: pattern)
Definition: o Mixed inflammatory infiltrate with
some eosinophils
A potentially fatal autoimmune skin disorder caused by • Direct immunofluorescence:
IgG antibody against desmoglein which is a component of o IgG or C3 binding to the intercellular
desmosomes that connects keratinocytes in the stratum cement substance in the mid-lower or
spinosum. entire epidermis of the perilesional skin
Etiology and pathophysiology: • Indirect immunofluorescence:
o Serum autoantibodies against
• Autoimmune disorder with production of desmosomal antigens
autoantibodies against desmoglein 3 o Netlike intercellular staining of IgG
• Strongly associated with HLA-DR4 and DR6 with human skin as a substrate
• Type 2 hypersensitivity reaction
• Acantholysis → separation of keratinocytes
Clinical presentation:

• Lesions can be localized or generalized

• Predilection for the trunk, groins, axillae, scalp,
face and pressure points

531
 • Deposition of fibrin, IgM and C3 at the dermal-
epidermal junction of blood vessels
• Loss of collagen fibers
• Granuloma formation is secondary to defective
neutrophil migration into the skin. Macrophages
take the place of neutrophils → granulomas
Histopathology:

• Scattered palisaded interstitial granulomatous

Figure 308: Net-like appearance on IgG staining in indirect dermatitis
immunofluorescence microscopy. Source:
• Involvement of the entirety of the dermis and
https://en.wikipedia.org/wiki/Pemphigus#/media/File:Pem
extension into the subcutaneous fat septum
phigus_immunofluorescence.jpg
• Normal epidermis
Bullous pemphigoid • Focal loss of elastic tissue and connective tissue
• This is a less severe disease than pemphigus sclerosis
vulgaris Epidemiology:
• Type 2 hypersensitivity reaction involving IgG • Female predominance
antibodies against hemidesmosomes
• More common in type 1 diabetics
o Hemidesmosomes connect the first
• Not related to glycemic control
epidermal cell line to the basement
membrane • Age of onset between 30 and 40 years
Clinical presentation:
• Tense blisters form that contain eosinophils. They
can occur anywhere except the oral mucosa • Yellow-brown, atrophic telangiectatic plaques
• Nikolsky’s sign is negative • Typically, in the pretibial surface
• Immunofluorescence microscopy reveals a linear • Lesions are first small, firm and red-brown
pattern of staining at the epidermal-dermal papules → progress to develop central epidermal
junction atrophy
• Ulceration occurs in one third of the lesions

Figure 309: Bullous pemphigoid results in tense bullae.

Immunofluorescence microscopy reveals a linear pattern of Figure 310: Necrobiosis lipoidica. Source:
staining. Source: https://en.wikipedia.org/wiki/Pemphigoid https://www.ncbi.nlm.nih.gov/books/NBK459318/
and http://www.pcds.org.uk/clinical-guidance/bullous-
pemphigoid1 Diagnosis:
Necrobiosis lipoidica: • A skin biopsy is indicated to differentiate the
Definition: condition from granuloma annulare and
necrobiotic xanthogranuloma
A rare, chronic, idiopathic granulomatous disease of Treatment:
collagen degeneration in the skin and predisposition to
ulceration seen in patients with type 1 diabetes mellitus. • Currently, untreatable
• Calcineurin inhibitors inhibit T-cell activation →
Etiology and pathophysiology:
useful in patients with ulcerations secondary to
• The exact cause is unknown necrobiosis lipoidica
• Vascular disturbances with immune complex
deposition and microangiopathic changes →
collagen degeneration
532
Sweet’s syndrome: Erythema nodosum:
Definition Definition:
An acute febrile neutrophilic dermatosis. Patients have Acute nodular septal panniculitis characterized by sudden
fever, leukocytosis, acute tender red plaques, and papillary onset of painful erythematous, firm, solid, deep nodules
dermal infiltration by neutrophils. and plaques.
Etiology and pathophysiology Etiology:

• Idiopathic (most common type) • Idiopathic in 50% of the cases

• Para-inflammatory (associated with SLE, • Infections:
inflammatory bowel disease, RA and other o Bacterial infections including
inflammatory conditions) streptococcal pharyngitis (28% of the
• Paraneoplastic (acute myelogenous leukemia and cases), tuberculosis, leprosy, Yersinia
lymphoma) species, mycoplasma pneumonia,
• Pregnancy-associated chlamydia, brucellosis, leptospirosis and
Pathophysiology: psittacosis
o Viral etiologies include EBV, hepatitis
• Dysregulated immune system and B and C, HIV, HSV, and para vaccinia
hypersensitivity to an eliciting bacterial infection o Fungal etiologies include
Histopathology: coccidioidomycosis, histoplasmosis and
blastomycosis
• Diffuse dense neutrophilic infiltrate in the o Parasitic etiologies include amebiasis
reticular dermis and giardiasis
• Leukocytoclastic nuclear deposits Drugs:
• Papillary dermal edema
• Spared epidermis oAntibiotics including penicillins and
Epidemiology: sulfonamides
o Oral contraceptives
• Female to male ratio is 3:1 o Bromides
• Most cases occur in those aged 30 to 50 years o TNF-alpha inhibitor
Clinical presentation: • Inflammatory bowel diseases
• Sarcoidosis – Lofgren’s syndrome is a triad of
• Abrupt onset of multiple tender erythematous erythema nodosum, acute arthritis and hilar
plaques and nodules lymphadenopathy
• The lesions can be vesicular or bullous • Pregnancy
• Targetoid lesions have been reported • Whipple disease
• Mainly on the face, neck, chest and back. • Behcet disease
Extremities may also be affected Pathophysiology:
• Fever and joint disease occur in up to 60% of the
cases • Non-specific cutaneous reaction to antigens
• Type 4 delayed hypersensitivity response
• Deposition of immune complexes in the venules
of subcutaneous fat
Epidemiology:

• Most common in women aged between 25 and 40

years
• Female to male ratio is 6:1
Figure 311: Sweet syndrome in a patient with Clinical presentation:
myelodysplastic syndrome. Source: Prodromal phase:
https://www.ncbi.nlm.nih.gov/books/NBK431050/
• Nonspecific symptoms such as fever, joint pain
Treatment: and abdominal pain
• Three to six days in duration
• Prednisone
• Recent nasopharyngeal infection

533
Stage phase: with kidney disease might be the trigger of
calciphylaxis
• Duration is 1 to 2 days Histopathology:
• Nodules appear on the extensor surfaces of the
legs and knees • A biopsy is needed to confirm the diagnosis
• Spontaneously painful, bilateral, and small in size • Ulceration and necrosis of the dermis and
• The nodules are warm and firm on palpation epidermis
• Ankle edema • Calcification of the small to medium sized blood
Regressive phase: vessels
• Fibrosis of the intimal layer of the blood vessels
• Spontaneous resolution within ten days • Diffuse calcification of small capillaries in
adipose tissues
Clinical presentation:
Note: Erythema nodosum never
involves necrosis, ulceration or • Extremely painful, ischemic cutaneous lesions
scarring. and nodules
• The skin might become violaceous, and the
subcutaneous nodules and plaques can be
erythematous
• The abdomen, thighs and buttocks are the most
commonly affected sites
• Patients seek medical attention because of
extreme pain

Figure 312: Erythema nodosum in a patient with recent

history of streptococcal pharyngitis. Source: Figure 313: Calciphylaxis of the abdomen in a patient with
https://en.wikipedia.org/wiki/Erythema_nodosum#/media/ end-stage kidney disease. Source:
File:ENlegs.JPG https://en.wikipedia.org/wiki/Calciphylaxis
Treatment:

• Extended rest Note: Calciphylaxis is difficult to

• Analgesics treat. A team effort between a
• Venous compressors nephrologist, dermatologist, wound
• Colchicine for symptomatic treatment surgeon, nurse, and pain
• Etiological-based treatment management specialist is often
Calciphylaxis: needed. Therefore, it is important to
Definition: focus on the prevention by rigorous
control of phosphate and calcium in
A rare, devastating disorder that occurs in patients with patients at risk (CKD patients).
end-stage renal disease. It is known as calcific uremic
arteriolopathy and is characterized by painful skin lesions
secondary to cutaneous arteriolar calcification.
Benign and Malignant Tumors of the Skin
Etiology and pathophysiology: Benign growths and tumors
• Calcification of the medial layer of the arterioles Acrochordons
and small arteries → reduced blood flow and • Skin tags
formation of microthrombi → luminal narrowing
• Fleshy growths of the skin with blood supply and
→ occlusion → ischemia, necrosis and ulceration
can be darker in color than surrounding skin
• Elevated calcium x phosphate product secondary
• Common in the armpit, groin, eyes and neck
to elevated parathyroid hormone levels in patients
534
 • Might be a marker of insulin resistance
• More common in obese people with family
history of skin tags
• Do not require treatment, however if the patient
requests, they can be frozen or snipped out

Figure 316: Lipoma. Source:

https://contourderm.com/lipoma/

Sebaceous hyperplasia:
• Skin-colored umbilicated small papules found on
the forehead and face.
• They result from overgrowth of sebaceous glands
Figure 314: A skin tag in the armpit. Source: • They have a yellow tint from their oily sebum
https://medical- composition
dictionary.thefreedictionary.com/acrochordon • They do not require any treatment
Seborrheic keratosis
• Benign superficial growths in the skin
• Can occur anywhere in the body except the soles
and palms
• Often multiple lesions that are keratin-filled cysts
• Onset after thirty years old
• They do not regress
• The lesions are darker than surrounding skin, and
have waxy or oily appearance
• Do not require treatment, however if the patient
Figure 317: Sebaceous hyperplasia. Source: DOI:
requests, they can be frozen or snipped out
10.7241/ourd.20151.29

They should be differentiated from basal cell carcinoma

Epidermal inclusion cyst
• Also known as epidermoid cyst
• They are benign cysts made of a thin layer of
squamous epithelium
Figure 315: Seborrheic keratosis. Source: • Caused by the implantation of the epidermis into
https://www.aad.org/public/diseases/bumps-and- the dermis from trauma
growths/seborrheic-keratoses

Leser-Trelat sign:

• Abrupt onset of seborrheic keratosis

• Indicative of a gastrointestinal malignancy
Lipoma:
• A benign tumor of fat tissue
• Soft, movable, rubbery lumps under the skin
arising from the subcutaneous fat
• Can be multiple, and familiar Figure 318: An inflamed epidermal inclusion cyst. Source:
https://link.springer.com/chapter/10.1007/978-3-319-
• Can become tender and painful
18627-6_28
• They usually do not require any treatment;
however, they can be surgically excised if needed Can produce bad-smelling white discharge which is not
pus

535
 • Incision and drainage if the lesion ruptures or for
cosmetics
• Milium is a clogged eccrine duct that is filled
with keratin and is a form of a tiny epidermal
inclusion cyst
• They occur in children
Pilar cyst
• A benign cyst that forms from a hair follicle on
the scalp Figure 321: A keloid on the earlobe. Source: Medscape
• They need to be excised
Solar Lentigo:
• Brown macules that can be single or multiple
• Occurs in skin-exposed areas secondary to
ultraviolet light induced damage
• Increases the risk of different skin cancers
• Untreatable, but can be prevented by wearing sun
protection

Figure 319: Pilar cyst. Source:

https://www.healthline.com/health/skin-disorders/pilar-cyst

Dermatofibroma
• Firm scar-like growths with peripheral rim of
hyper-pigmentation
• Dimples down when pinched
• Arises from spindle cell proliferation
• Induced by skin trauma
Figure 322: Solar lentigo. Source:
https://www.dermnetnz.org/topics/solar-lentigo/

Nevi:
Congenital nevi:

• A congenital melanocytic nevus or mole

• Found at birth
• Dome-shaped brown or black papule often on the
face
• Can have increased hair density in the nevus or it
Figure 320: Dermatofibroma. Source: can be mamillated
https://www.dermnetnz.org/topics/dermatofibroma/ • Congenital nevi < 20 cm do not increase the risk
of melanoma
Keloid • Any changes in the characteristics of the nevi
• A severe form of a hypertrophic scar where need to be carefully evaluated to exclude
scarring extends the original site of injury melanoma
• Often on the earlobes and upper trunk • Congenital nevi > 20 cm have a 10% risk of
• More common in African Americans developing into a melanoma
• Caused by disorganized collagen organization • They can be shaved or excised for cosmetic
o Hypertrophic scars have parallel reasons
collagen organization
• Treated with intralesional steroid injection
o Should not be resected because they
usually recur

536
Figure 323: A congenital nevus with increased hair density.
Source: https://www.alamy.com/stock-photo/congenital- Figure 324: Basal cell carcinoma on the nose. Source:
nevus.html https://en.wikipedia.org/wiki/Basal-cell_carcinoma

Acquired nevi: Pathogenesis:

• Not present at birth Ultraviolet light damages DNA in the basal layer of the
epidermis → basal cell carcinoma which originates from
• Benign melanocytic growths that are acquired
keratinocytes
after birth
• They usually appear on sun-exposed areas of the • PTCH is a tumor suppressor gene. It gets mutated
skin and onset is before age of 20 years by ultraviolet light exposure
• It is normal for acquired nevi to change their Nodular BCC:
color from brown to pink or skin colored papules
o The diameter must remain constant to • Pearly papule or nodule
be considered as a normal change • Telangiectasias
ABCDEs: • Found on the faced, head and neck
Superficial BCC:
• Any change in the characteristics of acquired or
congenital nevi other than the normal change in • Pink or translucent lesions
color from brown to pink in acquired nevi raises • Telangiectasias
the suspicion of malignancy, i.e. melanoma • Thin plaque
A. Asymmetry of the configuration of the nevus BBC can be also ulcerated, pigmented or have a combined
B. A change in the regularity of the borders of the morphology.
nevus
C. A change in the color of the nevus other than the Treatment:
normal progression described
D. A change in the diameter of the nevus • Curette and desiccation
E. An evolving nevus • Cryotherapy
Skin malignancies: • Excise surgery
Basal cell carcinoma: • Imiquimod/5-flourouracil cream
• Most common kind of skin cancer • Radiation
• Most commonly affect sun-exposed areas of the Mohs micrographic surgery:
skin (head and neck)
• Repeated histologic analysis of tumor margins
• Presents with a pearly pink papule during surgery
• More common in white people with fair skin • The goal is maximal tissue conservation
• Diagnosed by a shave biopsy which is indicated • Lower recurrence rate than other procedures
before excision because the surgeon is confident that the margins
are tumor-free
• Often used on the face

Note: BCC rarely metastasizes but

are locally invasive.

537
Actinic keratosis: Bowen’s disease:
• A pre-malignant lesion that can progress to
squamous cell carcinoma •Squamous cell carcinoma in situ
• Presents with scaly plaques on the face and •A well-circumscribed patch with a rough or scaly
forehead surface
• More common in old people with family history • Confined to the epidermis
of actinic keratosis and fair skin Treatment:
• They can occur on the lip and are known by the
• Similar to basal cell carcinoma
name actinic cheilosis
Dysplastic nevus syndrome:
• Because of their malignant potential, single
• Atypical mole syndrome, or familial atypical
actinic keratosis lesions should be treated with
multiple mole-melanoma syndrome
liquid nitrogen cryotherapy whereas multiple
• Multiple, unusual nevi in different parts of the
lesions can be treated with topical 5-flourouracil
body even in non-exposed areas of the skin
or imiquimod creams
• Increased risk of multiple melanomas or an
inherited pattern of melanoma (familial
aggregation)
• Patients typically have more than 50 nevi
appearing near puberty
• Melanomas may arise from the atypical nevi or
from normal looking skin

Figure 325: Actinic keratosis. Source:

https://en.wikipedia.org/wiki/Actinic_keratosis#/media/Fil
e:Close_view_of_actinic_keratosis.JPG

Squamous cell carcinoma:

• More common to occur on sun-exposed areas of
the skin in people with fair skin
• More aggressive than basal cell carcinoma with a
higher mortality rate Figure 327: Dysplastic nevus syndrome. Source:
• Up to 5% of patients have lymph nodes https://en.wikipedia.org/wiki/Dysplastic_nevus_syndrome
metastasis at time of diagnosis
• Arises from keratinocytes with p53 mutation Melanoma:
which is induced by ultraviolet light • A malignancy of the pigment-containing
• The following morphologies have been described melanocytes in the epidermis, mouth, intestines
with squamous cell carcinoma: or iris
o Scaly red, pink or skin-colored • Usually asymptomatic
nodules/papules or plaques • Patients present with a pigmented papule, plaque
o Exophytic or indurated growths or nodule
o Friable and pruritic • Early recognition is possible when the ABCDEs
• Squamous cell carcinoma is locally invasive, i.e. rule is followed when examining acquired or
it invades the dermis layer atypical nevi
Pathophysiology:

•Prolonged sun exposure → ultraviolet light

induced DNA damage in melanocytes →
melanoma
• P53 and BRCA2 gene mutations can result in
melanoma
• Can develop from a preexisting nevus or from
normal skin
Figure 326: Squamous cell carcinoma. Source: Epidemiology:
https://en.wikipedia.org/wiki/Squamous_cell_skin_cancer

538
 • Increased risk in the elderly • Female to male ratio is 3:1
• More common in immunocompromised patients, • Increased prevalence and severity with age
those with family history of melanoma, use of • Increased risk in people with occupations that
tanning booth, and in individuals with fair skin require high degree of repetition and force or use
• Increased risk in patients with dysplastic nevus of hand-operated vibratory tools
syndrome Risk factors:
• The prognosis is dependent on Breslow depth • Family history
scale. Most superficial tumors have the highest • Diabetes mellitus
cure rate • Obesity
Specific types: • Hypothyroidism
• Pregnancy
• Superficial melanoma spreads horizontally rather
• Rheumatoid arthritis
than vertically. They are the most common type
of melanoma • Occupational
• Lentigo maligna presents with slow horizontal
Pathophysiology
spread
Clinically relevant anatomy:
• Nodular melanoma has rapid vertical growth and
• The carpal tunnel is bordered superiorly by the
is associated with poor prognosis
transverse carpal ligament and inferiorly by the
• Acral lentiginous occur in people with darker skin
carpal bones
and the diagnosis is often delayed
• The median nerve along with nine flexor tendons
• Amelanotic melanoma do not have dark pigment,
pass through the carpal tunnel
i.e. skin-colored, and are often misdiagnosed
• Increased pressure within the carpal tunnel results
Treatment:
in CTS
• Surgical excision and biopsy Etiology:
• Anti-CTLA-4 target therapy with ipilimumab • Unknown exact cause
which increases the endogenous immune Pathology:
response against melanoma • Increased carpal tunnel pressure → compression
• BRAF inhibitors such as vemurafenib of the median nerve
• Lifelong use of sun protectors • The sensory fibers are the first to be affected
• The motor fibers are affected later, i.e. weakness,
is a late feature

Clinical Presentation
• The presenting feature is usually pain and
paresthesia in the distribution of the median
nerve:
o Palmar aspect of the thumb, index and
middle fingers
o Radial half of the ring finger
Figure 328: A superficial melanoma. Source: • Patients often awaken because of the pain and
https://en.wikipedia.org/wiki/Melanoma#/media/File:Mela need to shake out the hand to relieve the
noma.jpg symptoms
• Repetitive wrist flexion, hand elevation, driving,
Carpal Tunnel Syndrome or holding the phone for a long period can trigger
Definition paresthesia and/or pain
Carpal tunnel syndrome (CTS) is the most common
entrapment neuropathy of the upper extremity and is
caused by compression of the median nerve in the carpal
tunnel, i.e. at the wrist

Epidemiology
• Most common entrapment neuropathy of the
upper extremity
• 3% of the general population have CTS

539
 • Symptoms occur within 30 seconds if positive
• Often combined with other specific signs to
increase sensitivity and specificity
Tinel sign:
• Tapping over the volar surface of the patient’s
wrist
• Pain or paresthesia is felt in the distribution of the
median nerve when positive
Figure 329: Median nerve sensory distribution. Source: Thenar atrophy:
https://www.aafp.org/afp/2016/1215/p993.html • A very late finding but with excellent specificity

Physical examination: Diagnosis

The symptoms of CTS are not very specific. The main goal • Electrodiagnostic studies “nerve conduction
of physical examination is to check for the positivity of studies” are the gold standard for the diagnosis of
more specific signs of CTS and to exclude other diagnoses. CTS
Important diagnoses to be excluded by physical • EMG is also helpful in assessing the changes in
examination: the innervated muscles
• Carpometacarpal arthritis of the thumb: • The specificity of nerve conduction tests in
o Painful thumb motion confirming the diagnosis of CTS is 99%
• Cervical radiculopathy at C6 level: • Severe nerve conduction impairment =
o Neck pain incomplete recovery after surgery
o Positive Spurling test
• De Quervain’s tendinopathy: Treatment:
o Tenderness over the distal radial styloid Mild to moderate CTS:
• Raynaud syndrome: • Conservative management with splinting, local
o Relation of symptoms onset to cold corticosteroids injections, physical therapy, and
weather therapeutic ultrasound
o Associated color changes with pain • If no improvement after six weeks, consider
surgery
Specific signs for CTS: • Maximal benefit at three months
Flick sign: • NSAIDs are ineffective
• Excellent sensitivity and specificity Severe CTS:
• The patient describes history of awakening • Surgical decompression
because of the pain and that shaking of the hand • Endoscopic or open techniques are equally
provides relief effective
Positive Phalen maneuver: • Significant improvement within the first-week
• Average specificity and sensitivity post-op
• The patient’s wrist is flexed 90 degrees with • Postoperative splinting should be avoided as it
elbow in full extension can worsen the outcome
o If the patient feels pain or paresthesia in
the median nerve distribution within 60 Brachial Plexus Lesions
seconds, Phalen’s sign is positive Definition
Thumb abduction weakness: Brachial plexus injuries occur when the brachial plexus
• A late sign with above average specificity and trunks, divisions, cords or branches get compressed or
sensitivity pulled during delivery, by trauma or by a congenital
• The patient is instructed to raise the thumb in a abnormality as in thoracic outlet syndrome.
perpendicular position to the palm
• The examiner applies downward pressure on the Anatomy
distal phalanx
• The patient should resist the downward
movement
Median nerve compression test:
• Direct pressure is applied over the transverse
carpal ligament

540
 • Can occur in infants due to lateral traction on
neck during delivery or can be traumatic in adults
• The main affected muscles are the deltoid and
supraspinatus (inability to abduct the arm), the
infraspinatus (medial rotation of the arm) and the
biceps brachii (the arm is extended and pronated
because of loss of flexion and supination)

Figure 330: Anatomy of the brachial plexus. Source:

https://en.wikipedia.org/wiki/Brachial_plexus#/media/File:
Brachial_plexus_color.svg

• The nerve roots of the brachial plexus are from

C5 to T1
• The upper trunks come from C5 and C6 roots
• The middle trunk is C7
• The lower trunk is C8 and T1 Figure 331: Erb palsy. Source:
• Divisions of the brachial plexus result in a more http://gironeslawyers.com/tag/erbs-palsy/
complicated nerve-root distribution in the
terminal nerve branches: Klumpke palsy
o The lateral cord has C5, C6 and C7 • The main mechanism of injury is traction or tear
fibers of the lower trunk of the brachial plexus
o The medial cord has C8 and T1 fibers • Can occur in infants due to upward force on arm
o The posterior cord has C5, C6, C7, C8 during delivery or in adults secondary to grabbing
and T1 fibers a tree branch to break a fall
• The posterior cord gives rise to the axillary and • Remember, the lower trunk gives rise mainly to
radial nerves the ulnar nerve:
• The lateral cord gives rise to the o The main affected muscles are the
musculocutaneous nerve and gives some fibers to intrinsic muscles of the hand
the median nerve (lumbricals, thenar, interossei and
• The medial cord gives rise to the ulnar nerve and hypothenar) → result in a total claw
gives some fibers to the median nerve hand
o The median nerve arises from both the
lateral and medial brachial cords and
has fibers from C5 to T1
o The long thoracic nerve arises from C5
and receives fibers from C6, and C7 on
its way to the serratus anterior muscle
Truncal Injuries
The upper and lower brachial trunks can be injured during
Figure 332: Claw hand in Klumpke palsy. Source:
delivery or by trauma. Remember, the upper trunk comes
https://www.drabhimanulectures.com/2017/08/klumpkes-
from C5 and C6 and gives rise mainly to the lateral cord →
paralysis-klumpkes-palsy-or.html
musculocutaneous nerve and contribute to the median
nerve. The lower trunk gives rise mainly to the ulnar nerve Thoracic outlet syndrome
and contribute to the median nerve.
• Compression of the lower brachial trunk and
• Accordingly, a truncal brachial plexus injury will subclavian vessels by a cervical rib (congenital)
result in a picture similar to proximal or Pancoast tumor (acquired)
musculocutaneous nerve injury and ulnar nerve • Same clinical picture as Klumpke palsy in
injury, but more severe than a single nerve injury addition to vascular symptoms:
Erb palsy: o Ischemia
• Also known as waiter’s tip palsy o Pain
o Edema
• The main mechanism of injury is traction or tear
of the upper brachial trunk

541
 • Patients have a wrist drop

Common Pediatric Fractures

Definition:
Pediatric fractures are studied in depth because bone in
children has distinct features that differentiates it from
adult bone. The periosteum is thicker and stronger than in
adult bones. Accordingly, fractures in children tend to be
incomplete, i.e. do not involve the periosteum.
Figure 333: Thoracic outlet syndrome due to a Pancoast Greenstick Fracture
tumor. Source: Definition:
https://en.wikipedia.org/wiki/Pancoast_tumor#/media/File:
Pancoast_Tumor_1.jpg A partial thickness fracture where the cortex and
periosteum are interrupted on one side of the bone, while
the other side remains uninterrupted.
Individual Nerve Injuries
Injuries to the long thoracic nerve, posterior cord, axillary Mechanism of injury:
or radial nerve occur due to a pathology near the brachial • Most commonly, due to a fall on an outstretched
plexus, hence are covered with brachial plexus injuries. arm
Injuries to the median and ulnar nerve are considered as
• Can be seen in motor vehicle accidents, sports
peripheral nerve injuries not brachial plexus injuries.
injuries and child abuse
Winged scapula • Increased risk in malnourished children with
• Injury to the long thoracic nerve which has roots vitamin D deficiency
from C5 to C7 Epidemiology:
• A common mechanism is axillary node dissection • Most commonly occur in children younger than
after mastectomy 10 years
• The nerve can be injured in stab wounds • Equal incidence in males and females
• The affected muscle is the serratus anterior Pathology:
• Patients are unable to abduct the arm above
horizontal position. Inability to anchor the • Most commonly affect long bones including the
scapula to the thoracic cage fibula, tibia, ulna, radius and humerus
• The bone bends → increased tension on one side
opposite to the site of compression → fracture of
the tension side
o In torus fracture, the cortex buckles on
the compression side and the tension
side remains intact

Figure 334: Winging of the left scapula. Source:

https://commons.wikimedia.org/wiki/File:Scapula_Wingin
g_in_Long_Thoracic_Nerve_Palsy.jpg

Wrist drop
• Can occur secondary to posterior cord injury or
proximal radial nerve injury Figure 335: Pathophysiology in greenstick fracture.
Deltoid paralysis Source:
• Injury to the axillary nerve https://www.sciencedirect.com/science/article/abs/pii/S026
Saturday night palsy 3931913002597
• Radial nerve injury can be due to direct pressure
in the axilla as in Crutch palsy or secondary to Diagnosis:
compression of the radial nerve against the
• Patients present with localized pain and
humerus as in Saturday night palsy
tenderness over the fracture area. Physical
542
 examination cannot differentiate between • Patients present with pain, tenderness and
greenstick and classical fractures ecchymosis. Again, the clinical picture cannot
• A plain radiograph demonstrates bending injury differentiate between classical, greenstick and
of the bone, a fracture line on the other side torus fractures
(tension side), and the fracture line does not • Plain radiography reveals cortical buckling on the
completely go through the bone compression side. Can be difficult to recognize
Treatment:

• Similar to greenstick fractures

Lower Limb Nerve Injuries

Overview
After reviewing the anatomy of the Lumbosacral Plexus,
thigh, gluteal, and leg muscles; we discuss now the
possible lower limb nerve injuries, their mechanisms, and
clinical presentations.

Note: Please refer to the anatomy

lectures of the lumbosacral plexus
and the main muscles of the lower
limbs before studying the lower
Figure 336: A plain radiograph showing a green-stick limb nerve injuries.
fracture. Source:
https://en.wikipedia.org/wiki/Greenstick_fracture
Iliohypogastric nerve
Treatment: Mechanism of injury:
• During abdominal surgery near the inguinal
• Immobilization and casting region
Torus Fracture: Clinical presentation:
• Burning and pain in the surgical incision
Definition: • Radiation to the inguinal and suprapubic regions
Another bending incomplete fracture of pediatric bone
where the cortex buckles on compression side and Obturator nerve
fractures. Mechanism of injury:
• During pelvic surgery
Mechanism of injury: Clinical presentation:
• Decreased thigh sensation in the medial aspect
• Axial force applied to a long bone • Decreased thigh adduction
• The cortex buckles on compression side. The
tension side remains intact Femoral nerve
Mechanism of injury:
• Pelvic fracture
Clinical presentation:
• Decreased thigh flexion and leg extension

Sciatic nerve
Mechanism of injury:
• A herniated disc or a posterior hip dislocation
Figure 337: Axial force applied to immature bone can Clinical presentation:
result in a buckle fracture. Source: • A common presentation that represents tibial and
https://www.sciencedirect.com/science/article/abs/pii/S026 common peroneal nerve injuries
3931913002597
Common peroneal nerve
Diagnosis:
Mechanism of injury:

543
 • Trauma to the lateral aspect of the leg or a fibular The Unhappy Triad
neck fracture • This is a common injury seen in people involved
Clinical presentation: with contact sports
• Inability to evert and dorsiflex the foot → foot • It occurs because of lateral force applied to a
drop planted leg
• Loss of sensation on the dorsum of the foot • The affected ligaments are the anterior cruciate,
medial collateral and medial meniscus
• In some patients, the lateral meniscus can be also
injured
• Patients present with acute knee pain, joint
instability and swelling

Figure 338: Right foot drop in a patient with a common

peroneal nerve injury. Source:
https://en.wikipedia.org/wiki/Foot_drop
Tibial nerve:
Mechanism of injury:
• Knee trauma, Baker cyst, or tarsal tunnel
Figure 340: Mechanism of injury and pathology in the
syndrome
unhappy triad. Source: https://www.epainassist.com/sports-
Clinical presentation:
injuries/knee-injuries/unhappy-triad-or-blown-knee-or-
• Inability to invert and plantarflex the foot → the
terrible-triad
patient is unable to stand on tiptoes
• Loss of sensation on the sole Anterior Cruciate Ligament Injury
• The most commonly injured ligament of the knee
Knee Injuries
• Direct anterior trauma to the knee
Anatomy
• Anterior drawer test is positive:
o The patient lies supine
o The knee is flexed
o Anterior displacement of the knee =
anterior cruciate ligament injury
• Lachman’s test is upward pulling of a 20 degrees
flexed knee, and again it is positive in ACL injury
• The diagnosis is confirmed by MRI
• Arthroscopic repair is required
Figure 339: Anatomy of the knee. Source:
https://healthjade.com/ligaments/

• The fibular and tibial collateral ligaments are also

known as the lateral and medial collateral
ligaments respectively
• These ligaments are important for the stability of
the knee joint
• Specific exams exist to test the integrity of each
of these ligaments Figure 341: Anterior drawer test. Source:
• These are soft tissues, accordingly, they cannot be https://medisavvy.com/anterior-drawer-test/
visualized by plain radiography
• When a ligamentous injury is suspected, the
imaging modality of choice is always magnetic
resonance imaging (MRI)
• Sports’ injuries commonly involve one or more of
these ligaments

544
 Osteoid Osteoma
Definition:
A benign bone lesion that presents with pain and swelling
in the affected area.
Epidemiology:

• Peak incidence in the second decade of life

• Very rare in children
Figure 342: Anterior cruciate ligament on MRI. Source: • Male to female ratio is 2.3:1
https://commons.wikimedia.org/wiki/File:VKB- Most commonly affected sites:
Riss_MRT_T1_PDW_sag.jpg
• Femur and tibia
Posterior cruciate ligament injury: • Can occur anywhere else
Clinical presentation:
• Can be caused by direct trauma to the knee
• Positive posterior drawer test and reverse • Acute onset of pain localized to the lesion
Lachman’s test • Patient awakens at night because of pain
Medial and Lateral Collateral Ligaments Injury • Pain is very responsive to NSAIDs
• Can be injured by trauma to the opposite site of Diagnosis:
the injured ligament
o Lateral trauma to the knee results in Radiographic appearance:
medial collateral ligament injury and • Sclerotic lesion
vice versa
• Eccentrically placed in long bones
• Patients present with knee pain and swelling
• Lucent center
• The best, initial, and most accurate test is MRI
• Treatment: surgical repair
Meniscal Injuries
• Popping sound upon knee flexion and extension
• Especially while walking
• The diagnosis is confirmed by MRI
• Treatment is arthroscopic repair

Figure 344: Plain radiography findings in osteoid osteoma.

Notice the dense cortical sclerosis associated with a central
lucent area which the arrow points to. Source:
https://www.ncbi.nlm.nih.gov/books/NBK12539/
Histopathology:

Figure 343: Medial meniscus tear on MRI. Source: • Reactive bone surrounding a nidus of
https://drrobertlaprademd.com/complex-tear-of-the-medial- fibrovascular tumor
meniscus-medial-knee-injury/ • Cherry red nidus on gross examination
• Anastomosing bony trabeculae rimmed by
Bone and Cartilage Tumors osteoblasts
Osteoma • Highly vascular and has a lot of nerve fibers →
• Benign tumors seen in middle aged people with painful
Gardner syndrome Treatment:
• Most commonly affect the surface of the facial
bones • Surgery in patients not responding to NSAIDs

545
 • Only the nidus needs to be removed or ablated, • Biopsy is not needed
not the whole lesion Treatment:
Osteochondroma
Definition: • No treatment needed
• Can be removed for cosmetic reasons or if the
A benign cartilaginous lesion that is often referred to tumor starts to grow in size after the age of 30
exostosis. These are developmental defects caused by years
abnormal cartilaginous nests left behind in the growing Non-ossifying Fibroma:
epiphyseal plate. It can be hereditary. Definition:
Epidemiology: Common lesion seen in children (20% of children have at
least one lesion).
• Most common benign tumor of the bone
• Usually discovered in growing adolescents Characteristics:
• Equal frequency in males and females
Most commonly affected sites: • Most commonly, the lesion heals spontaneously
in the second decade of life
• Metaphysis of long bones adjacent to the • Very rarely, the bone can be weakened →
epiphyseal cartilage plate pathologic fracture
• Because the bone is growing, the tumor appears Clinical presentation:
to be moving away from the epiphyseal plate to
be eventually found in the middle of the • Painless fibromas in the metaphysis of long bones
metaphysis • The lesions are eccentric within the medullary
• Most of the tumors occur around the knee in the canal
femur > than the tibia • Thinned cortex
Clinical presentation: Diagnosis:

• Usually an incidental finding as it rarely produces • The lesions are benign

pain • If a biopsy is taken, it can show:
• Patients can complain of a smooth bump near the o Irregular thin rim of reactive bone
distal ends of the affected bones giving the lesion its characteristic soap
• Transformation into malignant chondrosarcoma is bubbles appearance on histopathology
extremely rare and is often associated with o The lesions are rich in spindle cells,
multiple exostosis (hereditary disease) multinucleated giant cells, and foamy
Hereditary multiple osseocartilaginous exostoses: histiocytes
Treatment:
• Male to female ratio is 3:1
• Autosomal dominant trait • No treatment is needed
• Multiple osteochondromas • Negligible risk of malignant transformation
• Increased risk of malignant transformation into Giant Cell Tumor
chondrosarcoma Definition:
Diagnosis: Also known as osteoclastoma, this is a benign but
aggressive tumor of the bone.
• Always share the cortex with the bone
Epidemiology:

• Represent 5% of all primary bone tumors

• Peak incidence in the third decade of life
• Extremely rare in prepubescent adolescents
• More common in females
Most commonly affected sites:

• Epiphyseo-metaphyseal tumors
• Most commonly at the distal femur and proximal
tibia
Figure 345: Radiography in osteochondroma

546
 • Always extend to the subchondral bone of an Metastasis workup:
articular surface
• Can cause significant morbidity if it occurs in the • Chest CT scan to exclude distant metastasis
spine or pelvis • MRI of the affected region to assess the extent of
Clinical presentation: local disease
Treatment:
• Pain and limitation of motion of the proximal
joint • Surgical excision and curettage
• Pathologic fractures • Excellent prognosis if the tumor does not recur
• Can grow very rapidly during pregnancy locally
• Can metastasize • Recurrences are treated aggressively → can result
Diagnosis: in amputation

Radiographic appearance: Chondroma and Enchondroma:

Definition:
• A well-demarcated lesion in the epiphysis of the
distal femur or proximal tibia Benign cartilaginous growths within the medullary cavity
• Can produce swelling due to the expansion of the of the bone.
bony cortex
• The tumors have equal frequency in both sexes
• Become clinically apparent during adolescence
• Produce no symptoms in most patients and are an
incidental finding
Most commonly affected sites:

• The short tubular bones of the distal extremities

• The most common bone tumor of the hand
• Arise from the epiphysis
Clinical presentation and diagnosis:

• The goal is to differentiate from low-grade

chondrosarcoma
LOW-GRADE
Figure 346: Giant cell tumor of the bone. Source: ENCHONDROMA CHONDROSARCOMA
https://orthoinfo.aaos.org/en/diseases--conditions/giant- CLINICAL - Painless - Painful
cell-tumor-of-bone/ PRESENTATION
RADIOGRAPHY - Does not - Penetrates bony
penetrate cortex
Histopathology: cortex - Has periosteal
- No periosteal reaction
• Benign spindle cell stroma with numerous reaction
- Radiolucent
reactive multinucleated giant cells and HISTOLOGY - Inactive - Active cartilage
mononuclear cells cartilage cells
• Mononuclear cells express RANKL Treatment:

• Regular follow-ups because of a small, but finite

risk of malignant transformation
• If surgically removed, excellent prognosis
Osteoblastomas
Definition:
Also known as osteogenic fibroma and is a rare bone-
producing lesion that affect long bones or vertebrae.
Epidemiology:

Figure 347: Histology examination in giant cell tumor. • Rare bone-producing

Source: https://orthoinfo.aaos.org/en/diseases-- • More common in males
conditions/giant-cell-tumor-of-bone/ • Usually in the second and third decade of life

547
Most commonly affected sites: • Most commonly affect the metaphysis of long
bones
• Vertebrae and long bones • Half of osteosarcomas originate around the knee
• The tumors are always more than 2 cm in size (distal femur more common than proximal tibia)
Clinical presentation: • The third most common location is the proximal
humerus
• Similar to osteoid osteoma but pain is
unresponsive to NSAIDs • 10% of the cases have involvement of the pelvis
Diagnosis: (especially children)
• 20% of patients have detectable metastatic
• Expansile lesion disease at time of diagnosis
• Eccentrically placed in the bone • 100% of patients have microscopic subclinical
• Often of the vertebra metastasis at time of diagnosis
• Does not break the cortex • Pathologic fractures
• CT is required Diagnosis:
• Identical histopathology picture to osteoid Radiographic appearance:
osteoma
• Lyric or sclerotic lesion
• Permeative destruction with poorly defined
borders
• Classically, a sunburst pattern secondary to radial
ossification of soft tissue
• Codman triangle from elevation of periosteum
• MRI or CT are important to evaluate the extent of
the tumor locally

Figure 348: CT scan in osteoblastoma

Treatment:

• Surgical excision and curettage are curative

Osteosarcoma
Definition:
Osteosarcoma is a malignant primary tumor of the bone
composed of spindle cells that produce osteoid. It is a Figure 349: Osteosarcoma of the tibia. Source:
highly aggressive disease of primarily adolescents and https://commons.wikimedia.org/wiki/File:Osteosarcoma_o
young adults. f_the_tibia.png

Epidemiology: Histopathology:
• Most common primary bone cancer (20% of all • Pleomorphic osteoid-producing cells (malignant
bone malignancies) osteoblasts)
• Peak incidence in people younger than 20 years
• More common in males
• Associated with Paget disease, bone infarcts,
radiation, and genetic predisposition in the elderly
o Familial retinoblastoma and Li-
Fraumeni syndrome can present with
osteosarcoma in older adults
Clinical presentation

• Localized pain Figure 350: Pleomorphic malignant cells in a delicate

• Soft tissue mass interlacing network of osteoid. Source:

548
https://www.ncbi.nlm.nih.gov/books/NBK13901/figure/A3 • Neuroectodermal origin
9553/?report=objectonly • Cytogenetic testing is required to confirm the
diagnosis:
Treatment: o t(11;22)
o Fusion protein EWS-LFII is expressed
• Aggressive surgery and chemotherapy by the tumor cells
• Primary tumors are usually responsive
• Secondary tumors have poor prognosis
Ewing’s Sarcoma:
Definition
Ewing’s sarcoma is a radiosensitive primary bone tumor
that was first described by James Ewing in 1921. It is
caused by a reciprocal translocation between chromosomes
11 and 22 “t(11;22)(q24;q12).
Epidemiology

• Incidence in people younger than 20 years is 2.9

per million Figure 351: Ewing sarcoma histopathologic findings.
• Slightly more common in males Source:
• Nine times more common in whites than in https://en.wikipedia.org/wiki/Ewing%27s_sarcoma#/media
blacks /File:Ewing_sarcoma_-_PAS_-_very_high_mag.jpg
Most commonly affected sites: diaphysis
Treatment:
• Pelvis (25%)
• Chemotherapy and surgery
• Femur (16%)
• Usually responsive
• Ribs (12%)
Chondrosarcoma:
• Spine (8%)
Definition:
Clinical presentation
A malignant primary tumor of bone that has malignant
• Localized pain and a palpable mass cartilaginous proliferation. Second in frequency to
• Pathologic fracture osteosarcoma.
• Systemic symptoms such as fever and weight loss
→ indicative of metastasis Epidemiology:
• Neurologic exam is important because a vertebral
tumor can result in focal neurological deficits • De novo tumors or secondary tumors after
• 25% of patients present with metastatic disease malignant degeneration of an osteochondroma or
• Most commonly involved site in metastasis is an enchondroma
lungs • Usually occurs in patients > 40 years of age
• Bone marrow infiltration can occur: • Can occur in younger patients → more aggressive
o Anemia and earlier metastasis
o Neutropenia • Equal frequency in both sexes
o Thrombocytopenia Most commonly affected sites:
• Elevated LDH level in some patients
• Most commonly in the pelvis and femur
Diagnosis
• Can also occur in flat bones such as the scapula,
Radiographic appearance: ribs, and skull
Clinical presentation:
• Lamellar (onion skin) lesion
• Codman triangle similar to osteosarcoma • Constant mild to moderate pain localized to the
• MRI to identify local extension of the tumor area
• Chest CT and radioisotope bone scans for • Most often, a normal physical examination | a
metastatic workup palpable mass in a few
Histopathology: Diagnosis:

• Small round blue cells that look like lymphocytes Radiographic appearance:

549
 • Ill-defined borders lesion Laboratory findings:
• Permeation of the bone
• A soft tissue extraosseous mass • Elevated calcium
• Chronic periosteal reaction • Decreased phosphate
• Extensive calcification • Elevated ALP
Histopathology: • Elevated PTH

• Malignant chondrocytes Paget’s Disease of Bone

• Binucleated or multinucleated cells Definition:
Treatment:
Abnormally excessive bone resorption and formation.
• The lesion is very destructive
Characteristics:
• Wide surgical resection is required
• Adjuvant radiation and chemotherapy are not •Increased repetition and acceleration of cyclic
useful osteon breakdown and rebuilding (remodeling of
bone)
Metabolic Bone Disorders • Disorganized bone with jigsaw puzzle or mosaic
Osteitis Fibrosa Cystica appearance
Definition: • Increased prevalence in older adults
Also known as brown tumors they are caused by • The bone becomes more vascular, less dense,
hyperparathyroidism. As the name implies, there is bone weaker and more prone to pathologic fractures
fibrous tissue deposition and cystic formation in • Typically affects the axial skeleton and proximal
subperiosteal location. parts of long bones
• Usually asymptomatic, but some patients might
Characteristics: present with bone pain, pathologic fractures, or
arthritis
• Excessive bone resorption secondary to increased • Because the bone gets larger, it can compress on
osteoclastic cell activity neurologic structures such as vertebral nerve
• Elevated PTH stimulates bone resorption roots
• Bone strength is decreased Radiographic appearance:
• Cyst formation can be seen on radiographic
imaging • Cotton wool spots
• Histopathology reveals fibrous tissue, • Sclerosis and whiter areas scattered in the bone
hemosiderin deposition and hemorrhage • Increased nuclear isotope uptake in affected
• Treatment of hyperparathyroidism prevents and bones
halts the progression of the disease

Figure 353: Paget's disease of a vertebra. Source:

https://en.wikipedia.org/wiki/Paget%27s_disease_of_bone
Figure 352: Radiographic appearance of brown tumors in
the long bones of a patient with hyperparathyroidism. #/media/File:PagetDiseaseIvoryVertL2.png
Source:
Laboratory findings:
https://en.wikipedia.org/wiki/Osteitis_fibrosa_cystica#/me
dia/File:Osteitis_fibrosa_cystica_tibiae_X-ray.jpg • Unaffected calcium, phosphate, and PTH level
• ALP can be normal or elevated

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Treatment: • Increased risk of pathologic fractures due to bone
fragility
• Bisphosphonates • Bone density is more than 2.5 standard deviations
Osteomalacia and Rickets below normal
Definition: • Osteopenia is a milder form of osteoporosis
where the bone density is 1 to 2.5 standard
Inadequate mineralization of bone results in defective bone deviations below normal
matrix. Rickets in children, osteomalacia in adults. • Bone density is measured by dual-energy X-ray
Characteristics: absorptiometry (DEXA) scan

• Inadequate mineralization occurs secondary to

insufficient calcium or phosphorus
• Most commonly secondary to vitamin D
deficiency
• Chronic kidney disease → impaired activation of
vitamin D → osteomalacia
• The bones are softer than normal → bone pain,
pathologic fractures
• In children, bone deformities such as bowing can Figure 355: Osteoporosis pathology. Source:
occur. Dental issues can be seen in children with https://en.wikipedia.org/wiki/Osteoporosis#/media/File:Ost
Rickets eoporosis_Locations.png
• Vitamin D supplementation and calcium are the
T-score and Z-score in DEXA scan:
main treatments
• T-score is the multiple of standard deviations
difference between your patient and an average
obtained from 30 years old matched controls of
same gender and ethnicity
• Z-score is the multiple of standard deviations
difference between your patient and an average
obtained from ethnicity/gender/age-matched
people
Primary osteoporosis:

• More common in white, older women with family

Figure 354: Bowing of long bones in a child with rickets. history of osteoporosis
Source: https://en.wikipedia.org/wiki/Rickets
• Can be caused by smoking, alcohol consumption,
hyperestrogenemia, hypocalcemia, sedentary
Laboratory findings:
lifestyle and a low BMI as in anorexia nervosa
• Decreased calcium and phosphate • Increased risk of fractures
• Elevated ALP Secondary osteoporosis:
• Elevated PTH • Caused by other diseases or medications
• Increased bone resorption in chronic
Osteoporosis corticosteroid use
Definition: • Decreased bone formation in patients with
hyperthyroidism or decreased growth hormone
Reduced bone matrix and in some cases mineralization.
level
Characteristics: • Cushing’s, hyperparathyroidism,
hyperthyroidism, hyperprolactinemia,
• Can be hereditary or acquired hypogonadism, gastric bypass surgery, Ehlers-
• Acquired causes include diet, advanced age, Danlos, osteogenesis imperfecta, myeloma, and
sedentary lifestyle and comorbidities lymphoma or leukemia can cause secondary
• Most common metabolic bone disorder osteoporosis
Diagnosis:

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 • DEXA scan is preferred over plain radiography Epidemiology
• Plain radiography can detect bony lesions only • Most common inflammatory arthritis
when > 30% of bony mass is lost • Lifetime prevalence is 1%
Treatment: • Peak incidence in patients aged 30 to 50 years
• Disability is common and often significant
• Calcium • Up to 35% of patients with rheumatoid arthritis
• Vitamin D supplements have a work disability 10 years after diagnosis
• Estrogen replacement therapy Risk factors:
• Calcitonin
• Selective estrogen receptor modulators such as • Older age
tamoxifen and raloxifene • Family history
• Bisphosphonates • Female gender
• Denosumab (RANK Ab inhibitor) • Current or prior cigarette smoking
• Teriparatide which is an anabolic hormone that is • Less common in multiparous women
a PTH analog • Breastfeeding decreases the risk
Osteogenesis Imperfecta • Early menarche and very irregular menstrual
Definition: periods increase the risk

Also known as brittle bone disease and Lobstein syndrome, Etiology and Pathophysiology
it is a genetic disorder caused by mutations in bone Etiology:
collagen genes that result in impaired bone formation with
defective bone matrices. • Multifactorial
• Genetic susceptibility is important → familial
Characteristics: clustering
• Associated with HLA-DR4 and DRB1
• More than 8 variants of mutations in bone
• Polymorphisms in STAT4 and CD40 loci
collagen gene were identified
Pathophysiology:
• Patients present with unexpected pathologic
fractures, family history of osteogenesis • Inflammation of the synovium → increased
imperfecta and blue sclera proliferation of synovial cells in joints → pannus
• The diagnosis is confirmed by DNA testing or formation and underlying cartilage destruction →
collagen analysis bony erosions
• Overproduction of pro-inflammatory cytokines
such as TNF, IL-6 and others contribute to the
destructive nature of the disease and the systemic
features

Figure 356: Blue sclera in a patient with osteogenesis

imperfecta. Source:
https://en.wikipedia.org/wiki/Osteogenesis_imperfecta

Treatment:

• No curative treatment
• Bisphosphonates and surgery for symptomatic
control

Rheumatoid Arthritis
Definition
Rheumatoid arthritis is an autoimmune systemic
inflammatory arthritis that affects the synovium of joints.

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 • Accelerated atherosclerosis → most common
cause of death in patients with rheumatoid
arthritis
• Pericarditis which can rarely lead to cardiac
tamponade
Eye:

•Keratoconjunctivitis sicca → secondary Sjogren

syndrome
• Peripheral ulcerative keratitis
• Episcleritis and scleritis which present as an
acutely painful red eye
Hematologic:

•Amyloidosis
•Felty syndrome:
o Neutropenia
o Thrombocytopenia
o Splenomegaly
Figure 357: Pathology in rheumatoid arthritis. Source: Pulmonary:
https://en.wikipedia.org/wiki/File:Rheumatoid_arthritis_joi
nt.gif • Caplan syndrome:
o Lung nodules and pneumoconiosis
Clinical Presentation • Interstitial lung disease:
• Most patients are old females o Resembles bronchiolitis obliterans
• Symmetric involvement of the joints of the upper o Idiopathic pulmonary fibrosis
and lower extremities o Pulmonary arterial hypertension
• Morning stiffness • Pleural effusion → typically exudative
o Lasting for more than one hour • Asymptomatic pulmonary nodules
o Improving with use Skin:
• Tender joints
•Rheumatoid nodules:
• Swollen joints o Typically, on pressure areas such as
• Systemic symptoms: olecranon
o Fever o Firm or rubbery
o Fatigue o Subcutaneous
o Weight loss o Fibrinoid necrosis with palisading
histiocytes on histology
• Vasculitis is rare but can increase mortality:
o More commonly seen in patients with
severe erosive, deforming and
seropositive rheumatoid arthritis
Complications of rheumatoid arthritis:

• Depression
• Infection
• Increased risk of lymphoma, lung cancer and skin
Figure 358: Swollen PIP and MCP joints in the right hand cancer especially in patients receiving
in a patient with rheumatoid arthritis. Source: immunosuppressant drugs
https://www.aafp.org/afp/2011/1201/p1245.pdf Specific joint deformities:

Extraarticular manifestations of rheumatoid arthritis: • They are becoming less common after the
widespread use of disease-modifying agents
Cardiac: • Cervical subluxation at C1-C2 level
• Ulnar finger deviation
• Swan neck deformity

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 • Boutonniere deformity • Juxta-articular osteopenia
• The disease tends to involve the • Soft tissue swelling
metacarpophalangeal (MCP), proximal • Subchondral cysts
interphalangeal (PIP) and wrist joints of the hand • Joint space narrowing
but not the distal interphalangeal (DIP) or the first Synovial fluid assessment:
carpometacarpal (CMC) joints
• Yellow, cloudy synovial fluid
• WBCs > 5000/mm3
Treatment
Goals:

• Minimizing joint pain and swelling

• Prevention of deformity such as ulnar deviation
• Prevention of progressive radiographic damage
such as erosions
• Maintaining quality of life
Figure 359: Swan neck deformity. Source: • Controlling extra-articular manifestations
https://en.wikipedia.org/wiki/Swan_neck_deformity#/medi Exercise and physical therapy:
a/File:Swan_neck_deformity_in_a_65_year_old_Rheumat
oid_Arthritis_patient-_2014-05-27_01-49.jpg • Decrease pain
• Improve muscle strength
Diagnostic Criteria • Improve quality of life
A scoring system has been recommended by the American NSAIDs and corticosteroids
College of Rheumatology and the European League
Against Rheumatism for the classification of rheumatoid • Pain control
arthritis. The diagnosis is confirmed when the patient has 6 • As a short-term anti-inflammatory treatment
points or more. • DMARDs are preferred
NOTES SCORE
Disease-modifying antirheumatic drugs (DMARDS)
CRITERION A
- 1 LARGE JOINT 0 Methotrexate:
- 2 TO 10 LARGE JOINTS 1
- 1 TO 3 SMALL JOINTS
- With or without large joints 2 • Inhibits dihydrofolate reductase
4 TO 10 SMALL JOINTS
- With or without large joints 3
-
- > 10 JOINTS - With at least one small joint 5 • Can cause liver toxicity, teratogenicity, hair loss,
CRITERION B At least one test needs to bone marrow suppression, and oral ulcers
- NEGATIVE RF AND ACPA (+) 0 Leflunomide:
- LOW POSITIVE RF OR ACPA 2
- HIGH POSITIVE RF OR 3
ACPA • Inhibits pyrimidine synthesis
CRITERION C At least one acute phase • Can cause liver toxicity, gastrointestinal
- NORMAL CRP AND ESR reactant needs to be 0 disturbances, and teratogenicity
- ABNORMAL CRP OR ESR abnormal 1
CRITERION D Hydroxychloroquine:
- DURATION < 6 WEEKS 0
- DURATION > 6 WEEKS 1 • Rarely, can cause ocular toxicity
Others:
Important laboratory tests in rheumatoid arthritis: • Sulfasalazine
• Minocycline
• CRP and ESR are acute phase reactants. They are
elevated when the patient has active disease • Gold sodium thiomalate
• ACPA is anti-citrullinated protein antibody → • Penicillamine
more specific for rheumatoid arthritis • Cyclophosphamide
• RF is rheumatoid factor (an IgM antibody that • Cyclosporine
targets IgG Fc region). It is found in 80% of the Biologic DMARDS:
patients, but is not specific for rheumatoid • Anti-TNF-alpha agents:
arthritis o Adalimumab (Humira)
Radiographic findings: o Certolizumab pegol
• Erosions o Etanercept

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 o Golimumab • Purine-rich foods such as nuts, asparagus,
o Infliximab legumes, mushrooms and oatmeal do not increase
• Others: the risk
o Abatacept Etiology and Pathophysiology:
o Anakinra • Precipitation of monosodium urate crystals in a
o Rituximab joint space → triggering of an immune response
o Tocilizumab → release of pro-inflammatory cytokines and
• These drugs are more expensive than the neutrophil recruitment
conventional DMARDs • Prolonged gout → irreversibly damaged joint,
• They are more likely to cause opportunistic chronic pain and disability secondary to a grossly
infections and tuberculosis deformed joint
Duration of treatment: • Tophi which are subcutaneous nodules comprised
of monosodium urate crystals in a matrix of lipid,
• Remission is achieved in up to 50% of patients on protein and mucopolysaccharides can be seen
DMARDs • Most commonly involve the first
• Remission is more likely in males, nonsmokers, metatarsophalangeal joint
younger than 40 years and those with late-onset • Can involve the ankles, knees, fingers, wrists and
disease elbows
• Medication dosages can be slowly decreased to
the minimum amount necessary once the disease
is controlled Note: Hyperuricemia is defined as a
serum uric acid level of 6.8 mg/dL |
Gout 405 µmol/L) or more
Definition
Gout is a painful joint inflammatory disease that most
commonly affect the first metatarsophalangeal joint and is
caused by the precipitation of monosodium urate crystals Pathophysiology
in the joint space.
• IgG binds to uric acid crystals → C3a and C5a
Epidemiology activation → recruitment of neutrophils to the
• Most common inflammatory arthropathy affected joint → neutrophils engulf the antibody-
• Affecting more than 8 million Americans uric acid complexes → neutrophilic lysis and
• Accounts for more than 7 million visits to release of proteolytic enzymes
medical care providers per year in the United • The main proinflammatory cytokines released
States locally in goat are IL-8, IL-6, IL-1 and TNF
• Increased prevalence in older people Clinical Presentation
Lesch-Nyhan syndrome:
• 12% prevalence in those aged 80 years and older
Risk factors: • X-linked recessive disease
• Genetic predisposition: • Age at presentation is 9 to 12 months
o Mutations that result in overproduction • Self-mutilation
or underexcretion of uric acid • Involuntary movements
o Overproduction is seen in patients with • Hyperuricemia:
Lesch-Nyhan syndrome and in tumor o Increased risk of gout and uric acid
lysis syndrome kidney stones
o Underexcretion is most often idiopathic • Hypoxanthine guanine phosphoribosyltransferase
but can be potentiated by renal failure 1 enzyme deficiency
and exacerbated by thiazide diuretics Presentations:
• Premenopausal women have a lower risk because
Asymptomatic hyperuricemia:
estrogen increases urinary excretion of uric acid
• Higher risk in African Americans • Hyperuricemia that meets the above-mentioned
• Consumption of alcoholic drinks, red meat, note but without symptoms of arthritis
seafood, shellfish, fruit juice, and beverages Acute gouty arthritis:
sweetened with high-fructose corn syrup increase
the risk of gout

555
 • Typically occurs in males aged between 40 and 4. Maximal
60 years inflammation/symptomatology
• Acute onset of monoarticular arthritis, typically within one day
of the first metatarsophalangeal joint 5. Hyperuricemia
• The swelling, erythema and warmth of the 6. Joint redness
affected joint can resemble cellulitis 7. Recurrent attacks that has the one
• Can be precipitated by hypothermia, dehydration, or more of the above characteristics
stress, or excessive alcohol intake 8. Pain or redness in the first
• Typically lasts for one week if untreated metatarsophalangeal joint
• Post-healing phase that is characterized by skin 9. Subcortical bony cyst that is not
desquamation erosive
10. Suspected tophus
Microscopy of joint fluid:

• Less often needed nowadays

• A joint or a tophus is aspirated
• Needle-shaped monosodium urate crystals,
usually intracellular, are seen
• Negative birefringence on compensated polarized
light microscopy
Treatment
• Avoid precipitants (alcohol, purine-rich diet, red
meats)
Figure 360: A tophus on distal digit. Source: • Weight loss
https://www.aafp.org/afp/2014/1215/p831.pdf Treatment of acute gouty attack:
Inter-critical gout: • NSAIDs – indomethacin
• Colchicine
• Recurrent episodes of acute gouty arthritis that
• Corticosteroids when NSAIDs and colchicine are
are few years apart
contraindicated
• The patient is asymptomatic between attacks o Gradually taper to avoid rebound flares
Chronic tophaceous gout: Prevention of future attacks in chronic gout
• Development of subcutaneous uric acid tophi (hyperuricemia):
• Extensive cartilage and joint destruction • Colchicine: typically for 3 to 6 months
• Inflammatory giant cells and urate crystals on o Can cause reversible axonal neuropathy
biopsy o Increases the risk of rhabdomyolysis
Diagnosis when used with statins or
Diagnostic criteria: clarithromycin
Like other rheumatologic diseases, the American College • Xanthine oxidase inhibitors such as allopurinol
of Rheumatology has put diagnostic criteria for gout. and febuxostat
o Patients of Han Chinese or Thai descent
The patient needs to have either criterion A, B, or C to should use febuxostat instead of
confirm the diagnosis: allopurinol because of increased risk of
severe hypersensitivity skin reaction
A. Urate crystals confirmed on joint fluid assessment • Probenecid in patients with hyperuricemia
B. Presence of a tophus that is proven to contain secondary to underexcretion
urate crystals by chemical testing or polarized o Contraindicated in patients with kidney
light microscopy disease or kidney stones
C. Presence of six or more of the following: • Pegloticase in refractory gout
1. Asymmetric swelling within a joint
confirmed by radiography Pseudogout
2. An attack of monoarticular arthritis Definition
3. Culture-negative joint fluid during Pseudogout is an inflammatory arthritis that is most
attack commonly caused by the deposition of calcium
pyrophosphate (CPP) crystals hence the name calcium
556
pyrophosphate dihydrate crystal deposition disease
(CPPD).

Clinical Presentation
• It occurs in older patients
• Associated with: Figure 361: A. Parallelepipedal crystals by light
o Hemochromatosis microscopy. B. CPP crystal as seen by phase contrast
o Hypothyroidism microscopy. C. Positive birefringence by polarized light
o Hyperparathyroidism → hypercalcemia microscopy. Source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045115/p
Presentations: df/oarrr-6-039.pdf
Asymptomatic CPPD: Radiography:
• Chondrocalcinosis on imaging • Chondrocalcinosis on plain radiography
• An incidental finding • CPP crystals can be seen in the joint fluid by
• No other symptoms ultrasonography
Acute CPP crystal arthritis:
• Patients are typically > 65 years
• Acute monoarticular or oligoarticular arthritis
• Large joints such as the knees, wrists and ankles
are commonly affected
• Joint pain, warmth and swelling are typical
findings
• Erythema is less common when compared to Figure 362: Chondrocalcinosis of different joints in a
gouty arthritis patient with CPPD
• Self-limiting arthritis that is triggered by medical Treatment
or surgical conditions Asymptomatic CPPD:
Chronic inflammatory CPP crystal arthritis: • No treatment
• Chronic, bilateral symmetrical deforming Acute CPP crystal arthritis:
inflammatory polyarthritis • Ice or cool packs
• Most commonly affects the wrists and • Rest
metacarpophalangeal joints • Joint drainage
• Tendon sheaths can be affected • Intra-articular glucocorticoid injection
• Can result in carpal tunnel syndrome or cubital • NSAIDs
tunnel syndrome • Oral colchicine in acute and preventive treatment
• Radiographic features: Chronic CPP crystal arthritis:
o Chondrocalcinosis • NSAIDs
o Subchondral sclerosis Methotrexate
o Epiphyseal geodes
o Osteophytes Sjögren Syndrome
o No marginal erosions Definition
Sjogren syndrome (SS) is a chronic systemic disorder of
Diagnosis autoimmune nature. It is characterized by lymphocytic
Synovial fluid analysis: infiltration of the exocrine glands.
• Identification of CPP crystals by compensated
polarized light microscopy Epidemiology
• Parallelepipedal form • Female to male ratio is 9:1
• Predominantly intracellular • Estimated prevalence is 0.1 to 4.8%
• Absent or weak positive birefringence • Secondary SS is seen in patients with established
connective-tissue disease such as SLE
• Up to 10% of patients develop lymphoma

557
Etiology and Pathophysiology
• The exact cause is unknown
o Exposure to unknown environmental
factors in a patient who is genetically
susceptible → an autoimmune response
• Lymphocytic infiltration of exocrine glands
(mainly salivary and lacrimal glands) is noted
• Increased B-cell activity →
hypergammaglobulinemia and presence of serum Figure 363: Schirmer test and slit-lamp exam in Sjogren's
autoantibodies syndrome. Source:
https://jamanetwork.com/journals/jama/fullarticle/186301
Clinical Presentation: Diagnosis:
Glandular manifestations: American/European Classification Criteria of SS:
Oral dryness: At least one ocular symptom:
• Destruction of glandular epithelium • Dry eyes > 3 months
• Parotid gland enlargement • Sandy sensation
• Difficulty swallowing and a sore mouth • Use of tear substitute > 3 times per day
At least one oral symptom:
• Increased risk of oral infections and dental carries
• Dry mouth > 3 months
• Fissured tongue, atrophy of filiform papillae and
angular cheilitis • Recurrent salivary gland swelling
• The parotid glands are firm to palpation • Need to drink water or liquid to aid swallowing
Ocular: At least one objective evidence of dry eyes:
• Sandy feeling or itchiness • Positive Schirmer test
• Reduced tear secretion and development of • Keratoconjunctivitis sicca
keratoconjunctivitis sicca At least one objective evidence of salivary-gland
Other: involvement:
• Skin dryness • Salivary gland scintigraphy
• Upper respiratory tract dryness • Parotid sialography
• Dyspareunia • Decreased unstimulated salivary flow
Systemic features Histologic features:
Nonspecific: • Lymphocytic infiltrate of a minor salivary gland
• Reversible hand deformities (nonerosive Autoantibodies:
arthropathy) • Anti-SSA (Ro) “more specific” or anti-SSB (La)
• Raynaud phenomenon antibodies
Confirmation of diagnosis:
• Fatigue
• Presence of at least six of the above criteria with
• Dry cough and dyspnea
a positive biopsy or positive SSB or SSA
• Hepatomegaly Treatment:
• Interstitial nephritis → mild chronic renal Symptomatic treatment:
compromise
• Artificial tears
Endocrine:
• Oral and vaginal moisturizers
• Autoimmune thyroid disease → hypothyroidism Nonspecific symptoms treatment:
• Autoimmune adrenal disease
• Exercise
• Autoimmune destruction of ovaries
• Antidepressants
Vasculitis:
• NSAIDs for joint pain
• Palpable purpura
Vasculitis treatment:
• Peripheral neuropathy
• Prednisolone
• Glomerulonephritis
• Cyclophosphamide
• Central nervous system vasculopathy
• Rituximab
Malignancy:
• Plasmapheresis
• Mucosa-associated lymphoid tissue lymphoma
• Diffuse large B-cell lymphoma
• Nodal marginal zone lymphoma

558
Seronegative Spondyloarthropathies • SpAs are characterized by inflammation of the
Definition: sites of tendons and ligaments insertion into bone
Seronegative spondyloarthropathies (SpA) are a group of (enthesitis)
rheumatologic disorders that share clinical and genetic • Environmental exposure to some organisms
associations. Namely, they are: increases the risk of SpAs like reactive arthritis
• TNF and IL-10 play an important role in the
• Ankylosing spondylitis pathology
• Psoriatic arthritis • New-bone formation, more commonly in
• Inflammatory bowel disease associated arthritis ankylosing spondylitis
• Reactive arthritis o Not seen in rheumatoid arthritis
They can be classified into: Histopathology:
• Non-radiographic axial SpA • Increased vascularity of the affected region
• Peripheral SpA • Macrophages, CD4+ and CD8+ T-cells
• Juvenile-onset SPA Clinical Presentation:
Epidemiology: Common features between different types of SpAs:
• Overall prevalence of SpAs is 1.9% in the United
States • RF negative
• Ankylosing spondylitis is the most common type • Asymmetric oligoarthritis
with a prevalence of 0.7% • Enthesitis
• Psoriatic arthritis has equal frequency in men and • Involvement of axial skeleton
women and has a prevalence of 0.2% and an Ankylosing spondylitis:
annual incidence of 0.006%
• Psoriatic arthritis is present in 4 to 30% of • More common in males
patients with psoriasis • Bilateral sacroiliitis
• IBD-associated arthritis is present in 3 to 13% of • Young age of onset
patients with IBD • The spinal vertebrae fuse
• Reactive arthritis is the least common type of the • Low-back and neck pain
SpAs and it has a prevalence of 0.04%. The most • Morning stiffness
common causative organisms are: • Inflammation of the tendons of the supraspinatus
o Chlamydia and Achilles
o Campylobacter • Limited spinal movements secondary to fused
o Salmonella vertebrae
o Shigella • Increased risk of vertebral fractures
o Clostridium difficile • Shoulder, hip and pelvic pain
Etiology and Pathophysiology: • Fever and weight loss
Etiology: • Extra-articular manifestations such anterior
uveitis and iridocyclitis
• A clear, very strong association with HLA-B27
o Strongest relationship is seen in
ankylosing spondylitis
o 90% of those diagnosed with ankylosing
spondylitis are HLA-B27 positive
o 7% of the general population are HLA-
B27 positive
• Psoriatic arthritis is more commonly seen in
patients with HLA-B27, DR7, and DQ3
• IBD-associated arthritis appears to be not Figure 364: Severe kyphosis in a patient with ankylosing
associated with a specific HLA type spondylitis secondary to vertebral fusion. Source:
• Reactive arthritis might be related to HLA-B27 https://www.merckmanuals.com/en-
• Based on this, one can conclude that SpAs are pr/professional/musculoskeletal-and-connective-tissue-
autoimmune in nature disorders/joint-disorders/ankylosing-spondylitis
Pathophysiology:
Psoriatic arthritis:

• Gradual onset

559
 • Asymmetrical oligoarticular or polyarticular pr/professional/musculoskeletal-and-connective-tissue-
• Sausage-shaped fingers disorders/joint-disorders/ankylosing-spondylitis

Reactive arthritis:

• Synovial fluid analysis is indicated to exclude

gouty and septic arthritis
Treatment:
Symptomatic treatment:

• NSAIDs
• Maintain good posture
• Physiotherapy
Axial ankylosing spondylitis:
Figure 365: Dactylitis in a patient with psoriatic arthritis.
Source: https://www.merckmanuals.com/en- • TNF-alpha inhibitors
pr/professional/musculoskeletal-and-connective-tissue- • Interleukin 17A inhibitor
disorders/joint-disorders/psoriatic-arthritis Peripheral SpAs:
Reactive arthritis: • Methotrexate and sulfasalazine
• More commonly affects the lower limbs joints
• After a genitourinary or a gastrointestinal Note: Intra-articular corticosteroids
infection injections should be avoided in
• Patients develop conjunctivitis, urethritis and SpAs because of the risk of tendon’s
arthritis rupture.
• Joint effusion and severe pain → joint arrest
o Can resemble septic arthritis
• Fever, weight loss and fatigue
Systemic Lupus Erythematosus
Diagnosis:
Definition
Ankylosing spondylitis and other SpAs:
Systemic lupus erythematosus (SLE) is a heterogenous
• Radiographic imaging of the sacroiliac joints: autoimmune disease that involves multiple organs’ systems
o Shiny corner due to sclerosis at the and displays a variable clinical course. The diagnosis is
attachment of the annulus fibrosis to the based on the presence of characteristic clinical findings of
anterior corner of vertebral bodies skin, joints, kidneys and central nervous system that are
o Bamboo spine due to calcification and supported by serologic parameters.
fusion of vertebral bodies
Epidemiology
o Squaring of vertebral bodies
• Estimated prevalence is 36 per 100,000
• MRI is useful in confirming the diagnosis of
enthesitis • Female to male ratio is 4:1
• HLA-B27 assessment • Onset in puberty
• Elevated ESR and CRP • 10-year-survival rate increased from 0% in the
1990s to 92% in 2003
• Most common cause of death in SLE in the first
years after the diagnosis is directly related to
disease activity and bacterial infections
• Most common cause of death in SLE patients
after 5 years of onset is cardiovascular disease
Etiology and Pathophysiology:
Etiology:

• Autoimmune disease
• African American women have an increased risk
Figure 366: Sclerosis between lumbar vertebrae and fusion • Drug-induced lupus:
in a patient with advanced ankylosing spondylitis. Source: o Chlorpromazine
https://www.merckmanuals.com/en- o Hydralazine

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 o Isoniazid Kidney disease:
o Procainamide
o Methyldopa • Lupus nephritis
o Quinidine • Proteinuria and hematuria
Pathophysiology: • Dysmorphic erythrocytes on urine microscopy →
glomerulonephritis
• Type III hypersensitivity reaction Cutaneous manifestations of SLE:
o Type II hypersensitivity reaction plays a
minor role Acute cutaneous SLE:
• Early complement proteins deficiency (C1q, C4
and C2) • Localized butterfly “malar” rash
• Decreased clearance of immune complexes • Oral mucosa erosions and ulcers
• Multiple organ damage • Non-scarring alopecia
• Autoantibodies bind to double-stranded DNA • Generalized maculopapular exanthema
(anti-dsDNA) which attracts early complement Subacute cutaneous SLE:
proteins resulting in immune complexes • Annular or papulosquamous lesions
• IgG-C3 immune complexes also attract • Photosensitivity
neutrophils to the affected organ → inflammation
• 90% anti-Ro/SSA positive
Clinical Presentation:
• Associated with increased risk of congenital AV
• Acute cutaneous lupus erythematosus such as block in offspring
butterfly rash
Discoid Lupus:
• Chronic cutaneous lupus erythematosus such as
localized or generalized discoid lupus • Localized in 80% of the cases
• Oral ulcers • Discoid erythematous plaques with firmly
• Non-scarring alopecia adherent follicular hyperkeratosis
• Synovitis of two or more joints • Healing with scarring → can cause scarring
• Tenderness on palpation of two or more joints alopecia
• Morning stiffness for 30 minutes or more
• Pleurisy, or pericardial pain for more than one
day due to serositis
• Elevated urine protein/creatinine ratio or 24-hour
urine protein > 0.5 g
• Seizures, psychosis and myelitis
• Hemolytic anemia
• Increased risk of recurrent bacterial infections
due to leukopenia
• Bleeding secondary to thrombocytopenia
Musculoskeletal system involvement in SLE:

• Myalgia and arthralgia

• Arthritis can involve small and large joints
• Tendinitis and synovitis
• Non-erosive recurrent small joint arthritis → Figure 367: A. Discoid lupus on the right cheek and ear. B.
Jaccoud arthropathy Discoid lupus on the scalp. C. Subacute cutaneous SLE. D.
Cardiovascular manifestations: Jaccoud arthropathy. Source:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558874/
• Liebman-Sacks endocarditis
• Pericarditis Other manifestations:
• Myocarditis
• Coronary arteritis • Fatigue, weight loss and fever
Pulmonary disease: • Raynaud’s phenomenon:
o Vasospasm
• Pleurisy o White or blue extremities/fingers when
• Lupus pneumonitis in cold environment
• Pulmonary fibrosis – rare o Extremely painful

561
 • Transient ischemic attacks and stroke Treatment:
• Nausea, vomiting, dysphagia and peptic ulcer First-line treatment:
disease
• Sjogren’s syndrome • Antimalarials such as hydroxychloroquine and
Antiphospholipid syndrome: chloroquine
• NSAIDs to control symptoms
• Primary or secondary (most commonly seen in • Glucocorticoids for short-term to control
SLE) symptoms
• Recurrent arterial or venous thrombosis Second-line treatments in non-responsive patients:
• Spontaneous abortion
• Azathioprine
• Lupus anticoagulant positive
• Methotrexate
• Lupus anticoagulant can cause prolonged PTT
• Mycophenolate mofetil
• Anticardiolipin antibodies can cause false-
Treatment of lupus nephritis:
positive VDRL/RPR
Diagnosis: • Continue antimalarials
In addition to the characteristic clinical features, SLE • Add cyclophosphamide for induction phase
diagnosis confirmed by immunologic criteria:
• Use glucocorticoids plus mycophenolate mofetil
• ANA levels: for maintenance phase
o First screening laboratory test in a • Calcineurin inhibitors and rituximab reserved for
suspected case of SLE refractory cases
o Sensitive but nonspecific Treatment of antiphospholipid syndrome:
• ESR and CRP – inflammatory markers
• Warfarin
• Blood count and urinalysis – to exclude o Long-term anticoagulation with INR
hemolytic anemia/leukopenia and lupus nephritis target of 2.5 to 3.5
Confirmatory laboratory tests:

• Anti-dsDNA which is specific to SLE but not Systemic Sclerosis

sensitive Definition
Systemic sclerosis, or scleroderma, is a rare connective
• Anti-Smith antibodies which have 100%
specificity tissue disorder that is thought to be an autoimmune disease
and is characterized by multiple organ fibrosis,
• Antiphospholipid antibodies (lupus anticoagulant)
telangiectasias and abnormalities of the gastrointestinal
to exclude antiphospholipid syndrome
system.
• Anti-SSA and anti-SSB to exclude Sjogren’s Diffuse systemic sclerosis:
syndrome and assess the risk of neonatal AV A diffuse, generalized and debilitating type of scleroderma.
block Cutaneous manifestations are more extensive than
• Anti-single-stranded DNA antibodies are found in localized scleroderma.
70% of patients Localized scleroderma:
Additional diagnostic tests based on involved organs: Calcinosis, Raynaud’s phenomenon, esophageal
dysmotility, syndactyly, and telangiectasias (CREST
• Skin biopsy
syndrome)
• Radiography of affected joints
• MRI to exclude soft-tissue inflammation Epidemiology:
• Sonography to exclude kidney disease
• Very rare
• GFR estimation in suspected kidney disease
• Global prevalence is estimated to be around 0.3
• Kidney biopsy to classify lupus nephritis. Type per 100,000
IV diffuse proliferative glomerulonephritis and • More common in the United States and Western
type V are indicative of impending renal failure Europe than in Asia
and established renal failure respectively
• Estimated incidence is 150 per 100,000 annually
• Cardiac assessment with echocardiography,
• Female to male ratio is 4:1 in diffuse systemic
catheterization, and scintigraphy
sclerosis
• Female to male ratio in CREST is 10:1

562
Etiology and Pathophysiology: • Myopathy
Etiology: End-organ damage:
• An inherited condition • Early in the disease
• Positive family history is the single most • Pulmonary fibrosis → pulmonary hypertension
important risk factor → leading cause of death in scleroderma
• Associated with HLA-B8, DR5, DR3, DQB2 and • Cardiac disease
DR52 • Renal disease
• CMV infection might be a risk factor CREST syndrome:
• Industrial exposure to vinyl chloride, solvent and • Insidious progression
silica increases the risk • Calcinosis
Pathophysiology: • Raynaud’s phenomenon
• Extensive activation of fibrosis by increasing the • Esophageal dysmotility
proliferation of fibroblasts • Sclerodactyly
• Excessive production of fibrosis-inducing • Telangiectasias
cytokines: • Development of end-organ damage is slower
o TGF-beta
o IL4
o Platelet-derived growth factor
• CMV increases the release of fibrosis-inducing
cytokines
• Vasculopathy is characteristic:
o Destructive lesions involving the small
vessels
o Progressive obliterative vasculopathy
o Endothelial dysfunction
o End-organ ischemia Figure 368: Calcinosis and sclerodactyly in a patient with
CREST. Source:
Clinical Presentation: https://commons.wikimedia.org/wiki/File:CREST1.JPG
Diffuse systemic sclerosis:
Skin: Diagnosis:
• Raynaud’s phenomenon • Mainly a clinical diagnosis
• Pruritus Antibody tests:
• Skin tightening – skin looks puffy and without • Anti-Scl-70 (topoisomerase I) – positive in 30%
wrinkles of patients with diffuse disease | negative in
CREST
• Finger pitting
• Anti-centromere antibody – positive in 60% of
• Ulceration
patients with CREST
• Claw fingers (sclerodactyly)
• ANA, RNA-polymerase III, and UI-RNP
• Skin atrophy
antibodies are often positive but nonspecific
• Telangiectasias Laboratory tests:
• Salt and pepper appearance due to alternating • Other laboratory tests include a complete blood
hypopigmentation/hyperpigmentation pattern in count → anemia
the upper and lower limbs
• Blood glucose level to exclude diabetes mellitus
GI:
secondary to the autoimmune destruction of beta-
• Difficulty swallowing cells of the islets of the pancreas
• Bloating • CRP, and ESR are often elevated
• Altered bowel movements Organ-specific tests:
• Weight loss Pulmonary disease:
Lungs: • Plain radiography
• Non-productive cough • High-resolution CT
• Chest tightness • Spirometry studies
• Chest pain • Lung biopsy
Musculoskeletal: Liver disease:
• Weakness • Liver function tests
• Joint pain

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 • Serum albumin Etiology:
• PT and PTT
Kidney disease: • Unknown cause
• Blood urea nitrogen level • Genetic and environmental factors contribute to
• Creatinine level the disease
• Serum electrolytes • Parvovirus B19, mycoplasma pneumoniae and
Heart disease: chlamydia pneumoniae have been implicated
• Echocardiography • Family history is less important than other
rheumatologic disorders
Treatment: • Linked to HLA-DR4
Raynaud’s phenomenon: Pathophysiology:
• Avoiding cold extremes • Mild synovitis in the proximal joints of the upper
• Vasodilator therapy with nifedipine is first-line limbs
Skin disease: • Mainly macrophages and activated CD4+ T
• Methotrexate lymphocytes
• Cyclophosphamide • Bursitis, tenosynovitis and synovitis explain the
Lung disease: symptoms
• Immunosuppressants • Increased local production of IL1, IL6, TNF-α
• Mycophenolate and IL8
• Azathioprine • Decreased number of circulating B-cells
• Cyclophosphamide Clinical Presentation:
• Pulmonary hypertension is treated with iloprost, • Bilateral shoulder pain and stiffness
endothelin-receptor antagonists or sildenafil • Upper arm tenderness
• Lung transplant as last resort • Pain and stiffness of the posterior neck muscles
GI system: • The muscles are sore, but not weakened
• High-fiber diet Clinical diagnostic criteria:
• Antacids
Kidney disease: • Symptoms occur in a patient who is older than 60
• Scleroderma renal crisis is treated with ACE years of age and last for one to two weeks (acute
inhibitors or subacute)
• Positive anti-RNA polymerase III antibodies • Bilateral shoulder, pelvic girdle, or both pain
increase the risk of scleroderma renal crisis • Morning stiffness > 45 minutes
• Patients develop accelerated hypertension, • Systemic symptoms such as low-grade fever,
oliguria and elevated serum creatinine level weight loss and depression
• Proper exclusion of sepsis, rheumatoid arthritis,
Polymyalgia Rheumatica other inflammatory diseases, cancer, and drugs
Definition such as statins
Polymyalgia rheumatica (PR) is the most common • Synovitis of proximal joints such as the shoulder
inflammatory rheumatic disease in old white people and is a • Tenosynovitis of the shoulder and rotator cuff
common indication for long-term treatment with muscles
glucocorticosteroids in the community. • Adhesive capsulitis
It is characterized by severe pain and stiffness of the
shoulders and proximal aspects of the arms bilaterally. Pain Note: There is a definite increased
and stiffness can also involve the neck. risk of temporal arteritis in patients
Epidemiology with PR (10%). This can lead to
• Rarely seen in individuals younger than 50 years blindness. Palpation and biopsy of
of age the temporal arteries are indicated in
the workup of a patient diagnosed
• Two-thirds of patients are women
with PR.
• Highest incidence in people above the age 65
years
• Most common in Scandinavian countries
Etiology and Pathophysiology:

564
 Treatment:
Glucocorticosteroids:

• Prednisone is first-line therapy

• Dramatic response in one to three days
(therapeutic and diagnostic of PR)
• Typically needed for several years
Other treatments:

• NSAIDs, methotrexate or anti-TNF-alpha are not

helpful
• Relapses can be treated by increasing the dose of
prednisone or the administration of a single
Figure 369: Areas of pain in patients with PR. Source: intramuscular injection of depo-
http://mrcpart1revision.blogspot.com/2011/09/polymyalgia methylprednisolone
-rheumatica.html Monitoring of patients:

Diagnosis: • Patients with PR receive low-dose corticosteroids

• Elevated ESR (> 40) and CRP for long periods
• Negative RF and antibodies to cyclic citrullinated • They are at risk of developing
peptide osteoporosis/osteoporotic stress fractures,
• Miraculous respond to prednisone is hyperglycemia, and abnormalities in WBC and
characteristic (within 24 to 48 hours) platelet count
o Patients who do not respond markedly • Bone density should be monitored every 1 to 2
to corticosteroids should be evaluated years
for the possibility of other diagnoses • Treatment should be against the symptoms and
• Ultrasonography of the affected joints which can not to solely normalize the ESR and CRP
reveal:
o Subdeltoid bursitis Polymyositis and Dermatomyositis
o Biceps tendon tenosynovitis Definition
o Synovitis of the glenohumeral joint Idiopathic inflammatory myositis is characterized by the
• Tests to exclude other diagnoses: presence of autoantibodies and inflammatory infiltration in
o Calcium level the muscles and it is thought to be an autoimmune disease.
o Creatinine and urinalysis Polymyositis and dermatomyositis (PD/DM) share the
o Thyroid function test following features:
o Creatine phosphokinase – normal in PR
o Blood glucose (to establish a baseline • Symmetric proximal muscle weakness
before starting long-term • Elevated serum CK levels
glucocorticosteroids) • Characteristic myopathic changes on EMG
• Nuclear studies (PET) show inflammation in • Characteristic muscle biopsy abnormalities
affected joints • Skin rash in dermatomyositis
Epidemiology
• The estimated prevalence of polymyositis and
dermatomyositis is 5 to 22 per 100,000
• Dermatomyositis has a bimodal age distribution
with one peak in children aged 5 to 15 years and
another in those aged 45 to 60 years
• Polymyositis is seen in patients aged between 50
to 60 years
• Female to male ratio is 3:1
Etiology and Pathophysiology
Etiology
Figure 370: Increased isotope uptake in the shoulders of a
patient with PR indicative of inflammation. Source: • Immune-mediated disease
https://www.thelancet.com/pdfs/journals/lancet/PIIS0140- • Multifactorial
6736(17)31825-1.pdf

565
 • Exposure to ultraviolet light, drugs, infections
and vitamin D deficiency are linked to
polymyositis and dermatomyositis
• Penicillamine, interferon-alpha, and TNF
inhibitors can cause polymyositis or
dermatomyositis
• Coxsackie virus positive serology in children A B
with dermatomyositis
• Associated with HLA-DRB1*0301 and HLA-
DQA1*0501
Pathophysiology

• The muscles are infiltrated by CD4 and CD8

positive T-cells, B-cells, macrophages, and
dendritic cells
• Microvascular disease → nail splinters and Figure 371: A. Gottron papules. B. Heliotrope rash..
decreased capillaries in muscle tissue Source: https://en.wikipedia.org/wiki/Dermatomyositis
• Humoral mechanism → autoantibodies in serum
• Complement and immunoglobulin deposition are Photosensitivity of the lesions:
seen on muscle biopsy
Histopathology • These lesions are aggravated by ultraviolet light
exposure
• Mononuclear inflammatory cell infiltrates Extra-muscular manifestations:
• Muscle fibers degeneration and regeneration
• Perifascicular atrophy of muscle fibers is • Arthritis
diagnostic of dermatomyositis • Raynaud’s phenomenon
• Endomysial inflammatory cellular infiltrate in • Interstitial lung disease
polymyositis • Increased risk of lung, breast, GI, ovarian cancers
• Perivascular and perimysial inflammatory cellular and myeloproliferative disorders
infiltrate in dermatomyositis Diagnosis:
Clinical Presentation Initial tests:
• Proximal muscle weakness
• Creatine phosphokinase (CPK) is elevated
o Difficulty getting up from sitting
positive, climbing stairs, lifting heavy • AST and ALT can be elevated
objects • LDH is elevated
• Gottron papule and heliotrope rash are • ESR and CRP are usually elevated
pathognomonic of dermatomyositis Objective confirmation of muscle inflammation:
Heliotrope rash:
• EMG which shows low-amplitude, short-duration
• Violaceous rash involving the eyelids polyphasic potentials
• Periorbital edema • MRI shows focal inflammation sites on STIR
Gottron papules: sequence and atrophy on T1 sequence
• Muscle biopsy to differentiate between
• Red rash with variable papules on the extensor polymyositis and dermatomyositis
aspects of the metacarpophalangeal, proximal Autoantibodies:
interphalangeal and distal interphalangeal joints
• Gottron sign is same as Gottron papules but the • Positive in 80% of patients
lesions are seen on the extensor surfaces of the • Classified into myositis-specific antibodies
elbows, knees and ankles (MSA) which have 90% specificity
Shawl sign: • Myositis-associated antibodies which are not
specific for idiopathic inflammatory myositis but
• A red rash on the anterior chest resembling the are commonly positive
letter V Myositis-specific antibodies:
• Can be also seen on the upper back
• Anti-synthetase antibodies that target cytoplasmic
aminoacyl-tRNA synthetase

566
 • Anti Jo-1 Etiology:
• Anti-Mi-2, anti-MDA4, anti-TIF, anti-SAE and MG - Autoimmune
anti-NXP are more specific for dermatomyositis - Production of anti-AChR antibodies
o Anti-Mi-2 indicates good prognosis - Activated CD4+ T cells need to interact with B-cells to
produce these high-affinity IgG antibodies →
• Anti-signal-recognition-peptide (SRP) antibodies thymectomy alleviate the symptoms of the disease
indicate the worst prognosis LEMS - Paraneoplastic
Myositis-associated antibodies: - Antibodies against voltage-gated calcium channels
(VGCC) are formed
- Smoking is a risk factor
• Not disease-specific - Associated with HLA-B8-DR3
• Seen in patients with overlap syndrome
• Anti-Ro and anti-LA are two examples
Other diagnostic tests: Pathophysiology:
MG - The anti-AChR antibodies increase complement binding
and activation at the neuromuscular junction
• A chest radiograph is indicated in all patients - Accelerates AChR endocytosis
• To exclude interstitial lung disease - Blockade of AChR receptor
LEMS Failure of calcium influx into the nerve terminal
• Pulmonary function tests and CT are indicated in -
- Failure to release ACh into the neuromuscular junction
patients with pulmonary symptoms or abnormal
plain radiography
• Age-appropriate screening for malignancies in Clinical Presentation
patients with dermatomyositis MG - Ptosis, diplopia and muscle weakness
- Involvement of the respiratory muscles → dyspnea
o Highest risk of malignancy is seen in - Decreased muscle strength with repeated muscle
patients with positive anti-NXP and contraction
anti-TIF antibodies - Improved after edrophonium test
LEMS - Proximal muscle weakness
Treatment: - Areflexia in the absence of significant muscle atrophy
• Glucocorticosteroids - Increased muscle strength and return of tendon reflexes
with repeated muscle contraction
• Immunomodulators including methotrexate, and - Autonomic symptoms such as dry mouth and impotence
cyclophosphamide
• Physical exercise therapy and rehabilitation Diagnosis
• Rituximab in patients with myositis-related MG - Edrophonium chloride test is positive
interstitial lung disease (anti-CD20 monoclonal o This is a short-acting acetylcholinesterase
inhibitor
antibody) o Increases the duration of action of ACh at the
Myasthenia Gravis (MG) and Lambert Eaton Myasthenic neuromuscular junction
Syndrome (LEMS) o Administered intravenously
- Ice-pack test in patients with ptosis when edrophonium is
contraindicated:
o Contraindications include cardiac disease and
Definition hypotension
MG - Most common neuromuscular junction disorder - Electrophysiologic tests:
- Autoantibodies against postsynaptic ACh receptor o Repetitive nerve stimulation reveals a
- Ptosis, weakness and worsened symptoms with repetitive progressive decrement in the evoked muscle
muscle use potential
LEMS - A neuromuscular junction paraneoplastic disorder o Single-fiber electromyography is the most
- Can be a primary autoimmune disorder in a minority sensitive test for MG
- 50% associated with small cell lung cancer - Anti-AChR serum concentration
- Chest CT or MRI in all patients to exclude a thymoma
- Baseline testing of thyroid functions in all patients
Epidemiology LEMS - Presence of VGCC antibodies
MG - Still an uncommon disease - Characteristic electrophysiologic findings
- Female predilection - Screening for malignancy if the diagnosis of small cell
- Mean age at presentation is 35 years lung cancer is not confirmed
- Can be seen in children or infants
LEMS - Very uncommon
- 46 times less common than MG Treatment
- Male predilection MG - Symptomatic treatment with acetylcholinesterase
- Mean age at presentation 58 years inhibitors
- Short-term immunomodulatory treatment with
Risk factors: plasmapheresis or intravenous immunoglobulin therapy
- Long-term glucocorticosteroids or other
MG - Thymoma
immunosuppressive therapies
- Thymic gland hyperplasia
- Thymectomy
LEMS - 50% associated with small cell lung cancer LEMS - No treatment. The prognosis is very bad as most patients
die because of the malignancy
Etiology and Pathophysiology

567
Acetaminophen Aspirin (Acetyl Salicylic acid)
Overview: Overview:
Acetaminophen is considered as antipyretic/Analgesic but
not NSAID

• Arachidonic acid released from cell membrane

Mechanism of Action phospholipids by phospholipase which is initiated
• Reversibly inhibit COX mostly in CNS by mechanical, chemical or physical stimuli
• Block production of prostaglandins • Arachidonic acid converted into 2 pathways
Metabolism ➢ Lipoxygenase pathway
• Acetaminophen metabolized in the liver ➢ Cyclooxygenase pathway
• Conjugated into two non-toxic metabolites
(Sulfate, glucuronide) Cyclooxygenase pathway
• Metabolized by P450 enzyme into N-acetyl-P-
benzo-quinone imine (NAPQI) which is toxic Prostacyclin ↓ Platelet aggregation
metabolite ↓Vascular tone
↓ Bronchial tone
• NAPQI then conjugated by glutathione into Non- ↓ Uterine tone
toxic metabolite
PGE2&PGF2 ↓Vascular tone
• N-acetylcysteine (NAC) is a glutathione ↓ Bronchial tone
precursor which replenishing glutathione stores ↓ Uterine tone
• Patients with hepatic diseases (Alcoholics) suffer Thromboxane A2 ↑Platelet aggregation
from Acetaminophen toxicity manifested by ↑Vascular tone
↑Bronchial tone
increased liver enzymes (ALT, AST)
Lipoxygenase pathway
LTC4& LTD4 Vasoconstriction
Bronchospasm

LTB4 Neutrophil chemotaxis

Mechanism of Action
• Irreversibly inhibit COX1& COX2 through
acetylation mechanism

Clinical Uses
Anti-Inflammatory
• Aspirin is considered as NSAID (non-steroidal
anti-inflammatory)

568
Analgesia NSAIDs
• Aspirin is effective in reducing pain of mild to Drug names
moderate intensity when administered at high • Ibuprofen
dose (2400-4000 mg) • Naproxen
Antipyretic • Indomethacin
• Aspirin is used to decrease body temperature • Ketorolac
through inhibition of COX enzymes in CNS when • Diclofenac
administered at intermediate dose (300-2400mg)
Antiplatelet Mechanism of Action
• When administered at low dose < 300mg • Reversibly inhibit COX1 &2
• Aspirin is indicated to reduce the risk of death in • Block production of prostaglandins
patients with unstable angina pectoris. Clinical uses
• The antiplatelet effect of Aspirin lasts 5-10 days • Analgesia-Pain control
(the life of the platelet). • Antipyretic
Myocardial infarction prophylaxis: • Anti-inflammatory
• Aspirin is used in patients at high risk for • Indomethacin closes patent ductus arteriosus
thrombotic events and used acutely for the (PDA)
management of myocardial infarction

NOTE:
• Arachidonic acid (AA) is formed by
phospholipase A2 and eventually AA is
metabolized by COX enzymes forming
intermediate Prostaglandin PGH2 which
considered the main source for Thromboxane A2
(responsible for platelet activation)
• Aspirin ↓ synthesis of TXA2 (inhibit coagulation)
and prostaglandins WITHOUT any effect on
prothrombin time (PT) and partial thromboplastin
time (PTT). Adverse effects:
Toxicity • Interstitial nephritis
• Contraindicated in children with virus infection • Gastric ulcer
(to avoid the complication of Reye’s syndrome ➢ Prostaglandins protect gastric mucosa
(Liver failure and encephalopathy) • Renal ischemia lead to acute renal failure
• Gastric ulceration which lead to bleeding due to • Aplastic anemia
inhibition of PG
COX2 Inhibitors:
• Tinnitus (ringing) affect cranial nerve 8 (CN VII). Celecoxib
• Chronic use lead to acute renal failure Mechanism of Action:
➢ Aspirin decreases vascular perfusion to • Reversibly inhibit COX-2
the kidney leading to ischemia • COX2 found in inflammatory cells, vascular
• Interstitial nephritis endothelium, pain mediators
• Chronic use lead to respiratory alkalosis • COX-2 inhibitors have analgesic, antipyretic &
combined with severe metabolic acidosis anti-inflammatory effects but with fewer GIT side
effects
➢ Aspirin stimulate the respiratory center • COX-2 inhibitor has minimal cardio protective
leads to ↓ Co2 and eventually ↑ PH effects (No effect on platelet aggregation)
➢ Aspirin induces Hyperpnea (increased • Platelet aggregation depend on COX-1
depth & rate of respiration) Clinical uses:
• Rheumatoid arthritis
• Osteoarthritis
• Patients with gastric ulcer
Toxicity
• Increase thrombosis

569
 • Celecoxib is a sulfonamide, so its Clinical uses:
contraindicative with patients with sulfa allergy • Chronic gout
Acetaminophen • Prophylaxis for patients with lymphoma and
• Reversibly inhibit COX mostly in CNS leukemia to prevent tumor lysis syndrome
• Block production of prostaglandins eventually lead to acute uric acid nephropathy
• Peripherally inactive • Note: Tumor lysis syndrome is a metabolic
• Acetaminophen is considered as abnormality occur during chemotherapy treatment
antipyretic/Analgesic but not NSAID characterized by high blood potassium
(hyperkalemia), high blood phosphate
Clinical uses (hyperphosphatemia), low blood calcium
• Pain (Hypocalcemia) and high blood uric acid
• Fever (hyperuricemia)
• To prevent Reye syndrome in children
Adverse effects:
Toxicity: • Drug interaction with azathioprine, 6-
• Acetaminophen metabolized in the liver mercaptopurines (increased concentration)
Febuxostat:
• Conjugated into two non-toxic metabolites
(Sulfate, glucuronide) • Xanthine oxidase inhibitor
• Used for patient with renal disease
• Metabolized by P450 enzyme into N-acetyl-P-
Probenecid (uricosuric drug):
benzo-quinone imine (NAPQI) which is toxic
metabolite • Enhance excretion of uric acid
• NAPQI then conjugated by glutathione into Non- • Block tubular reabsorption of uric acid in
toxic metabolite proximal convoluted tubule
• N-acetylcysteine (NAC) is a glutathione
Adverse effects:
precursor which replenishing glutathione stores
• Probenecid interferes with the renal secretion of
• Patients with hepatic diseases (Alcoholics) suffer
penicillin
from Acetaminophen toxicity manifested by
increased liver enzymes (ALT, AST) Drugs for acute gout:
Colchicine:
• N-acetylcysteine drug of choice for
Acetaminophen toxicity. • Bind tubulin and inhibit microtubule formaion
• Anti-inflammatory
Gout Drugs • Inhibit leukocyte migration and phagocytosis
Pathophysiology of Gout:
• Gout= Is inflammation arthritis caused by Adverse effects:
hyperuricemia and urate crystal deposits • Diarrhea
• Excessive production and inadequate excretion NSAIDs (non-steroidal anti-inflammatory drugs)
• Xanthine oxidase catalyzes hypoxanthine to • Inhibit urate crystal phagocytosis and prevent
xanthine &xanthine to uric acid leukocytes migration to inflamed joints such as:
• Plasma uric acid converted into urate crystals and • Naproxen
deposited in the joints • Indomethacin
Gout drugs • Ketorolac
• Ibuprofen
Acute gout Chronic gout

Colchicine Allopurinol
glucocorticoids
• Intra-articular glucocorticoids are a medication
Steroids Probenicid
that is injected into joints for treatment of acute
NSAIDS Febuxostat gout

Drugs for chronic gout:

Allopurinol
• Xanthine oxidase inhibitor
• Block production of uric acid
• Note useful for acute gout

570
Chapter 12:

Neuroscience

571
Neural Tube Defects • As the name implies, both the meninges and some
neural tissue herniate through the bony defect
Definition • The skin over the defect is very thin, or it can be absent
Neural tube defects are persistent connections between the Myeloschisis:
amniotic cavity and spinal canal. They are caused by failure • A bony defect that exposes the neural tissue without
of the neuropores to fuse, which is expected to happen at skin or meningeal covering
approximately the 4th week of gestation. • The roof plate, vertebral arch, and skin are all absent
above the bony defect
Epidemiology Anencephaly: Figure 2
The prevalence of neural tube defects is around 0.19 per • The previous types of neural tube defects affect the
1000 live births. The most important risk factor for neural spine. This type affects the head
tube defects is folic acid deficiency. The prevalence of • A major portion of the brain, skull and scalp are absent
neural tube defects before the initiation of widespread • It results when the rostral portions of the neuropore fail
fortification of flour was 0.25 per 1000 live births. Other
to fuse
important risk factors include:
• Folic acid deficiency and history of maternal use of
• Genetic and chromosomal abnormalities anticonvulsants are important risk factors
• Maternal diabetes
• The prognosis is death. It is incompatible with
extrauterine life
Pathology:
If the neuropores fail to fuse at the 4th week of gestation, a
neural tube defect might occur. Folic acid deficiency before
conception and during the pregnancy is recognized as the
most important risk factor for neural tube defects. Neural
tube defects can affect the spine or the head.

Types:
Neural tube defects can be classified into: Figure 1

Figure 373: A front view of an anencephalic fetus. You can

notice the absence of the forebrain and part of the skull of
the fetus. Source:
https://en.wikipedia.org/wiki/Anencephaly#/media/File:An
encephaly_front.jpg
Figure 372: An illustration of the three types of spinal neural
tube defects. Source: http://www.evieswarriors.com/spina- Diagnosis:
bifida-101/ Anencephaly, myelomeningocele, and meningocele are
associated with an elevated level of α-fetoprotein in
Spina bifida occulta: maternal serum. On the other hand, spina bifida occulta is
• Most common type not associated with an elevated level of α-fetoprotein.
• The caudal neuropore fails to close. There is no Ultrasound can identify two important clues that the
herniation pregnant woman might have a fetus with a neural tube
• Occurs at lower vertebral levels defect:
• The dura is intact - Polyhydramnios - Visualization of the defect
• Commonly associated with a tuft of hair or a skin Acetylcholinesterase is an enzyme that is found in the
dimple at the level of the bony defect central nervous system. When there is a neural tube defect,
Meningocele: you would expect this enzyme level to be elevated in the
• Least common type amniotic fluid.
• The meninges tend to herniate through the bony defect
• No neural tissue is found in the herniated part Treatment:
Associated with spina bifida cystica Meningomyelocele: The three different types of spinal neural tube defects can be
• Most severe type corrected surgically. The prognosis is variable and is
dependent on the exact type of the defect.

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There is no treatment for anencephaly because most of those notochord. The neural plates fold on each other to form a
affected die in-utero or in the first few hours after delivery. neural tube which is separated from the surface. Source:
Prevention is possible. The following measures have been https://en.wikipedia.org/wiki/Neural_tube#/media/File:Neu
associated with a reduction in the incidence of neural tube ral_crest.svg
defects:
• The administration of folic acid to women who are at The neural tube has two ends:
high-risk • A rostral end, which is responsible for the development
• Fortification of flour, rice and other products of the brain. The neuroectoderm cells form within the
• The identification of drugs associated with an increased rostral end and migrate to the caudal end
risk of neural tube defects and limiting their use during • A caudal end, which is responsible for the development
pregnancy of the spinal cord

Neural Development Regional specification of the developing brain:

Definitions: When the neural tube closes, bulges and bends begin to
Neurulation is the beginning of the formation of the central appear at the rostral end. They gradually form three primary
nervous system and is the process in which the neural plate vesicles:
forms into a neural tube. Regional specification of the • The prosencephalon or forebrain
developing brain is a term that is used in embryology to refer • The mesencephalon or midbrain
to the observation that the neural tube is segmented into • And the rhombencephalon or hindbrain
different segments as it develops, and each segment
develops into specific adult derivatives. The prosencephalon is further segmented into the
telencephalon and the diencephalon. The mesencephalon
Neural development does not undergo any further segmentation. The
The process of neurulation is dependent on the expression rhombencephalon is segmented into the metencephalon and
of certain induction molecules by the notochord that signal myelencephalon. The following adult derivatives develop
the ectoderm to differentiate into a neuroectoderm. This is from these five secondary vesicles:
finished by the formation of a neural plate. The telencephalon gives rise to:
From the neural plate, the neural tube and neural crest cells • The cerebral hemispheres
arise. The notochord undergoes degeneration to form the The diencephalon gives rise to:
nucleus pulposus of the interverbal discs in adults. • The thalamus
• The hypothalamus
Note: While the notochord is The mesencephalon gives rise to:
responsible for the induction of the The metencephalon gives rise to:
differentiation of the ectoderm into
• The pons
neuroectoderm, it is not part of the
• The cerebellum
adult central or peripheral nervous
The myelencephalon gives rise to:
systems.
• The medulla The midbrain
The principle that each secondary segment gives a specific
structure of the brain is known as regional specification.
The neural plate develops two neural folds which come
closer to each other until they fuse at approximately the 4 th
week of gestation, see Figure 1. When they fuse, the neural
Note: The development of the brain
tube is formed. The dorsal plate of the neural tube is
starts during the first weeks of
responsible for the production of sensory nuclei, whereas the
gestation, i.e. during neurulation, and
basal plate is motor.
continues after birth.

Development of other important structures in the nervous

system:
The neural tube is lined by neuroepithelia. They are
responsible for the development of the central nervous
system neurons, ependymal cells, oligodendrocytes, and
astrocytes.
Figure 374: The process of neurulation. The main inducer of The neural crest cells give rise to the peripheral nervous
the differentiation of the ectoderm into neuroectoderm is the system neurons and Schwann cells.

573
Finally, the mesoderm that is found within the developing • Missing Drugs: Non-Compliance: Most common
central nervous system gets to differentiate into microglia, cause
which are like macrophages. 1. Acute alcohol withdrawal, benzodiazepines
• Miscellaneous:
Seizures 2. Psych origin (check EEG) Pseudo seizure
Definition 3. Eclampsia > Treatment is Magnesium sulphate and
A Seizure is a transient occurrence of signs and/or deliver baby
symptoms due to abnormal neuronal activity, see Figure 1, • Intoxications:
in the brain which could be either excessive firing or 1. Illicit drugs such as cocaine
increased synchronous activity. Epilepsy is a condition of 2. lithium
the brain that is characterized by predisposition to generate 3. lidocaine
recurrent seizures. The occurrence of two unprovoked 4. lead poisoning
seizures that are 24 hours apart is enough to diagnosis 5. CO poisoning
epilepsy. • Infections:
1. Sepsis
2. Bacterial/viral meningitis
• Ischemic stroke
• Increased intracranial pressure

Common etiologies of epilepsy are:

1. Structural such as focal cortical dysplasia – A common
cause of drug-resistant epilepsy.
2. Idiopathic, which now refers to genetic epilepsy
syndromes.
Figure 375: an abnormal electrical discharge as seen on 3. Metabolic such as glycogen storage diseases.
scalp EEG. An unknown cause

Epidemiology Types of epileptic seizures:

Epilepsy is a very common neurologic disorder. A seizure can be either focal onset, generalized onset or
Approximately, 1 in 26 people will develop epilepsy during unknown onset in this new classification.
his or her lifetime. The incidence of a single unprovoked • Focal onset seizures: “Partial Seizures”
seizure is between 23 to 61 per 100,000 people per year. The 1. Unilateral epileptogenic network that
incidence of acute provoked seizures is around 39 per involves a single hemisphere.
100,000 population per year. Age has an influence on the 2. Can be subclassified into: focal onset
incidence of epilepsy and seizures. The very young, i.e. < 1 with awareness “simple partial seizures”,
year, and the very old, i.e. > 65 years have the highest annual or focal onset with impaired awareness
incidence of new onset seizures. “complex partial seizures”.
3. Can be subclassified into: with motor
Etiology of Seizures: onset, or nonmotor onset.
It is important to understand the difference between a 4. The last level of subclassification can be
provoked seizure and an unprovoked seizure with known with focal to bilateral tonic-clonic or
etiology. A provoked seizure is not included in the definition without focal to bilateral tonic-clonic, i.e.
of epilepsy and it can be caused by one of the following secondary generalization.
causes: • Generalized onset seizures
• Metabolic: 1. A bilateral epileptogenic network that
1. Hypernatremia <120 mEq involves both hemispheres at the onset of
2. Water intoxication the seizure.
3. Low blood glucose 2. Can be subclassified into motor onset:
4. Hypocalcemia tonic-clonic for example, or nonmotor
5. Uremia such as absence seizures.
6. Thyroid storm Diagnosis:
7. Hyperthermia • If the patient has a known history of an epilepsy
• Mass lesions: disorder:
1. Tumor 1. Check antiepileptic levels in the blood to ensure
2. Intracranial or subarachnoid hemorrhage compliance

574
• If this is the first seizure: 2. Time the seizure’s onset and monitor the
1. A complete blood count to check for leukocytosis vital signs.
which could be indicative of sepsis or meningitis 3. Assess peripheral oxygen saturation.
2. A chest radiograph 4. Start ECG monitoring.
3. Electrolytes 5. Exclude hypoglycemia and treat if found.
4. Liver function tests 6. Check electrolytes, CBC, toxicology
5. Blood glucose levels to exclude hypoglycemia screen, and antiepileptic drug levels.
6. Renal function tests to exclude uremia • Initial therapy phase:
7. Calcium level 1. IV or IM benzodiazepines such as
8. A lumbar puncture to exclude meningitis lorazepam. Rectal diazepam is an option.
9. A CT scan of the brain if the patient has persistent • Second therapy phase: Only if the seizure does not
new-onset focal neurological deficits resolve
10. A pregnancy test to exclude eclampsia 1. Intravenous fosphenytoin, valproic acid,
• An EEG is helpful in confirming the diagnosis of an or levetiracetam.
epileptogenic seizure. • Third therapy phase: Only if the seizure does not
• Other forms of brain imaging such as MRI might be resolve
needed in some cases. 1. Induce anesthesia with thiopental and
commence continuous EEG monitoring.
Treatment:
In the emergency department, you should follow the airway- Basal Ganglia
respiratory-circulation protocol to secure them. Once your Definition
patient is stable, you can move on to specific treatments as The “basal ganglia” is a term used by neuroanatomists to
follows: refer to a group of subcortical nuclei that are responsible for
• Primary monotherapy antiepileptic treatment for motor control and the initiation of voluntary movements.
focal-onset seizures: These nuclei are also related to motor learning, executive
1. Carbamezapine, levetiracetam, functions, behaviours and emotions.
phenytoin, or zonisamide are first-line
therapies. Neuroanatomy:
• Primary monotherapy antiepileptic treatment for The basal ganglia refer to the striatum, or caudate-putamen,
generalized-onset tonic-clonic seizures: and globus pallidus. The related nuclei that are connected to
1. Lamotrigine, topiramate, or valproic acid the basal ganglia include the subthalamic nucleus, the
are first-line therapies. substantia nigra, and the pedunculopontine nucleus, see
2. Phenytoin and Carbamezapine are Figure 1.
second-line therapies because they have
been associated with aggravation of
generalized-onset tonic-clonic seizures
in some patients.
• Primary monotherapy antiepileptic treatment for
generalized-onset absence seizures:
1. Ethosuximide or valproic acid are first-
line therapies.
2. Gabapentin should be avoided because it
is useless in this category. Figure 376: A sagittal section of the brain that shows the
different subcortical nuclei of the basal ganglia. Source:
Status epilepticus: https://en.wikipedia.org/wiki/Basal_ganglia#/media/File:A
Status epilepticus is defined as more than 30 minutes of natomy_of_the_basal_ganglia.jpg
either continuous seizure activity, or two or more sequential
seizures within 30 minutes without full recovery of Functional neuroanatomy:
consciousness in between. Treatment of status epilepticus is The basal ganglia and related nuclei can be classified into
started whenever a seizure passes 5 minutes in duration. input, output and intrinsic nuclei.
• Stabilization phase: Input nuclei:
1. Stabilize the patient’s airway, breathing, • Receive information from cortex, thalamus, and
circulation and perform a disability substantia nigra
exam. • Include the caudate, putamen, and accumbens
nuclei

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Output nuclei: Motor cortex Motor functions
• Send information to the thalamus
• Similar to the direct pathway, the motor cortex first sends an
• Include the globus pallidus and the substantia excitatory signal to the striatum.
nigra pars reticulata
Striatum Function: refining and initiation of movement
Intrinsic nuclei:
• Connect the input and output nuclei • The caudate and putamen receive the signal.
• The cells release an inhibitory signal to the globus pallidus
• Include the external segment of the globus externus.
pallidus, the subthalamic nucleus, and the • Ach neurons also activate this pathway.
substantia nigra pars compacta Globus pallidus
externus Connected to the subthalamic nucleus
• Again, the cells within the globus pallidus externus are also
Note: The appropriate function of inhibitory, they release GABA to inhibit the subthalamic
the different nuclei of the basal nucleus.
ganglia is dependent on dopamine. Subthalamic
nucleus Connected to the globus pallidus internus
Accordingly, most movement • The cells within the subthalamic nucleus are excitatory, they
disorders such as Parkinson’s release glutamate.
disease, chorea, and tics, have some • They activate the globus pallidus internus.
Globus pallidus Refining of movement. Connected to the
sort of dopamine dysfunction. internus ventrolateral nucleus of the thalamus
• The cells within the globus pallidus internus are inhibitory. They
inhibit the ventrolateral nucleus of the thalamus.
The direct pathway: • The ventrolateral nucleus gets inhibited and the motor cortex
activity is inhibited, i.e. controlled.
The goal of the direct pathway is to activate the correct set
of muscles that we need to initiate a particular kind of Role of dopamine:
movement. The steps of the direct pathway are summarized Dopamine is released from dopaminergic neurons within the
below: substantia nigra compacta. The direct pathway has D 1
Pre-frontal cortex Function: decision making and planning receptors, which once bound to dopamine activates the
pathway. On the other hand, the indirect pathway has an
• The person decides to initiate a movement. The pre-frontal cortex is activated.
• Send appropriate activating signals to the motor cortices. abundance of D2 receptors, which once bound to dopamine
Motor cortex Motor functions inhibits the indirect pathway.
• Motor cortices send signals, glutamate, to the basal ganglia. Accordingly, a dopamine dysfunction, loss of dopamine as
• The reason is to refine movement and decide which group of muscles need seen in Parkinson’s disease, will result in:
to be
activated. 1. Loss of the activation of the direct pathway, i.e.
Striatum Function: refining and initiation of movement inhibition → problems with movements’ initiation.
• The caudate and putamen receive the signal. 2. Loss of inhibition of the indirect pathway, i.e.
• The cells in the striatum are inhibitory, i.e. they release GABA. activation → further slowing of movements due to
• The globus pallidus internus is inhibited. uncontrolled inhibition of the motor cortices by the
The ventrolateral thalamic nucleus is always inhibited by indirect pathway.
Thalamus the globus pallidus
• The inhibition of the globus pallidus by the striatum results in loss of inhibitory
Tongue Development
tone to the ventrolateral thalamic nucleus.
Anatomy:
• The motor cortices are now more active and they are able to induce contraction
of the muscles we need to initiate movement. The tongue is subdivided
into an anterior portion and a
posterior one. The anterior two thirds of the tongue are
The indirect pathway: composed of:
The indirect pathway is activated at the same time whenever • Apex
we activate the direct pathway to initiate a movement. • Medial sulcus
Instead of eventually activating the motor cortex, it inhibits • Body of the tongue
it. The goal of activating this pathway is to inhibit or prevent The posterior one third of the tongue is composed of:
muscle contractions from competing voluntary movements, • Lingual tonsils
i.e. refining of the movement. The steps of the indirect • Palatine tonsils
pathway are summarized below: • Tongue root
The two parts of the tongue are separated by the sulcus
terminallis and vallate papillae. Figure 1 summarizes the
anatomy of the tongue.

576
 Motor innervation
Motor innervation to the tongue is mainly via cranial nerve
XII. The following muscles are innervated by CN XII:
• Hyoglossus: retracts and depresses the tongue.
• Genioglossus: protrudes the tongue.
• Styloglossus: draws the sides of the tongue upward
during swallowing.
The most posterior part of the tongue is elevated during
swallowing by the action of the palatoglossus muscle which
Figure 377: An illustrative picture of the anatomy of the is innervated by cranial nerve X.
tongue. Notice that the sulcus terminallis separates the
tongue into anterior two thirds and a posterior one third. Sleep Physiology
Source: http://healtharchives.info/the-human-tongue- Definition
anatomy/the-human-tongue-anatomy-anatomy-of-the- Sleep is a resting state that humans, among other animals,
tongue-anatomy-of-the-tongue-human-anatomy-diagram- need to go into for optimum physiologic functions while
physiology/ awake. Sleep consists of distinct stages and these stages are
known to be cyclic.
Embryology Non-rapid eye movement (NREM) sleep represents 75% of
The anterior two thirds of the tongue come from the 1st sleep. During NREM, the breathing and heart rate are slow
branchial arch. The posterior third, on the other hand, comes and regular. Blood pressure is low. The person during
from the 3rd and 4th branchial arches. NREM is still and does not move.
The embryogenic development of the tongue is important Rapid eye movement (REM) sleep represents 25% of sleep.
because it helps you understand the distribution of the Humans dream during REM sleep stage. Motor tone is lost,
sensory innervation of the tongue. brain utilization of oxygen is increased, and extraocular
movements occur.
Sensory innervation
Sensory innervation of the tongue can be subdivided into Sleep stages
general sensation, i.e. pain, and specialized sensation, i.e. The following table summarizes the different sleep stages
taste. See Figure 2. and the expected EEG waveforms that you would obtain if
Anterior two thirds of the tongue: you are recording scalp EEG during sleep.
STAGE DESCRIPTION EEG WAVEFORMS
• Pain: cranial nerve V, third branch. AWAKE, EYES Alpha activity from
• Taste: cranial nerve VII, from the solitary nucleus. CLOSED the posterior parts of
Posterior one third of the tongue: the head, i.e. occipital
alpha rhythm.
• Pain: cranial nerves IX and X. AWAKE, EYES OPEN This is the stage when Beta activity that is
• Taste: cranial nerves IX and X, from the solitary we are alert, active, low in amplitude.
and concentrating Suppression of
nucleus. posterior alpha
activity.
Note: The solitary nucleus gives rise
NREM SLEEP
to sensory fibers of taste in the STAGE N1 5% of sleep. Theta activity is
seventh, ninth and tenth cranial Light sleep. abundant on the EEG.
nerves. STAGE N2 45% of sleep. Sleep spindles and K
Most of our sleep is complex.
NREM Stage N2.
Teeth grinding
occurs.
STAGE N3 25% of sleep. Slow-waves in the
Clinically important delta frequency
because range.
sleepwalking, night
terrors and
bedwetting occur
during this stage.
REM SLEEP 25% of sleep. Beta activity is
Loss of motor tone. abundant.
Increased oxygen
Figure 378: Taste (pink) and sensation (blue) innervation of utilization by the
the tongue. Source: https://neupsykey.com/the-chemical- brain.
senses-of-taste-and-smell/

577
 Elevations in heart • The cavernous sinuses
rate and blood
pressure.
Dreaming and The midline dural venous sinuses are:
nightmares occur.
May be important for
• Superior sagittal sinus
memory processing. • Inferior sagittal sinus
Extra-ocular • And the straight sinus
movements occur
because of the The posterior dural venous sinuses are:
activation of the • Occipital sinus
paramedian pontine
reticular formation. • And the confluence of the right and left transverse
Occurs every 90 sinuses
minutes. The lateral dural venous sinuses are:
• Superior petrosal sinus
CNS regulation of sleep
• Transverse sinuses
Sleep is a cycle and not a stationary state. The circadian
• Inferior petrosal sinus
rhythm of sleep is regulated by the suprachiasmatic nucleus
of the hypothalamus (SCN). • And the sigmoid sinuses
ACTH, prolactin, melatonin, and norepinephrine are all The dural venous sinuses are connected to each other and
blood flow follows the following scheme, see table below:
regulated by SCN. SCN responds to changes in light by LEVEL 1 LEVEL 2 LEVEL 3 LEVEL 4
regulating norepinephrine release. Norepinephrine works on
the pineal gland, which releases melatonin. When in dark, Superior sagittal Confluence of
sinus transverse
the pineal gland is stimulated to release melatonin which is sinuses
the hormone of sleep. Confluence of
Inferior sagittal Straight sinus to transverse
Common sleep disorders and their treatment sinus confluence of sinuses to right
transverse and left
Sleepwalking and sleep terrors occur during NREM Stage sinuses transverse Internal jugular
N3. Because we do not dream during this stage, patients who Occipital sinus Confluence of sinuses vein
suffer from sleep terrors might wake up, but they will not transverse
sinuses
remember a nightmare. They will just be very frightened.
Nightmares occur during REM. Sphenoparietal Cavernous Petrosal sinuses
Accordingly, the treatment of sleep terrors and sleepwalking sinuses sinuses to drain into
will be accomplished by prescribing a drug that decreases petrosal sinuses transverse or
sigmoid sinuses
the duration of NREM N3 and REM. This results in going
back to NREM N1 and N2 more rapidly, without developing
Comparison to other veins
any of the sleep disorders we mentioned. Benzodiazepines
The following table summarizes the differences between the
are useful in this scenario.
structure of the walls of the dural venous sinuses and those
Abuse of alcohol, benzodiazepines, and barbiturates is
of other systemic vascular veins.
associated with depression and some memory processing
impairments. This happens because these drugs decrease the FEATURE DURAL VEINS
duration of REM. VENOUS
SINUSES
WALL Dura mater lined Tunica externa,
Dural Venous Sinuses COMPOSITION with endothelium tunica media, and
Definition They lack tunica tunica interna
The dural venous sinuses, also known as cranial sinuses, are media lined with
endothelium
venous channels found between the endosteal and the dura VALVES Absent Present
around the brain. The dural venous sinuses receive blood
and cerebrospinal fluid. Clinical relevance
Blood comes from the internal and external veins of the A clot might form within the dural sinuses when there is
brain → the dural venous sinuses → which empty into the damage to the dura mater or when an infection ascends from
internal jugular vein. the ophthalmic vein due to orbital cellulitis. Patients present
The cerebrospinal fluid comes from the subarachnoid space with:
after being filtered out by the arachnoid granulations. • Headaches
• Focal neurologic deficits
Anatomy • Seizures
The anterior dural venous sinuses are: Dural sinus thrombosis is also associated with
• The sphenoparietal sinuses hypercoagulable states such as pregnancy, history of factor

578
V Leiden disease, or oral contraceptive use. The ipsilateral medial deviation of the eye due to unopposed
confirmation of the diagnosis is possible with a CT scan of action of the medial rectus muscle.
the brain with radiocontrast in the venous phase, see Figure
1. Cerebral Perfusion Pressure
Definition:
Cerebral perfusion pressure is the pressure gradient that
causes cerebral blood flow. Cerebral perfusion is the
movement of blood through cerebral arteries and brains
supplying the brain. The intracranial pressure is the pressure
imposed on the cerebral blood vessels that impede cerebral
blood flow and is dependent on the three components that
are found within the cranium: blood, cerebrospinal fluid,
and the brain.
Figure 1: CT scan with contrast in venophase showing a CBF = CPP/CVR
filling defect in the sagittal sinus. Most likely diagnosis is where CBF: cerebral blood flow;
sagittal sinus thrombosis. Source: CPP: cerebral perfusion pressure;
https://en.wikipedia.org/wiki/Cerebral_venous_sinus_thro CVR: cerebrovascular resistance.
mbosis#/media/File:Sagital_sinus_thrombus.JPG CPP = MAP – ICP
where CPP: cerebral perfusion
Cavernous sinuses pressure; MAP: mean arterial
The cavernous sinuses are found at the base of the skull. pressure; ICP: intracranial pressure.
They are bordered by the temporal bone of the skull and the
sphenoid bone, and they are located lateral to the sella
turcica where the pituitary gland lies. They are part of the Cerebral perfusion:
dural venous sinuses. Figure 2 shows the cavernous sinuses. From the first equation above, we can conclude that CPP is
dependent on cerebral blood flow which is known as
cerebral perfusion. It is also evident that CPP is dependent
on cerebrovascular resistance.
The cerebral blood flow will decrease if the cerebral
vascular resistance increases, i.e. in the case of
vasoconstriction. The opposite will happen in the case of
vasodilation. Cerebrovascular resistance is regulated by four
mechanisms:
• Metabolic autoregulation
• Pressure autoregulation
• Arterial pCO2 and pO2
Figure 2: The cavernous sinuses at the base of the skull.
Source: • Neural control
https://en.wikipedia.org/wiki/Cavernous_sinus#/media/File In most cases, the autoregulation mechanisms of the brain
:Cavernous_sinus.png are trying to impose a tight control over CPP while changing
CVR and CBF. To better understand this, let us have an
The cavernous sinuses are very important from a clinical example:
point of view for the following reasons:
Example:
• The internal carotid artery passes through the
In normal circumstances, arterial
sinus.
pCO2 might be 40 mmHg. In that
• The cranial nerves III, IV, the first and second case. CBF rate will equal 50 mL per
branches of cranial nerve V, and cranial nerve VI
100g per min. If that person develops
also pass through the sinus. respiratory acidosis for some reason,
• Accordingly, a thrombus of the cavernous sinuses the pCO2 will get elevated. If that
might adversely affect any of these structures happens, the CBF rate will also
Cranial nerve VI “abducens nerve” is the most commonly increase. This is mediated by
affected one when a cavernous sinus thrombus occurs. The cerebral vasodilation, i.e. decreased
abducens nerve innervates the lateral rectus muscles of the cerebrovascular resistance.
eye, i.e. abducts the eyes. Therefore, an abducens nerve
palsy due to a cavernous sinus thrombus will result in

579
Cerebral perfusion pressure Clinical significance:
In order for the blood to flow within the cerebral In some cases, we aim to decrease the CBF in an attempt to
vasculature, a pressure gradient needs to exist between mean decrease the intracranial pressure. This is usually needed in
arterial pressure and the intracranial pressure. Accordingly, an acute setting while treating acute cerebral edema due to
a hypotensive patient might have a decreased cerebral stroke or traumatic brain injury. If you decrease the CBF
perfusion pressure if you take into account the second over a long period of time, you risk cerebral ischemia.
equation we presented. Regardless, this can be achieved by therapeutic
The autoregulation mechanisms we have in place will try to hyperventilation. A decrease in pCO2 leads to cerebral
solve this by decreasing the cerebrovascular resistance, vasoconstriction which in turn decreased CBF and ICP.
vasodilation, in an attempt to maintain good cerebral
perfusion. Circle of Willis
Definition:
Note: In traumatic brain injury, the A system of anastomoses exists between the anterior and
intracranial pressure might be posterior blood supplies to the brain. This system of
elevated because of an intracranial anastomoses is known as the circle of Willis. The three main
hematoma. This might have a cerebral arteries branch from the circle of Willis, i.e. namely
deleterious effect on CPP and CBF. the anterior cerebral artery, middle cerebral artery, and
Accordingly, most of the intensive posterior cerebral artery. This system of anastomoses
care management of traumatic brain connects the internal carotid arteries with the basilar artery.
injury patients is based on lowering
the intracranial pressure and Anatomy:
improving CBF. See Figure 1.

The diagram below, Figure 1, depicts the different changes

in CBF that you would expect to see when pCO2, pO2, or
MAP are changed.

Figure 380: Origins and branches of the circle of Willis.

Source: https://www.knowyourbody.net/circle-of-
willis.html
Origins:
The circle of Willis comes from two important arterial
Figure 379: CBF regulation by pCO2, pO2, and MAP. The sources:
optimum CBF of 50 mL/100g/min occurs when pCO2 is • The internal carotid artery, which is a branch of the
around 40 mmHg, pO2 is around 70 mmHg, and MAP is common carotid artery
between 70 and 150 mmHg. • The basilar artery, which is made up by the fusion of
the two vertebral arteries
Intracranial pressure: The vertebral arteries come from the subclavian artery.
From the second equation, we see that CPP is dependent on Before the two vertebral arteries fuse, they give rise to three
intracranial pressure. The most simplified view of the important arteries:
components that influence the intracranial pressure states:
• One anterior spinal artery
• You have three main components in a closed
• And two posterior spinal arteries
space, the cranium.
Branches:
• These three components determine the ICP. To better understand the different branches of the circle of
• If you have an increase in any of the three Willis, it is advisable to think of the origins of each part of
components, you will expect that the ICP is going the circle to understand which parts of the brain are supplied
to get elevated. by branches coming from there:
• The three components are blood, brain tissue, and • The anterior part of the circle of Willis comes mainly
cerebrospinal fluid. from the internal carotids. It gives rise to the following
Based on these statements, you would expect that the ICP branches:
will get elevated if the patient develops an intracranial bleed o Anterior communicating artery → as the name implies
or a brain tumor for instance. connect the two anterior cerebral arteries.

580
o Anterior cerebral artery → supplies the anterior medial
parts of the brain, Figure 2.
o Middle cerebral artery → supplies the lateral parts of
the brain, Figure 2.
o Anterior choroidal artery
o Three lenticulostriate arteries

• The posterior part of the circle of Willis comes from the

basilar artery. It gives rise to the following branches:
o Posterior cerebral artery → supplies the posterior parts
of the brain, Figure 2.
o Multiple pontine arteries → supply the pons.
o Superior cerebellar artery
o Anterior inferior cerebellar artery
o Posterior communicating arteries → as the name
implies, connects the posterior cerebral arteries with the
middle cerebral arteries.
• The posterior inferior cerebellar artery comes from the
vertebral artery.

Figure 382: Blue areas are known as cortical border zones.

Red areas are known as internal border zones. These are the
most commonly affected zones in ischemic stroke and in
severe hypotension. Source:
https://www.pinterest.com/pin/748230925566541520/

Ventricular System of the Brain:

Definition
The ventricular system of the brain consists of four
communicating cavities within the brain that are filled with
Figure 381: An illustration of the different brain regions
supplied by the three main cerebral arteries. Source: cerebrospinal fluid (CSF). Namely, they are the two lateral
ventricles, the third ventricle and the fourth ventricle.
https://en.wikipedia.org/wiki/Cerebral_circulation#/media/
File:Cerebral_vascular_territories.jpg Anatomy:

Clinical significance:
Because of the extensive network of anastomoses and
communications between the different arteries of the circle
of Willis, an occlusion of one of the arteries will usually
result in minimum damage. It will only affect the parts of
the brain that are supplied by that terminal branch if the
occlusion occurs before the site of the communication.
Figure 383: Anatomy of the ventricular system of the brain.
Source: DOI: 10.1007/s00381-013-2321-3
The brain blood supply is not as homogenous as one might
The lateral ventricles:
expect. Accordingly, we have watershed zones between the
There are two lateral ventricles in the brain. They are
anterior/middle cerebral arteries and posterior/middle
divided into:
cerebral arteries. If a patient develops severe hypotension,
these cortical border zones might be affected and become • A body
ischemic. • An atrium
• Three horns, anterior, posterior (occipital) and inferior
Figure 3 demonstrates this important clinical observation The body of the lateral ventricles is found within the
about the blood supply of the brain. parietal lobe. It extends from the foramen of Monro to the
corpus callosum and fornix. The important anatomical
landmarks of the lateral ventricles are:

581
• The lateral wall which is formed by the caudate nucleus This type of hydrocephalus is also known as obstructive
and the thalamus hydrocephalus. As the name implies, there is an obstruction
• The medial wall which is formed by the septum in CSF-flow. The level of the obstruction determines two
pellucidum and the body of the fornix things:
• The floor which is formed by the thalamus • Which ventricles are going to be enlarged?
• And the roof which is formed by the body of the corpus • And the most likely etiology
callosum For example, an obstruction at the foramen of Monro will
The anatomy of the lateral ventricles is depicted in Figure 1. result in dilation of the lateral ventricles. And it will be most
The third ventricle: likely caused by a colloidal cyst.
The third ventricle is narrow, and funnel shaped. It is a Stenosis of the aqueduct of Sylvius can be congenital or
midline cavity located at the center of the head. It acquired. Both, the lateral ventricles and the third ventricle
communicates superiorly with the lateral ventricles via the will be dilated.
foramen of Monro, and posteriorly with the fourth ventricle Finally, an obstruction at the level of the foramina of
via the aqueduct of Sylvius. Luschka or Magendie as is the case in Dandy-Walker
The fourth ventricle: malformation would result in dilation of all four ventricles
This is a broad, tent-shaped midline cavity located at the of the brain.
center of the posterior fossa between the brainstem and the
cerebellum. The important landmarks of the fourth ventricle Note: In most clinical cases, there is
are: a complex picture of communicating
• Posterior wall: the cerebellum and non-communicating
• Anterior wall: the pons and upper half of the medulla hydrocephalus. For example, in
• Lateral walls: the cerebellar peduncles intraventricular hemorrhage,
The fourth ventricle is connected to the central canal of the hydrocephalus could be
spinal cord via the foramen of Magendie and the foramina communicating at first, but
of Luschka. eventually progress to non-
communicating because of the
CSF Route deposition of blood clots at the
The CSF is made by the ependymal cells of the choroid different foramina mentioned here.
plexus which lines the ventricles. It travels to the
subarachnoid space via the foramina of Luschka and
Magendie to be reabsorbed by the arachnoid granulations.
Eventually, it gets drained into the dural venous sinuses.

Clinical Significance
Cellular waste products, and nutrition are found within the
CSF. Our central nervous system is bathed within the CSF.
Because of this, we need the ventricular system of the brain
to be patent. If the ventricular system of the brain becomes
dysfunctional, hydrocephalus and increased intracranial
pressure would develop. This dysfunction can be in two
forms: communicating or noncommunicating Figure 384: Intraventricular and intracerebral hemorrhage as
hydrocephalus. seen on non-contrast CT scan of the head. Note the dilation
Communicating hydrocephalus: of the lateral ventricles of the brain, which is consistent with
It is also known as non-obstructive hydrocephalus. The main hydrocephalus.
problem is impaired CSF reabsorption. This could be related Source:
to functional impairment of the arachnoid granulations. https://en.wikipedia.org/wiki/Hydrocephalus#/media/File:I
Most common causes include: ntracerebral_hemorrhage.jp
• Subarachnoid or intraventricular hemorrhage see
Cranial Nerve Nuclei
Figure 2
Definition:
• Meningitis
A cranial nerve nucleus is defined as a collection of neurons
• Congenital absence of the arachnoid villi where synapses are formed between a cranial nerve and a
Inflammation and fibrosis of the arachnoid granulations is higher-order neuron within the brainstem. Per this
thought to be the main mechanism of communicating definition, a cranial nerve nucleus is considered as gray
hydrocephalus in hemorrhagic and infectious etiologies. matter, whereas, the cranial nerve is white matter.
Non-communicating hydrocephalus:

582
Classification by function: o And two visceromotor nuclei of CN IX and VII
Some cranial nerves are purely sensory, i.e. the olfactory • Sensory nuclei:
nerve, others are purely motor, i.e. the oculomotor nucleus, o Main trigeminal nucleus (CN V)
and some of them are both motor and sensory. o And the cochlear and vestibular nuclei of CN VIII
Motor cranial nerve nuclei:
• The motor efferent nuclei of CN III in addition to the Nuclei in the medulla:
autonomic efferent nuclei of that nerve • Motor nuclei:
• CN IV, V, VI, VII, IX, X, and XII also have motor o Laterally, we have the nucleus ambiguous of CN IX, X
nuclei within the brainstem and XI
• Motor nuclei are found in a more ventral position o Medial to it, we have the hypoglossal nucleus of CN
within the brainstem XII
Sensory cranial nerve nuclei: o Posteriorly, we have another visceromotor nucleus of
• CN V, VII, VIII, IX, and X have somatic sensory or CN X
specialized sensory nuclei within the brainstem • Sensory nuclei:
• The sensory nuclei are found in a more dorsal position o The spinal trigeminal nucleus of CN V
within the brainstem relative to the motor nuclei o The solitary nucleus responsible for taste of CN VII,
IX, and X
Classification by location:
This classification of the cranial nerve nuclei is more Clinical significance:
important for medical students as it tests your knowledge in Understanding the anatomy of the cranial nerve nuclei is
neuroanatomy. Figure 1 demonstrates the locations of the helpful because it can give us a clue about the possible
main cranial nerve nuclei. cranial nerve palsies that would occur if one of these nuclei
become damaged.

Note: Damage to a cranial nerve

nucleus will result in ipsilateral
weakness/sensory loss except for the
motor nucleus of CN IV which if
damaged would result in
contralateral loss of function due to
decussation.

Figure 385: An illustration of the cranial nerve Nuclei. The Cranial Nerves
red nuclei are motor, whereas the blue ones are sensory. The Definition:
distribution of motor and sensory nuclei is bilateral, but in A cranial nerve, as the name implies, is a nerve that emerges
this illustration, they are viewed separately. Source: directly from the brain (or the brainstem) and it can be motor
https://en.wikipedia.org/wiki/Cranial_nerve_nucleus#/medi or sensory in function. Ten of the twelve cranial nerves
a/File:Gray696.svg emerge from the brainstem, the remainder two emerge
directly from the brain.
Nuclei in the midbrain:
• In the midbrain, there is one sensory cranial nerve Overview of the Cranial Nerves
nucleus and three motor nuclei CN I:
• From superior to inferior, we have the CN III motor • This is the first cranial nerve
nucleus, the CN III visceromotor Edinger-Westphal • Also known as the olfactory nerve
nucleus, and the CN IV motor nucleus • It goes directly to the brain
• Most inferior in the midbrain, we have the sensory • It is responsible for the sense of smell
nucleus of the trigeminal nerve known as the CN II:
mesencephalic trigeminal nucleus (CN V) • It is known as the optic nerve
Nuclei in the pons: • It transmits visual information, sensory
• Motor nuclei: • It goes and synapses directly to the brain
o Trigeminal motor nucleus (CN V) CN III:
o Abducens nucleus (CN VI) • The oculomotor nerve
o Facial nucleus (CN VII) • Responsible for part of the eye movements

583
 • Supplies all the muscles of the eye except for the • Responsible for the movement of the tongue, i.e.
superior oblique and the lateral rectus muscles supplies the different tongue muscles
• Also responsible for the constriction of the pupils
in light Pathologic Examples of the Cranial Nerves
• Also elevates the eyelids
CN IV: Note: In this section, we always refer
• The trochlear nerve to lower motor neuron type of
• Supplies the superior oblique muscle of the eye damage, unless otherwise specified.
• The only cranial nerve that comes from the
contralateral side of the brainstem CN I:
CN V: • If damaged, the patient might develop anosmia
• Has three parts: (loss of smell sense) or parosmia (distortion of the
o The ophthalmic, maxillary and sense of smell)
mandibular branches form the trigeminal CN II:
nerve • Based on the exact site of the lesion, the patient
o Provide facial sensation will lose sight of objects on the left or right side of
o Controls the muscles of mastication their body (homonymous hemianopsia), or have a
CN VI: problem in seeing objects outside their visual field
• The abducens nerve (bitemporal hemianopsia) or be blind
CN III:
• Supplies the lateral rectus muscle, which is
responsible for the lateral abduction of the eye ball • If damaged, the patient will develop strabismus,
ptosis, and mydriasis
• It is the longest cranial nerve and travels a long
way at the skull base • Medial adduction of the eye will be lost, see Figure
1
• This feature makes it more likely to be injured in
increased intracranial pressure or when there is a
temporal or basilar skull fracture
CN VII:
• The facial nerve
• Responsible for the motor function of the muscles
of the face
• Also responsible for the sense of taste
CN VIII:
• The vestibulocochlear nerve
Figure 386: CN III palsy. The patient is trying to look to the
• A purely sensory nerve that transmits information
right side. The left eye fails to go to the nasal position due
from the senses of hearing and balance
to CN III palsy. Source:
CN IX:
https://en.wikipedia.org/wiki/File:Lawrence_1960_14.13.p
• The glossopharyngeal nerve ng
• Provides sensory and taste sensation to the back of
the tongue CN IV:
• Also responsible in part for the gag reflex • The superior oblique muscle will be paralyzed
CN X:
• See Figure 2
• The vagus nerve
• The most important parasympathetic nerve in the
body. Innervates many organs and structures
• It is also responsible in part for the gag reflex
CN XI:
• The accessory nerve
• Supplies the trapezius and the sternocleidomastoid
muscles
CN XII: Figure 387: CN IV palsy. Inability to look upward and
• The hypoglossal nerve inward in the left eye. Source:
• Different from other cranial nerves in that it https://en.wikipedia.org/wiki/File:Lawrence_1960_14.13.p
receives innervations from both motor cortices ng

584
CN V: • If damaged, the patient could develop hoarseness
• If damaged, the patient might lose sensation in the of the voice, issues in the control of blood pressure
affected division’s distribution and heart rate, or gastric dumping syndrome
• Trigeminal neuralgia is a very painful condition depending on the level of the lesion
due to trigeminal nerve damage. It responds to CN XI:
carbamazepine • If damaged, might result in a winged scapula due
CN VI: to trapezius muscle paralysis or inability to turn the
• If damaged, the lateral rectus muscle will be head to the ipsilateral side of the lesion. See Figure
paralyzed. See Figure 3 5

Figure 388: CN VI palsy. The patient is unable to abduct the

left eye laterally. Source:
https://en.wikipedia.org/wiki/File:Lawrence_1960_14.13.p
ng

CN VII:
Figure 390: Winging of the right scapula due to CN XI
• Facial nerve palsy, or Bells’ palsy damage. Source:
• Mechanical damage to the nerve will also result in https://en.wikipedia.org/wiki/File:Lawrence_1960_14.14.p
facial nerve palsy that is more permanent than ng
Bells’ palsy
CN VIII: CN XII:
• If damaged, the patient might develop tinnitus or • Damage to this cranial nerve will result in
hearing loss weakness or atrophy of the tongue. It is important
• Vestibular nerve inflammation, which is usually to differentiate between tongue weakness due to
viral, will result in severe vertigo upper motor neuron disease (cerebral stroke) or
• Damage to the nerve could also result in lower motor neuron disease (direct damage to the
nystagmus hypoglossal nerve)
CN IX:
• If damaged, you will see the uvula pointing
towards the ipsilateral side of the lesion. See Note: Upper motor neuron diseases
Figure 4 will result in weakness of the tongue
but without fasciculations or atrophy.
Damage of the nerve itself, i.e. lower
motor neuron disease, will result in
atrophy and fasciculations of the
tongue. The tongue will deviate to
the ipsilateral side of the lesion in
lower motor neuron disease of the
tongue.

Spinal Cord Tracts

Definition
Sensory information is delivered to the brain all the time via
Figure 389: CN IX palsy. Source: the ascending spinal cord tracts, whereas, motor information
https://en.wikipedia.org/wiki/File:Lawrence_1960_16.9.pn is transmitted from the brain to the spinal cord causing the
g body to move via the descending spinal cord tracts.
CN X:
585
Accordingly, the spinal cord tracts are axons going to and
coming from the brain.

White Matter and Gray Matter of the Spinal Cord

The organization of the white matter “axons” and gray
matter “neuronal cell bodies” in the spinal cord is different
from what is found in the brain.
In the brain, the gray matter is found on the outer border of
the brain tissue and forms what is known as the cerebral
cortex. However, there are also gray matter islands scattered
within the brain in what is known as subcortical gray matter Figure 393: ANS pathway.
or subcortical nuclei. Figure 392: SNS pathway.
UMN is cell body in the
On the other hand, the gray matter in the spinal cord is UMN is cell body in the
hypothalamus → LMN is
found in the inner portions of the spinal cord. It is primary motor cortex →
neurons coming from the
surrounded by white matter in what is known as the spinal descends ipsilaterally at
autonomic ganglia, i.e.
cord tracts. Figure 1 demonstrates the difference in the first but decussate at
preganglionic neuron.
organization of gray matter and white matter in the spinal caudal medulla →
Source:
cord and the brain. descends contralaterally in
http://www.napavalley.ed
the lateral corticospinal
u/people/briddell/documen
tract. They synapse at the
ts/bio%20218/15_lecture_
cell body of anterior horn
presentation.pdf
and the LMN leaves the
spinal cord to synapse with
muscle fibers at the
neuromuscular junction.
Source:
http://www.napavalley.ed
Figure 391: The organization of the gray and white matter u/people/briddell/documen
of the spinal cord and the brain. Source: ts/bio%20218/15_lecture_
http://memorise.org/wp-content/uploads/2014/04/gray.jpg presentation.pdf

The Descending Tracts of the Spinal Cord: The descending spinal cord tracts are:
• The lateral corticospinal tract
Note: The descending spinal cord • The anterior corticospinal tract
tracts transmit motor information. The organization of the descending fibers in the lateral
corticospinal tract is “lower limbs in the outer parts, whereas
The naming of a spinal cord tract is systemic and can give upper limbs and cervical fibers in the inner part”. Figure 4
you a clue of whether it is an ascending or a descending shows the main descending tracts of the spinal cord.
tract. Ascending tracts usually start with “spino” whereas
descending tracts end with “spinal”.
Motor information in the central nervous system is
transmitted via two systems:
• The somatic nervous system (SNS) is responsible
for voluntary movements, i.e. contraction of
skeletal muscles. See Figure 2.
• The autonomic nervous system (ANS) controls the
glands, smooth muscles of the gastrointestinal
tract, and the cardiac muscle. See Figure 3.
Figure 394: The lateral and anterior corticospinal tracts, in
blue. Source:
http://www.napavalley.edu/people/briddell/documents/bio
%20218/15_lecture_presentation.pdf

The Ascending Tracts of the Spinal Cord

The three major sensory tracts of the spinal cord are:

586
 • The posterior column tract http://www.napavalley.edu/people/briddell/documents/bio
• The spinothalamic tract %20218/15_lecture_presentation.pdf
• The spinocerebellar tract
These ascending tracts have three orders of neurons: Epidural and Subdural Hematoma
• First-order neuron is in the dorsal or cranial root Epidural Hematoma
ganglion
• Second-order neuron is an interneuron in the Definition
posterior horn of the spinal cord or brain The traumatic accumulation of blood between the skull and
• Third-order neuron is a neuron that transmits the dural membrane. The condition is usually associated
information from the thalamus to the cerebral with a skull fracture. The source of blood is arterial.
cortex.
Epidemiology
Note: The posterior column tract Epidural hematoma (EDH) occurs in up to 2% of all head
decussates in the medulla and trauma cases. Reasonably, the rate of occurrence of EDH is
ascends contralaterally as the medial higher in patients with severe traumatic brain injury, i.e.
lemniscus, whereas the 10%.
spinothalamic tract decussates in the The estimated mortality rate of EDH ranges from 5 to 43%.
spinal cord at the same level via the
anterior white commissure to ascend Pathology
contralaterally. Up to 80% of EDHs are in the temporoparietal region. This
is the location of the middle meningeal artery, which is the
The posterior column tract: most commonly lacerated artery in EDH. The following
• Responsible for proprioception, fine touch, and points summarizes the most important pathophysiologic
pressure sensation. characteristics of EDH:
• The final destination of the tract is the contralateral • Source of blood is usually arterial
primary sensory cortex. • Most commonly affected artery is the middle
The spinothalamic tract: meningeal artery
• Lateral spinothalamic tracts are responsible for the • 20% of the cases are frontal or occipital. The
transmission of pain and temperature sensations. prognosis is usually better when it is not
• Anterior spinothalamic tracts transmit crude touch temporoparietal
and pressure sensations. • They can expand and result in a midline shift or
• They both end up after their third-order neuron in subfalcine herniation of the brain
the contralateral primary sensory cortex.
The spinocerebellar tract: Clinical Presentation
Immediate, brief loss of consciousness after head trauma is
• The posterior spinocerebellar tracts transmit
proprioception to the ipsilateral cerebellar cortex. not indicative of an EDH. However, the following signs and
symptoms should raise the suspicion of an EDH in a head
• The anterior spinocerebellar tracts also transmit
trauma patient:
proprioception mostly to the ipsilateral cerebellar
cortex but also to the contralateral cerebellar • The patient remains unconscious after the head
cortex. trauma
Figure 5 shows the main sensory tracts of the spinal cord. • Sudden neurologic deterioration after a period of
stability
• Severe headache
• Repeated vomiting
• Seizures
• Dangerous mechanism of injury

Note: A lucid interval presentation is

very suggestive of EDH, however it
occurs only in 20% of the cases. The
patient will regain consciousness,
Figure 395: There are three ascending tracts in the spinal talk with you, and a minute later the
cord. The posterior columns, spinothalamic, and patient will become apneic, and
spinocerebellar tracts. Source: comatose due to brain herniation.

587
Diagnosis Pathology:
Laboratory testing: High-speed impact to the skull is the most common cause of
• CBC is helpful especially in infants who could a subdural hematoma (SDH). The brain will accelerate or
develop hemorrhagic shock due to an EDH decelerate relative to the dura, tearing small blood vessels,
• Coagulation profile should be checked i.e. bridging veins.
Imaging studies: The elderly persons are more prone to SDHs after minor
• Non-contrast head CT scan is the diagnostic trauma because of brain atrophy which leaves more space
modality of choice for the brain to move after the trauma, stretching and tearing
• It can demonstrate the location, volume, effect and the bridging veins.
other associated injuries of an EDH Because the source of blood is venous, it could take days or
• The volume of EDH should be determined because weeks until there is enough blood to cause any symptoms.
it has an impact on the management Accordingly, the history of minor head trauma might not be
Figure 1 shows an EDH on an unenhanced head CT. recalled by some patients.
Like EDH, a huge SDH can result in a midline shift and
brain herniation.

Clinical Presentation
Acute SDH: They occur immediately after injury
• History of a head trauma
• The trauma is usually severe
• Patients are usually comatose at the time of injury
and do not regain consciousness, in contrast to
EDH
• Patients are usually older than those who have
traumatic EDHs
• Subacute SDH presents 4 to 21 days after injury,
whereas chronic SDH presents more than 21 days
Figure 396: Non-contrast CT scan of the head showing a
after injury
traumatic fronto-temporal EDH. Notice that it is biconvex in
Chronic SDH:
shape. Source:
• The history of head trauma might not be recalled
https://en.wikipedia.org/wiki/Epidural_hematoma#/media/
File:Traumatic_acute_epidual_hematoma.jpg • The patient will develop headaches, gait
disturbances, cognitive changes, motor deficits, or
Treatment
After establishing an IV access line, administering oxygen, a decreased level of consciousness gradually
and IV fluids the patient should receive a neurosurgical • History of coagulopathy, use of blood thinners, or
consultation. Emergent evacuation of the epidural old age in these patients is usually present
hematoma is needed in most cases, especially when there are
signs of increased intracranial pressure. Diagnosis
A coagulation profile is more important here because
Subdural Hematoma: coagulopathy is a very important risk factor for SDH and
Definition can influence the management.
This is a collection of blood/blood clot between the inner Imaging studies:
layer of the dura and the brain and arachnoid membrane. • Non-contrast CT scan of the head is the diagnostic
Subdural hematomas are more common than EDH. The modality of choice for SDH
source of blood is usually venous. • The blood collection will be crescent-shaped
The differentiation between acute, subacute and chronic
Epidemiology SDH is possible with non-contrast CT scan. Figure 2 shows
Up to 25% of those who sustain a head injury can develop a the main differences.
subdural hematoma. Spontaneous subdural hematomas can
be seen in old patients who are on chronic anticoagulant
treatment. There is a male predominance with a 3:1 male to
female ratio. The mortality rate is reported to be between 36
to 79%.

588
 A. This is the accumulation of blood within the brain
parenchyma due to rupture of a cerebral artery or aneurysm.
Intraventricular hemorrhage:
This is the accumulation of blood within the ventricular
system of the brain due to extension of an intracerebral
hemorrhage.

B. Epidemiology:
Intracerebral hemorrhage occurs in 8 to 13% of all strokes.
The incidence of intracerebral hemorrhage is 15 per 100,000
individuals per year.
More than 20,000 individuals die of an intracerebral
hemorrhage in the United States each year. The 30-day
mortality rate of intracerebral hemorrhage is 44%. Pontine
and brainstem hemorrhages carry the highest mortality rate,
i.e. 75% within 24 hours of onset. Intraventricular
hemorrhage occurs in one third of the patients who have an
intracerebral hemorrhage.
C.
Figure 397: A. An acute SDH that is crescent-shaped and Pathology:
hyperdense. Notice there is a midline shift and obliteration The pathophysiology of intracerebral hemorrhage is
of the right lateral ventricle. B. A subacute SDH that is summarized in the following points:
crescent-shaped and isodense. Again, there is a midline • Hypertensive damage to blood vessel walls is the
shift, but less severe as compared to the acute SDH in (A.). most common etiology
C. Bilateral chronic SDH that are hypodense and crescent- • It can also occur after ischemic stroke due to
shaped. There is no midline shift because of the bilateral reperfusion injury or a hemorrhagic
mass effect. Source: transformation
https://emedicine.medscape.com/article/1137207-
• Rupture of aneurysms or arteriovenous
workup#c9
malformations is also implicated in the
A patient might have a mixed picture of subacute on chronic
pathogenesis of some cases
SDH.
The most commonly affected sites are:
• The basal ganglia (50%)
Treatment:
The treatment of SDH should take into consideration the • The cerebral lobes (20%)
likelihood of survival and the appropriate allocation of • The thalamus (10%)
resources. It can be summarized in the following: • Pons (10%)
• Secure IV access, airway, breathing and • Cerebellum (5%)
circulation • Other brainstem sites (5%)
• Consult neurosurgery to determine the prognosis Clinical Presentation:
after surgical evacuation The symptoms of an intracerebral hemorrhage are:
• If the brain tissue is not ischemic and the prognosis • Alteration in level of consciousness
is favorable, emergent evacuation is indicated • Nausea and vomiting
• Otherwise, you should aim to the correction of any • Seizures
coagulopathy and preserve surgical intervention • Headaches
only when it is life-saving • Focal neurological deficits
The signs of an intracerebral hemorrhage include:
Intracranial and Subarachnoid Hemorrhage: • Hypertension and autonomic dysfunction
Intracranial Hemorrhage: • Neck rigidity
Definition: • A decreased Glasgow-Coma-Scale score
The term “intracranial hemorrhage” refers to any pathologic • Anisocoria
blood accumulation within the cranial vault. In this • Focal neurologic deficits (see table below)
discussion, we limit our definition of intracranial
hemorrhage to intracerebral and intraventricular
hemorrhage.
Intracerebral hemorrhage:
589
 SITE MOTOR SENSORY OCULAR OTHER
PUTAMEN - Contralateral - Contralateral sensory - Contralateral conjugate - Aphasia
hemiparesis loss gaze paresis - Neglect
- Homonymous - Apraxia
hemianopia
THALAMUS - Contralateral - Contralateral sensory - Homonymous - Aphasia
hemiparesis loss hemianopia - Confusion
- Miosis
LOBAR - Contralateral - Contralateral sensory - Contralateral conjugate - Aphasia
hemiparesis loss gaze paresis - Neglect
- Homonymous - Apraxia
hemianopia
CAUDATE - Contralateral --- - Contralateral gaze - Confusion
hemiparesis paresis
BRAINSTEM - Quadriparesis --- - Gaze paresis - Decreased LoC
- Facial weakness - Ocular bobbing - Autonomic
- Miosis instability
CEREBELLUM - Ataxia - Ipsilateral sensory loss - Gaze paresis - Decreased LoC
- Ipsilateral facial - Skew deviation
weakness - Miosis

Diagnosis
Laboratory testing:
• CBC
• Coagulation profile should be checked
• Serum electrolytes and osmolarity to exclude SIADH
• Toxicology screen
Imaging studies:
• Non-contrast head CT scan is the diagnostic modality of choice
• CT or MR angiography to determine the bleeder and guide treatment
• Conventional catheter angiography is diagnostic and therapeutic
Figure 1 shows an intracerebral hemorrhage.

Figure 398: Non-contrast CT scan of the head showing a thalamic intracerebral hemorrhage with leakage into the lateral and
third ventricles. Source: https://en.wikipedia.org/wiki/Intracerebral_hemorrhage#/media/File:Intracerebral_hemorrhage.jpg

Treatment
Conservative treatment can be summarized in the following points:
• Tracheal intubation and initiation of IV fluid therapy
• Control of blood pressure
• Correction of coagulopathy with factor VIIa, fresh frozen plasma, vitamin K, protamine or platelet transfusions as
appropriate
• Anticonvulsant treatment in patients with lobar intracerebral hemorrhage.
• Corticosteroids are CONTRAINDICATED.

Note: Corticosteroids are helpful in vasogenic brain edema, not in cytotoxic brain edema. Therefore,
they are used in patients with brain edema due to brain tumors but not in hemorrhagic patients as they
were shown to increase mortality.

590
Surgery is indicated when:
• Diameter of the hematoma is greater than 3 cm
• Presence of a vascular lesion such as an aneurysm or an AVN
• Lobar intracerebral hemorrhage in a young patient
Treatment options include:
• Catheterization and embolization
• Aspiration of blood especially in basal ganglia hemorrhages
• Craniectomy to relieve increased intracranial pressure not responsive to medical treatment.

Subarachnoid Hemorrhage:
Definition
Subarachnoid hemorrhage (SAH) is the collection of blood in the subarachnoid space. It can be traumatic or spontaneous.
When we talk about subarachnoid hemorrhage as a stroke, we refer to spontaneous hemorrhage due to aneurysmal rupture.

Epidemiology
SAH occurs in one individual per 10,000 per year. Ischemic stroke and intracerebral hemorrhage are more common in males,
whereas SAH is more common in females. Half of the cases of SAH occur before the age of 55 years old. It represents 5%
of all strokes.

Pathology
A cerebral aneurysm is implicated in most cases of spontaneous SAH. The aneurysm is usually located in the circle of Willis.
Cocaine abuse has been associated with an increased risk of SAH.

Note: Cerebral vasospasm is believed to be an important pathology in SAH, and it occurs few days
after the hemorrhage. This complication occurs because of the release of different products from the
degenerating blood within the subarachnoid space and can lead to brain ischemia.

Clinical Presentation:
The symptoms of spontaneous SAH are:
• Sudden, severe headache that is usually described as the worst headache the patient has ever experienced.
• The headache is usually in the back of the head
• Vomiting and seizures are common. 1 in 14 patients with SAH will develop symptomatic seizures.
The signs of spontaneous SAH are:
• Fever
• Neck rigidity is present
• Anisocoria
• Focal neurological deficits

Diagnosis:
Laboratory testing:
• Same as intracerebral hemorrhage
Imaging studies:
• In the acute setting, a non-contrast CT scan is the imaging modality of choice. See Figure 2
• If the patient presents several days after the onset of symptoms, MRI is the imaging of choice

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Figure 399: Non-contrast CT scan of the head showing SAH. Source: https://www.merckmanuals.com/en-
ca/professional/neurologic-disorders/stroke/subarachnoid-hemorrhage-sah

The Fisher Grade classification system is helpful in classifying the degree of subarachnoid hemorrhage on CT scan, see table
below.
GRADE DESCRIPTION
1 SAH is not seen
2 SAH is less than 1 mm thick
3 More than 1 mm thick
4 Diffuse SAH with or without “intraventricular or intracerebral hemorrhage”

Lumbar puncture:
• An elevated number of red blood cells is present in all CSF bottles
• Xanthochromia is a helpful sign in delayed presentation, occurs due to the metabolism of hemoglobin into bilirubin.
Needs at least 12 hours to occur
Angiography:
• Catheter angiography is diagnostic and therapeutic. It allows for coiling of the bleeding vessel or aneurysm

Treatment:
The management of SAH is like that of intracerebral hemorrhage, with one exception:
• In SAH, it is advisable to do catheterization as early as possible to perform coiling

Head Trauma and Intracranial Pressure

Definition:
Traumatic brain injury can be defined as damage to the brain resulting from external mechanical forces. Examples of external
mechanical forces that can cause brain injury include:
• Rapid acceleration or deceleration
• Direct impact
• Penetration by a projectile

Pathophysiology:
In normal physiologic conditions, the cerebral perfusion pressure (CPP) is maintained at higher than 70 mmHg. The cerebral
perfusion pressure is equal to the mean arterial pressure minus the intracranial pressure. The normal intracranial pressure
(ICP) is between 5 to 15 mmHg.

Note: In normal conditions, changes in the CPP between 50 to 150 mmHg do not cause significant
changes in the cerebral blood flow because of cerebrovascular autoregulation mechanisms. This
feature is lost in traumatic brain injury, where cerebral blood flow becomes directly related to the
mean arterial blood pressure.

The cranium is a closed space where the ICP is dependent on the sum of three intracranial volumes:
• Brain

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 • Blood
• Cerebrospinal fluid
Any change in the volume of these three components will result in a change in the ICP. Brain damage, and the symptoms
of traumatic brain injury, are mostly due to increased ICP.
Effects of an increased ICP on the brain:
• Cerebral blood flow and CPP are decreased when the ICP is above 20 mmHg. This could lead to ischemia
• Transtentorial herniation is a life-threatening complication to increased ICP. It presents with:
o Compression of the oculomotor nerve → bilateral dilated pupils
o Loss of consciousness
o Brady cardia
o Respiratory compromise

Note: Cushing triad is suggestive of transtentorial herniation. The patient develops hypertension,
bradycardia and respiratory distress.

Classification:
Head injuries can be:
• Open injuries with brain matter out
• Closed injuries
• Scalp injuries without significant brain or skull damage
• Skull fractures, which could be open or closed
Classification of the severity of traumatic brain injury:
• Minor: GCS 13-15
• Moderate: GCS 9 -12
• Severe: GCS 3 -8
The Glasgow-Coma-Scale score is calculated based on the following table in adults:
DOMAIN DESCRIPTION SCORE
No eye opening 1
To pain 2
EYE OPENING
To speech, i.e. not to command 3
Spontaneous 4
None 1
Incomprehensible sounds 2
VERBAL RESPONSE Inappropriate words 3
Confused, not oriented 4
Oriented 5
None 1
Extensor response to painful stimuli 2
Flexor response to painful stimuli 3
MOTOR RESPONSE
Withdrawal from pain 4
Localizes to pain 5
Obeys commands 6
The GCS total score can range from 3 to 15.
Types:
The types of head injury include:
• Blunt: most commonly result in a closed head injury
• Penetrating: an object penetrates the skull and directly injure the brain tissue. Will result in an open head injury
• Other mechanisms of injury such as blast over-pressure, or acceleration/deceleration
Mechanisms of Brain Injury:
Brain injury can be primary or secondary. Primary brain injury is usually irreversible.
Primary brain injury:
• Types include: diffuse axonal injury from shearing of grey-white matter interface, cerebral concussion, cerebral
contusion, and cerebral laceration

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 • Very little to be done. Damage is usually irreversible. Best treatment is prevention
Secondary brain injury:
• Understanding the mechanisms of secondary brain injury is the key for the successful management of traumatic
brain injury
• The disturbance of the brain autoregulatory and systemic physiology mechanisms is the main cause of secondary
brain injury
• Hypotension and hypoxia are the most important causes of secondary brain injury
Possible causes of brain hypoxia:
• Other associated injuries such as pneumothorax might result in hypoxemia
• Brainstem compression might result in apnea
• Excessive loss of blood might result in hypoxemia due to anemia and hypotension
The other important factor of secondary brain injury is increased intracranial pressure. The intracranial pressure might be
increased in the following situations:
• If the patient develops hypercapnia, the cerebrovascular resistance is expected to decrease. Vasodilation will result
in increased volume of blood in the cranium → increased intracranial pressure
• Intracranial mass effect due to epidural or subdural hematomas
• An increase in the volume of the brain tissue due to brain edema
The concept of coup and contrecoup injury: See Figure 1
• A trauma to one pole of the head will result in damage to the brain directly below the site of trauma but also on
the opposite pole of the brain. This happens because the brain will shake, and it will strike the bony skull vault on
the other side.

Figure 400: An illustration of the mechanism of injury known as coup-contrecoup in TBI.

The different mechanisms described above will result in the following types of secondary brain injury if they are not
counteracted by the treating physician properly:
• Expanding intracranial hematomas
• Cerebral edema
• Brain ischemia
• Infection
• Posttraumatic seizures
• Metabolic or endocrine abnormalities such as SIADH
A non-contrast CT scan of the brain is the imaging modality of choice for the identification of intracranial hematomas,
cerebral edema, or skull fractures. See Figure 2.

B.

A.

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Figure 401: A. Punctate hemorrhages suggestive of diffuse axonal injury on a non-contrast CT scan. Source:
http://learningradiology.com/caseofweek/caseoftheweekpix2008-2/cow315-1lg.jpg B. A traumatic epidural hematoma and
a linear skull fracture. Source: www.klinikaikozpont.u-szeged.hu/radiology/radio/surgos/asurg10c.htm

Basal Skull Fracture:

It is important to be able to identify basal skull fracture clinically for two reasons:
• They are difficult to diagnose on imaging studies
• They are associated with an increased risk of meningitis and other infectious complications
The clinical signs of basal skull fracture include:
• Raccoon eyes due to periorbital ecchymosis
• Battle sign which is posterior auricular ecchymosis
• Hemotympanum
• Rhinorrhea or otorrhea due to CSF leakage

Treatment:
Pre-hospital care is as per ATLS guidelines. The first measure to lower the intracranial pressure is by putting the patient in
a reverse Trendelenburg position.
Blood pressure and oxygenation management:
• Prevent SBP < 90 mmHg
• Treat hypoxia. Aim for a SaO2 > 90%
• Mean arterial pressure should be above 90 mmHg
• Intubate patients with a GCS < 9
Increased ICP management:
• Treat ICP only when above 20 mmHg
• Start with mannitol
• Mannitol might induce diuresis. Be careful of hypovolemia
• Sedation with morphine or fentanyl
• Hypothermic therapy
• High-dose barbiturate might be needed
• Surgical drainage of intracranial hematomas, especially of epidural or subdural hematomas that are associated with
midline shift
Seizures’ management:
• Phenytoin, carbamazepine or phenobarbital can be used for the prevention of early posttraumatic seizures
Infection control:
• Antibiotics are indicated for penetrating head injuries or those with basal skull fractures and signs suggestive of
CSF leak

Cerebrovascular Disease
Definition:
Stroke is defined as the sudden onset of a focal neurological deficit lasting more than 24 hours because of a vascular
pathology. It is also known as cerebrovascular accident. An acute stroke is the first 24-hour period post-stroke.

Epidemiology
Globally, and in the United States, cerebrovascular accidents are considered as the second leading cause of death and is
responsible for 8.7 to 12.8% of all deaths. Fortunately, stroke mortality has been declining worldwide mainly due to:
• The introduction of curative treatments
• The prevention of stroke by the adequate treatment of hypertension, atherosclerosis and diabetes
Stroke is also the second leading cause of disability in high-income countries such as the United States and in the European
region.

Classification
The simplest classification of stroke is into ischemic and hemorrhagic stroke.
Ischemic stroke:
• 85% of all strokes are ischemic

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 • Can be thrombotic or embolic.
• Thrombotic ischemic stroke is strongly associated with atherosclerosis and is more common in the elderly. It comes
without any previous warning in 80% of the cases. In the remainder 20%, transient ischemic attacks might occur
few months before the occurrence of the thrombotic stroke.
• Embolic stroke is seen in patients with atrial fibrillation.

Note: The main pathology in ischemic stroke is the inability of the brain neurons to generate ATP
because glucose metabolism is mainly aerobic in the brain. This results in less ATP production, and
the activation of cellular-inducing-death pathways. Eventually, necrosis occurs, and a liquefactive
infarction ensue.

Hemorrhagic stroke:
• 15% of all strokes.
• It can be in the form of subarachnoid or intracerebral hemorrhage.
• Both types can extend into the ventricular system, causing an intraventricular hemorrhage.
• Mortality is very high.
• Rupture of a berry aneurysm is a common cause.

Clinical Presentation:
The clinical presentation of acute stroke is dependent on the affect vascular territory. The following table summarizes the
clinical picture seen after the occlusion of one of the different cerebral arteries.

ARTERY AFFECTED BRAIN REGIONS PRESENTATION NOTES

MIDDLE CEREBRAL - Frontal lobe - Contralateral paralysis and sensory - Could be associated with right
- Temporal lobe loss (face and upper limbs) superior quadrant visual field
FIGURE 1 A - Motor and sensory cortices - Aphasia if in dominant hemisphere defect if in the dominant side
- Hemineglect if in nondominant
hemisphere
ANTERIOR CEREBRAL - Motor and sensory cortices - Contralateral paralysis and sensory
loss (lower limbs)
- Urinary incontinence
LENTICULOSTRIATE - Striatum - Contralateral paralysis - Commonly seen in hypertensive
- Internal capsule - No neglect, aphasia or visual field patients
FIGURE 1 B defects - Due to arteriosclerosis
- A lacunar infarct

ANTERIOR SPINAL - Lateral corticospinal tract - Contralateral paralysis of upper - Medial medullary syndrome is an
- Medial lemniscus and lower limbs example
- Hypoglossal nerve - Contralateral proprioception loss
- Ipsilateral hypoglossal
dysfunction
PICA - Lateral medulla - Dysphagia and hoarseness - Also known as lateral medullary
- Nucleus ambiguous of CN IX, X - Loss of gag reflex syndrome or Wallenberg syndrome
FIGURE 1 C and XI - Vertigo and nystagmus
- Vestibular nuclei - Loss of pain and temperature
- Inferior cerebellar peduncle sensation contralaterally
- Lateral spinothalamic tract - Ipsilateral Horner syndrome
- Ipsilateral ataxia
AICA - Lateral pons - Facial paralysis - Lateral pontine syndrome
- Facial nucleus - Decreased lacrimation and
- Vestibular nuclei salivation
- Spinothalamic tract - Loss of taste from anterior two
- Middle and inferior cerebellar thirds of tongue
peduncles - Vertigo and nystagmus
- Labyrinthine artery - Loss of pain and temperature
sensation contralaterally
- Ipsilateral Horner syndrome
- Ipsilateral ataxia
- Ipsilateral sensorineural deafness
BASILAR ARTERY - Pons, medulla and lower - Consciousness is preserved
midbrain - Quadriplegia
- Corticospinal and corticobulbar - Loss of horizontal but not vertical
tracts eye movements
- CN III nuclei - Locked-in syndrome

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 - Pontine reticular formation
POSTERIOR CEREBRAL - Occipital lobe - Contralateral hemianopia with
- Primary and secondary visual macular sparing
FIGURE 1 D cortices - Alexia without agraphia

Table: Clinical presentation of common stroke syndromes.

A B

C D
Figure 402: MRI and CT studies of stroke patients depicting the affected brain region in four common examples of ischemic
stroke.

Central post-stroke pain syndrome:

• Neuropathic pain
• Due to thalamic lesions
• Initial presentation is paresthesia which evolve over weeks to months to allodynia
• It is contralateral to the lesion site
• Affects 10% of stroke patients
Aphasia is a common presentation of stroke that affects the dominant hemisphere. It is defined as the inability to understand,
produce or use language appropriately. In right-handed individuals, the dominant hemisphere is the left one. There are four
types of aphasia.

Expressive aphasia:
• Also known as Broca aphasia
• The patient’s speech is non-fluent
• The patient’s comprehension is spared
• The affected region is the Broca area in the inferior frontal gyrus

Receptive aphasia:
• Also known as Wernicke aphasia
• The patient is fluent
• Comprehension is impaired
• The patient’s speech makes no sense
• The affected region is the Wernicke area in the superior temporal gyrus

Conduction aphasia:
• The affected region is the arcuate fasciculus
• The patient’s speech is fluent
• The patient’s comprehension of language is intact

Global aphasia:
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 • Arcuate fasciculus, Broca and Wernicke areas are all affected
• The patient is neither fluent nor able to comprehend language
Dysphasia is the motor inability to speak and is not a form of aphasia.

Transient Ischemic Attack

A transient ischemic attack is a unilateral focal neurological deficit that last for few minutes up to 24 hours without
permanent damage and no evidence of necrosis on brain imaging. It is a very important warning sign of an impending stroke.
Up to 35% of those who develop a transient ischemic attack are at risk of developing an ischemic stroke.
Risk factors for transient ischemic attacks:
• Older age
• Hypertension
• Hypercholesterolemia or dyslipidemia
• Diabetes mellitus
• Coronary artery disease
• Family history of stroke
• Presence of a carotid bruit
• Sickle cell anemia and polycythemia vera
Clinical presentation of transient ischemic attacks:
• Temporary loss of vision which is known as unilateral amaurosis fugax
o Suggestive of atherosclerotic disease of the carotid artery
o Due to partial blockage of the ophthalmic artery
• Temporary aphasia
• Temporary hemiparesis or paresthesia
• Transient ischemic attacks due to basilar artery disease:
o Temporary dizziness
o Temporary diplopia
o Temporary vertigo
o Temporary ipsilateral facial weakness with contralateral limb weakness
o Temporary dysarthria or dysphasia
o Headaches

Lacunar Stroke
A deep, subcortical structure is affected but the cortex is spared. The following characteristics are specific to lacunar infarcts:
• Hypertension is the etiology in 90% of the cases
• The most common pathology is arteriosclerosis of the middle cerebral artery or the anterior choroidal artery that
supply the internal capsule
Clinical presentation:
• Contralateral anesthesia
• Contralateral arm and leg weakness
• No higher cortical symptoms such as aphasia, neglect or visual field defects

Cerebrovascular Disease
Stroke Scales:
The first step in the evaluation of a patient with an acute focal neurological deficit is to use a validated stroke scale. The best
option is the National Institutes of Health Stroke Scale NIHSS.
ITEM RESPONSE SCORE
LEVEL OF CONSCIOUSNESS 0 Alert
1 Drowsy
2 Obtunded
3 Unresponsive
ORIENTATION 0 Fully oriented
1 Partially oriented
2 Not oriented
RESPONSE TO COMMANDS 0 Perform two tasks correctly
1 Perform one task correctly
2 Does not respond to commands
GAZE 0 Normal
1 Partial gaze palsy

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 2 Complete gaze palsy
VISUAL FIELDS 0 Normal
1 Partial hemianopia
2 Complete hemianopia
3 Bilateral hemianopia
FACIAL MOVEMENT 0 Normal
1 Minor facial weakness
2 Partial paralysis
3 Complete unilateral palsy
MOTOR FUNCTION 0 No drift
1 Drift before 10 seconds/5 for legs
2 Falls before 10 seconds/5 for legs
3 Unable to move against gravity
4 No movement
LIMB ATAXIA 0 No ataxia
1 Ataxia in 1 limb
2 Ataxia in 2 limbs
SENSORY 0 Normal
1 Mild sensory loss
2 Severe sensory loss
LANGUAGE 0 Normal
1 Mild aphasia
2 Severe aphasia
3 Global aphasia
ARTICULATION 0 Normal
1 Mild dysarthria
2 Severe dysarthria
NEGLECT 0 Absent
1 Mild
2 Severe
Table: The NIHSS score is used in the emergency evaluation of acute stroke. As a medical student, it is advisable to
understand that such scoring systems exist, and they influence management, but there is no need in memorizing the table.

Brain Imaging in Acute Stroke:

Brain imaging is perhaps the most important diagnostic tool that is known to influence the immediate management of acute
stroke. The following points summarizes the current recommendations for brain imaging in acute stroke:
• A non-contrast CT scan is mandatory in all patients
• The CT scan should be performed within 20 minutes of admission to the emergency department
• MRI and diffusion-weighted images are helpful, but should not delay the immediate management of acute stroke

Other Diagnostic Tests:

All the following tests need to be performed at the emergency department only after the initiation of IV alteplase.

Note: The only test that you must perform before starting IV alteplase is the assessment of blood
glucose level.

Laboratory investigations:
• Blood glucose levels; see note above
• CBC
• PT and PTT
• Serum electrolytes
• Baseline troponin assessment
Other tests:
• A chest radiograph is obtained only if there is evidence of acute pulmonary or cardiac disease
• Baseline ECG is recommended in all acute ischemic stroke patients → to exclude atrial fibrillation as the cause of
embolic stroke

Non-specific Management:
The non-specific management of acute stroke is the only management that you are allowed to provide before the
administration of IV alteplase:
• Airway support and breathing assistance in any patient with decreased level of consciousness
• Supplemental oxygen therapy → Peripheral oxygen saturation > 94%
• Treatment of hypotension and hypovolemia

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 • Treatment of hypoglycemia if blood glucose < 60 mg/dL
Hypertensive patients should receive special attention before starting IV alteplase:
• Systolic BP should be lowered to < 185 mmHg
• Diastolic BP should be lowered to < 110 mmHg
• IV labetalol or nicardipine are the antihypertensives of choice

IV Alteplase:
IV alteplase is considered as curative in the treatment of acute ischemic stroke in the properly selected patient. The following
eligibility criteria must be met for the patient to benefit from IV alteplase:
If within 3 hours of onset of symptoms:
• Age > 18 years
• All stroke patients within this time window who are proven to have acute ischemic stroke
If within 3 to 4.5 hours of onset of symptoms:
• Age < 80 years and:
o No history of diabetes
o No history of prior stroke
o NIHSS score < 25
o Imaging evidence of less than one third of MCA territory
Contraindications to IV alteplase:
• Duration of symptoms is > 4.5 hours
• CT scan shows intracranial hemorrhage
• History of ischemic stroke within 3 months
• History of severe head trauma within 3 months
• History of intracranial or intraspinal surgery within 3 months
• Subarachnoid hemorrhage
• GI malignancy within 3 weeks
• GI bleed within 3 weeks
• Coagulopathy

Mechanical Thrombectomy:
Patients who meet the following criteria should receive a mechanical thrombectomy after the administration of IV alteplase:
• Pre-stroke mRS score of 0 to 1
• Cause of ischemic stroke is occlusion of internal carotid or MCA segment 1
• Age > 18 years
• NIHSS score > 6
• ASPECTS score > 6
• Duration of symptoms < 6 hours

Note: These scoring systems are complicated. In summary, patients with occlusion to a major early
segment artery such as the carotid or MCA segment 1 might benefit from thrombectomy after IV
alteplase.

Treatment after the first 24 hours of acute stroke:

• Antiplatelet therapy with aspirin
• Admission to a specialized stroke unit
• Enteral diet should be started within 7 days after admission
• DVT should be prevented by intermittent pneumatic compression
• Statins
• Stroke rehabilitation
• Management of increased intracranial pressure, or cerebral edema if they occur

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Headaches:
General Classification:
Headaches can be classified into primary and secondary. The following table summarizes the main primary and secondary
headaches.
PRIMARY HEADACHES SECONDARY HEADACHES
Tension-type headache Due to infection such as meningitis or sinusitis
Migraine headache Due to intracranial hemorrhage such as SAH
Cluster headache Due to increased ICP
Chronic daily headache Due to a brain tumor

There are two important questions to answer before we discuss the primary headaches in more detail. Does the patient have
any red-alarm signs suggestive of a secondary headache, and when brain imaging is indicated?
Red-alarm signs:
• Systemic symptoms such as fever or weight loss
• History of HIV or systemic cancers
• New-onset focal neurological deficits
• New-onset altered mental status
• Sudden and abrupt onset
• New onset of recurrent progressive headaches
• Any change in the characteristics from previous headaches
• Postural headache
Brain imaging is indicated in the following situations:
• Patients with history of recurrent headaches who now present with recent substantial change in headache pattern
• History of seizures
• New-onset focal neurological deficits
If brain imaging is indicated:
• Perform an MRI in most cases that need imaging per the above-mentioned criteria
• Perform non-contrast CT scan if you suspect acute SAH or intracranial hemorrhage

Tension-type Headache:
Definition:
Bilateral headache that is often associated with stress.
Diagnostic criteria:
Infrequent episodes of mild to moderate bilateral head pain that is tightening and pressing and lasts for minutes to days. IHS
diagnostic criteria:
A. > 10 episodes on < 1 day per month plus all criteria from B to D
B. Duration of 30 minutes to 7 days
C. Two or more of the following: 1 bilateral, 2 tightening non-pulsating, 3 mild-to-moderate intensity, 4 not
aggravated by routine physical activity
D. No nausea, vomiting or photophobia
E. Cannot be attributed to another disorder
Treatment:
• Identify risk factors such as known stressors and triggers to avoid
• NSAIDs, acetaminophen, and aspirin
• Amitriptyline

Migraines:
Definition:
Unilateral mild to severe headache that is debilitating and might be associated with an aura.
Diagnostic criteria: without an aura
Recurrent headaches lasting between 4 and 72 hours. Headaches are unilateral, pulsating, moderate-to-severe in intensity,
aggravated by routine physical activity, and associated with nausea and photo or phonophobia. IHS diagnostic criteria:
A. Occurrence of 5 attacks or more fulfilling criteria B to D
B. Duration of 4 to 72 hours if untreated
C. Two or more of the following: 1 unilateral, 2 pulsating, 3 moderate-to-severe intensity, 4 aggravated by routine
physical activity

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 D. Experience of one or more of the following: 1 nausea, 2 vomiting, 3 photophobia, 4 phonophobia
E. Not attributed to another disorder
Diagnostic criteria: with aura
A. Occurrence of 2 attacks or more that have two or more of the following features:
1 unilateral, 2 moderate-to-severe, 3 pulsating, 4 aggravated by routine physical activity
Aura that is has one of the following features:
1 various neurological symptoms
2 visual and tactile disturbances
3 paresthesia
4 hemiplasia
5 dysarthria
B. Not attributed to another disorder
Acute (abortive) treatment:
• NSAIDs or acetaminophen
• Specific treatments:
o Triptans
o Ergotamine
• Antiemetics such as metoclopramide
• Should be started as early as possible
Prophylactic treatment for patients with two or more attacks per week:
• Anticonvulsants such as topiramate
• Beta-blockers such as metoprolol and propranolol
• Tricyclic antidepressants such as fovatriptan
• Divalproex sodium

Cluster Headache:
Definition:
Unilateral retro-orbital headache associated with lacrimation, nasal drainage, and redness of eyes. Headaches occur in
clusters of 6 to 12 weeks in duration and recur every one year or so.
Diagnostic criteria:
A. 5 attacks or more fulfilling criteria B to E
B. Severe to very severe unilateral pain lasting 15 to 180 minutes if untreated
C. One or more of the following:
1. Ipsilateral conjunctival injection and/or lacrimation
2. Ipsilateral nasal congestion and/or rhinorrhea
3. Ipsilateral eye edema
4. Ipsilateral forehead and/or facial swelling
5. Ipsilateral miosis and/or ptosis
6. Sense of agitation
D. Attacks occur every other day or up to 8 times per day but in clusters
E. Not attributed to another disorder
Acute (abortive) treatment:
• Administration of 100% oxygen
• Subcutaneous sumatriptan
Prophylactic treatment which should be started with the abortive treatment above:
• Calcium channel blocker such as verapamil
• + prednisone for the first two weeks

Chronic Daily Headaches:

Definition:
Daily headaches that develop after the chronic use of NSAIDs or migraine-specific therapies. There are no official diagnostic
criteria for this type of headache.
Treatment:
• Because the pathology is poorly understood, there are no specific treatments
• Cognitive behavioral therapy might be beneficial
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 • Discontinuation of current headache’s medications is recommended
• Preventive treatments used for migraines can be used after drug-dependency issues have been resolved.

Parkinson’s Disease
Definition
Parkinson’s disease is a neurodegenerative disorder that affects the basal ganglia. It is characterized by the loss of
dopaminergic neurons in the substantia nigra.

Epidemiology:
Parkinson’s disease is one of the most common neurodegenerative disorders:
• Approximately, 1 million Americans are affected
• The incidence is 20 cases per 100,000 per year
• Mean age of onset is 60 years
• It has a 3:2 male to female ratio
• The prevalence of Parkinson’s disease in individuals 60 years or older is 1%
Risk factors:
• Hypercholesterolemia
• Repeated head trauma
• Methcathinone exposure
• Amphetamine abuse
• Genetic predisposition and family history
Secondary parkinsonism:
• Post-encephalitis
• Use of neuroleptic drugs such as tetrabenazine, lithium, haloperidol, thiothixene, and risperidone
• Vascular multi-infarct disease
• Hypothyroidism
• Prion disease

Pathophysiology:
The main pathology in Parkinson’s disease is the progressive degeneration of dopaminergic neurons in the substantia nigra
pars compacta.
• These neurons project to the striatum
• When lost, the direct pathway is left inhibited
• The indirect pathway becomes overactivated
Histopathological features of Parkinson’s disease include:
• The presence of Lewy bodies which are intracellular cytoplasmic aggregates of proteins
• Lewy bodies are found mainly in the dopaminergic neurons in the substantia nigra
• Alpha-synuclein misfolded protein aggregates are also characteristic of Parkinson’s disease
Other pathologic characteristics of Parkinson’s disease include:
• Presence of beta-amyloid especially in patients with significant cognitive disturbances
• An elevation in the biomarkers of neuroinflammation

Clinical Presentation:
The diagnosis of Parkinson’s disease is based on the identification of characteristic clinical features and the proper exclusion
of other diagnoses.
The classical triad of Parkinson’s disease include:
• Bradykinesia
• Cogwheel rigidity
• 4 to 6 Hz tremor at rest
As the disease progress, postural instability and dysarthria occur.
The onset of the motor symptoms of Parkinson’s disease is usually late in the disease process, i.e. after 80% loss of
dopaminergic neurons. The nonmotor symptoms of the disease occur earlier and should be identified by the physician to
delay the progression of the disease.
The nonmotor symptoms of Parkinson’s disease include:

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 • Autonomic dysfunction
• Mild cognitive impairment
• Depression
• Anxiety
• Other neuropsychiatric disorders
• Sensory symptoms such as hyposmia and unexplained chronic pain
• Sleep disturbances
• Fatigue and weight loss

Note: Unfortunately, the early symptoms of Parkinson’s disease are nonspecific. Accordingly, any
patient who presents with several unexplained autonomic and cognitive disturbances should be
evaluated for the possibility of Parkinson’s disease.

Diagnosis:
The diagnosis of Parkinson’s disease is based on the following:
• The presence of the classical triad or multiple early nonmotor symptoms
• Supportive evidence obtained from nuclear imaging studies that show deposition of alpha-synuclein on PET or
loss of dopaminergic neurons of the substantia nigra
• The proper exclusion of other diagnoses
Exclusion of structural brain lesions:
• Basal ganglia tumors, or lacunar infarcts can be excluded by MRI
• Subdural hematomas can be excluded by CT
• Multi-infarct disease can be also excluded by brain imaging
Exclusion of metabolic disorders:
• Hypothyroidism, hypoparathyroidism, and vitamin B12 deficiency can be excluded by laboratory testing
• Wilson’s disease can be excluded by laboratory testing as well

Note: The level of certainty of the diagnosis of Parkinson’s disease is classified as definitive, probable
or possible. This is the case because the diagnosis can be confirmed only with post-partum
histopathological examination of the substantia nigra.

Treatment:
Unfortunately, there is no proven treatment for Parkinson’s disease that slows the progression or provide a neuroprotective
effect. Because of this, it is very important to focus on the early recognition of Parkinson’s disease before the development
of the classical triad.
Medications for motor function:
• Levodopa
• Levodopa plus peripheral dopamine decarboxylase inhibitor such as carbidopa
• Possible side effects of levodopa: nausea, vomiting, hypotension, motor fluctuations and dyskinesia
Motor fluctuations in levodopa:
• Wearing off, delayed on, on/off phenomenon, or no on
• Due to fluctuating plasma levels of levodopa or maybe because of disease progression
Medications for early Parkinson’s disease:
• Dopamine agonists such as ergot derivatives: bromocriptine or pergolide, or non-ergot derivatives: apomorphine
or piribedil.
• Can induce severe cardiac valvular disease and pleural or pericardial fibrosis
Other treatments:
• Monoamine oxidase inhibitors such as selegilene or rasagiline for early Parkinson’s disease
• Anticholinergics which should be used only when no longer responsive to levodopa
• Patients who show wearing response to levodopa or prolonged off phenomenon:
o Add a COMT inhibitor (catechol-o-methyl transferase inhibitor) such as entacapone
o Increase the dose of levodopa

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 o Decrease the interval between the doses of levodopa
Treatment of nonmotor symptoms of Parkinson’s disease:
• Anxiety and sleep disorders are treated with benzodiazepines
• Mild cognitive impairment or dementia is treated with a cholinesterase inhibitor such as rivastigmine

Huntington’s Disease
Definition
Huntington’s disease is a dominantly inherited neurodegenerative disease with full penetrance and is characterized by
cognitive, motor and psychiatric disturbances.

Etiology
Huntington’s disease (HD) is caused by an autosomal dominantly inherited CAG trinucleotide repeat expansion in the
huntingtin (HTT) gene. The HTT gene is found on chromosome 4. The trinucleotide repeat expansion results in:
• Abnormal huntingtin protein with long polyglutamine repeat
• Patients with more than 39 CAG repeats will develop the disease
• Carriers of less than 36 CAG repeats are less likely to develop symptoms
• Anticipation is an important characteristic. Anticipation occurs only when the gene is passed paternally

Epidemiology:
Huntington’s disease is a common neurodegenerative disorder:
• The prevalence in Europe and the United States ranges from 10.6 to 13.7 cases per 100,000
• The disease is less common in Japan and other Asian countries with an estimated incidence of 1 case per million
• The age of onset is from 15 to 50 years

Pathophysiology:
The accumulation of the mutant HTT protein results in neuronal dysfunction and death. Macroscopic features of HD are
dependent on the disease progression grade at the time of death.
Grade 0:
• Clinical symptoms and signs suggestive of HD
• No microscopic or macroscopic abnormalities
Grade 1:
• Clinical symptoms and signs of HD
• Microscopic examination reveals fibrillary astrocytosis
• No macroscopic abnormalities
Grade 2:
• Same as grade 1 but with macroscopic changes in the caudate and putamen
• No changes in the globus pallidus
Grades 3 and 4:
• Microscopic and macroscopic changes in the globus pallidus are present

Note: The pattern of neuronal dysfunction seen in HD is characterized by loss of acetylcholine and
GABA in the affected nuclei such as the caudate and putamen.

Clinical Presentation:
Symptoms of HD manifest in patients aged 15 to 50 years and they include:
Motor symptoms:
• Chorea, which are jerky dancing movements
• Athetosis
Cognitive symptoms: they start before motor symptoms
• Impaired emotional recognition
• Abnormalities in executive functioning
• Progressive dementia

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Psychiatric symptoms:
• Apathy
• Anxiety
• Obsessive compulsive behavior
• Psychosis
The natural history of HD ends with the death of the patient in his or her fifties, see Figure 1.

Figure 403: Natural history of HD. Source: https://www.ncbi.nlm.nih.gov/pubmed/27188817

Diagnosis:
The diagnosis of HD is confirmed when all the following criteria are met:
• Symptoms and signs suggestive of HD, especially chorea
• Confirmed family history of HD or positive genetic testing.
Genetic testing is the gold standard in confirming the diagnosis of HD, especially when in earlier grades that do not have
any form of macroscopic changes that might be seen on MRI.
Brain imaging in HD:
• Early in the disease process, structural imaging might not reveal any abnormalities
• MR spectroscopy allows for the measurements of GABA and acetylcholine in selected brain regions
• If compared to controls, it might increase the certainty of the diagnosis
• In later stages, structural MRI can show atrophy of the head of the caudate, due to neuronal cell death

Treatment:
Unfortunately, there is no proven treatment for HD that slows the progression or provide a neuroprotective effect.
Symptomatic management is available.
Medications for motor symptoms:
• Tetrabenazine is used to treat chorea
• Deutetrabenazine has the same effect as tetrabenazine but with a longer half life
Medications for cognitive symptoms:
• Behavioral therapy focusing on coping strategies
• Limited efficacy of cholinesterase inhibitors
Medications for psychiatric symptoms:
• Treatment is specific to the type of psychiatric abnormalities

Note: More than 20 clinical trials are undergoing right now which are based on the identification of
possible disease modifying drugs. Early results are promising.

Dementia Syndromes
Definition
Dementia is defined as a significant cognitive decline in one or more cognitive domains that is associated with significant
negative influence on social or occupational functioning.
Mild cognitive impairment is an intermediate state between normal cognition and dementia where cognitive abnormalities
exist but do not significantly affect social and occupational functioning.

Alzheimer’s Disease
Definition:

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A neurodegenerative disease that is characterized by progressive loss of neurons and synapses due to the accumulation of
amyloid plaques and neurofibrillary tangles in cholinergic neurons.
Epidemiology:
• Most common neurodegenerative cause of dementia
• Patients with Down syndrome are at an increased risk
• Mutations in ApoE-4 are associated with sporadic AD
• Mutations in APP, presenilin-1 or presenilin-2 are associated with familiar AD and with an earlier onset
Pathophysiology:
• Widespread cortical atrophy
• Decreased hippocampal volume
• Senile plaques in gray matter which are extracellular beta-amyloid
• Amyloid angiopathy → intracranial hemorrhage
• Neurofibrillary tangles which are intracellular hyperphosphorylated tau protein
• Number of neurofibrillary tangles is correlated with the degree of dementia
Diagnosis:
• Gradual cognitive decline that cannot be attributed to another cause
• Positive family history of AD adds more certainty to the diagnosis
• PET can be used to assess cerebral amyloid deposition
• Structural MRI can reveal cerebral cortical and hippocampal atrophy. Neither are specific for AD
Treatment:
• No curative treatments are available
• Cholinesterase inhibitors improve cognitive functioning in AD. Donepezil, rivastigmine, and galantamine
• NMDA receptor antagonists such as memantine are approved for moderate to severe AD

Vascular Neurocognitive Disorder:

Definition:
The condition is simply known as vascular dementia. It is defined as dementia due to multiple arterial infarcts in the cortex
or in subcortical regions.
Epidemiology:
• The second most common cause of dementia in the elderly
• Late onset of memory impairment
Pathophysiology:
• Multiple ischemic infarcts of different brain regions related to cognitive functioning
• Evidence of multiple lacunar infarcts
Diagnosis:
• Dementia plus MRI that shows multiple cortical or subcortical infarcts
Treatment:
• Cholinesterase inhibitors are given a trial because of the frequent co-occurrence of neurodegenerative disease with
vascular disease
• Correction of the vascular etiology such as the treatment of hypertension might slow the progression

Frontotemporal Lobar Degeneration:

Definition:
It is also known as Pick disease. In addition to dementia, there are early manifestations of personality and behavioral changes.
Aphasia is also seen in some patients. Can be associated with parkinsonism.
Epidemiology:
• The third most common cause of dementia in the elderly
• The mean age of onset is in the sixties
• The duration of survival after the diagnosis is 6 to 11 years after onset of symptoms
Pathophysiology:
• Degeneration of the frontal and temporal lobes
• Deposition of hyperphosphorylated tau bodies (Pick bodies)
• Accumulation of ubiquitinated TDP-43

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Diagnosis:
• Dementia plus imaging evidence of frontal and temporal lobes degeneration
Treatment:
• No curative treatment
• Memantine helps symptomatically in some patients
• No role of cholinesterase inhibitors
Dementia with Lewy Bodies:
Definition:
Dementia that is associated with visual hallucinations, fluctuating cognition, and REM sleep disturbances. Symptoms of
parkinsonism are also seen in some patients.
Epidemiology:
• The second most common neurodegenerative dementia
Pathophysiology:
• The aggregation of misfolded alpha-synuclein (Lewy bodies)
Diagnosis:
• Dementia that is fluctuating and associated with hallucinations plus positive findings of decreased dopamine from
PET
Treatment:
• No curative treatment
• Cholinesterase inhibitors, especially rivastigmine, are more effective in this type of dementia as compared to AD
• Memantine is used in severe dementia with Lewy bodies
• Dopamine blocking agents are contraindicated, such as haloperidol
• Benzodiazepines might be helpful if the patient has significant REM sleep disturbances

Prion Disease and Dementia:

Definition:
This is a rapidly progressive form of dementia that is caused by a prion disease such as Creutzfeldt-Jakob disease (CJD).
The patient also has myoclonus.
Diagnosis:
• The diagnosis is confirmed by a biopsy or an autopsy
• EEG might show periodic sharp waves
Treatment:
• There is no treatment
• The condition is usually fatal
• Patients die with few months after the onset of dementia

Idiopathic Intracranial Hypertension

Definition
Idiopathic intracranial hypertension, formally known as pseudotumor cerebri, is a condition that is characterized by an
increase in the intracranial pressure without an apparent cause.

Epidemiology
Idiopathic intracranial hypertension has shown a rapid increase in its incidence in the recent years.
• The estimated incidence is 20 per 100,000 in obese women
• The incidence in normal weight individuals is 1 per 100,000
• 90% of affected patients have evidence of visual impairment at time of diagnosis
Risk factors for idiopathic intracranial hypertension (IIH):
• Female gender
• Obesity
• Vitamin A excess
• History of danazol or tetracycline use
Pathophysiology:
IIH is characterized by an elevation in the intracranial pressure without an apparent structural cause on brain imaging. The
etiology and pathogenesis of the condition are still poorly understood.

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Clinical Presentation:
The classical presentation of IIH includes:
• Severe headache
• Visual disturbances
• Bilateral papilledema
Other, less specific, symptoms of IIH include:
• Tinnitus
• Diplopia due to CN VI palsy

Diagnosis:
The diagnosis of headache due to IIH is confirmed if the patient meets the following criteria:
A. Headache that meets criterion C
B. Confirmed diagnosis of IIH, see below
C. Headache is caused by IIH:
1. Headache developed in temporal relation to IIH
2. Headache is relieved after reducing intracranial pressure
3. Headache is aggravated when intracranial pressure is increased
D. Headache cannot be attributed to any other possible cause
IIH diagnosis is confirmed in the following situation:
A. Presence of bilateral papilledema
B. Normal neurologic examination except for cranial nerve abnormalities
C. Neuroimaging reveals no structural cause like hydrocephalus, mass, or structural lesions
D. Normal CSF composition
E. Elevated lumbar puncture opening pressure, i.e. > 250 mm
F.

Note: Patients without papilledema who have all the other criteria from B to E can still be diagnosed
with IIH.

Treatment:
The treatment options for IIH can be nonpharmacologic, pharmacologic, or surgical.
Nonpharmacologic treatment:
• Weight loss
Pharmacologic treatments:
• Acetazolamide
• Furosemide and topiramate have limited efficacy
Surgical treatments:
• Only used in refractory cases
• Aim to decrease intracranial pressure
• Placement of a CSF shunt is an option
• Patients with visual loss might be candidates for optic nerve sheath fenestration

Multiple Sclerosis:
Definition
Multiple sclerosis is an autoimmune inflammatory condition of the brain and the spinal cord (CNS) that is characterized by
demyelination and eventually axonal damage.

Epidemiology
Multiple sclerosis (MS) is a common condition in the United States.
• Estimated prevalence is 58 to 95 per 100,000
• More common in women: male to female ratio is 2.3:1
• Average age at diagnosis is 29 years in women, 31 years in men
• MS is more common in northern Europe when compared to the tropics

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Pathophysiology
Examination of demyelinating lesions reveal:
• Myelin loss
• Destruction of oligodendrocytes
• Reactive astrogliosis
• Axons can be spared or destroyed
Inflammatory cells infiltrate the brain parenchyma, brainstem, optic nerves, and the spinal cord. These are the same sites of
MS plaques. The symptoms of the patient depend on the affected site.
The following pathways are commonly affected in MS:
• Pyramidal and cerebellar pathways
• Medial longitudinal pathway → can lead to internuclear ophthalmoplegia or monocular nystagmus
• Optic nerve
• Posterior column pathway → loss of touch and vibration sensations

Clinical Presentation
Attacks of symptoms occur that are separated in in time and place. This means that the first presenting feature might be optic
neuritis, which will resolve overtime and then after months or years the involvement of another pathway will occur. The
duration of MS attacks should be longer than 24 hours
Classic symptoms of MS:
• Paresthesia
• Spinal cord symptoms which could be motor or autonomic
• Cerebellar symptoms (dysarthria, nystagmus, and intention tremors)
• Optic neuritis
• Trigeminal neuralgia
• Facial myokymia
• Pain
• Constitutional symptoms
• Psychiatric symptoms
• Visual symptoms such as painful eye movements or diplopia

Different Courses of MS
Relapsing-remitting MS:
• Recurrent MS attacks that are separate in time and place
• Completely resolve between attacks
• 85% of MS cases
Secondary progressive MS:
• 50% of those with relapsing-remitting MS progress to this type
Primary progressive MS:
• Progressive disease that is continuous but without relapses
• 10% of MS cases
Progressive-relapsing MS:
• Progressive decline in functioning with superimposed recurrent MS attacks
• 5% of MS cases
Clinically isolated syndrome:
• A subtype of relapsing-remitting MS
• A single episode of an MS attack without recurrent attacks
Benign MS:
• A subtype of relapsing-remitting MS
• Completely resolve between attacks
• Accumulation of neurologic disability after 15 or 20 years is minimal

Prognosis
The prognosis of MS is dependent on the type of MS. Worse prognosis is seen in patients with:
• Very frequent attacks
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 • Cerebellar symptoms at time of diagnosis

Diagnosis
The following table summarizes the currently recommended criteria for the diagnosis of MS:

CLINICAL PRESENTATION ADDITIONAL DATA NEEDED TO DIAGNOSE MS

- Two or more attacks - Diagnosis of MS is confirmed
- Clinical evidence of involvement of two or
more different pathways
- Two or more attacks - Dissemination in space confirmed by MRI
- Clinical evidence of involvement of a single
pathway
- One attack - Dissemination in time confirmed by MRI, or
- The attack involves two or more different - Waiting for a second attack, or
pathways - CSF-specific oligoclonal bands
- One attack of a single pathway - Dissemination in space confirmed by MRI plus dissemination in time
Primary progressive MS:
- Insidious neurologic decline suggestive of MS
- Dissemination in space by MRI
- Positive CSF-specific oligoclonal bands

Treatment:
Treatment of an acute MS attack:
• IV steroids
Disease-modifying treatments that slow progression of relapsing-remitting MS:
• Beta-interferon
• Glatiramer
• Natalizumab
Side-effects of interferons:
• Flu-like symptoms
Symptomatic treatments:
• Neurogenic bladder is treated by catheterization or muscarinic antagonists
• Spasticity is treated by baclofen or GABA receptor agonists
• Neuralgia is treated by tricyclic antidepressants, carbamazepine, or gabapentin

Guillain-Barre Syndrome
Definition
Guillain-Barre syndrome (GBS) is an acute onset monophasic immune mediated disorder of the peripheral nervous system
that is characterized by demyelination. It is the most common type of acute inflammatory demyelinating
polyradiculoneuropathy (AIDP).

Epidemiology:
GBS is more common in the United States and northern Europe as compared to Japan or the tropics.
• Estimated annual incidence of GBS is 1 to 2 per 100,000
• The lifetime likelihood of any individual to develop GBS is 1 per 1000

Pathophysiology:
The condition is often associated with recent history of a viral or campylobacter jejuni infection. An inflammatory response
occurs that is characterized by the destruction of the myelin sheath of peripheral nerves. The immune mediated disease is
believed to be T-cell mediated.
Cranial nerves III to XII are also involved, especially the motor fibers of these cranial nerves.

Clinical Presentation:
History of an unremarkable infection such as an upper respiratory tract infection can be seen in most patients. The infection
is typically 14 days prior to the onset of GBS.
The diagnostic criteria for GBS are:
• Abrupt distal symmetrical onset of paresthesia and limb weakness
• Less than 4 weeks of progression to clinical nadir

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Other symptoms include:
• Pain
• GBS is essentially a motor neuropathy
• Life-threatening autonomic disturbances such has arrhythmia

Diagnosis:
The presence of the symptoms discussed above is highly suggestive of GBS. However, one should look for the following
red-flags that can raise the possibility of another diagnosis behind the patient’s neurologic deterioration:
• Fever at onset
• Severe pulmonary dysfunction without prominent limb weakness at onset
• Severe sensory abnormalities without prominent limb weakness at onset
• Asymmetry of weakness
• Elevated numbers of mononuclear cells in CSF
Other diagnostic criteria that can support the diagnosis of GBS:
• Elevated CSF protein with normal cell count
• Electrodiagnosis confirms the pathology is demyelinating and not axonopathy

Treatment:
Respiratory support is critical. The most common cause of death in GBS is respiratory failure.
Disease modifying treatments:
• Must be given in the first few weeks of disease onset
• Plasmapheresis
• IV immunoglobulins
• No role for corticosteroids

Acquired Demyelinating Diseases

Definition:
Demyelination is a process that is characterized by a loss of the myelin sheath surrounding the axons, while preserving the
axons from damage. The lost of myelin can be due to damage to the myelin protein or the death of the cells that produce
myelin.

Acute Disseminated Encephalomyelitis:

Definition and epidemiology:
This is an inflammatory demyelinating disease of the central nervous system that affects mainly children. The estimated
incidence is 0.4 per 100,000 per year.
Pathophysiology:
The condition is characterized by the following:
• T-cell mediated immune response
• Post-infectious. Most commonly associated with history of a recent infection with measles, mumps, rubella, or
infectious mononucleosis. It can be also associated with mycoplasma pneumoniae and campylobacter jejuni
• Recent vaccination history is reported in some few cases
Clinical presentation:
Patients have a history of a recent viral or bacterial infection, typically 3 weeks before the onset of encephalomyelitis.
Classical presentation:
• Ataxia
• Headache
• Weakness
Patients could also have vomiting, slurring of speech, cranial nerve palsies, seizures, lethargy, or delirium.
The prognosis of the condition is excellent, with 80% of those affected making a full recovery. The condition is monophasic
in 95% of the cases.

Acute Hemorrhagic Leucoencephalitis:

Definition and epidemiology:
This is most likely a hyperacute severe variant of acute disseminated encephalomyelitis. The condition is rare and fatal.

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Pathophysiology:
The same pathology of acute disseminated encephalomyelitis with few exceptions:
• This condition is typically confined to a single lobe or hemisphere
• In addition to demyelination, hemorrhagic and necrotic tissues are seen
Clinical presentation:
Patients present with fever, headache, vomiting and multifocal neurological deficits. The disease progresses over the course
of two to three days to coma, followed by death.

Progressive Multifocal Leukoencephalopathy:

Definition and epidemiology:
This is a viral demyelinating disease that is caused by the papovavirus known as JC virus. Up to 75% of adults have
serological evidence of JC virus infection. The virus remains latent in the central nervous system and gets reactivated in
patients with impaired cell-mediated immunity. It occurs in up to 4% of AIDS patients.

Pathophysiology:
Patients who have impaired cell-mediated immunity due to AIDS, organ transplantation, leukemia or lymphoma are at risk
of reactivation of the JC virus. If activated, it will destroy the oligodendrocytes which are responsible for the production of
myelin in the CNS.

Clinical presentation:
Patients present with motor dysfunction, speech problems, and visual issues. Cognition is also affected. The diagnosis is
confirmed by PCR. MRI shows multiple small lesions in the white matter, especially of the occipital lobes.
The prognosis of the disease has improved recently after the introduction of highly-active antiretroviral treatment. Cases of
remission have been reported in AIDS patients.

Central Pontine Myelinolysis:

Definition and epidemiology:
This is a monophasic demyelinating disease that affects mainly the pons and lower midbrain. It is associated with alcoholic
liver disease or the rapid correction of hyponatremia.

Pathophysiology:
The most likely mechanism of central pontine myelinolysis is massive demyelination in response to rapid osmotic changes.
This occurs when rapid correction of hyponatremia is commenced.

Clinical presentation:
Patients typically present with acute paralysis, speech problems, dysphagia, diplopia and loss of consciousness. It can cause
locked-in syndrome.
If good supportive care is provided, most patients will survive but with permanent neurological deficits which can be
devastating to the patient and his or her caregivers.

Neurocutaneous Diseases
Definition:
Neurocutaneous diseases are group of disorders that affect the skin and the central nervous system. The genetic and clinical
features of neurocutaneous diseases are different from each other, but they share one common feature. All of them occur
due to impaired development of primitive embryonic ectodermal tissue.

Neurofibromatosis Type 1:
Definition and pathology:
This is also known as von Recklinghausen disease. It occurs due to a mutation in the NF1 gene found on chromosome 17.
The NF1 gene is a tumor suppressor gene, therefore if mutated the patient is expected to develop tumors. Neurofibromatosis
type 1 is the most common neurocutaneous disease.
The mode of inheritance is autosomal dominant with 100% penetrance.
Diagnostic criteria:
The patient needs to have two of the following to be diagnosed with neurofibromatosis type 1:
• Six or more café au lait spots:

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 o > 5 mm in diameter in pre-pubertal children
o > 15 mm in diameter in post-pubertal children
• Two or more neurofibromas or one plexiform neurofibroma
• Axillary or inguinal freckling
• Optic nerve glioma
• Two or more Lisch nodules
• Distinctive bony lesions
• First-degree relative with a confirmed diagnosis of neurofibromatosis type 1

Figure 404: café au lait spots in NF1. Source: https://commons.wikimedia.org/wiki/File:NF-1-Tache_cafe-au-lait.jpg

Neurofibromatosis Type 2:
Definition and pathology:
This condition occurs when there is a mutation in the NF2 gene which is found on chromosome 22. Again, this is a tumor
suppressor gene. It is an autosomal dominant disorder.
Diagnostic criteria:
Patients should meet one of the following criteria (A to C) to be diagnosed with neurofibromatosis type 2:
A. Bilateral vestibular schwannomas
B. First degree relative with neurofibromatosis type 2 and:
1. Unilateral vestibular schwannoma, or
2. Two of the following: meningioma, glioma, fibroma, schwannoma, posterior subcapsular lenticular
opacities
C. Unilateral vestibular schwannoma and criterion 2 from B

Tuberous Sclerosis Complex:

Definition and pathology:
This is a genetic neurocutaneous disorder that is caused by a mutation in the TSC1 or TSC2 genes. Both are tumor suppressor
genes. TSC1 is found on chromosome 9, whereas TSC2 is on chromosome 16. The mode of inheritance is autosomal
dominant.
Clinical presentation:
There are diagnostic criteria for tuberous sclerosis complex, but they are too complex for the USMLE. Instead, focus on the
symptoms and signs of tuberous sclerosis:
• Hamartomas in the CNS and skin
• Angiofibromas
• Mitral regurgitation
• Ash-leaf spots
• Cardiac rhabdomyoma
• CNS tubers
• Intellectual disability
• Renal angiomyolipoma
• Seizures
• Shagreen patches

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Patients are at an increased risk of subependymal giant cell astrocytomas.

Figure 405: Ash-leaf spot in tuberous sclerosis complex. Source: https://step1.medbullets.com/neurology/113051/tuberous-

sclerosis

Sturge-Weber Syndrome:
Definition and pathology:
This condition is also known as encephalotrigeminal angiomatosis. It is not an inheritable disease. The condition is, however,
congenital.
The condition is caused by a somatic mosaicism in the GNAQ gene. The mutation renders the gene active. Small capillary
blood vessels are affected.
Clinical presentation:
Patients typically have a port-wine stain on the face (nevus flammeus) at birth. In addition to that, patients also have:
• Ipsilateral leptomeningeal angiomas
• Seizures and epilepsy due to ipsilateral leptomeningeal angiomas
• Intellectual disability
• Episcleral hemangiomas
• Early-onset glaucoma

A B
Figure 406: A. Port-wine stain of the face. B. A leptomeningeal angioma. Source:
https://www.researchgate.net/figure/Representative-Photographs-and-Magnetic-Resonance-Imaging-MRI-Scans-from-
Study_fig1_236664805

Von Hippel-Lindau Disease:

Definition and pathology:
The disease is caused by a deletion of the VHL gene on chromosome 3p. Mode of inheritance is autosomal dominant. The
condition is characterized by the development of benign and malignant tumors.
Clinical presentation:
• Hemangioblastomas in the brain, brainstem, cerebellum and spine
• Angiomatosis
• Renal cell carcinoma
• Pheochromocytoma

Introduction to General Anesthesia

Introduction
General anesthesia is defined as a pharmacologically induced reversible state of unconsciousness which is not interrupted
despite noxious stimuli such as performing incisions. A successful general anesthesia attempt should be characterized by
the following:
• Complete lack of awareness
• Amnesia or lack of memory to the events taking place in the operation room

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 • Analgesia. Subconscious reactions to pain such as movement or withdrawal, and autonomic reflexed need to be
blocked
• Akinesia which is defined as the lack of overt movement
A combination of inhaled, intravenous, and muscle relaxants is used to achieve what is known as a balanced anesthesia.
Balanced anesthesia is characterized by:
• Improved hemodynamic stability
• Good muscle relaxation
• Rapid return of respiratory function and consciousness after discontinuation of the anesthesia
• Good practice in post-operative pain control with opioids

Stages of Anesthesia
Induction:
• The induction of an unconscious state in a rapid way
• Maintenance of hemodynamic stability
• The airway and breathing should be secured
• Inhaled agents, intravenous agents, and succinylcholine are used during the induction stage
Maintenance:
• If one stop administering medications after the induction phase, the patient would wake up within minutes
• Therefore, anesthetics need to be administered at a controlled rate to maintain anesthesia
• Inhaled agents, opioids, and non-depolarizing muscle relaxants are used in the maintenance stage

Important Principles
General anesthetics work on the central nervous system. Accordingly, they should be:
• Able to cross the blood-brain barrier
• Lipid soluble
From a chemistry point of view, if you increase the lipid solubility of a drug, you would decrease its solubility in water.
Accordingly, a good anesthetic is expected to have low solubility in the blood.
The potency of an inhaled anesthetic is inversely proportional to its MAC as is depicted in the equation below:
1
𝑃𝑜𝑡𝑒𝑛𝑐𝑦 =
𝑀𝐴𝐶
Where MAC stands for minimal alveolar concentration
Minimal alveolar concentration:
• When an inhaled anesthetic agent is used, you have a two-compartment system:
o First compartment is the alveoli
o Second compartment is the active site (brain)
• The alveolar partial pressure of the inhaled agent reflects the partial pressure in the brain
• Concentration of an inhaled agent in the alveoli that is required to prevent movement in 50% of patients when a
standard incision is made is the definition of minimal alveolar concentration
• MAC can be influenced by several factors:
• It can be increased by the following factors:
o Young age
o Hyperthyroidism
o Hyperthermia
o Chronic alcohol use
o Cocaine use
• And it can be decreased by the following factors:
o Advanced age
o Pregnancy
o Hypothermia
o Acute alcohol intoxication
o Use of CNS depressants
• In clinical practice, you will generally provide 0.5 MAC of the inhaled agent
• An agent with a high MAC will have fast induction but low potency, whereas one that has a low MAC will have
good potency but slow induction

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Lipid solubility:
• N2O has high lipid solubility and is insoluble in blood:
o Accordingly, it works best for induction of anesthesia
o It has fast onset and offset
o It needs to be terminated moments before the completion of the procedure
• Isoflurane has moderate lipid solubility and high solubility in blood:
o It has excellent potency for the maintenance of anesthesia
o It has slow induction
o The offset is slower; accordingly, it needs to be terminated five to ten minutes before the completion of
the procedure

Inhaled Anesthetic Agents

Introduction
• Inhaled agents are volatile agents (desflurane, sevoflurane and isoflurane) and nitrous oxide. They are rarely used
in induction of anesthesia but are cornerstone in anesthesia maintenance.
• The mechanism of action is poorly understood
• These agents are given in doses expressed as volume percent concentration
• The volume percent concentration delivered = alveolar gas concentration = concentration in the brain
• They are typically given at 0.5% of their MAC because they are often combined with other agents and with opioids
Desflurane:
• This is a volatile inhaled anesthetic
• Used for maintenance of anesthesia
• Unknown mechanism of action
• Dose: titrated to effect
• Onset is relatively fast because of its low solubility in blood
• Offset is less than 10 minutes
• Mainly eliminated by the pulmonary system
Effects:
• CNS depressant, hypnotic and analgesic
• Sympatho-excitation is the concentration of desflurane is increased rapidly
• Postoperative headache, agitation and dizziness
• Dose-related hypotension
• Tachycardia and hypertension if sympatho-excitation occurs
• Respiratory depression
• Laryngospasm and bronchospasm in some patients
• Immune-mediated hepatotoxicity, rare
• Malignant hyperthermia
Patients with previous history of malignant hyperthermia should not receive desflurane.

Sevoflurane
• Used for maintenance
• Induction in children
• Could be used for status asthmaticus
• Unknown mechanism of action
• Onset is relatively fast
• Offset is around 10 minutes. Generally slower than desflurane
• Mainly eliminated by pulmonary system. 5% elimination by hepatic metabolism
Effects:
• CNS effects like desflurane in addition to increased risk of increased ICP and delirium
• Not irritating to the respiratory tract
• Nausea and vomiting
• Potential nephrotoxicity
Contraindicated in patients with history of malignant hyperthermia

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Isoflurane:
• Used for maintenance
• Unknown mechanism of action
• It has a higher solubility in blood → slower onset and offset
• Offset is within 15 minutes
• Mainly eliminated by pulmonary system
Effects:
• CNS effects similar to sevoflurane
• Dose-related hypotension
• It is irritating to the respiratory tract
Contraindicated in patients with history of malignant hyperthermia

Halothane:
• Halothane is associated with an increased risk of hepatotoxicity when compared to other volatile agents

Note: Malignant hyperthermia is a rare life-threatening condition that is associated with inhaled
volatile anesthetics and succinylcholine. It is characterized by:
Fever
Severe muscle contractions
Genetic predisposition especially in patients with RYR1 gene mutations
Treatment is with dantrolene, which is an RYR receptor antagonist. RYR stands for ryanodine
receptor

Other Inhaled Volatile Anesthetics:

• Methoxyflurane is associated with nephrotoxicity
• Enflurane can be epileptogenic

Nitrous Oxide:
• This is an inhaled anesthetic
• Not a volatile agent
• Adjunct to general anesthesia
• Cannot be used solely in general anesthesia
• Usually combined with a volatile agent
• Used alone for sedation and analgesia in obstetric and dental procedures
• Mechanism of action is unknown
• Usually delivered in a volume percent concentration of 50 to 70% in oxygen
• Onset is immediate
• Offset is immediate
• Elimination is via the pulmonary system
Effects:
• CNS analgesia
• Increases cerebral blood flow
• Increases intracranial pressure
• Modest decrease in heart rate and blood pressure
• Mild respiratory depression
• It should be avoided in patients with pulmonary hypertension
• This gas tends to expand in gas-containing spaces. Accordingly, it should be avoided in patients with pneumothorax
or an emphysematous bleb
• It should be avoided in patients with increased intracranial pressure
• It is contraindicated in patients with coronary artery disease

Regional Anesthesia

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Introduction
• The principle here is to perform the surgery while the patient is awake and to render the nerves that supply the
surgical site insensate
• Regional anesthesia is also known as neural blockade or nerve block
• Physiologic status monitoring and management is important
• The ability to convert to a general anesthetic at any point should be available
Drugs
Classification:
• Esters such as procaine, tetracaine, and benzocaine
• Amides such as lidocaine, mepivacaine, and bupivacaine
Mechanism of action:
• Blockage of sodium channels
• Most effective in rapid firing neurons
• They penetrate the membrane to bind to the ion channel
• Small-dimeter fibers are blocked faster than large diameter fibers
• Myelinated fibers are blocked faster than unmyelinated fibers
• Pain is lost, followed by temperature sensation, touch, and finally pressure sensation
Side effects:
• CNS excitation
• Severe cardiotoxicity especially with bupivacaine
• Hypertension or hypotension
• Arrhythmias
• Methemoglobinemia with benzocaine

Epidural Anesthesia
Technique
• A tiny plastic catheter is placed in the epidural space
• The site of insertion is dependent on the type of procedure, see following table
• A local anesthetic solution is administered via the catheter
• It blocks the nerves at the level and below
• The procedure must be done under strict sterile conditions
PROCEDURE LEVEL OF EPIDURAL CATHETER INSERTION
CAESERIAN SECTION T4
INGUINAL HERNIA REPAIR T10
REPAIR OF A FRACTURED HIP L1
TOTAL KNEE ARTHROPLASTY L2
HEMORRHOIDECTOMY S4

Spinal Anesthesia
Technique:
• The local anesthetic is injected into the intrathecal space
• It is safer when below the level of spinal cord termination
• It will block the spinal cord nerves at or below the level of injection
• Smaller amounts of the local anesthetic are needed in comparison to epidural anesthesia
• The onset is also faster when compared to epidural anesthesia
The following table summarizes the differences between spinal anesthesia and epidural anesthesia.
COMPARISON POINT EPIDURAL ANESTHESIA SPINAL ANESTHESIA
AMOUNT OF LA REQUIRED Larger Smaller
TIME OF ONSET Longer Shorter
MOTOR BLOCKAGE To a smaller extent Occurs
COMPLICATIONS Site infection Site infection
Cardiovascular toxicity Cardiovascular complications are rare
Headache due to dural puncture

Contraindications to spinal and epidural anesthesia:

• Lack of consent, resuscitative equipment, known allergy, and familiarly with the technique
• Coagulopathy

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 • Sepsis
• Increased intracranial pressure
• Shock

Intravenous Anesthesia
Overview
• N2O can be effectively used for induction because it has an immediate onset, however, most inhaled anesthetic
agents are designed for maintenance
• Intravenous anesthetic agents, on the other hand, are more appropriate for induction
• Total intravenous anesthesia refers to the practice of using intravenous agents alone without inhaled agents in the
induction and maintenance phases
• The current recommendation is to use total intravenous anesthesia whenever possible, and to reserve inhaled
anesthetic agents for specific cases

Propofol:
• An alkylphenol agent
• Typically used for induction of general anesthesia
• Can be also used for sedation
• Effective for maintenance of anesthesia when total intravenous anesthesia is utilized
• Onset in 20 seconds
• Offset is within 5 to 8 minutes after discontinuation
• Metabolized by the liver, then excreted by the kidneys
Mechanism of action:
• The exact mechanism of action is unknown
• It is hypothesized that the drug potentiates GABAA receptors
Effects:
• CNS:
o Depressant
o Decreases cerebral metabolic rate
o Decreases intracranial pressure
o Can induce brief tonic-clonic movements
• CVS:
o Myocardial depression
o Hypotension
o Use with caution in patients with systolic dysfunction or coronary artery disease
• Respiratory:
o Depression of respiratory system
o Brief apnea
o Blunts airway responses to manipulation → facilitates intubation
• Contraindicated in patients with egg or soy allergy

Sodium Thiopental:
• A short-acting barbiturate
• Rarely used for induction in current practice
• Has anticonvulsant properties
• Can induce rapid reduction in intracranial pressure
• Onset is within 20 seconds
• Offset after a single induction dose is 5 to 10 minutes
• Metabolized by the liver, then excreted by the kidneys
Mechanism of action:
• Increases the binding and efficiency of GABA at GABAA receptors
• Depression of the reticular activating system
Effects:
• CNS:
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 o Depressant
o Decreases cerebral metabolic rate
o Decreases intracranial pressure
o Twitching and tremors can occur
o Associated with postoperative confusion and delirium
• CVS:
o Myocardial depression
o Hypotension
o Use with caution in patients with systolic dysfunction or coronary artery disease
• Respiratory:
o Depression of respiratory system
o Brief apnea
o Does not blunt airway responses to manipulation → not appropriate for facilitation of intubation
• Contraindicated in patients with porphyria

Ketamine:
• A phencyclidine derivative
• Used for induction, especially in patients with hypotension
• Sedation for painful procedures such as endoscopy examinations
• Onset within 20 seconds
• Offset within 15 minutes, but return of full orientation only after 30 minutes
• When used for sedation, it causes a dissociative state where the patient is unable to form new memories
• Metabolized by the liver, then excreted by the kidneys
Mechanism of action:
• Acts on NMDA receptors, blocking them
Effects:
• CNS:
o Dissociative anesthesia
o Excellent analgesia
o Patients become unconscious, however, their eyes can remain open and their limbs move
o Increases cerebral metabolic rate, cerebral blood flow, and intracranial pressure
• CVS:
o Sympathomimetic → increases heart rate, blood pressure, and cardiac output
• Respiratory:
o No apnea or respiratory depression
o Bronchodilation
• Contraindicated in patients with elevated intracranial pressure, coronary artery disease, psychiatric disease and
history of recent eye surgery

Etomidate:
• A short-acting hypnotic agent
• Used for induction of anesthesia
• Appropriate for patients with hemodynamic instability
• Onset is within 20 seconds
• Offset after a single induction dose is 5 to 10 minutes
• Metabolized by the liver, then excreted by the kidneys
Mechanism of action:
• Similar to thiopental → facilitates GABA effects on GABAA receptors
Effects:
• CNS:
o Depressant
o Decreases cerebral metabolic rate and intracranial pressure
o Cerebroprotective → appropriate for patients with traumatic brain injuries undergoing surgery
o Can induce seizure-like activity

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 • CVS:
o Not significant
• Respiratory:
o Causes a brief period of apnea

Midazolam:
• A short-acting benzodiazepine
• Sedation or an adjunct to general anesthesia
• Anxiolytic
• No analgesic effect
• Onset is within 3 to 5 minutes
• Offset after a single induction dose is 1 to 4 hours
• Metabolized by the liver, then excreted by the kidneys
Mechanism of action:
• Facilitate GABAA receptor
Effects:
• CNS:
o Anxiolysis, amnesia, and hypnosis
o Decreases cerebral blood flow
o Can cause postoperative delirium
• CVS:
o In large doses in hypotensive patients can lead to profound hypotension and tachycardia
• Respiratory:
o Respiratory depression
o More severe in the elderly

Opioids:
Overview:
• Opioids are used preoperatively, intraoperatively and postoperatively
• The main goal is to provide analgesia without requiring too much anesthetic agents for maintenance during surgery
• Synthetic intravenous opioids such as fentanyl, sufentanil, remifentanil and alfentaruil have a shorter duration of
action when compared to morphine and meperidine

Note: The potency of an opioid is directly related to its lipid solubility.

Example: 10 mg morphine = 100 mg meperidine = 100 µg fentanyl = 10 µg sufentanil in terms of
potency

The following table summarizes the pharmacologic characteristics of three opioids that are commonly used by
anesthesiologists:
FENTANYL SUFENTANIL REMIFENTANIL
LOADING DOSE µG/KG 4 – 20 0.25 – 2 0.5 – 1
ONSET IN MIN 8 6 2
DURATION IN MIN 45 45 1–4

Note: The large variability in the loading dose is dependent on the patient’s age and general status, in
addition to the nature of surgical procedure being performed

Efficacy of the different opioids:

• Full opioid receptor agonists: morphine, meperidine, methadone, codeine
• Partial opioid receptor agonists: buprenorphine
• Mixed agonist/antagonist effects: nalbuphine, pentazocine
• Antagonists: naloxone, naltrexone, methylnaltrexone

Mechanism of Action:
• There are four types of opioid receptors (mu, delta, kappa and opioid receptor like-1)

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 • Only mu and kappa opioid receptors are clinically important
• Both receptors have G-protein mechanism
• When an opioid agonist interacts with mu or kappa opioid receptors, the receptor is phosphorylated
• The G-protein component is responsible for the activation potassium channels and blockage of calcium channels
• Eventually, the receptor undergoes recycling
• The blockage of calcium channels and activation of potassium channels result in the following changes at the
synaptic transmission machinery:
o Decreased synaptic transmission
o Activation of inhibitory interneurons that synapse with the pain-transmitting neurons
o Inhibition of the release of acetylcholine, norepinephrine, 5-HT, glutamate and substance P
o Analgesia, respiratory depression, bradycardia, euphoria and decreased gastrointestinal motility → driven
by mu opioid receptors
o Analgesia, sedation and miosis → driven by kappa opioid receptors
The following figure summarizes the mechanism of opioids.

Figure 407: Mechanism of action of opioids. Source: http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1934470

Indications:
• Opioids are indicated for the control of moderate to severe pain, and refractory pain
• As adjunct agents in induction and maintenance of general anesthesia
• As cough suppressants “dextromethorphan”
• For the treatment of diarrhea
• Acute pulmonary edema
• Maintenance programs for heroin addicts which include controlled regimens of methadone or buprenorphine plus
naloxone

Side Effects:
• Nausea and vomiting
• Decreased gastrointestinal motility → constipation
• Pruritus
• Respiratory depression → apnea
• Sphincter of Oddi spasm
• All opioids cause miosis except for meperidine which causes mydriasis
• Can result in addiction
• Overdose is treated with naloxone
• Prevention of relapse in a detoxified addict is treated with naltrexone

Contraindications:
• If intravenous opioids are going to be administered, it is contraindicated to do so if the institution cannot provide
ventilatory support in case of apnea
Patients with cardiogenic shock are better off if they do not receive opioids.

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Anticonvulsants
Overview
• Anticonvulsants are a diverse group of pharmacological agents used in the treatment of epileptic seizures
• Seizures defied as uncontrolled electrical activity in the brain, which may produce a physical convulsion
• Seizures result from episodic electrical discharges in cerebral neurons associated with prolonged depolarization,
during which sustained, high-frequency, repetitive firing (SHFRF) occurs, followed by prolonged
hyperpolarization
• Anticonvulsants are also being used in the treatment of neuropathic pain and as mood stabilizers in the treatment
of psychiatric disorders such as bipolar disorder.

Mechanism of action of anticonvulsants

• ↓ axonal conduction by preventing Na+ influx through fast Na channels. Carbamazepine, Phenytoin
• ↑ inhibitory tone by facilitation of GABA-mediated hyperpolarization. barbiturates, benzodiazepines
• ↓ excitatory effects of glutamic acid—lamotrigine, topiramate (blocks AMPA receptors); felbamate (blocks
NMDA receptors)
• ↓ presynaptic Ca2+ influx through type-T channels in thalamic neurons. ethosuximide and valproic acid
• The goal of drug management is restoration of normal patterns of electrical activity. Different types of drugs used
for different types of seizures

Types of seizures
Types of
seizures

Partial Generalized

Simple Complex

Level of
conscisnousnes
s

Intact Impaired
Conscisnousnes Conscisnousnes
s s

Unilateral tonic Postictal

seizures confusion

Automatism

Partial seizures (Focal seizures)

• Will affect one area of the brain
• Doesn´t cause loss of consciousness
Generalized seizures
• Loss of consciousness
• Tonic-clonic (grand male): tonic phase is associated with loss of consciousness, generalized body rigidity, loss of
control over fecal and urinary sphincters
• Clonic phase is characterized by sudden, jerky movements of muscles of the body
Absence (or petit mal) seizures

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 • Temporary
• Common in children under 14
• are brief, usually less than 15 seconds, and they have symptoms that may be barely noticeable
Myoclonic seizures
• Brief, don´t lase more than a second or two
• Shock-like jerks of a muscle or a group of muscles
Febrile seizures
• Seizures induced by high temperature above 100.4°F (38°C).
Epileptic seizures
• These are recurrent seizures with period of complete consciousness between the two episodes of seizure

Carbamazepine
Overview
• Epilepsy can be caused by genetic or environmental factors. Genetic factors include mutations of ion channels,
including Na+, Cl-, K+, and Ca2+
• Ionotropic dysfunctions in epilepsy, accounting for depolarization and hyperexcitability
• Increased depolarization results from overactivation of channels such as AMPA, NMDA, and Nav1.2.
• Increased Na+ concentration could lead to a higher frequency of action potentials
Mechanism of action of Carbamazepine
• Blocks Na+ channels. Increases GABA-mediated inhibition. Decreases Ca2+ influx.

By blocking Na channels, it makes action potential more difficult to occur

Limiting the spread of seizure activity and reducing seizure propagation

• Shortens refractory period, shorten QT interval, shortens duration of action potential

Clinical uses
• Drug of choice for trigeminal neuralgia
• Partial and tonic clonic seizures
• Used as an off-labeled drug for treatment of bipolar disorder
Pharmacokinetics
• Stimulate the metabolism of other drugs by inducing microsomal enzymes
• Co-administration of carbamazepine with valproate, lamotrigine, tiagabine and topiramate may lower their
concentration

Side effects
• Diplopia (double vision)
• Aplastic anemia
• Agranulocytosis
• Liver toxicity
• Increase risk of hyponatremia (Increase ADH secretion)
• SIADH
• Stevens-Johnson syndrome: Started with flu-like symptoms, followed by a painful red or purplish rash that spreads
and blisters
• Teratogenic:
1. Congenital malformations like spina bifida, and developmental disorders
2. Cleft lip and palate

Ethosuximide
Mechanism of action of Ethosuximide
• Blocks T-type Ca2+ channels in thalamic neurons
Clinical uses
• Treatment of petit mal epilepsy (Absence seizures in children)

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Toxicity
• Fatigue
• GI distress
• Headache
• Steven Johnson syndrome

Gabapentin
Mechanism of action of Gabapentin
• Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in
neuronal tissues, and reduces the release of mono-amine neurotransmitters.
• GABA analogue
• Inhibits high voltage activated ca+2 channels
• Gabapentin has high lipid solubility, is not metabolized by the liver, has no protein binding

Clinical uses
• Anticonvulsants
• Peripheral neuropathy
• Partial and tonic-clonic seizures
• Post-herpetic neuralgia
• Migraine prophylaxis
• Bipolar disorder
• Post-operative pain
• Treatment of spasticity in multiple sclerosis, tremor
Toxicity
• Double vision
• Slurred speech
• Drowsiness
• Lethargy
• Ataxia

Lamotrigine
Mechanism of action of Lamotrigine
• Na+ channel blocker, that may suppress the release of glutamate and aspartate, two of the dominant excitatory
neurotransmitters in the CNS
Clinical uses
• Treatment focal seizures
• Generalized tonic-clonic seizures
• Bipolar disorders
Side effects
• Steven Johnson syndrome

Levetiracetam (Keppra)
Mechanism of action of Levetiracetam

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 • Unknown mechanism
• Modulate GABA and glutamate release
• Binds to synaptic vesicle glycoprotein SV2A, inhibits neurotransmitter release at the nerve terminal
Clinical uses
• Treatment of partial seizures (Simple and complex)
• Treatment of tonic clonic convulsions

Phenytoin
Overview
• Epilepsy can be caused by genetic or environmental factors. Genetic factors include mutations of ion channels,
including Na+, Cl-, K+, and Ca2+
• Ionotropic dysfunctions in epilepsy, accounting for depolarization and hyperexcitability
• Increased depolarization results from overactivation of channels such as AMPA, NMDA, and Nav1.2.
• Increased Na+ concentration could lead to a higher frequency of action potentials

Mechanism of action of phenytoin

• Blocks Na+ channels. Increases GABA-mediated inhibition. Decreases Ca2+ influx.

By blocking Na channels, it makes action potential more difficult to occur

Limiting the spread of seizure activity and reducing seizure propagation

• Shortens refractory period, shorten QT interval, shortens duration of action potential

• Phenytoin reduces the post-tetanic potentiation at synapses, leading to prevention of cortical seizure foci from
detonating adjacent cortical areas

Clinical uses
• First line of treatment for treatment of generalized tonic-clonic (grand mal) and partial seizures.
• Used for simple and complex seizures
• Prophylaxis for status epilepticus
• prevention and treatment of seizures occurring during or following neurosurgery

Pharmacokinetics
• Metabolized by Cytochrome-P 450

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 • Zero-order kinetics that means: Small increases in maintenance doses commonly result in large (non-linear)
increases in plasma levels, and signs of toxicity
Side effects
• Hirsutism (Excessive body hair in men or women)
• Nystagmus (Involuntary eye movement called dancing eyes)
• Osteomalacia (Decrease vitamin D)
• Gingival hyperplasia (overgrowth of gum tissue around the teeth)
• Megaloblastic anemia (Decrease folate)
• Aplastic anemia (check hematology lab results)
• Yellow browning of the skin
• Neuropathy, ataxia, vertigo and headache
• Teratogenic effects:
1. Cleft palate
2. Congenital heart malformation
3. Fetal hydantoin syndrome
4. Prenatal growth deficiency
5. Mental deficiency

Rare side effects

• Stevens-Johnson syndrome
• DRESS syndrome
• SLE-like syndrome

Tiagabine
Mechanism of action of Tiagabine
• GABA reuptake inhibitor, by blocking GABA transporter 1 (GAT-1) hence increasing the level of GABA in CNS
Clinical uses
• Treatment of partial seizures (Simple and complex)
• Used as off labeled drug for treatment of anxiety and panic disorders
Side effects
• Dizziness
• Interfere with visual color perception

Topiramate
Mechanism of action of Topiramate
• Blocks Na+ channels and glutamate receptors and enhances GABA activity
Clinical uses
• Treatment of partial seizures (Simple and complex)
• Treatment of tonic clonic convulsions

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 • Used as off-label drug for weight reduction in patients with obesity or diabetes
Side effects
• Sedation
• Mental dulling
• Word-finding difficulty
• Kidney stones
• Weight loss
• Glaucoma

Valproic acid
Overview
• Considered as anti-convulsant drug
Mechanism of action of Valproic acid
• Enhance GABA inhibitory action by reducing GABA metabolism and increasing GABA neurotransmission
Note: GABA is an inhibitory neurotransmitter, this increase
results in increased inhibitory activity.
• GABA is the potent inhibitor of presynaptic and postsynaptic discharge in the brain.
• This acid modulates the synaptic sodium by prolonging inactivation, which decreases the ability of the neurons to
respond at high frequency

Clinical uses
• First line of treatment of tonic-clonic seizures
• Management of complex partial seizures and simple or complex absence seizures
• Treatment of Generalized tonic-clonic seizures, absence seizures, Myoclonic seizures
• Emergency treatment of status epilepticus
• Migraine prophylaxis
Pharmacokinetics
• Inhibits cytochrome P450s
Side effects
• GI distress
• Hepatotoxicity (Check liver functions)
• Thrombocytopenia
• Pancreatitis
• Alopecia
• Weight gain
• Teratogenic effects:
• Spina bifida (Neural tube defects)

Vigabatrin
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Mechanism of action of Vigabatrin
• Irreversibly inhibit GABA transaminase
• GABA transaminase, the enzyme responsible for the catabolism of GABA, which increases the level of GABA in
the brain.
Clinical uses
• Treatment of partial seizures (Simple and complex)
Side effects
• Permanent visual loss (black box warning)

Barbiturates
Drug names
• Phenobarbital
• Pentobarbital
• Thiopental
• Secobarbital
Mechanism of action of Barbiturates
• Prolong GABA activity through ↑ duration of Cl− channel opening→ Hyperpolarization of the cell
• Do not act through BZ receptors
• Have their own binding sites on the GABAA complex

Clinical uses
• First time used in children with simple or generalized seizures
• Sedation for anxiety
• Insomnia
• Induction of anesthesia (thiopental)
Pharmacokinetics
• Liver metabolized, sometimes to active compounds
• General inducers of cytochrome P450s
• Contraindication in porphyrias
Comparison between barbiturates and benzodiazepines
Benzodiazepines Barbiturates
Low liability to induce drug abuse Tolerance
Dependence
No hyperalgesia Hyperalgesia ( sensitivity to pain)
Not enzyme inducers-Less drug interactions Potent enzyme inducers
Specific antagonist Flumazenil No antagonist
Floppy baby syndrome if given prior to delivery Pronounced respiratory depression

Benzodiazepines
Overview
• GABA is the main inhibitory neurotransmitter in the brain
• benzodiazepines enhance GABA effect (Positive allosteric modulators PAMs)
• Benzodiazepine receptors are located on the alpha subunit of the GABA receptor

Drug names
• Diazepam.
• Lorazepam.
• Clonazepam.

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 • Alprazolam.
• Oxazepam.
• Triazolam.
• Chlordiazepoxide.
Mechanism of action of Benzodiazepines
• Benzodiazepines modulate GABA effect by binding to specific site, therefore facilitate GABA action and increase
the frequency Chloride channel opening (Hyperpolrization)

Clinical uses
• Seizures (status epilepticus).
• Muscle spasm.
• Alcohol withdrawal-delirium tremens.
• Anxiety.
• Night terror
• Sleep walking.
• Hypnotic (insomnia).
• Treatment of obesity, disorders of gallbladder

Pharmacokinetics
• Liver metabolites are also active compounds, except for oxazepam, temazepam, and lorazepam
• Benzodiazepines do not directly act to open chloride ion channels, and therefore, are not lethal in overdose as are
barbiturates
• Benzodiazepines are highly lipid soluble.
• There is rapid diffusion into the CNS followed by redistribution to inactive tissue sites. Benzodiazepines have a
high volume of distribution and rapidly cross the placenta.
Toxicity
• CNS depression
• Dependence
• Addiction
• Diminished reflexes
• Coma and confusion
• Benzodiazepines overdose and toxicity are treated with Flumazenil (GABA receptor antagonist).

Ramelteon and Suvorexant

Overview:
These two medications are used in the treatment of insomnia and other sleep disorders. Ramelteon binds selectively to MT1
and MT2 receptors and act a sleep agent. Suvorexant is also a medication used in the treatment of insomnia and is orexin
receptor antagonist. It has been placed on the list of schedule IV-controlled substances by the US Drug Enforcement
Administration (DEA).

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Ramelteon:
• Common trade name is Rozerem
• Prescription only drug
• 1.8% bioavailability
• 82% protein-bound
• Mainly metabolized by the liver
• Mainly excreted by the kidneys
• Half-life is 1 to 2.6 hours
Suvorexant:
• Common trade name is Besomra
• Prescription only drug
• 82% bioavailability
• 99% protein-bound
• Mainly metabolized by the liver
• Mainly excreted in feces
• Half-life is 12 hours
Mechanism of Action
Ramelteon:
• It interacts with melatonin receptors, specifically MT1 and MT2
• The activation of these receptors play an important role in sleep-induction and the maintenance of the sleep
circadian rhythm
Suvorexant:
• It is an antagonism of orexin receptors
• These receptors are important for wakefulness
• Blocking them will result in sleep

Indications
• Ramelteon is used in delayed sleep onset
• Ramelteon is also useful in preventing delirium in medically ill patients
• Suvorexant is used in the treatment of insomnia in patients with difficulties in in sleep initiation or maintenance

Drug Interactions
• Ramelteon can interact with amiodarone, ciprofloxacin and ticlopidine.
• Suvorexant is contraindicated in patients with hepatic disease or those with narcolepsy. It should be avoided in
patients taking medications that inhibit the CYP3A liver enzyme like itraconazole, clarithromycin, verapamil or
erythromycin

Adverse Effects:
Ramelteon:
• No potential for dependence or abuse
• Somnolence
• Dizziness
• Nausea
• Headache
• Rebound insomnia on discontinuation
Suvorexant:
• Can cause addiction
• Nightmares
• Sleep terror
• Strange and abnormal dreams

Pentazocine:
Overview

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Pentazocine is a painkiller that is used in the treatment of moderate to severe pain. It is considered an opioid because it works
on certain opioid receptors, however it does not share the same side effects’ profile of typical opioids.
• Common trade name is Talwin
• Prescription only drug
• 20% bioavailability
• Onset of action is within 15 minutes
• Mainly metabolized by the liver
• Mainly excreted in urine
• Half-life is 3 hours

Mechanism of Action
Pentazocine is a kappa-opioid receptor agonist and an antagonist to μ-opioid receptors.
The analgesic effects of the drug are believed to be related to its activity on these two receptors

Indications
• Pentazocine is used to treat moderate to severe pain
• Its efficacy has a ceiling effect
• It is becoming less commonly used in current clinical practice

Adverse Effects
• Psychotomimetic side effects such as hallucinations and delusions are more common as compared to other opioids
• Elevated blood pressure
• Tachycardia
• Respiratory depression
It is rarely associated with agranulocytosis and toxic epidermal necrolysis.

Note: Severe necrosis has been reported at the site of injection of pentazocine. The necrosis is so
severe that amputation was required in some cases.

Pharmacological Treatment of Glaucoma

Overview
Glaucoma is a common cause of blindness. Pharmacological treatments are available for chronic open-angle glaucoma.
Acute closed-angle glaucoma is a surgical emergency

Prostaglandin Analogues
• First-line treatment
• They are applied once per day at night
• Topical application
• Latanoprost, travoprost, tafluprost, and bimatoprost are examples
• The main mechanism of action is increasing the uveoscleral outflow of aqueous humor
Local side effects:
• Conjunctival hyperemia
• Lengthening and darkening of the eyelashes
• Discoloration of the iris
• Increased risk of uveitis and macular edema
Systemic side effects:
• Almost no systemic side effects except for headache

Carbonic Anhydrase Inhibitors

• First or second line treatment
• They need to be applied two to three times per day
• Topical application
• Dorzolamide is a common example.

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 • Acetazolamide is available via the oral route
• They reduce the production of aqueous humor
Local side effects:
• Dry eyes
• Burning sensation
Systemic side effects:
• More often with oral acetazolamide
• Paresthesia
• Nausea, diarrhea, loss of appetite, and taste
• Increased risk of kidney stones

Beta-Adrenergic Blockers
• Second-line treatment
• One time per day in the morning
• Topical application
• Examples include timolol, metipranolol, and betaxolol
• They reduce the production of aqueous humor
Local side effects:
• Dry irritable eyes
Systemic side effects:
• Contraindicated in patients with:
o Asthma
o Chronic obstructive pulmonary disease
o Bradycardia

Alpha-Adrenergic Agonists
• Second-line treatment
• Needs to be applied up to three times per day
• Topical application
• Examples include brimonidine, and apraclonidine
• They reduce the production of aqueous humor and increase outflow
Local side effects:
• Dry eyes
• Allergic reaction
Systemic side effects:
• CNS effects
• Respiratory arrest
• Postural hypotension
• Renal or hepatic failure
• Cerebral or coronary hypoperfusion

Cholinergic Agonists
• Third-line treatment
• Need to be applied four times per day
• Topical application
• Pilocarpine and carbachol are two examples
• They increase aqueous humor outflow
Local side effects:
• Ocular irritation
• Induced myopia
• Decreased visual acuity
Systemic side effects:
• Headaches, especially in young patients

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Parkinson disease drugs
Overview
• Parkinson´s disease (PD): progressive neurodegenerative disease that involves genetic and environmental factors
• Substania nigra is part of basal ganglia, it produces dopamine. Dopamine plays an important role in controlling
movements through striatum
• dopamine is a precursor to NE in diffuse noradrenergic pathways and is an inhibitory neurotransmitter in several
dopaminergic pathways

Pathophysiology
• Accumulation of Lewy bodies (alpha-synuclein intracellular inclusions) plays a role in the progression of
Parkinson’s
• degeneration of nigrostriatal dopamine tracts with imbalance between dopamine (↓) and ACh (↑)

PD is due to loss of dopaminergic neurons in the substantia nigra

Reduce the amount available of striatal dopamine (inhibitory effect)

This led to increase in acetylcholine (Excitatory effects)

Difficulty in controlling voluntary movement

Clinical presentations
• Bradykinesia
• Resting tremor
• Pill-rolling tremor
• Masklike facies
• Cogwheel rigidity
• Shuffling gait
Cogwheel rigidity: rachet – like rhythmic contractions of the muscle that occur when the limbs are passively stretched

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Drugs
• Levodopa
• Carbidopa
• Bromocriptine
• Amantadine
• Selegiline
• Entacapone
• Antimuscarinics

Pharmacological strategy
• Restore dopamine levels in the brain and decrease acetyl choline activity

Levodopa (L-Dopa)
MOA
• Prodrug of dopamine that is administered to patients with Parkinson's due to its ability to cross the blood-brain
barrier

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 • Administered with a dopa decarboxylase inhibitor like Carbidopa to prevent metabolism until after it has crossed
the blood-brain barrier
• Carbidopa reduces side effects of peripheral L-dopa conversion into dopamine (eg, nausea, vomiting).
• Levodopa is able to cross the blood-brain barrier while dopamine is not

Side effects
• Long term administration (2 years) of L-Dopa might expose the patient to ON/OFF phenomena
• Suddenly, the patient goes from full control of movement to bradykinesia, tremor for 30 then restores the control
again
• Nausea
• Vomiting
• Arrythmias
• Postural hypotension
• Dyskinesia
• Hallucinations

Pharmacodynamics
• Oral levodopa has a short half-life of 50 minutes but when combined with a peripheral dopa decarboxylase
inhibitor, the half-life is increased to 1.5 hours

Drug interactions (L-dopa can´t be used with the following drugs)

• Non-selective MAO inhibitors
• Pyridoxine
• Antipsychotics

Carbidopa
• The coadministration of carbidopa with levodopa has been shown to increase the half-life of levodopa more than
1.5 times while increasing the plasma level and decreasing clearance.
• Because its unable to penetrate blood brain barrier, it used to reduce the peripheral conversion of levodopa to
dopamine.

Summary of Mechanism of Action:

Figure 1 summarizes the mechanism of action of the drugs used in the treatment of motor symptoms of Parkinson disease
which can be considered as more specific for Parkinson disease.

Figure 408: Levodopa is converted to dopamine. Carbidopa prevents the conversion of levodopa to dopamine in the blood
so that most of the drug is available for conversion within the brain tissue. COMT inhibitors such as entacapone prevent the

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degradation of levodopa in the blood. Other Parkinson disease treatments are depicted in the second picture on the right.
Source: https://pdfs.semanticscholar.org/ce3c/5890b804a00b5d67e81be19d9220210c403e.pdf Dopamine agonist

Dopamine
agonist

Ergot Non-Ergot
derivatives derivatives

Bromocriptine Pramipexole

MOA
• Binds specifically to D2 receptors
• Considered as a second line of treatment after L-dopa
• Increased DA activity without increasing concentration so allows↓ carbidopa-levodopa dose

Bromocriptine
• Used to treat hyperprolactinemia and acromegaly
• Commonly used with L-dopa

Side effects
• Hallucinations
• Delirium
• Cardiac arrhythmias
• Nausea
• Vomiting
• Postural hypotension

Amantadine
• Anti-viral drug
• Block muscarinic receptors and ↑ dopamine release

Side effects
• Ataxia
• Atropine like
• livedo reticularis

Livedo reticularis:
• blotchy skin discoloration occurs due to capillary blood vessels dilated and blood
circulation become stagnant

Selegiline
• Moab selective inhibitor
• Block dopamine uptake in the synapse, hence, increases its concentration
• Used as adjunctive therapy for patients with declining response to levodopa

Catechol-o-methyl transferase inhibitors (COMT)

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• Tolcapone and entacapone
• Prevents peripheral l-DOPA degradation to 3-O-methyldopa (3‑OMD) by
inhibiting COMT, therefore Prolong the action of levodopa

Antimuscarinic drugs
• Drugs: Benztropine, trihexyphenidyl
• Drugs decrease Acetyl choline
• These drugs decrease tremor, rigidity and little effect on bradykinesia

Side effects
• Atropine like side-effects such as:
• Decreases the parasympathetic response.
• Sedation.
• Dry mouth.
• Constipation.
• Mental confusion.
• Urinary retention.

Centrally acting Skeletal muscle relaxants

MOA
• Drugs that reduce skeletal muscle tone by selective action in the cerebrospinal axis

Baclofen
• GABAB receptor agonist
• It inhibits reflex activity mainly in the spinal cord, therefore, reduce spasticity and spasms
• Similar action to benzodiazepines but with less side effects

Clinical uses:
• Reduce spasticity resulting from multiple sclerosis, particularly for the relief of flexor spasms and associated pain and
clonus, in addition to muscular rigidity
• Muscle pains
• Arthralgia
• Severe spinal and cerebral origin spasticity
• Dystonia

Cyclobenzaprine
• Skeletal muscle relaxant effect through acting on serotonergic activity
• Action on the brainstem is thought to result in diminished activity of efferent alpha and gamma motor neurons, and
ultimately depressed spinal cord interneuron activity

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Chapter 13:

Psychiatry

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Transference and Countertransference • The patient might choose to go with the therapist
Transference: treatment plan because of these feelings
Definition: • On the other hand, if the patient develops
negative feelings, this can result in less
The patient projects feelings and personal experiences about adherence to the therapy
an important person onto the therapist. Such feelings can be
positive or negative. The nature of the feelings that the Countertransference:
patient might have are dependent on stereotypical, and Definition
situational behaviors or attributes of the therapist.
The moment that you recognize the patient might start to
The patient will transfer a response based on internal project feelings about an important person onto the therapist,
construction of the therapist, and this response will affect the you will come to realize that the opposite can also happen.
alliance with the therapist. In this case, the doctor might project feelings about an
important person in his or her life onto the patient.
Case example: Case example:
The patient suffers from depression. Psycho-analysis A therapist has been working with a patient for one year.
approach reveal that the possible trauma of being raised by The patient suffers from gambling disorder and he keeps
a neglecting mother to be the main struggle for the patient. talking about his daughter and how she keeps controlling his
The mother always said that she does not have time for her spending and that he does not like that.
daughter, she was always late, and that she thinks her The therapist father had a gambling problem that left her
daughter is boring. The mother always humiliated her. family broke. Because of this, the father eventually left her
The therapist has the following stereotypical attributes: she and her mother when she was young.
is a well-dressed woman who is very attentive and always Back to the session, the patient states that his daughter
on time. She listens carefully to the patient in every session. should not have the authority to tell him what to do with his
The therapist at the end of today’s session state that she money. And he states that he is the one who is paying for
needs to finish this session earlier because she is needed for her college. At some point, the patient states that he is going
an emergency consultation at the hospital. The patient to stop paying for her college.
agrees, but in her mind she starts to think that the therapist
must think that I am boring and that is why she wanted me The therapist thinks for a moment that the patient is
to leave earlier. Now, the patient thinks of the therapist as a abandoning his daughter just like her father abandoned her.
mother-figure and started to transfer negative feelings onto She sees that the therapy sessions are not helping the patient
her. The patient calls before her next scheduled session and as she would have hoped. She no longer looks forward to
states that she would like to cancel her next appointment. seeing the patient and she wishes if the patient would cancel
When the therapist asks her why, she states that she is sure the next session.
the therapist has better use of her time than spending it on Because she stopped paying attention for a moment, the
her. patient notices. He states that this therapy thing is expensive
and is not working and he states he does not see the point of
Analysis of the above scenario: having these sessions.

• Things were going well for this patient, until she Analysis of the above scenario:
transferred her feelings about her mother onto the • The therapist thinks that this is because of
therapist countertransference
• The therapist did not do anything wrong, as she • She transferred her feelings about her own father
had an emergency appointment onto her patient
• The therapist tried to ask the patient why she • Because of this, she is no longer interested in the
wants to cancel in an attempt because she thought patient
transference might have occurred Effects on therapy:
• She wanted the patient to understand that she • If the therapist transfers her feelings onto the
cares if she comes or not and she is interested in patient, this will influence the patient-doctor
treating her relationship
Effect on therapy: • If the transferred feelings are positive, this can
result in inappropriate relationship with the patient
• If the therapist does not recognize the possibility
of transference, the patient will start to transfer or in forming feelings of guilt if the patient
positive or negative feelings onto the therapist commits suicide for example

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 • On the other hand, if the feelings that are • Level II defense mechanisms are immature. They
transferred are negative, this can result in less than are unhealthy and can lead to mental illness.
optimal performance from the therapist However, they are not pathological
• Level III defense mechanisms are intermediate or
Defense Mechanisms neurotic. These are somewhere in between
Definition normal and immature defense mechanisms
Defense mechanisms are unconscious psychological • Level IV defense mechanisms are mature or
mechanisms that our ego uses to protect our psychological normal. Under trauma, the individual is still
integrity in a given situation or stimulus. These defense expected to show some sort of a defense
mechanisms can result in healthy or unhealthy (mental mechanism to the psyche or ego. When this
illness) consequences. defense mechanism is appropriate and
constructive, it will be considered as mature
Individual Psyche Structures Pathological Defense Mechanisms
Id: • These are very pathological defense mechanisms
• People who show them are viewed as irrational or
This is the unconscious drive forces a person to seek what
insane by others
he or she wants. These needs are selfish and childish. This
part of the psyche has no ability to delay instant • They aim in rearranging external experiences in
gratification. an attempt to avoid coping with reality
• While they are found in psychosis, these defense
Example: mechanisms can be normal in children or when
we dream
Someone wants to have sex. Denial:
Refusal to accept external reality. The patient tries to not
Superego: argue about an anxiety-provoking stimulus by stating that
This is a group of morals that the individual has gained it does not exist. This type of defense mechanism might be
from societal and parental standards of what is considered seen in some patients with physical disease such as cancer
as good and bad. in the early stages after they receive the news.

Example: Distortion:

That person who wants to have sex knows going to a Instead of denying the traumatic reality, the patient might
prostitute is wrong. reshape the external reality to meet what he or she wants

Ego: Immature Defense Mechanisms

• These defense mechanisms are seen in adults
This is a moderator between pleasure sought by the id and • These defense mechanisms, if extensively used,
the morals of the superego. can be seen as socially undesirable
• Overuse of these mechanisms can lead to
Example: unhealthy consequences such as inability to cope
That person who wanted to have sex gets into a long-term with future stressors
relationship and now has a girlfriend. Their relationship is • These defense mechanisms are common in
healthy and is way more than just having sex like the id patients with major depression disorder and
wanted at first. personality disorders
Schizoid fantasy:
Classification
Defense mechanisms can be seen in a hierarchy The patient retreats into fantasy in an attempt to avoid
perspective. Depending on the developmental maturity of dealing with inner or outer conflicts and stressors.
the individual and the individual’s ability to cope with a
Acting out:
new trauma, four different levels of defense mechanisms
can be employed. Expressing unacceptable feelings or thoughts through
actions without consciously choosing to.
• Level I defense mechanisms are pathological or
psychotic. They are the least immature and can Passive-aggressive behavior:
often lead to mental illness
Hostile feelings and indirect opposition even when in a
nonconfrontational situation.

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Example: Replacement of a negative impulse or wish with a positive
feeling or idea, even though it is not what the patient really
An employee who is not satisfied with his work conditions wants to express.
might always come late to work, however he might not
admit he is doing this in an attempt to get back at the Example:
employer.
A patient with lustful thoughts about his wife’s friend takes
Projection: his wife out for a fancy and romantic dinner.
Attributing an unacceptable internal thought or impulse to Repression:
an external source.
Subconsciously withholding an impulse or a feeling that is
Example: known to the patient to result in suffering or to be
dangerous.
An employee who thinks he is making too little at his job
in a restaurant thinks about taking some money. He then Example:
claims that the employer is doing a scam to not pay work
insurance for the employee. A patient who has social anxiety does not recall that his
father used to verbally abuse his mother for years when he
Neurotic Defense Mechanisms was a child.
• These are common defense mechanisms in adults
• They have short-term benefits in coping Regression:
• Unfortunately, the long-term effect is usually Regressing to an earlier developmental stage when coping
negative on social and occupational life of the with a stressor.
patient
Displacement: Example:
Redirection of emotions or impulses to a third neutral Someone’s mother has just died. He is crying, even though,
party. he knows how to speak and say that he is sorry. Whining
can be seen as a defense mechanism here.
Example:
Isolation:
The same employee from above who had an impulse about
stealing from his employer might tell his wife that she is Separating emotions from ideas and events.
spending too much on shopping and that is why they have
a financial issue. Example:

Dissociation: An eye-witness is stating a graphic murder without feeling

upset or sad about what he or she is describing in the court.
Transient, but drastic, change in personality, memory or
motor behavior to avoid emotional stress. The patient will Mature Defense Mechanisms
not remember the traumatic event, or have an incomplete • Emotionally healthy adults use these defense
recall. mechanisms to cope with stressors
• They optimize the individual’s social and
Example: occupational life
• The goal in most psychodynamic approaches in
A young woman is walking in the street in her old town.
psychotherapy is to help the patient to use these
She sees someone and then becomes numb and detached.
defense mechanisms instead of the immature or
That person has sexually abused her when she was in high-
pathological ones
school. Later on, her friends tell her what is wrong and she
Suppression:
does not know why she felt numb and detached for a
moment. Consciously choosing to delay attention to an idea, or an
impulse to cope with the current situation or reality.
Intellectualization:
Example:
Focusing on the logic and factual part of a problem in an
attempt to distance someone’s self from the emotional A medical graduate chooses to suppress thinking about the
distress that the stressor might cause. results of the matching process until they become available
Reaction formation:
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and he knows which residency program he was accepted Normal intelligence but can be associated with learning
at. difficulties. DSM-5 criteria are used to diagnose attention
deficit hyperactivity disorder.
Anticipation:
Diagnostic criteria:
Realistic planning for a known future problem or
discomfort. A. A persistent pattern of inattention and/or
hyperactivity-impulsivity that interferes with
Example: functioning or development characterized by 1.
and/or 2.
Studying before an exam.
1. Inattention: Six or more of the
Altruism: following, persisted for six months or
more:
Alleviating negative feelings by providing constructive i. Fails to pay attention to details
service to others to bring them pleasure. ii. Difficulty sustaining attention
in tasks
Example: iii. Does not seem to listen when
A banker decides to give a substantial amount of money to spoken to
help those with bank loans to help them payback their iv. Does not follow through on
debts. instructions
v. Problems with organizing
Sublimation: tasks, or keeping things in
order
Transforming unhelpful and negative instincts into healthy vi. Does not engage in tasks that
actions and behaviors. require focusing or attention
vii. Often loses necessary thinks
Example: like mobile phones or keys
An aggressive person joins the football team to transform viii. Forgetful to daily activities
his aggression into a game.
2. Hyperactivity and impulsivity: six or
Humor: more of the following, for six months or
more:
Appreciating the amusing or funny nature of a stressor. i. Often Fidgets or squirms in
seat often
Example:
ii. Often leaves seat in situations
A student has an upcoming neurology exam. He jokes with where seating is expected
his colleagues about how the body is presented in the iii. Often runs in situations where
motor cortex. it is inappropriate
iv. Often unable to engage in
Attention Deficit Hyperactivity Disorder leisure activities quietly
Definition: v. Often on the go as described
Attention deficit hyperactivity disorder is characterized by by the parents
an ongoing pattern of inattention and/or hyperactive vi. Often talks too much
impulsivity in a child that interferes with functioning and vii. Often answers a question
development. before the question is
completed
Risk Factors: viii. Often has problems in waiting
• Family history for his or her turn
• Exposure to cigarettes, alcohol, or illicit drug use ix. Often interrupts others
during pregnancy B. Symptoms were present before 12 years
• Exposure to high levels of lead at a young age C. Symptoms are present in two or more different
• History of traumatic brain injury situations or places (school, home, with friends
• Low birth weight and parents)
• More common in males D. Symptoms reduce quality of life
E. Symptoms cannot be explained by another
Clinical Findings: psychiatric or medical disorder

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Treatment: A. Repetitive and persistent pattern of behavior
Cognitive behavioral therapy where the basic rights of others and social norms
are violated by the presence of at least three of
Drugs: the following in the last 12 months with one of
them present in the last 6 months:
• CNS stimulant: methylphenidate
1. Aggression to people and animals by
• Atomoxetine bullying others, starting fights, being
• Guanfacine cruel to people or to animals
• Clonidine 2. Destruction of property by setting fire to
cause serious damage or other means
Oppositional Defiant Disorder and Conduct Disorder 3. Theft and deceitfulness by breaking into
Definition of ODD someone’s house or building, or
A pattern of hostile defiant behavior against authority obtaining favors by lying to others
figures in the absence of serious violations of social norms. 4. Violation of rules by staying at night
This is a childhood/early-onset disorder. despite parental prohibitions or has run
away from home overnight at least
Clinical Findings of ODD:
twice while living with the parents
DSM-5 criteria are used to diagnose oppositional defiant
B. The symptoms should be associated with
disorder.
significant distress in the individual’s immediate
Diagnostic criteria: social context or impact his/her social,
educational and occupational functioning
F. Angry or irritable mood, defiant behavior, or C. Symptoms onset before 18 years of age and
vindictiveness for at least six months by showing cannot be explained by another medical or
at least four of the following symptoms and the psychiatric disorder
second individual cannot be a sibling:
1. Often loses temper Treatment
2. Easily annoyed Cognitive behavioral therapy
3. Often angry
4. Often argues with authority figure “for Separation Anxiety Disorder
children this is usually an adult” Definition
5. Often defies to comply with the The presence and persistence of overwhelming fear of
authority figure requests separation from an attachment figure lasting for four weeks
6. Often annoys others or more in a child that is older than four years. This
7. Often blames others for his/her mistakes behavior is considered as normal in children younger than
8. Has been vindictive at least twice within 4 years.
the past six months
G. The symptoms should be associated with Clinical Findings
significant distress in the individual’s immediate DSM-5 criteria are used to diagnose separation anxiety
social context or impact his/her social, disorder.
educational and occupational functioning
H. Symptoms cannot be explained by another Diagnostic criteria:
psychiatric or medical disorder I. Persistence of three or more of the following
symptoms for four weeks or more
Treatment of ODD 1. Recurrent distress when anticipating
Cognitive behavioral therapy separation from attachment figures
Definition of Conduct Disorder 2. Excessive worry about losing
attachment figures
Repetitive and pervasive behavior that violates the basic
rights of others or societal norms by an individual who is 3. Excessive worry about being in a
situation that can cause separation from
younger than 18 years of age. Those older than 18 are
attachment figures
reclassified as antisocial personality disorder.
4. Refusal to go out away from home
Clinical Findings of Conduct Disorder 5. Refusal to sleep away from home
DSM-5 criteria are used to diagnose conduct disorder. 6. Repeated nightmares of separation
7. Repeated complaints of factitious
Diagnostic criteria: physical symptoms to avoid separation

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 J. Symptoms cannot be explained by resistance to B. The tics occur many times during a day, nearly
change as seen in autism spectrum disorder or every day, or intermittently over a year with no
any other psychiatric disorder tic-free period more than 3 consecutive months
Treatment C. Age at onset < 18 years
While the symptoms might seem benign, they can lead to D. The disturbance is not due to effects of a
factitious physical complaints to avoid school or being stimulant or a medical condition such as
separated. Treatment options include: Huntington disease or post-viral encephalitis
Coprolalia which is involuntary obscene speech (40% of
• Cognitive behavioral therapy patients and is not part of the criteria)
• Play therapy
• Family therapy Treatment
Tourette Syndrome • Psychoeducation
Definition • Behavioral therapy
Tourette syndrome is a genetic neurological disorder and Patients with more severe and persistent tics
also a psychiatric disorder that is characterized by chronic
motor and vocal tics beginning before adulthood. • Haloperidol or fluphenazine
• Tetrabenazine
Epidemiology • Alpha-2 agonists such as clonidine
• The estimated prevalence is 0.7% • Atypical antipsychotics
• More common in children from white ethnic Pervasive Developmental Disorders
background Definition
• More common in boys This is a diagnostic category that refers to a group of
• The condition persists throughout life, but by the disorders that are characterized by delays in development
age of 18, 50% are free of tics of multiple basic functions related to socialization and
Etiology communication. They include all autism spectrum
• The condition appears to be genetic disorders and Rett syndrome.
• There appears to be an autosomal dominant mode
Autism Spectrum Disorder
of inheritance
This disorder is characterized by poor social interactions,
• 70% penetrance in women, 99% in men →
deficits in social communication, repetitive behaviors and
explains why the condition is found more often in
restricted interests. For the diagnosis to be made, the
men
symptoms’ onset must be in early childhood. More
• DLGAP3 gene is a candidate gene common in boys. While most affected individuals have
• Also associated with obsessive-compulsive some sort of intellectual disability, a few can have unusual
disorder and attention deficit hyperactivity abilities (savants).
disorder
Pathophysiology DSM-5 criteria are used to diagnose autism spectrum
• A disorder that involves neurotransmission in the disorder.
basal ganglia and inferior frontal cortex
• No brain structural lesions Diagnostic criteria:
• Low levels of glutamate in the globus pallidus K. Persistent deficits in social communication and
and low levels of cAMP in the cortex social interaction, for example:
Diagnostic Criteria 1. Deficits in social-emotional reciprocity:
Tics are sudden, rapid, recurrent nonrhythmic stereotyped reduced sharing of interests and
motor or vocal symptoms. emotions, failure to initiate or respond
DSM-5 diagnostic criteria for Tourette syndrome are as to social interactions, and failure of
follows: normal back-and-forth conversation
2. Deficits in nonverbal communicative
A. Multiple motor and one or more vocal tics have behaviors such as maintaining eye-
been present for some time during the illness contact
1. Motor tics: eye blinking, head jerking, 3. Deficits in developing, maintaining and
nose twitching, facial grimacing, understanding relationships
shoulder shrugging, and mouth L. Restricted and repetitive patterns of behavior with
movements at least two of the following:
2. Vocal tics: throat clearing, grunting, 1. Stereotyped motor movements
sniffing, and coughing 2. Insistence on sameness

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 3. Highly restricted and fixated interest A. A positive test showing a MECP2 mutation (X-
4. Hyper or hypo-reactivity to sensory chromosome)
input B. All the following symptoms:
M. Symptoms must be present in early childhood 1. Decreased or loss of fine motor skills
N. Symptoms cannot be explained by intellectual (cannot use hands to play with toys)
disability or global developmental delay 2. Decreased or loss of verbal speech
Asperger Syndrome 3. Abnormal gait
This diagnosis has been removed from the DSM-5 manual 4. Repetitive hand movements (wringing,
as it is now part of the autism spectrum disorder. The squeezing, or clapping)
DSM-IV diagnostic criteria can be used to define what is C. None of the following:
meant by Asperger syndrome. 1. Traumatic brain injury, neurometabolic
disease, or severe CNS infection
Diagnostic criteria: 2. Abnormal psychomotor development
during the first six months of life
A. Impairment in social interaction characterized by
Patients are typically females (x-linked) and the following
at least two of the following:
symptoms can also occur but are not needed for the
1. Marked impairment in nonverbal
diagnosis:
communicative behaviors
2. Failure to develop or maintain peer • Breathing disturbances
relationships • Impaired sleep pattern
3. Lack of spontaneous seeking to share
• Abnormal muscle tone → often mistakenly
enjoyment with other people
diagnosed as cerebral palsy
4. Lack of social and emotional reciprocity
• Scoliosis or kyphosis
B. Restricted and repetitive patterns of behavior with
one or more of the following: • Intellectual disability
1. Preoccupation with one or more • Growth retardation
stereotyped pattern of interest Childhood Disintegrative Disorder
2. Inflexible adherence to specific routines This disorder was removed from DSM-5 as it is now
and rituals considered as part of the autism spectrum disorders.
3. Repetitive motor movements However, the DSM-4 diagnostic criteria can be used to
4. Preoccupation with parts of objects define this disorder.
C. The disturbance causes clinically significant Diagnostic criteria:
impairment in social, occupational or other
important areas of functioning A. Normal development for the first 2 years of life
D. No delay in language development with normal verbal and nonverbal communication
E. No significant delay in cognitive development B. Significant loss of previously acquired skills
other than social interaction before the age of 10 years, manifested by at least
F. Criteria are not met for another psychiatric two of the following:
disorder 1. Deficits in expressive or receptive
Difference from autism: language
2. Deficits in social skills or adaptive
• In autism, other cognitive developmental deficits behavior
and language deficits are present 3. Deficits in bowel or bladder control
Rett Syndrome 4. Deficits in ability to play with others
After the recent understanding of the molecular 5. Deficits in motor skills
mechanisms of Rett syndrome, it was removed from the C. Abnormal functioning in two or more of the
category pervasive developmental disorders. The current following areas:
understanding of Rett syndrome agrees that autistic 1. Social interaction and nonverbal
features are present in the disease just like you would communication
expect in fragile-X or Down syndrome, but this is 2. Verbal communication
explained by medical cause and is therefore not an autism 3. Restricted, repetitive and stereotyped
spectrum disorder. Onset of symptoms is typically after the patterns of behavior, interests, and
first year of life to four years. motor mannerisms
Diagnostic criteria: D. The disturbance is not explained better by another
pervasive developmental disorder or
schizophrenia

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Rationale of removing Asperger and childhood • Earlier presentation in men (in the 20s in men,
disintegrative disorder from DSM-5: while in the 30s in women)
Diagnostic criteria:
• You can notice the similarity in the symptoms of
these three disorders • Presence of two or more of the following for one
• The current understanding is that autism, month or more with at least one symptom from
Asperger, and childhood disintegrative disorder the first three:
are the same disorder but with different degrees o Delusions
of severity o Hallucinations
• Accordingly, the collective diagnosis “autism o Disorganized speech
spectrum disorder” was introduced o Disorganized or catatonic behavior
Schizophrenia Spectrum and Other Psychotic Disorders o Negative symptoms
Important Definitions Related to Psychosis The first four of these symptoms are considered as positive
Psychosis: symptoms. Negative symptoms include:

A period where perception of reality is distorted by • Affective flattening

delusions, hallucinations and other types of disorganized • Avolition
thought. Psychosis can occur in psychiatric illness and also • Asociality
in organic medical conditions. • Alogia
• Anhedonia
Delusions:
Other features:
These are unique, false and fixed idiosyncratic beliefs that
cannot be shaken off despite evidence of being false and • Brain MRI might reveal ventriculomegaly
are not part of the patient’s culture or religion. Grandiose, • Increased risk of suicide
jealous, or persecutory delusions are some examples. Treatment:

Disorganized thought: • First-line treatment is atypical antipsychotics such

as risperidone
The process of thought is disorganized, and this results in • First generation typical antipsychotics can be
incoherent speech “word salad”, or the speech can have used for positive symptoms:
loss of association. o Haloperidol
o Thiazine and chlorpromazine
Hallucinations: • Negative symptoms show little response to
These are defined as perceptions or experiences in the treatment, however atypical antipsychotics might
absence of external stimuli. Illusions are misperceptions of alleviate them:
external stimuli. Examples: o Ziprasidone
o Risperidone
• Visual – more common in medical illness o Olanzapine
• Auditory – more common in psychiatric illness o Clozapine
• Olfactory – seen in temporal lobe epilepsy Brief Psychotic Disorder
• Gustatory – epilepsy • One or more positive symptom lasting for less
• Tactile – seen in alcohol or stimulant withdrawal than one month in a patient under stress
Schizophrenia • Total duration of decline in functioning is less
This is a chronic mental illness that has distinct periods of than one month
psychosis and abnormal behavior and thought. This should Schizophreniform Disorder
result in a decline in functioning lasting six months or • Same as schizophrenia but the total duration of
more. decline in functioning is less than six months
Schizoaffective Disorder
The condition is associated with increased dopaminergic • Meets the diagnostic criteria of schizophrenia
activity and decreased dendritic branching. • Meets the diagnostic criteria of major depressive
or bipolar disorder
Epidemiology:
• Patients have solely psychotic symptoms (without
• More frequent in cannabis users a major mood episode) for more than 2 weeks
• Life-time prevalence is 1.5% Delusional Disorder
• More common in males

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 • A fixed, persistent and false belief system lasting Major Depressive Disorder
for more than one month without any other Diagnostic criteria:
functional impairments • A depression episode that has five symptoms or
• Can be shared by individuals in close more from the previous list
relationships “shared delusional disorder” • Must have depressed mood or anhedonia
Mood Disorder with Psychotic Features • For at least 2 weeks
• Meets diagnostic criteria of major depressive • Not attributable to other medical conditions or
disorder or bipolar disorder type 1 substances
• Brief period of psychotic symptoms < 2 weeks Treatment:
with a major mood episode • Psychotherapy
Other Psychotic Disorders • Selective-serotonin-reuptake inhibitors
Schizoid personality disorder • serotonin-norepinephrine-reuptake inhibitors
• MAO inhibitors
• Lack of interest and detachment from social
• Tricyclic antidepressants
relationships, apathy and restricted emotional
expression • Electroconvulsive therapy in refractory cases
Schizotypal personality disorder Persistent depressive disorder (dysthymia):
• Milder than major depressive disorder
• Extreme discomfort interacting socially, distorted • Two or more depression symptoms lasting for
cognitions or perceptions, strange beliefs and two years or more
magical thinking • No more than two months without depressive
Mood Disorders symptoms
Definition:
A mood disorder is characterized by an abnormal range of Bipolar Disorders:
mood and internal emotional states with loss of control over Bipolar I:
them. These abnormal moods and emotional states need to One episode of mania with or without (a hypomanic or a
cause impairment in social and occupational functioning. depressive episode).
Bipolar II:
Mood Episodes: At least one episode of hypomania and one episode of
Depression episode: at least five and lasting for two weeks depression plus no history of manic episodes
or more Cyclothymic disorder:
• Depressed mood Alternating periods between hypomanic symptoms and
• Sleep disturbance depressive symptoms without meeting criteria for
• Loss of interest (anhedonia) hypomanic episode or depressive episode that persists for
• Guilt two years or more. Treated with cognitive behavioral
• Energy loss therapy, lithium and atypical antipsychotics.
• Concentration problems Treatment:
• Appetite changes • Mood stabilizers such as lithium or valproate
• Psychomotor retardation • Lamotrigine
• Suicidal ideation • Atypical psychotics for an acute manic episode
Manic episode: at least three, lasting for one week or more, • Patient’s mood often normalizes between
and causes marked functional impairment and often episodes
hospitalization
• Distractibility Adjustment Disorder:
• Impulsivity • Mood and anxiety symptoms less than 3 months
after a stressor
• Grandiosity
• Resolves within 6 months
• Flight of ideas – not loss of association
• Treat with psychotherapy and medications for
• Psychomotor agitation
insomnia or nausea if prominent
• Decreased need for sleep
• Pressured speech Bipolar Disorders
Hypomanic episode: Definition
Similar to a manic episode, but with less severe symptoms Distinct period of abnormal and persistent elevated,
that do not impair social and occupational functioning expansive and irritable mood with increased activity and
severely. Lasts for 4 days or more lasting for 1 weeks or more occur in bipolar disorders.

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Epidemiology • Presence of a hypomanic episode and a
• Prevalence of 3.7% depressive episode
• Typical onset between 18 and 44 years • Never had a manic episode
• More than half of the patients do not seek medical Treatment
help within the first five years of onset of Psychotherapy in addition to mood stabilizers and atypical
symptoms antipsychotics.
• The diagnosis was made 8 years in average after
the onset of symptoms Mood stabilizers:
• Equal frequency in males and females • Lithium:
• Age of onset in bipolar II is slightly higher (22) o Recommended in patients with manic
than that of bipolar I (18) euphoric, mild, moderate or severe
Manic Episode episodes
A. At least three of the following symptoms, or any o Side effects:
number of symptoms that require hospitalization; ▪ Nephrogenic diabetes
and duration of symptoms lasting > 1 week: insipidus → block ADH
1. Distractibility receptors
2. Impulsivity – patients seek pleasure ▪ Hypothyroidism → decreased
without regard to consequences free T4 and T3 | elevated TSH
(hedonistic) ▪ If taken during pregnancy →
3. Grandiosity – inflated self-esteem Ebstein anomaly
4. Flight of ideas where the thoughts are • Valproic acid:
described as racing in their mind o Recommended in patients with severe
5. Increased activity or psychomotor manic episodes or in patients with rapid
agitation cycling manic episodes
6. Decreased need for sleep o Side effects:
7. Talkativeness and pressured speech ▪ If taken during pregnancy →
B. The symptoms should result in significant neural tube defects such as
impairment of social or occupational functioning, spina bifida
or require hospitalization • Carbamazepine:
Hypomanic Episode o Can cause agranulocytosis
A. At least three of the following symptoms with a Atypical antipsychotics:
duration of symptoms lasting > 4 consecutive
days Clozapine
1. Distractibility
2. Impulsivity – patients seek pleasure Major Depressive Disorder
without regard to consequences Depressive Episode
(hedonistic) A. At least five of the following symptoms,
3. Grandiosity – inflated self-esteem symptoms must include either depressed mood or
4. Flight of ideas where the thoughts are anhedonia or both; and duration of symptoms
described as racing in their mind lasting > 2 week:
5. Increased activity or psychomotor 1. Depressed mood
agitation 2. Sleep disturbance
6. Decreased need for sleep 3. Loss of interest (anhedonia)
7. Talkativeness and pressured speech 4. Guilt
B. The symptoms must not lead to severe 5. Energy loss
impairment in social and occupational 6. Concentration problems
functioning, or require hospitalization 7. Appetite changes
Diagnostic Criteria 8. Psychomotor retardation
Bipolar I: 9. Suicidal ideation
Sleep disturbances in a depressive episode include:
• Presence of at least 1 manic episode, with or • Decreased rapid-eye-movement latency
without a hypomanic or depressive episode
• Increased rapid-eye-movement in the early phase
• The episodes can be separated by any length of of the sleep cycle
time
• Increased total duration of rapid-eye-movement
Bipolar II:
sleep

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 • Repeated nighttime awakenings Severe major depression with psychotic features:
• Early-morning awakening → terminal insomnia • An antidepressant combined with an
• On EEG: decreased slow-wave sleep antipsychotic
• For more information about sleep physiology, • Electroconvulsive therapy can be considered
please go to Neurology – Sleep Physiology • Tricyclic antidepressants plus an antipsychotic is
a common regimen
Major Depressive Disorder: Final goals:
A. A major depressive episode that meets the criteria • Once pharmacotherapy is started, assess
described above fortnightly
B. The symptoms should result in significant • Re-evaluate at 4 weeks:
impairment of social or occupational functioning o Remission → continue using same drug
C. The patient should not have a history of a manic o Partial response → increase dose
episode → reclassified as bipolar I o No response → switch to a different
D. The symptoms cannot be explained by another class of antidepressants or consider
medical or mental illness electroconvulsive therapy

Other Types of Depression Disorders: Panic Disorder

Persistent depressive disorder: Definition
A. Also known as dysthymia Panic disorder is characterized by recurrent unexpected
B. Milder than major depressive disorder panic attacks that are followed by one month or more of
C. Two or more depressive symptoms persistent concern about having additional attacks or worry
D. Lasting for two years or more about the implications of having a future attack or a
E. No more than two months without depressive significant change in behavior related to the attacks.
symptoms
Major depressive disorder with seasonal pattern: Epidemiology
A. Lasting two years or more • Prevalence of 2.2%
B. Two or more major depressive episodes • Typical onset between 20 and 29 years
associated with a seasonal pattern (e.g. winter) • Higher risk in females
C. Atypical symptoms are common, and they • 25% also have agoraphobia
include hypersomnia, hyperphagia, and leaden • Increased risk of developing major depressive
paralysis disorder
Depression with atypical features: • Increased risk of suicide
A. Mood reactivity (improved mood in response to • Family history is a risk factor – possible role of
positive events but briefly) genetics
B. Hypersomnia and hyperphagia Panic Attacks
C. Leaden paralysis A. Periods of intense fear and discomfort that peak
D. Long-standing interpersonal rejection sensitivity in 10 minutes and have > 4 of the following
E. Most common subtype of depression features:
1. Palpitations
Treatment 2. Paresthesia
Definitions related to response to treatment in depressive 3. Depersonalization
disorders: 4. Derealization
• Recovery is remission and return to normal 5. Abdominal distress
function 6. Nausea
• Response is a reduction in 50% or more in the 7. Intense fear of dying
symptoms of major depressive disorder 8. Intense fear of losing control
• No response is a reduction less than 20% in the 9. Light-headedness
symptoms of major depressive disorder 10. Chest pain
First-line treatments: 11. Chills
• Cognitive behavioral therapy with an SSRI, SNRI 12. Chocking
(venlafaxine), bupropion, mirtazapine or 13. Sweating
agomelatine 14. Shaking
• For severe depression SSRIs and SNRIs are more 15. Shortness of breath
important than cognitive behavioral therapy, Diagnostic Criteria:
however psychotherapy is still needed

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 A. Occurrence of a panic attack that is not triggered • Life-time prevalence is 10%
followed by > 1 month of > 1 of the following: Diagnosis:
1. Persistent concern about future attacks
2. Worrying about the consequences and • Severe and persistent > 6 months fear or anxiety
implications of an attack due to the presence of a specific object or
3. Behavioral change related to the attacks situation
Diagnostic criteria of agoraphobia which is common in • Fear is out of proportion to imminent threat
patients with panic disorder: • The symptoms interfere with daily activities
• Exposure to the stimulus induces immediate fear,
A. Anxiety about being in places or situations where whereas, removing the stimulus reduces anxiety
escape might be difficult • Social anxiety disorder is excessive fear of
B. Avoidance of situations and places that meet embarrassment in social situations such as public
criterion A speaking or using public restrooms
C. Symptoms not better accounted for by substance Treatment:
abuse, another medical or mental disorder
Treatment: • Systematic desensitization
First-line: • Cognitive behavioral therapy
• SSRIs or SNRIs such as venlafaxine
• Cognitive behavioral therapy
Treatment of performance type social anxiety disorder:
• SSRIs
• SNRIs such as venlafaxine • Beta-blockers or benzodiazepines when needed
Acute panic attack treatment: Obsessive-Compulsive Disorder
• Equal frequency in males and females
• Benzodiazepines → facilitate GABA by binding
• Lifetime prevalence is 3%
to GABAA receptors
• Associated with other anxiety disorders, tic
• Potent anxiolytics
disorders, and especially Tourette syndrome
Anxiety Disorders
Diagnosis:
Generalized Anxiety Disorder:
• More common in women • Obsessions which are recurrent thoughts that
• Life-time prevalence is 5 to 10% persist despite trying to ignore
Diagnosis: • Compulsions which are the actions “rituals” one
take to reduce the anxiety that they might develop
A. Symptoms of anxiety lasting > 6 months
as a result of their obsessions
B. Unrelated to a specific person, situation or event
Treatment:
C. Associated with restlessness, irritability, sleep
disturbance, fatigue, muscle tension, or difficulty • Cognitive behavioral therapy
concentrating • SSRIs or SNRIs such as venlafaxine
D. If the symptoms occur in response to an • Clomipramine
identifiable stressor that happened within 3
Body dysmorphic disorder:
months and last < 6 months → adjustment
disorder • The preoccupation with minor or imagined defect
Treatment: in appearance that results in significant emotional
distress and impaired functioning
First-line treatments:
• Patients often seek cosmetic treatment
• Cognitive behavioral therapy or medication • The condition is treated with cognitive behavioral
• Medications include SSRIs and SNRIs therapy
Second-line treatments: Post-Traumatic Stress Disorder
Diagnosis:
• Buspirone
• Tricyclic antidepressants • The patient experiences a life-threatening
• Benzodiazepines situation then develop any of the following:
Risk of rebound anxiety upon discontinuation of o Persistent hyperarousal
medication. o Avoidance of associated stimuli
o Intrusive re-experiencing of the event in
Specific Phobias: the form of nightmares or flashbacks
• More common in women

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 o Changes in cognition or mood (horror or Appearance and Behavior
distress) The body habitus, eye contact, interpersonal style and style
• The disturbance must last for more than one of dress are noted.
month and cause significant distress in social and
occupational functioning Appearance:
• Acute stress disorder lasts between 3 days and 1 • Attention to detail
month • Comment on attire, scars, tattoos, grooming and
Treatment: hygiene
Behavior:
• Cognitive behavioral therapy, SSRIs, or an SNRI • Observe the patient and comment if the patient is
(venlafaxine) candid, congenial, cooperative, defensive,
• Prazosin → reduces nightmares engaging, guarded, hostile, irritable, open,
• Acute stress disorder does not require relaxed, resistant, shy, or withdrawn
pharmacotherapy Eye Contact:
Treatment Algorithm • Comment on whether the patient can make good
• Multistep approach in the treatment to avoid eye contact or is it fleeting or sporadic. Note if
polypharmacy there is no eye contact
Step 1: Example of abnormalities in appearance and behavior:
• The diagnosis of an anxiety disorder has been • An irritable patient might have anxiety
made • A paranoid patient could have a psychotic
• Prescribe either an SSRI | NSRI, or, CBT disorder
Evaluate the patient to look for full response → if yes, • Those who make poor eye contact could have
continue same treatment depression or a psychotic disorder
Step 2:
Mood and Affect
• The patient did not fully respond to step 1 Mood:
• Augment treatment chosen in step 1 use This is the subjective report of the inner emotional state by
combined therapy (CBT + Medication) the patient using his/her own words
Step 3:
You can ask a direct open-ended question “how is your
• If the patient still does not show full response, use mood?”
one of the following options:
Affect:
o Used combined pharmacotherapy or add
This is the objective observation of the patient’s emotional
benzodiazepines
state by the psychiatrist or medical doctor.
o Repetitive TMS, ECT, or vagal nerve
stimulation. • Neutral, euthymic, dysphoric, apathetic,
inappropriate
Mental Status Examination Motor Activity
Definition
Facial Expressions:
The mental status examination is a tool used in the
Notice the range of emotions the patient is expressing with
assessment of systemic, neurologic and psychiatric his/her face.
disorders such as delirium, dementia, bipolar disorder or
schizophrenia. A mini-mental status examination is a • Flat, blunted, restricted, full or normal, labile or
relatively brief version of the complete mental status expansive
examination. A mental status examination is not a • Congruence with reported mood by the patient
neuropsychological evaluation, the latter being highly Movements:
detailed and time-consuming.
• Akathisia:
Excessive motor activity such as pacing, wringing
General Observations
of hands, or inability to sit still
The mental status examination has two main categories of
components: general observations and cognitive • Bradykinesia:
functioning. Psychomotor retardation which can be seen in
depression, or a symptom of a physical disease
(Parkinson’s disease)

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 • Catatonia: • Declarative memory can be tested with a simple
Immobility with muscular rigidity question such as when is your birthday
Example of abnormalities in motor activity: • Ask the patient to repeat three words immediately
and then again in five minutes to test declarative
• Akathisia might be seen in anxiety, mood memory
disorders, PTSD, or schizophrenia • Ask the patient to sign his or her name while
• Bradykinesia might be seen in depression or answering unrelated questions to test procedural
Parkinson’s disease memory
• Catatonia is seen in patients with schizophrenia, Example of abnormalities in memory:
severe depression and other psychotic disorders.
• Long-term deficits are seen in advanced
Cognitive Functioning dementia, amnesia, dissociative disorder, and
Attention: previous stroke
Ability to focus on internal or external priorities. The • Short-term deficits are seen in ADHD, dementia,
patient can be asked to count by sevens or fives. inattention or substance abuse
Orientation:
Example of abnormalities in attention: The ability of the patient to recognize his place in relation
to time and space. Orientation to time, space and person is
• Could have deficits in ADHD, delirium, tested.
dementia, mood disorders, or psychotic disorders
Executive Functioning: • Questions about what year or month is it, what
The ordering and implementation of cognitive functions city/building or floor are you in, what is your
necessary to perform appropriate behaviors. The patient name, and when were you born?
could be asked to draw a clock with hands set to 10:30 or Example of abnormalities in orientation:
to alternate numbers with letters in ascending order.
• Head trauma
Example of abnormalities in executive functioning: • Amnesia, delirium, dementia, mania, stroke,
severe depression
• Impaired in delirium, dementia, mood disorders,
Thought Content:
and stroke
Here, you try to identify what the patient is thinking in
Gnosia:
terms of delusions, hallucinations, homicidal ideation,
The ability to name common objects and their function.
obsessions, phobias and suicidality.
Example of abnormalities in gnosia:
• Ask about thoughts or images that the patient
• Temporal lobe epilepsy, advanced dementia, or cannot get out of his/her head
stroke • Excessive fears
Language: • Whether they think people are trying to hurt them
Check the quality of speech not the content: • Whether they think people are talking behind
their back
• Appropriateness of speech • Whether they think people are stealing from them
• Rate of speech (> 100 words per minute is • Questions related to suicidal ideation: ask in this
normal, < 50 words per minute is abnormal) order:
• Appropriate for education level o Do you feel life is not worth living?
Example of abnormalities in language and speech: o Have you ever thought about hurting
yourself? If so, how would you do it?
• Rapid and pressured speech in mania o Have you ever thought the world would
• Slow or impoverished speech in delirium, be better off without you?
depression and schizophrenia • Questions about hallucinations:
• Inappropriate conversation in schizophrenia o Do you see things that upset you?
• Inappropriate for education level in dementia, o Do you see, hear, smell or feel things
depression, or stroke that are not really there?
Memory: o Have you ever heard something that
The recall of past events. Can be classified not declarative other people could not?
and procedural. Procedural memory is the ability to • Have you ever thought about hurting others or
complete a learned task without conscious thought. getting even with those who have wronged you?
Example of abnormalities in thought content:
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 • Delusions can be seen in patients with mania, • Visuospatial proficiency
psychotic disorders, or major depressive disorder More appropriate for medical conditions rather than
with psychotic features psychiatric disorders.
• Hallucinations can be seen in patients with
delirium, dementia, schizophrenia, or substance Personality Disorders Clusters
abuse Cluster A Personality Disorders
• Homicidal ideation can be seen in patients with These individuals are described as odd or eccentric. They
mood, personality, or psychotic disorders have problems in developing meaningful social
relationships, however they do not have full-blown
• Obsessions are seen in patients with OCD, PTSD,
psychosis. Genetic predisposition to other psychotic
and psychotic disorder
disorders and schizophrenia.
• Phobias in specific phobic disorders
• Suicidality is seen in depression, PTSD and Paranoid:
substance abuse
Thought Processes: • Pervasive distrust (accusatory) of others
This domain is concerned with the organization of thoughts • Suspiciousness of others
in a goal-oriented pattern. • Very strong cynical view of the world
Schizoid:
Circumferential:
• Voluntary withdrawal from social interactions
The patient goes through multiple related thoughts before (aloof)
arriving at the right answer for the question that was asked
• Limited emotional expression
Disorganized thoughts: • Prefers social isolation
Schizotypal:
Patient moves from one topic to another without coherence
or logic. • Eccentric appearance
• Odd beliefs and magical thinking
Tangential: • Interpersonal awkwardness
Cluster B Personality Disorders
The patient avoids to answer the question by listening to
These are dramatic and erratic emotional individuals that
the question and then begins discussing related thoughts
are at an increased risk of mood disorders and substance
but never answers the question.
abuse.
Visuospatial Proficiency:
Antisocial:
This test is more useful in medical conditions such as
delirium, dementia and stroke. The patient is instructed to • More common in males
copy intersecting pentagons or a 3D cube on paper. It tests • Patient must be 18 years or older
the patient’s ability to perceive and manipulate objects in
• Must have history of conduct disorder before age
space.
15
Insight: • Repeated violation of rights of others and rules,
Does the patient understand and recognize his or her lack of remorse, and criminality
illness. The patient is inquired about his/her explanation of Borderline:
the current problem and his/her awareness about treatment
options. Graded as good, fair or poor. • More common in females
• Unstable mood which leads to unstable
Judgement:
interpersonal relationships
Tests the patient’s ability to make sound and reasoned
• Impulsivity
decisions. It is important because it can affect handling of
• Self-mutilation
treatment plan. Graded as good, fair or poor.
• Suicidal ideation or attempts
Mini-Mental Status Examination: • Sense of emptiness
Only takes the following domains into account: Histrionic:

• Attention • Excessive emotionality and excitability

• Language • Attention seeking behavior
• Memory • Sexually provocative
• Orientation • Overly concerned with appearance

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Narcissistic: B. Not compatible with any known neurologic
medical condition
• Grandiosity The condition often occurs following an acute stressor.
• Sense of entitlement Patients are aware of the nature of the symptoms, but are
• Does not empathize with others and requires indifferent toward them. The condition is more common in
excessive admiration adolescent and young adult females.
• Demands the best of others
• Reacts to criticism with anger and rage Malingering and factitious disorders are defined as follows:
Cluster C Personality Disorders Malingering:
These are individuals that are described as anxious and A. Not a mental disorder
fearful. There is predisposition to anxiety disorders. B. Symptoms are made up intentionally for an
Avoidant: intentional motivation
C. The individual seeks specific gains
• Hypersensitive to rejection D. The individual might exaggerate an existing
• Socially inhibited and timid medical condition for the secondary gain
• Feelings of inadequacy E. Complaints go away after gain
• Still, wants to be with others Factitious disorder:
Obsessive-compulsive: A. Symptoms are intentional, but motivation is
unconscious
• Preoccupation with control, and perfectionism B. The patient consciously creates the
• Behavior consistent with one’s own beliefs and physical/psychological symptoms
attitudes C. The goal is to assume sick role to seek medical
Dependent: attention and sympathy
D. Mainly internal gain
• Always need for support E. When the condition results in multiple hospital
• Low-self-esteem and confidence admissions and willingness to go for invasive
• Tend to get stuck in abusive relationships procedures → Munchausen syndrome | more
common in females and healthcare workers
Somatic Symptom Disorder F. When the illness is caused by a caregiver in a
Definitions and Subclassifications child or an elderly → Munchausen syndrome by
Symptoms are physical and real to the patient; however they proxy → considered as form of child/elder abuse
are unconscious. Motivation should be absent in a somatic Epidemiology of Somatic Symptom Disorder
symptom disorder, in contrast to factitious disorder or • Estimated prevalence is 0.1%
malingering. These conditions are more common in women • Those who partially meet the diagnostic criteria
(10:1 female to male ratio for somatic symptom disorder). of somatic symptom disorder can be as high as
11% of the general population
Somatic symptom disorder: • The estimated prevalence of conversion disorder
in psychiatric inpatient wards is 15%
A. One or more somatic symptoms that cause
• Symptoms should start in adolescence → onset of
significant distress and disruption in daily life
somatic symptoms in a patient who never had
B. One or more excessive thoughts, feelings, or
somatization issues before → search for an occult
behaviors related to the somatic symptoms medical condition
C. Symptoms include pain, or fatigue and they
should last for six months or more (six months of Treatment
being symptomatic, but the same symptom does • Regular office visits with the same physician to
not have to last for six months) build a relationship in combination with
Illness anxiety disorder: psychotherapy
A. Also known as hypochondriasis • Try to not treat the somatic symptoms as much as
B. Excessive preoccupation with acquiring or having you can
a serious illness despite medical evaluation
C. Minimal somatic symptoms Eating Disorders
Conversion disorder: Definition
A. Somatic symptom disorder with prominent Eating disorders are characterized by abnormal eating
neurologic symptoms such as paralysis patterns which can have long-term impacts on the patient.

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Anorexia Nervosa Epidemiology:
Epidemiology: • Higher prevalence than anorexia nervosa, 1.5%
• Prevalence is 1% • More common in women, aged 16 to 22 years
• More common among young women and • Can be classified into binge-eating and non-
adolescent girls purging types
• Poor prognosis Diagnosis:
Diagnosis: The DSM-5 diagnostic criteria for bulimia nervosa are the
The DSM-5 diagnostic criteria for anorexia nervosa are the following:
following: A. Recurrent episodes of binge eating. An episode of
A. Restriction of intake relative to requirements binge eating must include the following two
which result in a significantly low body weight characteristics:
which must be less than the minimal normal for 1. Eating large quantities of food in a
the patient’s age small amount of time
B. Intense fear of gaining weight or becoming fat 2. Lack of control over eating during the
and persistent behavior that interferes with weight episode
gain B. Recurrent inappropriate compensatory behavior
C. Disturbance in the way in which one’s body to prevent weight gain such as induced vomiting,
shape is perceived or experienced use of laxatives, diuretics, fasting or excessive
The body mass index (BMI) is used to classify anorexia exercise
nervosa by severity: C. These two behaviors of binge eating, and
• Mild: BMI > 17 kg/m2 compensatory behaviors occur at least once per
• Moderate: BMI 16 – 16.99 kg/m2 week for three months
• Severe: BMI 15 – 15.99 kg/m2 D. Self-evaluation is influenced by body shape and
• Extreme: BMI < 15 kg/m2 weight
The following clinical findings and characteristics are seen E. Does not occur during episodes of anorexia
in patients with anorexia nervosa: nervosa
• BMI is < 18.5 The patients have the following characteristics:
• Amenorrhea secondary to loss of pulsatile GnRH • BMI > 18.5 but less than 25
secretion • Electrolyte disturbances similar to anorexia
• Hypokalemia nervosa
• Hypophosphatemia • Russell signs:
• Hypomagnesemia Calluses and abrasions on the dorsum of the hand
caused by repeated contact with the incisors
• Bradycardia and arrhythmias secondary to
hypokalemia during self-induced vomiting
• Dental carries
• Metabolic alkalosis
• Enamel erosion from repeated acidic exposure to
• Osteopenia which can be irreversible
the teeth due to vomiting
• Restricting or binge-eating subtypes
Treatment:
Treatment:
• Cognitive behavioral therapy
• Psychotherapy, usually cognitive behavioral
therapy • Fluoxetine or other SSRIs do help with bulimia
nervosa symptoms
• Treatment of the physical symptoms
• SSRIs can be also used for comorbid symptoms
• Fluoxetine or other SSRIs for the treatment of
such as anxiety and depression
comorbid depression or anxiety
• Avoid bupropion → can cause seizures
Refeeding syndrome:
• Severely malnourished patients who start
Binge-Eating Disorder
receiving energy intake suddenly might develop
Epidemiology:
hyperinsulinemia
• Prevalence > 3%
• The increased insulin secretion results in
hypophosphatemia, hypokalemia and • Equal occurrence in men and women
hypomagnesemia • Prevalence among obese people is > 50%
Diagnosis:
• This can result in cardiac arrhythmias,
rhabdomyolysis and seizures The DSM-5 diagnostic criteria for bulimia nervosa are the
following:
Bulimia Nervosa

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 A. Recurrent episodes of binge eating. An episode of
binge eating must include the following two
characteristics:
1. Eating large quantities of food in a
small amount of time Preparation Action

2. Lack of control over eating during the

Termination
episode
B. The binge-eating episodes are associated with > 3
of the following: Contemplation Maintenance
1. Eating is more rapid than normal
2. Eating does not stop until the patient is
uncomfortably full
Relapse
3. Eating large amounts of food even when
not hungry
Precontemplat
4. Eating alone because the patient feels
ion
embarrassed about how much he/she
eats Figure 409: Stages of change. The goal of successful
5. Feeling disgusted with oneself and therapy of addiction is to go to termination instead of
guilty relapse after maintenance.
C. Marked distress regarding binge eating
D. Occurs once per week or more for three months Precontemplation
Patients with binge-eating disorder are characterized by the Definition:
following:
• Older than your typical bulimia nervosa or The addict is not thinking seriously about change. They are
anorexia nervosa patients not interested in help and they can rationalize and defend
their bad habits. To them, there is no problem in the first
• Binge-eating without compensatory behavior as
in bulimia nervosa place to start with.
• Complications related to obesity such as Techniques:
dyslipidemia and increased cardiovascular risk
• Limited ability to lose weight • The goal of any intervention at this stage is to
Treatment: make the addict enter contemplation stage
• Cognitive behavioral therapy is first-line • You should validate the lack of readiness
treatment • It is important to assure them that the decision is
• Sibutramine can be used for weight loss theirs
• Orlistat is also helpful • Encourage self-exploration
• SSRIs are used for comorbid depression or • Explain the risks of current behavior in a
anxiety personalized approach
• Lisdexamfetamine Contemplation
Definition:
Stages of Change
Definition and Theory The patient becomes aware that there is a problem and they
Psychologists and psychiatrists often deal with patients who can understand the consequences of such bad habits. They
are addicts. Understanding the different stages of change can might consider the possibility of changing but are still
help the psychiatrist in understanding his or her clients and ambivalent about it. Patients might start saying this like
offer the appropriate therapy or intervention. they want to change, but not right away because they are
A lot of research has been done on this topic which lead to not ready yet.
the identification of five distinct stages of change. In fact, Techniques:
most addiction programs focus on the understanding of
these stages of change in the first step in overcoming an • The goal is to make the patient enter the
addiction. These intentional behavior changes occur along a preparation stage
temporal dimension and involve cognitive and behavior • Validate the lack of readiness
components. • Again, clarify that the decision is theirs and they
are not forced to do anything

658
 • At this stage, it is important to use cognitive • Discussion of relapse and how to cope with it
behavioral techniques and ask the patient to think should be started
of the pros and cons of behavior change Relapse
• Set new expectations and promote them in your Definition:
future sessions
Preparation Returning to old behaviors and abandoning new changes.
Definition: This does not always happen but should be considered as
part of the stages of change. If this happen, it just means
The patient is finally ready to change. He or she are testing we need to start over. It does not mean that the addict is
the waters of change and really consider changing within weak, bad, or not up to the challenge.
the next month.
Techniques:
Techniques:
• It is extremely important to identify the trigger
• Use a reward system and appreciate the patient’s for relapse
readiness • Reassess the motivation of the patient. In some
• Identify the obstacles that the patient might face cases, you can help the patient to enter the
and solve them contemplation stage without going through
• Help the patient to identify with social support precontemplation again
groups and suggest addiction meetings or other Plan stronger coping strategies to fight future urges and
types of support prevent relapses.
• Encourage the patient to take small initials steps
and not to expect to change in one night Anti-Psychotics (Neuroleptics
Overview
Action
• Psychosis is used to describe conditions that
Definition:
affect the mind, where there has been some loss
At this stage, the patient is already doing new behaviors of contact with reality.
and the old behaviors are dying out. The new, better, Symptoms of psychosis:
behavior lasts for three to six months in this stage. • Delusions (false beliefs)
Willpower is important. • Hallucinations (seeing or hearing things that
others do not see or hear).
Techniques: • Other symptoms include incoherent or nonsense
speech, and behavior that is inappropriate for the
• This is a true milestone in the recovery of the
situation.
addict, acknowledge that
• A psychotic person might experience depression:
• Your sessions should focus on cues and social 1. Anxiety
support
2. Sleep problems
• Encourage the patient to be confident and use 3. Social withdrawal
self-efficacy in dealing with obstacles 4. Lack of motivation
• Patients tend to start experience feelings of loss,
therefore it is important to remind them about the Typical Antipsychotic drugs
long-term benefits • Haloperidol
Maintenance • Chlorpromazine
Definition: • Fluphenazine
• Trithioperazine
The patient is still practicing the new behaviors and he/she
• Thioridazine
is committed to change. This last from six months to
multiple years, because there is always the risk of relapse. • Note: Antipsychotic drugs are not curative and do
The goal is for the patient to reach termination where not eliminate the chronic thought disorder, but
former bad behaviors are no longer perceived as desirable. they often decrease the intensity of hallucinations
and delusions
Techniques: Mechanism of Action
• Dopamine receptor-blocking activity in the brain
• Follow-up support (Mostly D2 receptors):
• Reinforce internal rewards 1. Nigro-strial (psychiatric tract) Extrapyramidal
system

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 2. Substania Nigra (Neurological tract)
3. Tubero-infundibular tract (Endocrine tract) Anticholinergic
Indications • Constipation
• Psychosis • Urinary retention
• Bipolar disorder • Dry mouth
• Delirium • Tachycardia
• Tourette syndrome •  Seizures threshold
• Huntington disease Alpha blockade
• OCD • Postural hypotension
• Schizophrenia Sedation
Dopamine hypothesis • Block histamine release
• Symptoms arise because of excessive Cardiac effects
dopaminergic activity in mesolimbic system. • QT prolongation- Thioridazine
• Dopamine agonists cause psychosis. Ophthalmologic
• Dopamine antagonists have antipsychotic • Chlorpromazine-Corneal deposits
actions. • Thioridazine-retinitis pigmentosa, which may
• Serotonin is increasingly seen as a part of the lead to blindness
etiology of schizophrenia.
Metabolic and endocrine effects
Positive Symptoms Negative symptoms • ↑ Prolactin (galactorrhea, amenorrhea,
Thought disorders Amotivation gynecomastia)
Delusions Social withdrawal
Hallucinations Flat affect • ↑ Eating disorders (weight gain)
Paranoia Poverty of speech • Neuroleptic malignant syndrome.
Neuroleptic malignant syndrome (NMS)
• Rare, but life-threatening, idiosyncratic reaction
• Typical Antipsychotics reduce positive symptoms
to neuroleptic medications that occurs shortly
only
after the initiation of neuroleptic treatment, or
after dose increases
Toxicity:
Signs and Symptoms
Extrapyramidal
• Severe muscular rigidity
• Acute dystonia (after 4 hours).
o Muscle spasm • Hyperthermia (temperature >38°C)
o Stiffness • Autonomic instability
o Oculogyric crisis • Changes in the level of consciousness
• Treatment: Treatment
o Benztropine • Dantrolene (Muscle relaxant)
o Diphenhydramine • Bromocriptine (Dopamine agonist)
Case study
• Akathisia (restless leg syndrome) after 4 days • A 25 male with history of psychosis present at
• Treatment: emergency department with 41, muscle rigidity
o β-blockers tachycardia, hypotensive, CK= 50,000
o Benztropine • Diagnosis: NMS
o Benzodiazepines
High Potency drugs Low potency drugs
Example Haloperidol Thioridazine
• Bradykinesia (after 4 weeks) Trithioperazine Chlorpromazine
• Treatment: Fluphenazine
Potency High Low (require more drug
o Benztropine required to achieve
o Amantadine therapeutic levels of D2
receptor blockade)
Extrapyramidal More Less
• Tardive dyskinesia (after 4 months). irreversible EPS
• Orofacial chorea Autonomic side Less more
effects
• Treatment:

o Switch to atypical antipsychotic (eg, clozapine),

tetrabenazine, reserpine
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Atypical anti-Psychotics (Neuroleptics) • Used as antipsychotic/antidepressant
Atypical antipsychotic drugs • Prevention of acute manic attacks
• Olanzapine
• Risperidone Mechanism of Action
• Quetiapine • Prevents recycling of
• Clozapine inositol (↓ PIP2) by
• Aripiprazole blocking inositol
• Ziprasidone monophosphatase
• Modulation of glutamate
Typical Anti-psychotic Atypical Anti-psychotic receptors
First generation anti-psychotic Second generation anti-psychotic
• ↓ cAMP

Cause Extrapyramidal side effects Less Extrapyramidal side effects Toxicity:

More side effects More side effects
• Nephrogenic diabetes insipidus (↓ ADH effect);
manage with
Fewer withdrawal side effects Fewer withdrawal side effects amiloride
• Teratogenicity:
Ebstein’s anomaly
Mechanism of action (malformed tricuspid
• Block serotonin (5-HT) receptors in the brain, valve)
particularly 5-HT2A receptors the vital players in • Hypothyroidism with
schizophrenia goiter (↓ T3 and T4
• In addition, atypical antipsychotics also act on with a compensatory
adrenergic, cholinergic (muscarinic), and increase in TSH)
histamine receptors • Narrow therapeutic window requires close
• Less effective than typical antipsychotic at monitoring of serum levels.
treating positive symptoms, but they treat • Tremors
negative symptoms well

Clinical uses
• Schizophrenia (Both positive and negative
symptoms)
• Clozapine used for treatment-resistant
schizophrenia or schizoaffective disorder and for
suicidality in schizophrenia
• Bipolar disorder
• Major depressive disorder Drug interaction:
• Autism • Thiazides
• OCD • Non-Steroidal anti-inflammatory drugs
• Mania
• Tourette syndrome Selective Serotonin reuptake inhibitors
Drug names
Toxicity • Fluoxetine
• Olanzapine/clozapine causes significant weight • Paroxetine
gain. • Escitalopram
• Clozapine causes agranulocytosis (watch WBC • Citalopram
weekly) and seizures • Sertraline
• Ziprasidone causes prolonged QT interval • Note: Antidepressants in general require 4-8 to
• Risperidone causes hyperprolactinemia produce an effect
(amenorrhea, galactorrhea, gynecomastia). MOA
• Selective blockade of 5HT reuptake
Lithium
Clinical Uses Clinical uses
• Drug of choice for bipolar disorder • Major depression

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 • OCD
• Bulimia MOA
• Anxiety disorders (chronic treatment/acute, • Inhibit 5-HT and NE reuptake
benzodiazepines) Clinical uses
• Premenstrual dysphoric disorder (PMDD) • Depression
• Social anxiety • General anxiety disorder
• premature ejaculation • Diabetic neuropathy
• Venlafaxine is also indicated for social anxiety
Toxicity disorder, panic disorder, PTSD and OCD
• Sexual dysfunction (anorgasmia,  libido). • Duloxetine is also indicated for fibromyalgia.
• GI distress Toxicity
• Serotonin syndrome: • Significant increase in blood pressure, stimulant
1. Hyperthermia effects due to  NE
2. Muscle rigidity •  heart rate
3. Confusion • Dry mouth, fluid retention, excessive retention
4. Cardiovascular collapse • Sedation
5. Flushing • Nausea
6. Diarrhea
7. Seizures Introduction of Depression
Definition
Side effects • Depression is a common but serious mood
• Anxiety disorder. Depression is actually opposite of
• Agitation happiness. It is characterized by extreme sadness,
• Bruxism general loss of interest in daily activities,
• Sexual dysfunction insomnia, and change in appetite and loss of self-
• Weight loss esteem.

Case study
• 54 years old female presented to primary care,
through analysis it appeared that she is under
Fluextine for 6 months without any significant
improvement. She was shifted to Venalfaxine
BUT suddenly she presented muscle rigidity,
fever with 40, confusion, low blood pressure and
seizures
• Diagnosis: Serotonin syndrome
• Treatment: Cyproheptadine 5-HT2a antagonist

Drug interactions
• ↑ 5HT: serotonin syndrome
Clinical presentations
• Symptoms: sweating, rigidity, myoclonus,
• Persistent sad, anxious, or empty mood most of
hyperthermia, ANS, instability, seizures
the day, most days
• Drugs: MAOIs, TCAs, and meperidine
• Feelings of worthlessness or excessive guilt
• Most inhibit cytochrome P450 enzymes (in
particular, fluvoxamine and fluoxetine) • Loss of interest or pleasure in activities anhedonia
• Persistent loss of energy or fatigue
• Important interaction includes increased levels of
benzodiazepines in treatment of anxiety disorders • Insomnia, early morning awakening, or
oversleeping hypersomnia
• Citalopram is safer for interactions
• Significant change in appetite resulting in
Selective Serotonin norepinephrine reuptake inhibitors unintended weight loss or weight gain
Drug names • Observable psychomotor agitation or restlessness
• Duloxetine (Diabetic neuropathy) • Feelings of hopelessness or pessimism; recurrent
• Venlafaxine thoughts of death or suicide, suicide attempts
• Desvenlafaxine

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Tricyclic antidepressants (TCAs)
Overview MOA
• Nonspecific blockade of 5HT and NE reuptake,
therefore, increasing NE,5HT at receptor sites.
• Nonspecific blockade: in most TCA, other
receptors (including receptors outside CNS) are
also affected such as H1 receptor, -receptor, M1
receptor

Clinical uses
• Depression
• ADHD
• Nocturnal Enuresis (Imipramine)
• Panic disorder (Imipramine)
• Neurons communicate with one another at • OCD (clomipramine)
junctions called synapses. • Eating disorder
• At the synapse, the firing of an action potential in • Narcolepsy
one neuron—the presynaptic, causes the
transmission of a signal to another neuron— Side effects
the postsynaptic, making the postsynaptic neuron Pharmacological Actions Adverse Effects
either more or less likely to fire its own action Alpha 1 receptor blockade Orthostatic hypotension
potential. Muscarinic receptor blockage Dry mouth
• The action potential triggers the presynaptic (Anticholinergic) Tachycardia
neuron to release neurotransmitters. These Blurred vision
Glaucoma
molecules bind to receptors on the postsynaptic Sexual dysfunction (loss of libido,
cell and make it more or less likely to fire an Impaired erection)
action potential. Confusion
Hallucination
• Serotonin or 5-hydroxytryptamine (5-HT) is a
monoamine neurotransmitter Toxicity
• 5-HT is released into the synaptic cleft. While, it • Convulsions
can be reuptake via 5-HT transporters (SERT)
• Coma
and deactivated to 5-HTAA by monoamine
• Cardiotoxicity (arrhythmia due to Na+ channel
oxidase (MAO).
inhibition)
• Once released from presynaptic axonal terminals,
5-HT binds to receptors
Case study
• 19 years old female with a history of depression,
Clinical presentations of serotonin deficiency
showed signs of depression, inconspicuousness
1. Poor memory
(coma), heart rate= 150 (Tachycardia), ECG
2. Low mood showed widening QRS complexes
3. Craving for sweet
• Diagnosis: TCA overdose
4. Sleep disturbance
• Treatment: Sodium bicarbonate
5. Low self-esteem Mechanism of sodium bicarbonate
6. Anxiety (1) it allows for ion trapping of the medication and
7. Aggression increased renal excretion
• Depression has been linked to low levels of (2) it helps correct the sodium channel blockade of
serotonin the TCA, preventing cardiac arrhythmias.
TCAs drugs Drug interactions
• Clomipramine • Hypertensive crisis with MAO inhibitors
• Amoxepin • Serotonin syndrome with SSRIs, MAO inhibitors,
• Doxepin/desipramine and meperidine
• Imipramine • Prevent antihypertensive action of α2 agonists
• Nortriptyline
• Amitriptyline

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Contraindication • Bupropion is indicated for the treatment of major
• Agranulocytosis depressive disorder (MDD)
• Sever liver damage • Sexual disorders
• Glaucoma • Obesity
• Prostatic hyperplasia • Help in smoking cessation (reduces cravings and
• Epilepsy withdrawal symptoms)
• Lactation MOA
• Inhibiting the enzymes involved in the uptake of
Atypical antidepressant drugs the neurotransmitters norepinephrine and
Types dopamine from the synaptic cleft, therefore
• Bupropion prolonging their duration of action within the
• Mirtazapine neuronal synapse and the downstream effects of
• Maprotiline these neurotransmitters.
• Trazodone Toxicity
• Stimulant effect.
• Tachycardia.
• Hypertension
• Insomnia.
• Headache
• Bupropion has been associated with seizures in
patients with purging bulimia

Mirtazapine
Indication
• Moderate to severe depression
• Used for increasing appetite and decreasing
nausea in cancer patients.
MOA

Mechanism of actions
• Atypical antidepressant usually affects
neurotransmitters such as dopamine, serotonin
and norepinephrine.
• Changing the balance of these chemicals seems to
help brain cells send and receive messages that
enhance mood

When atypical antidepressant drugs are used? • Mirtazapine exerts antagonist activity at
• Atypical antidepressants are frequently used in presynaptic α2-adrenergic inhibitory
patients with major depression who have autoreceptors. This is thought to lead to enhanced
inadequate responses or intolerable side effects noradrenergic and serotonergic activity, which
during first-line treatment with SSRIs are known to improve the symptoms of
depression and form the basis of antidepressant
• However, atypical antidepressants are often first- therapy.
line treatment if the drug has a desirable Toxicity
characteristic (eg, sexual side effects and weight • Wait gain- increase appetite
gain occur less often with bupropion than SSRIs). • Dry mouth

Bupropion Maprotiline
• Norepinephrine/dopamine-reuptake inhibitor Indication
Indication • Treatment of depression

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 • Effective at reducing symptoms of anxiety Indication
associated with depression. • Treatment of major depressive disorder
MOA MOA
• Inhibition of presynaptic uptake of • Serotonin reuptake inhibitor (SRI) through
catecholamines, thereby increasing their inhibition of the serotonin transporter,
concentration at the synaptic clefts of the brain • Partial agonist of the 5-HT1B receptor, an agonist
• Antagonist at central presynaptic α2-adrenergic→ of 5-HT1A, and antagonist of the 5-HT3, 5-
 NE, 5HT HT1D, and 5-HT7 receptors.
• Peripheral α1 adrenergic antagonist, which may Toxicity
explain the occasional orthostatic hypotension • Nausea
Toxicity • Sexual dysfunction
• Orthostatic hypotension • Sleep disturbances
• Anticholinergic effects
Trazodone • May cause serotonin syndrome if taken with other
Indication serotonergic agents.
• Treatment of depression
• Insomnia Monoamine oxidase inhibitors
Overview
MOA
• Inhibit the reuptake of serotonin
Toxicity
• Priapism (Persistent penile tissue erection that
may cause permanent damage if not treated
promptly)
• Nausea
• Orthostatic hypotension
• Sedation
• Suicide attempts

Atypical antidepressant new drugs

Varenicline
• Varenicline is an alpha-4 beta-2 neuronal Monoamine oxidase is an intramitochondrial enzyme
nicotinic acetylcholine receptor partial agonist. responsible for the breakdown of intracellular dopamine,
Indication norepinephrine, and serotonin.
• Used to treat smoking addiction. • MAOIs inhibit monoamine oxidase, resulting in
MOA an increase in the concentration
• Partial nicotinic acetylcholine receptor agonist of monoamines in the synapse.
Toxicity • The MAO enzyme is located within the neuron’s
• Headache cytoplasm, unlike the reuptake inhibitors that are
• Sleep disturbance affected by TCAs
Vilazodone • Monoamine oxidase A metabolizes
Indication norepinephrine, serotonin and dopamine
• Used to treat major depressive disorder • Monoamine oxidase B metabolizes dopamine
MOA selectively
• Selectively inhibits serotonin reuptake • Selegiline (deprenyl) is a selective irreversible
• partial agonist of 5HT-1A receptors inhibitor of monoamine oxidase B at normal
Toxicity doses, but at higher doses it inhibits monoamine
oxidase A as well
• Headache
• Diarrhea
Monoamine oxidase inhibitors drugs
• Nausea
• Tranylcypromine
• Anticholinergic effects
• Isocarboxazide
• May cause serotonin syndrome if taken with other
• Phenelzine
serotonergic agents.
• Selegiline (Parkinson’s disease)
Vortioxetine

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 • Insomnia
MOA • Tachycardia
• Nonselective MAO inhibition→ levels of amine • Diaphoresis
neurotransmitters (norepinephrine, 5-HT, • Ethanol: Delusions, Hallucinations and delirium
dopamine). tremens (2-4 days after last drink)
• Benzodiazepines: Rebound insomnia and anxiety
Clinical uses • Barbiturates: Delirium, life-threatening
• Atypical depression, which is characterized by cardiovascular collapse
hypersomnia, hyperphagia, and leaden paralysis
• Hypochondriasis Opioids
• Anxiety Examples: Heroin, oxycodone, hydrocodone
• MOA: Pain killers through binding to μ (mu)
Toxicity opioid receptors in the CNS- Endorphins are the
• Hypertensive crisis due to tyramine ingestion natural agonist for opioid receptors
(Avoid cheese and wine) Therapeutic uses: Euphoria, analgesia, sedation, cough
• ↑ BP, arrhythmias, excitation, hyperthermia suppression
• Neurotransmitter involved: NE, DA, 5HT and
Drug interactions and contraindication GABA
• Tyramine • Intoxication clinical presentation:
• Selective serotonin re-uptake inhibitors (SSRIs). • Euphoria
• Tricyclic anti-depressants. • respiratory and CNS depression
• Meperidine. • Decrease gag reflex
• St. john’s herb. • pupillary constriction (pinpoint pupils)
• Dextromethorphan (Anti-tussive products) • seizures (overdose)
• Co-administration of MAO inhibitors with the • Antidote: Naloxone
previous drugs lead to serotonin syndrome • Long-acting oral opiate used for heroin
detoxification or long-term maintenance therapy
Withdrawal
Psychoactive drugs • Lacrimation
Depressants/ Sedatives • Yawning sweating
Examples: Alcohol, Barbiturates, benzodiazepines • Muscle cramping
• MOA: Potentiation of GABA interaction with • Diarrhea
GABAA receptors therefore prolong the duration • Anxiety
of channel opening and chloride flux, eventually
• Dysphoria
potentiate GABA signalling
• Dilated pupils
• Effect: CNS depression
• Piloerection (Cold turkey)
• Note: GABA is an inhibitory neurotransmitter
• Treatment: Supportive treatment and Methadone,
• Intoxication clinical presentation
Buprenorphine
• Decrease anxiety
• Respiratory depression and hypotension Stimulants
(Benzodiazepines and Barbiturates) Examples: Cocaine, Amphetamines, Ecstasy, caffeine
• Drowsiness and Nicotine
• Ataxia MOA:
• Incoordination • Cocaine: Blocks DA, NE, and 5HT reuptake in
• Slurred speech CNS; local aesthetic action from Na+ channel
• Euphoria blockade
Flumazenil: Antidote for benzodiazepines toxicity • Amphetamines: Blockade of reuptake of NE and
DA (Increase synaptic NE and DA), weak MAO
Common withdrawal signs inhibitors
• Seizures (Due to decreased GABA tone and • Nicotine: agonist on cholinergic receptors
increased excitability of the brain) • Caffeine: Enhance dopamine effect
• Anxiety
• Tremors Cocaine and amphetamine share the following effects
• Hallucinations

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 1. Increase NE: sympathomimetic effect Withdrawal
with increased heart rate and • Irritability, insomnia, nausea, and decreased
contractility, blood pressure, changes, appetite.
mydriasis, and central excitation, • Treatment: Supportive
hyperactivity
2. Increase DA: psychotic episodes, Physiological and social implications
paranoia, hallucinations, possible • Low testosterone in men
dyskinesias, and endocrine disturbances • Decreased ovulation in females
3. Increase 5HT: behavioural changes, • Low birth weights in neonates
aggressiveness, dyskinesias, and • Increased neonatal malformation
decreased appetite
• A motivational syndrome
• Gateway drug
• Intoxication clinical presentation:

Amphetamine Cocaine
Hallucinogens
• Euphoria • Impaired judgment Examples: LSD, Psilocybin, mescaline
• Grandiosity, • Pupillary dilation
• Pupillary dilation, • Hallucinations MOA: Interaction with 5-HT, LSD activates serotonin
• prolonged wakefulness (including tactile)
and attention, • Paranoid ideations
receptors in the limbic system, neocortex and brainstem
• Hypertension, • Angina, sudden Intoxication clinical presentations:
tachycardia, anorexia, cardiac death. • Hallucinations, delusions (See beautiful rippling
paranoia • Chronic use may lead
• Skin excoriations with to perforated nasal colors) LSD
methamphetamine use septum due to • Mydriasis
• Severe: cardiac arrest, vasoconstriction and
seizures. resulting ischemic
• Tachycardia
necrosis. • Sweating
• Ataxia
1. Excess NE: cardiac arrhythmias, generalized ischemia with
possible MI and strokes; acute renal and hepatic failure • Tremor
2. Excess DA: major psychosis, cocaine delirium • LSD is not addictive and does not cause a
3. Excess 5HT: possible serotonin syndrome
4. All of the above: convulsion, hyperpyrexia, and death
withdrawal syndrome
• Psilocybin → Paranoia, Euphoria
Treatment: Benzodiazepines (Lorazepam), Haloperidol • MDMA (“Ecstasy”), MDA, MDEA:
(Psychosis) amphetamine-like with strong 5HT pharmacology
and therefore hallucinogenic
Withdrawal
• Craving, severe depression, anhedonia and Dissociative
anxiety • PCP Phencyclidine (PCP, Angel Dust), Ketamine
• MOA: NMDA-receptor antagonist
Cannabinoids • Effect: Combination of euphoria and
Examples: Marijuana, Hashish, Synthetic blends hallucinations ended by aggressiveness
MOA: Intoxication clinical presentations:
• Interaction of THC with CB1 and CB2 • Horizontal and vertical nystagmus
cannabinoid receptors in CNS and periphery that • Paranoia
inhibit adenylate cyclase and cAMP production • Rhabdomyolysis
• Uses: Dronabinol: used as antiemetic • Rage
(chemotherapy) and appetite stimulant (in AIDS). • Erythema of the skin
Intoxication clinical presentations: • Dilated pupils (like amphetamine or cocaine
• Euphoria intoxication or opiate withdrawal)
• Anxiety • Delusions
• paranoid delusions • Amnesia
• perception of slowed time • Nystagmus
• Impaired judgment • Skin dryness
• Social withdrawal, appetite, dry mouth Treatment: Benzodiazepines and antipsychotics
• Conjunctival injection
• Hallucinations
Treatment: Lorazepam
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Chapter 14:

Renal

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Embryology and Congenital Malformations • It is the most common site of obstruction of the
Embryology urinary tract system which can lead to prenatal
Nephrogenesis: hydronephrosis
• Three embryonic parts are formed, some • Prenatal hydronephrosis can be detected on
disappear, others evolve into the urinary system prenatal ultrasound
or genital system in males
• The pronephros is formed at the 4th week of Potter Sequence
gestation, it then degenerates. They are Definition:
rudimentary and nonfunctional Potter’s sequence is a rare fatal disorder that occurs in
• The mesonephros functions as an interim kidney sporadic and autosomal recessive forms. It is characterized
for the 1st trimester. Later on, it contributes to the by multiple limb deformities, facial anomalies, and
male genital system pulmonary hypoplasia mainly due to compression of the
• The metanephros is the permanent embryonic developing fetus. The fetus is compressed because of
precursor to the adult kidneys. They first appear oligohydramnios.
in the 5th week of gestation. Nephrogenesis and Epidemiology:
kidney development continues through 32 to 36th • Annual incidence is 1 in 4000 births
weeks of gestation • Babies born with this condition are either still
Ureters embryogenesis: born or die during the neonatal period
• Ureteric buds originate from the caudal end of the • Mainly affects male babies
mesonephric duct Pathology:
• The ureteric buds give rise to the ureter, pelvises, • Severe oligohydramnios which may be caused by
calyces, and collecting ducts polycystic kidneys, bilateral renal agenesis or
• These structures are fully canalized by the 10th obstructive uropathy during middle gestational
week of gestation weeks → renal failure is the cause of severe
Metanephric mesenchyme: oligohydramnios
• Ureteric buds interact with the metanephric • Premature birth, breech presentation, atypical
blastema of the metanephros facial appearance, and limb malformations are
• This interaction induces the differentiation and common
formation of the glomerulus through to the distal • The most common cause of death is severe
convoluted tubule (DCT) respiratory insufficiency
• Alterations between the metanephric • Compression of the developing fetus’s limbs →
mesenchyme and the ureteric buds may result in limb deformities
renal agenesis, or multicystic dysplastic kidneys • Facial features include flattened nose, recessed
chin, prominent bilateral epicanthal folds and
low-set ears with wide pinna
• Compression of the chest and lack of amniotic
fluid aspiration into fetal lungs → pulmonary
hypoplasia → the cause of respiratory
insufficiency in the neonatal period and death

Figure 410: The ureteric bud meets the metanephric

mesenchyme. It gives rise to the pelvises, calyces and Figure 411: Potter's facial features include from left to
collecting ducts of the kidney. Source: doi:10.1007/978-3- right: recessed chin, prominent bilateral epicanthal folds,
540-87597-0_1 and low-set ears with wide pinna.
Ureteropelvic junction: POTTER sequence:
• Last part of the upper urinary tract system to • Pulmonary hypoplasia
canalize • Oligohydramnios

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 • Twisted face
• Twisted skin
• Extremity defects
• Renal failure in utero

Horseshoe Kidney
Definition:
The abnormal fusion of the inferior poles of both kidneys
result in the anomaly known as horseshoe kidney.
Epidemiology:
• Affects 1 in 500 births
• More common in men Figure 412: CT scan of the lower abdomen showing a
• Usually, an incidental diagnosis horseshoe kidney. Source:
Pathology: https://en.wikipedia.org/wiki/Horseshoe_kidney#/media/Fi
• Kidneys normally develop in a lower position le:Hufeisenniere_CT_axial.jpg
than they are found in adults
• They ascend during fetal development. Horseshoe Congenital Solitary Functioning Kidney
kidneys get trapped under the inferior mesenteric
artery and they remain low in the abdomen
• Horseshoe kidney often function normally, Definition:
however due to the abnormal anatomy, few A condition that is defined as being born with a single
complications might arise: functioning kidney. Most patients are asymptomatic;
o Kidney obstruction at the ureteropelvic however, anomalies of the contralateral kidney are
junction. This can lead to urinary stasis, common. There is compensatory hypertrophy of the
hydronephrosis, infection and/or stone contralateral kidney. The diagnosis is often incidental.
formation Unilateral renal agenesis:
o Half of the patients with horseshoe • Failure of development of a ureteric bud
kidney also have vesicoureteral reflux. • This prevents the induction of differentiation of
This increases the risk of urinary tract the metanephric mesenchyme
infections • There is complete absence of the kidney and
o Associated with an increased risk of ipsilateral ureter
renal cancers such as transitional cell Multicystic dysplastic kidney:
carcinoma, Wilms tumors, and carcinoid • Abnormal induction of differentiation of the
tumors metanephric mesenchyme by the ureteric bud
Etiologies of horseshoe kidney: • The issue is often unilateral, otherwise it would
• Exposure to teratogens such as thalidomide, cause Potter sequence
ethanol, ACE inhibitors, cocaine, gentamycin, • The affected kidney has multiple cysts and
corticosteroids, NSAIDs and vitamin A abundant connective tissue. It is nonfunctional
• Chromosomal aneuploidy syndromes such as • The condition is predominantly nonhereditary
Turner syndrome, and trisomies 13, 18 and 21 Duplex Collecting System
Diagnosis and management: Definition:
• Horseshoe kidney is often an incidental finding Duplicated ureter or duplex collecting system is a
on imaging. Ultrasonography is the first imaging congenital condition in which the ureteric bud splits
modality to detect the anomaly “where the resulting in two ureters draining a single kidney. The
examiner notices the absence of the kidneys in bifurcation needs to occur before the ureteric bud enters the
their normal location” metanephric blastema. Rarely, it can occur when two
• Management should focus on treating the ureteric buds reach and interact with one metanephric
complications of horseshoe kidney, not the blastema.
condition itself Epidemiology:
• The most common renal abnormality occurring in
approximately 1% of the population
• The additional ureter might result in ureterocele
or an ectopic ureter
• More common in females and in whites
Diagnosis:
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 • Most commonly, presents as neonatal urinary • Understanding the gross anatomy of the kidney is
tract infection in a neonate with hydronephrosis important
• Because of the increased risk of vesicoureteral • A sagittal section of the kidney is made across the
reflux, children with duplex collecting system Y axis. This gives you access to the renal artery
often have recurrent UTIs and vein, and the ureter
• If the ectopic ureter enters the vagina, urethra or • You can also see the renal pelvis, calyces,
vestibule in a female, it can result in urinary medullary pyramids, medulla, and cortex of the
incontinence kidney
Classification: • The medullary pyramids are also known as renal
• Partial: two ureters drain into the bladder via a papillae. It is this structure that is injured in renal
single common ureter papillary necrosis
• Complete: two ureters drain separately. More Vascular anatomy of the kidney:
clinically relevant
• The kidney is supplied by a main artery, known
as the renal artery
• Segmental arteries arise from the renal artery
• Interlobar artery arises from the segmental artery.
The interlobar artery gives rise to the arcuate
artery, which gives rise to the interlobular artery
• Interlobular artery → afferent arteriole →
glomerulus → efferent arteriole
• After filtration in the glomerulus, blood enters the
efferent arteriole to later go to the vasa recta and
peritubular capillaries and end up in venous
outflow
• Blood arrives to the glomerulus by the afferent
Figure 413: Duplex collecting system of the left kidney.
arteriole and leaves the glomerulus by the efferent
Source:
arteriole
https://en.wikipedia.org/wiki/Duplicated_ureter#/media/Fil
e:IVP_Duplication.jpg • The medulla receives significantly less blood
flow than the renal cortex which makes it more
prone for hypoxic-ischemic injury
Posterior Urethral Valves o Renal ischemia can lead to papillary
Definition: necrosis
PUV is an obstructive developmental anomaly of the male • The left renal vein is longer than the right one →
urethra. It is defined as an obstructing membrane in the the left kidney is taken during living donor
posterior male urethra due to abnormal in-utero transplantation because it is easier to ligate the
development. left renal vein
Epidemiology: • The left renal vein receives two additional veins,
• The most common cause of bladder outlet the left suprarenal and left gonadal veins → a
obstruction in male newborns tumor in the left side that is invading the left renal
Diagnosis and management: vein and obstructing it can result in left scrotal
• Presents prenatally as hydronephrosis and a thick- varicose veins
walled dilated bladder on ultrasound
• Voiding cystourethrogram is more specific for the
diagnosis
• Treated endoscopically with either “vesicostomy
or pyelostomy” followed by valve ablation or
solely valve ablation

Kidney and Ureters Anatomy, and Glomerular Structure

Kidney Anatomy and Glomerular Structure:

Sagittal section of the kidney:

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 •The distal part is supplied by the internal iliac and
superior vesical arteries
Common points of ureteric obstruction:

• Ureteropelvic junction
• Pelvic inlet
• Ureterovesical junction

Note: Urine reflux in the ureter is prevented by

the action of the muscle fibers of the intramural
part of the ureter.

Figure 414: Kidney anatomy. Source: Fluid Compartments

https://en.wikipedia.org/wiki/Kidney#/media/File:Blausen_ Overview
0592_KidneyAnatomy_01.png • The human body and its individual body fluids
can be divided into various fluid compartments
• The two main fluid compartments are the
intracellular and the extracellular compartments
• The intracellular compartment is the space within
the cell. It is separated from the extracellular
compartment by cell membranes
• Two-thirds of the total body water in humans is
held inside cells, mostly in the cytosol. The
remainder is ECF
• The interstitial fluid is 75% of the ECF
• The plasma is 25% of the ECF “this means that
the volume of transcellular compartment is really
Figure 415: Glomerular structure. Source: so small”
https://en.wikipedia.org/wiki/Glomerulus_(kidney)#/media • Erythrocyte volume is around 2.8 L in a 70 kg
/File:Renal_corpuscle-en.svg man
• 60% of body mass is water
Ureters Anatomy • Hematocrit % is the percentage of RBCs to blood
Course of the ureters: volume
o Normal HCT is 45%
• They arise from the renal pelvis and travel down o HCT can be calculated by the following
under the gonadal arteries formula: HCT (%) = 3x Hb in g/dL
• It then goes over the common iliac artery Volume examples of a 70 kg subject:
• Finally, it passes under the uterine artery/vas • Total body water is 0.6 x 70 = 42 kg = 42 L
deferens retroperitoneally o Non-water mass is 0.4 * 70 = 28 kg
Clinical significance of studying the course of the ureters: • Extracellular fluid volume is 0.33 * 42 = 13.9 L
o Interstitial fluid = 0.75 x 13.9 = 10.5 L
• When the ureters pass over the common iliac
o Plasma volume = 0.25 * 13.9 = 3.4 L
artery, this results in kinking. This is therefore a
common site for kidney stones • Intracellular fluid volume is 0.67 * 42 = 28 L
• Gynecologic procedures where the uterine artery
Intracellular Fluid
or ovarian vessels are ligated may damage the
Definition:
ureter due to its proximity → ureteral obstruction
The intracellular fluid compartment is found in the cytosol
or leak
of the cells. It contains all fluid contained inside cells and
Blood supply to the ureter:
is estimated to be around 28 L. There is a small amount of
• The proximal part of the ureter is supplied by the fluid inside the nucleus of cells known as nucleosol.
renal arteries Nucleosol volume is very small, that it is usually ignored
• The middle part is supplied by the gonadal artery, when dealing with total body water volumes.
aorta, common and internal iliac arteries • Potassium is mainly intracellular

672
 • Magnesium and organic phosphate such as ATP composition to plasma but better tailored towards
are also mainly intracellular its function “e.g. ependymal cells in the CNS
• The cell membranes are the outer barrier that produce CSF from blood plasma”
separates between the intracellular and
extracellular fluid compartments Glomerular Filtration
• The cellular organelles are suspended within the Glomerular Filtration Barrier:
cytosol • The constituents of plasma are filtered based on
• Under ordinary circumstances, the intracellular their size and charge. The glomerular filtration
fluid compartment remains in osmotic barrier is responsible for the selectivity of this
equilibrium with the extracellular compartment process
• It is composed of fenestrated capillary
Extracellular Fluid endothelium. Below the endothelium, there is a
Definition: basement membrane with type IV collagen chains
The extracellular compartment contains one third of the and heparan sulfate. Finally, there is a visceral
total body water. It consists of the interstitial, intravascular epithelial layer consisting of podocyte foot
and transcellular compartments. Extracellular volume can processes
be measured by inulin or mannitol. • Glomerular diseases affect this filtration barrier.
Interstitial compartment: This barrier is negatively charged; hence it
• The interstitial fluid provides the immediate normally propels negatively charged proteins.
microenvironment that allows the movement of Therefore, when there is glomerular disease with
ions, proteins and nutrients across the cell barrier an altered glomerular filtration barrier, you expect
• The fluid is continually being refreshed by the to find proteinuria
blood capillaries • In addition to the charge barrier, the glomerular
• The lymphatic capillaries recollect the interstitial filtration barrier only permits molecules that are
fluid less than 100 nm in size and prevents the
• In the average male adult, the interstitial fluid filtration of blood cells. The fenestrated capillary
volume is 10.5 L endothelium is responsible for this size selectivity
• This compartment is mainly composed of sodium, • The podocyte foot processes interpose with the
chloride, bicarbonate and albumin basement membrane to form a slit diaphragm that
Intravascular compartment: prevents the entry of molecules larger than 60 nm
• This refers to the fluid in the blood. It contains a in size into the Bowman capsule → therefore,
mixture of blood cells, globulins, and solutes such molecules that are larger than 60 nm but smaller
as glucose and ions than 100 nm while might escape the fenestrated
• The average volume of plasma is 3.5 L. Blood endothelium, they will not be filtered out due to
also contains cells, and fluid within these cells is the slit diaphragm configuration
intracellular not extracellular. The estimated
average of RBC volume is 2.8 L
• The intravascular fluid volume is regulated by the
hydrostatic pressure gradient and by the kidneys
• Because albumin is uniformly distributed in the
plasma and is the main constituent, radiolabeling
albumin can be used to measure plasma volume
• Serum osmolality is 285 to 295 mOsm/kg H2O
Transcellular compartment:
• Fluid within the CNS, peritoneal, and pleural
cavities and in joints is known as transcellular
compartment
Figure 416: Glomerular filtration barrier. Source: PMID:
• This compartment has very important functions, 27583259
yet their volume is quite small
• For instance, the cerebrospinal fluid volume in Renal Clearance
the entire CNS is 150 mL Renal clearance is a measurement of how much of a
• The transcellular compartment fluid is produced molecule is cleared by the kidney per minute. It is
actively by specialized cells that utilize plasma to dependent on the concentration of the molecule in the urine
produce specific fluids that have a similar

673
and plasma and urine flow rate. Normal urine flow rate is 1 serum creatinine, age, whether the patient is black
mL/min. or not, and the patient’s gender
MDRD can also include BUN and albumin for more
UX × V
Cx =
PX
accurate measurements of the GFR
eGFR with MDRD formula:
Where CX is clearance of molecule X in mL/min, UX is the eGFR
concentration of X in the urine, V is the urine flow rate and = 186 x [Serum Creatinine]−1.154 × Age−0.203 × [1.212 if Black]
PX is the concentration of X in the plasma × [0.742 if Female]

Interpretation of renal clearance of different substances: Measurement of GFR using hydrostatic and oncotic
pressures of the glomerular capillary and Bowman capsule:
• If CX < GFR, then the substance is either
GFR = Kf × [(PGC − PBS ) − (πGC − πBS )]
reabsorbed in the tubules of the nephron or it is
not freely filtered Where Kf is filtration coefficient, PGC is hydrostatic
• If CX = GFR, then there is no net secretion or pressure of glomerular capillary, PBS is hydrostatic pressure
reabsorption of the substance and it is freely of Bowman capsule, πGC is glomerular capillary oncotic
filtered pressure and πBS is Bowman capsule oncotic pressure
• If CX > GFR, then there is net tubular secretion of
the substance • Because you do not expect proteins to be filtered
• Therefore, if we choose a substance that is known into the Bowman capsule in physiologic
to have no net tubular secretion or reabsorption circumstances, you expect πBS to be equal to zero
and we measure renal clearance, that value can be Creatinine clearance for the measurement of GFR:
used interchangeably with GFR. This is one way
to measure GFR. Inulin is a typical example of • Creatinine is moderately secreted by the renal
tubules
such a substance
Glomerular Filtration Rate • Therefore, it slightly overestimates GFR
Glomerular filtration rate (GFR) is the volume of fluid Effective Renal Plasma Flow
filtered from the renal glomerular capillaries into the • The effective renal plasma flow is a measurement
Bowman’s capsule per unit time. The basal tone of the that can be used to estimate renal blood flow
afferent and efferent arterioles play an important role in • In this scenario, we use a solute that is 100%
regulating GFR. Normal GFR is 100 mL/min. excreted and not freely filtered or reabsorbed
• Para-aminohippuric acid (PAH) is the typical
• GFR is equal to the clearance rate when the solute substrate used to measure eRPF
is freely filtered and neither reabsorbed nor • The clearance of PAH will be equal to eRPF and
secreted by the kidneys. In that case, same the following formula is used to measure eRPF:
equation of renal clearance is used to measure eRPF =
UPAH × V
GFR with CX substituted with GFR PPAH

• Reductions in GFR are gradual and they define • Renal blood flow is then calculated using the
the stages of chronic kidney disease (CKD) following formula:
Measurement of GFR using inulin: RPF
RBF =
1 − Hct
• Inulin is injected into the plasma
• The rate of excretion is directly proportional to • RBF is usually 20 to 25% of cardiac output
the rate of filtration of water and solutes across • It should be noted that eRPF underestimates true
the glomerular filter renal plasma flow
• The inulin clearance technique slightly Normal values:
overestimates GFR compared to MDRD formula.
Therefore, in early stage of renal disease, inulin • RBF = 1000 ml/min
clearance may remain normal due to • RPF = (1 – Hct) X RBF = 0.6 X 1000 = 600
hyperfiltration ml/min
𝐺𝐹𝑅 𝑚𝑒𝑎𝑠𝑢𝑟𝑒𝑚𝑒𝑛𝑡 𝑢𝑠𝑖𝑛𝑔 𝑖𝑛𝑢𝑙𝑖𝑛: • Effective RPF using PAH is 540 ml/min
𝐺𝐹𝑅 =
𝑈𝑖𝑛𝑢𝑙𝑖𝑛 × 𝑉 Filtration
𝑃𝑖𝑛𝑢𝑙𝑖𝑛
• In renal physiology, filtration fraction is the ratio
• The MDRD (Modification of Diet in Renal of the GFR to RPF
Disease (MDRD) formula takes into account the

674
 • It represents the proportion of the fluid reaching Reabsorption rate = Filtered load − Excretion rate
the kidneys that passes into the renal tubules. It is Secretion rate = Excretion rate − Filtered load
normally 20%
• While GFR is the most common and most • Fractional excretion of sodium is the percentage
important measure of renal function, filtration of filtered sodium to excreted sodium
fraction is helpful in conditions where blood flow • It is measured in terms of plasma and urine
to the kidneys is reduced for example in renal sodium not urinary sodium concentration alone
artery stenosis • It is important because urine sodium
• Filtration fraction will be increased in renal artery concentration can vary with water reabsorption
stenosis in order to perform the normal functions Calculation of fractional excretion of sodium:
of the kidney Na excreted V × UNa
Filtration fraction and the afferent and efferent arterioles: FeNa =
Na filtered
=
GFR × PNa
V × UCr
GFR = . therefore, the above equation become:
• Catecholamines increase FF by inducing PCr
V × UNa
vasoconstriction of the afferent and efferent FeNa =
V × UCr
, where V cancels V and the final equation is:
arterioles PCr
× PNa
• Angiotensin II preferentially constrict the efferent FeNa =
PCr × UNa
UCr × PNa
arteriole which increases the GFR and this in turn
increases FF Glucose Clearance
o ACE inhibitors decrease angiotensin II • In normal conditions at a glucose plasma level of
→ reduces GFR and FF 60 to 120 mg/dL, glucose is completely
• Prostaglandins preferentially dilate the afferent reabsorbed in the proximal convoluted tubule by
arteriole which increases RPF and GFR. Because the Na/glucose co-transporter
both are increased, you expect FF to not be • The threshold for glucosuria in adults is 200
changed mg/dL
• Normal FF is 20% and is calculated using the • Na/glucose co-transporter is fully saturated at the
following formula: rate of 375 mg/min
GFR 120 ml/min
FF = =
RPF 600 ml/min
= 20% • Glucosuria is an important clue to diabetes
mellitus
• Filtered load of a solute is equal to GFR X Pregnancy and glucose clearance:
plasma concentration. The unit of filtered load is
mg/min • In pregnancy, GFR is increased → increased
Changes in glomerular dynamics: filtration of all substances including glucose
• Threshold of glucosuria is lowered → glucosuria
GFR RPF FF
AFFERENT Decreased Decreased ---
even at normal plasma glucose level
ARTERIOLE
CONSTRICTION
EFFERENT Increased Decreased Increased Note: Sodium-glucose co-transporter 2 (SGLT2)
ARTERIOLE inhibitors (drugs that end in -
CONSTRICTION flozin) inhibit the reabsorption of glucose in the
INCREASED Decreased --- Decreased PCT → glucosuria at plasma
PLASMA PROTEIN concentration < 200 mg/dL.
CONCENTRATION
DECREASED Increased --- Increased
PLASMA PROTEIN
CONCENTRATION
CONSTRICTION OF Decreased --- Decreased Splay phenomenon:
URETER
DEHYDRATION Decreased Markedly Increased • Splay is the difference between urine threshold
decreased
Reabsorption and Secretion Rate for a substance before it appears in the urine and
the saturation of the transporters that reabsorb
• The reabsorption or secretion rate is the
that substrate
difference between the amount filtered across the
glomerular capillaries and the amount excreted in • The term is usually used when describing glucose
clearance because other substrates typically do
urine
not show splay
Calculation of reabsorption and secretion rates:
• Splay appears to occur because the kidney
Filtered load = GFR × Plasma concentration nephrons have different tubular maximum for
Excretion rate = V × Urine concentration

675
 glucose → some nephrons excrete glucose before Potassium:
others
• It also occurs because the maximum reabsorption • 65% of filtered potassium is reabsorbed in the
rate (Tm) cannot be achieved until the PCT
amount/min of glucose being presented to the • Most of filtered potassium is resorbed by the two-
renal tubules is great enough to fully saturate the paracellular mechanisms known as solvent drag
transporters in all nephrons and simple diffusion
Urea:

• 50% of filtered urea is reabsorbed in the PCT by

the solvent drag mechanism
• When water leaves the lumen, urea concentration
increases → facilitates urea diffusion in the late
PCT
Phosphate:

• 80% of filtered phosphate is reabsorbed in the

early PCT
• PTH reduces reabsorption of phosphate in the
PCT, however it also increases intestine
reabsorption of phosphate and resorption of
phosphate from bones to blood → no significant
Figure 417: Glucose clearance showing splay which is net effect on phosphate level in blood
represented by the portion of the titration curve between Citrate:
threshold and Tmax. Source:
https://step1.medbullets.com/renal/115012/glucose- • Up to 90% of filtered citrate is reabsorbed in the
clearance PCT
• Acidosis increases absorption, whereas, alkalosis
Nephron Transport Physiology decreases it
Early PCT: Other functions of the PCT:
Divisions:
• It generates NH3 which enables the kidney to
• The proximal tubule can be divided into secrete more H+
convoluted and straight o Most of the ammonium formed by the
• The proximal convoluted tubule is further divided PCT is via the breakdown of glutamine
into two ultrastructure divisions: S1 and S2 to alpha-ketoglutarate
Salt and water reabsorption: • Angiotensin II stimulates Na/H exchange which
increases sodium, water and bicarbonate
• Two-thirds of salt and water are reabsorbed in the reabsorption permitting contraction alkalosis
early PCT Thin Descending Limb of Loop of Henle:
• Water and salt move through the cells and Definition:
passively across the basolateral membrane via
transcellular transport The descending limb of the loop of Henle is a portion of
• The apical/luminal membrane actively resorb the renal tubule that constitutes the first part of the loop of
sodium via the Na/K/ATPase pump Henle. It consists of simple squamous epithelium cells. The
• Solutes are absorbed isotonically in that osmotic descending limb has thick and thin segments; however, the
potential of the fluid leaving the proximal tubule thick segment is not important physiologically. Therefore,
is the same as that of the initial glomerular filtrate the term “descending limb of loop of Henle” refers to the
Glucose and aminoacids: thing segment.

• 100% of filtered glucose is reabsorbed in the Ions reabsorption:

early PCT in normal conditions
• Low permeability to sodium and chloride → can
• Glucose, aminoacids, and inorganic phosphate are be considered as impermeable
reabsorbed via a secondary active transport Urea:
system “co-transporter” that utilize sodium
gradient to drive substrate reabsorption • Moderate permeability

676
Water: • The basolateral surface expresses an ATP-
dependent Na/K antiporter pump, and an active
• Highly permeable Na/Ca transporter in addition to an ATP
• Water is reabsorbed passively by osmosis dependent calcium transporter
• Water is reabsorbed to peritubular capillaries • The ATP-K antiporter pump is important because
Thick Ascending Limb of Loop of Henle: it produces a Na gradient within the cell that
Definition: facilitates the absorption of sodium by the Na/Cl
symporter in the apical surface and for calcium to
The ascending limb of loop of Henle has two segments,
be reclaimed into the blood by the Na/Ca
thin and thick. Here, the thick segment is the more
basolateral antiporter
important segment functionally. The thin ascending limb of
• The DCT secretes potassium and absorbs sodium
the loop of Henle is found in the medulla of the kidney,
pH regulation:
and the thick portion can be divided into part that is in
renal medulla and another in the renal cortex. The • Bicarbonate is reabsorbed, and protons are
ascending loop of Henle is much thicker than the secreted into the filtrate in the DCT
descending one. It consists of simple squamous epithelium. • The DCT is also capable of absorbing protons
Thin ascending limb: and secreting bicarbonate when needed
Differences between PCT and DCT:
• Impermeable to water PCT DCT
• Permeable to ions, most likely through passive APICAL BRUSH BORDER Present Absent
diffusion EOSINOPHILICITY More Less
CYTOPLASM More Less
Thick ascending limb: READILY DISCERNIBLE Less likely More likely
NUCLEI
• Impermeable to water
• Sodium, potassium and chloride ions are Collecting Tubule:
reabsorbed by active transport Definition:
• Mainly by the Na/K/Cl cotransporter system
NKCC2 and the sodium/hydrogen exchanger The collecting duct system connects the nephrons to a
NHE3 minor calyx. It is responsible for electrolyte and water
• Approximately, 25 to 30% of total Na balance and is regulated by the action of hormones
reabsorption occurs in the thick ascending limb of aldosterone and antidiuretic hormone.
the loop of Henle
Functions:
• Paracellular reabsorption of magnesium and
calcium by the lumen potential generated by • Reabsorbs sodium in exchange for secreting
potassium backleak potassium and protons. This is regulated by
• Makes the urine less concentrated aldosterone
• Loop diuretics act here by blocking Na/K/Cl o Aldosterone acts on mineralocorticoid
transporter receptor → increased mRNA and
• Aldosterone increases sodium reabsorption in this protein synthesis in principal cells →
part increased apical potassium conductance,
Distal Convoluted Tubule: increased expression of
This is the portion of the nephron between the loop of sodium/potassium pump, and increased
Henle and the collecting tubule. It is important for the epithelial sodium channel activity →
regulation of potassium, calcium, sodium and pH. lumen negativity → potassium secretion
into the lumen
Na/Cl cotransporter: o In alpha-intercalated cells → sensing of
• Thiazide-sensitive Na-Cl cotransporter is lumen negativity → increased activity
expressed on the apical side of DCT of hydrogen ATPase activity →
increased hydrogen secretion and
• This cotransporter is responsible for the further
increased bicarbonate/Cl exchanger
reabsorption of sodium from the urine, making it
activity
very diluted
Other functions: • The connecting tubule of the collecting duct
system also expresses vasopressin 2 receptors
• The DCT is impermeable to water which in the presence of ADH increase the
• It is permeable to calcium via the TRPV5 channel
677
 insertion of aquaporin H2O channels on apical • The descending loop of Henle passively
side reabsorbs water.
Main cell types in the collecting tubule: • The ascending loop of Henle reabsorbs sodium,
REABSORBS SECRETES
potassium and chloride. It is impermeable to
PRINCIPAL CELLS - Sodium via - Potassium water and makes urine less concentrated. Loop
sodium diuretics inhibit the Na/K/2Cl transporter on the
channels and apical surface in ascending loop of Henle
ENaC
- Regulated by • The DCT expresses thiazide sensitive Na/Cl
aldosterone transporters
- Water via
aquaporin • The collecting tubules are the main site of action
channels of ADH and aldosterone. They regulate sodium,
- Regulated by water, and pH
ADH
Α-INTERCALATED - HCO3 via - Hydrogen Renal tubular defects:
CELLS Cl/HCO3 ions via
exchanger on apical • Fanconi syndrome first, the remainder are in
the basolateral H/ATPase
membrane and H/K
alphabetic order
exchanger • PCT defect: Fanconi syndrome
Β-INTERCALATED - Hydrogen via - HCO3 via • Ascending loop of Henle defect: Bartter
CELLS basal apical
H/ATPase Cl/HCO3 syndrome
exchanger • DCT defect: Gitelman syndrome
• Collecting tubule defect: Liddle syndrome or
Summary: syndrome of apparent mineralocorticoid excess
(SAME)
Fanconi Syndrome:
Defects:

• Generalized reabsorption defect in the PCT

• Increased excretion of glucose, aminoacids,
bicarbonate (can lead to metabolic acidosis and
proximal renal tubular acidosis), and phosphate
• Median age at diagnosis is 1.7 years
• More common in males
Clinical findings: from most common to least common

• Failure to thrive
• Polyuria
• Bone deformities: osteopenia due to
hypophosphatemia
• Recurrent vomiting
• Recurrent fever with dehydration
Figure 418: Nephron Transport Physiology. Source: • Tetany
https://en.wikipedia.org/wiki/Descending_limb_of_loop_of Causes:
_Henle#/media/File:Kidney_nephron_molar_transport_dia
gram.png • Hereditary: Wilson disease, tyrosinemia,
glycogen storage disease
Renal Tubular Function and Tubular Pathology • Ischemia
Renal Tubular Functions: • Multiple myeloma
These were extensively described in the previous lecture • Nephrotoxins such as ifosfamide and cisplatin
“Nephron Transport Physiology”. In summary: • Lead poisoning
• The PCT contains a brush border. It reabsorbs all Treatment:
glucose and aminoacoids, in addition to • Replacement of lost bicarbonate by the
significant amounts of bicarbonate, sodium, administration of bicarb
chloride, phosphate, potassium, water and uric
• Prevention of dehydration
acid
• Replacement of other substances lost in the urine

678
Bartter Syndrome • 11-beta-HSD converts cortisol to cortisone, the
Defects: latter being inactive on mineralocorticoid
receptors
• A defect in the Na/K/2Cl cotransporter in the • Hereditary 11-beta-HSD deficiency increases the
thick ascending loop of Henle levels of cortisol which increases
• Median age at diagnosis is 1.5 years mineralocorticoid receptor activity → this is the
• Metabolic alkalosis, hypokalemia and main defect in syndrome of apparent
hypercalciuria are common findings mineralocorticoid excess (SAME)
• Similar to chronic loop diuretic use • This is associated with metabolic alkalosis,
Clinical findings: from most common to least common hypokalemia, hypoaldosteronism and an elevated
level of cortisol
• Failure to thrive Causes:
• Polyuria • An autosomal recessive disorder, however it can
• Bone deformities be an acquired disorder
• Recurrent fevers with dehydration • Glycyrrhetinic acid which is present in licorice
• Tetany blocks the activity of 11-beta-HSD → acquired
Causes: SAME
Treatment:
• Autosomal recessive disorder
• Treated with potassium-sparing diuretics which
Gitelman Syndrome decrease mineralocorticoid effects
Defects: • Exogenous corticosteroids decrease endogenous
cortisol production → helpful in SAME
• A defect in NaCl transporter in DCT
• Associated with metabolic alkalosis, Renin-Angiotensin-Aldosterone System
hypomagnesemia, hypokalemia, and Production of Angiotensin II:
hypocalciuria
• The liver produces angiotensinogen
• Similar to lifelong thiazide diuretic use
• In the presence of RAAS activators such as
• Less severe than Bartter syndrome hypotension, decreased NaCl delivery, or
Clinical findings: from most common to least common increased sympathetic tone, renin is released by
• Milder clinical picture similar to Bartter the juxtaglomerular cells
syndrome • Renin converts angiotensinogen to angiotensin I
Causes: • Angiotensin I is then converted to angiotensin II
(the active form) by the action of ACE
• Autosomal recessive disorder o ACE is also responsible for the
Liddle Syndrome breakdown of bradykinin in the lungs
Defects: o ACE is produced by the kidneys and
• A gain of function mutation in sodium channels lungs
in the collecting tubule • Most of the actions of the RAAS system are
• Increased activity of sodium channels → mediated by angiotensin II
increased sodium reabsorption Renin:
• Associated with metabolic alkalosis, • Secreted by the juxtaglomerular cells in response
hypokalemia, hypertension and to decreased renal perfusion
hypoaldosteronism • Decreased renal perfusion pressure is detected by
• An autosomal dominant disorder renal baroreceptors in the afferent arteriole
Clinical findings: • Also secreted in response to increased renal
• Presents similarly to hyperaldosteronism but sympathetic discharge which is mediated by beta-
aldosterone is nearly undetectable 1-adrenergic effects and in response to decreased
Treatment: NaCl delivery which is sensed by the macula
• Amiloride densa cells
• Renin is needed for the production of angiotensin
SAME I from angiotensinogen
Defects: Angiotensin II:
• Cortisol activates mineralocorticoid receptors in • The main function of angiotensin II is to maintain
the collecting tubules blood volume and pressure

679
 • It limits reflex bradycardia in response to • Increases sodium reabsorption by increasing
hypotension epithelial sodium channel activity (ENaC)
• In the systemic circulation, angiotensin II acts on Juxtaglomerular Apparatus:
angiotensin II receptor type 1 to induce • Consists of mesangial cells, juxtaglomerular cells
vasoconstriction → increase blood pressure which are modified smooth muscle cells of the
• It constricts the efferent arteriole → increases afferent arteriole, and macula densa cells
filtration fraction by preserving GFR while • The macula densa is a NaCl sensor that is located
decreasing RBF at distal end of loop of Henle
• It increases the activity of Na/H in PCT cell → • Juxtaglomerular cells secrete renin
increases sodium, bicarbonate, and water • Macula densa cells sense sodium-chloride
reabsorption permitting contraction alkalosis delivery to the DCT
• Acts on the hypothalamus to promote thirst and • When renal blood pressure is decreased,
the release of ADH from the posterior pituitary. sympathetic tone is increased, or NaCl delivery to
ADH acts on the principal cell to increase water DCT is decreased → renin is released → efferent
reabsorption by increasing aquaporins arteriole vasoconstriction → increased or
• It acts on the adrenal glands to promote preserved GFR with decreased RBF → increased
aldosterone secretion filtration fraction
ANP and BNP: • Beta-blockers which are used in the treatment of
• Atrial natriuretic peptide and ventricle natriuretic hypertension have two main mechanisms of
peptide (ANP and BNP respectively) are released action:
in response to increased circulating volume o Direct vasodilatory effect
• They inhibit the renin-angiotensin-aldosterone o Inhibition of beta1-receptors in the
system and relax the vascular smooth muscle by juxtaglomerular apparatus → decreased
increasing cGMP renin release → decreased activity of
• They increase GFR and dilate the afferent RAAS
arteriole → therefore, renal blood flow is
increased, and renin secretion is inhibited
• Promote natriuresis
• They are markers of heart failure
ADH:
• Regulates serum osmolality in response to
osmolality or low blood volume
• Stimulates the reabsorption of water in the
collecting ducts by increasing the expression of
apical aquaporins
• Increase the reabsorption of urea in the collecting
duct to maintain corticopapillary osmotic gradient
Aldosterone:
• Angiotensin II promotes the release of Figure 419: RAAS. Source:
aldosterone https://upload.wikimedia.org/wikipedia/commons/3/36/Re
• Aldosterone regulates the extracellular fluid nin-angiotensin-aldosterone_system.svg
volume and sodium content to correct low blood
volume states, and hyponatremia Renal Endocrinology
• Also responds to hyperkalemia by increasing Erythropoietin
potassium excretion Production:
Functions of aldosterone on the alpha-intercalated cells:
• Released by interstitial cells in peritubular
• Increases hydrogen secretion by increasing capillary bed
H/ATPase activity • Increased release in response to hypoxia
Functions of aldosterone on the principal cells: Function:
• Increases sodium reabsorption and potassium • Stimulates RBC proliferation in bone marrow
secretion • Supplemented in chronic kidney disease to treat
• Increases potassium conductance by increasing anemia
the activity of Na/K ATPase

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 • When supplemented, can cause hypertension • When measured PCO2 is lower than predicted PCO2
• Polycythemia is seen in patients with renal cell → concomitant respiratory alkalosis
carcinoma secondary to overproduction of Winters formula to calculate predicted PCO2 :
erythropoietin PCO2 = 1.5 × [HCO−3 ] + 8 ± 2
Calciferol
• Proximal convoluted tubule cells convert 25-OH- Acidosis and Alkalosis:
vitamin D3 to 1,25-(OH)2-vitamin D3 known as
calcitriol
• This is the active form of vitamin D
• Therefore, patients with CKD develop bone
disease secondary to vitamin D decreased activity - -

in addition to hypophosphatemia
Prostaglandins
• Paracrine secretion
• Vasodilates afferent arterioles → increases RBF —

• NSAIDs block renal-protective prostaglandin • • •

synthesis → constriction of afferent arteriole and

—
•
• •
•
• •
•
• •

decreased GFR → acute kidney injury in low • •

•
•
•
•

•
•

renal blood flow states as in dehydration +

• •
• •
• •
•

NSAID use
Dopamine: In patients with metabolic acidosis, it is important to
• Secreted by proximal convoluted tubule cells distinguish between high-anion gap and normal anion gap
• Promotes natriuresis metabolic acidosis. The following formula is used to
• At low doses, dilates interlobular arteries, afferent calculate the anion gap:
arterioles, and efferent arterioles which increased Anion gap = Na+ − (Cl− + HCO−3 )
RBF but has no effect on GFR
• At higher doses, it is a vasoconstrictor Compensatory mechanisms in acid-base primary disorders:
Renal Tubular Acidosis and Acid-Base Physiology
P PCO HCO3 COMPENSATOR
Acid-Base Physiology and Henderson-Hasselbalch H 2 - Y RESPONSE
Equation METABOLIC
• The blood’s pH is tightly regulated ACIDOSIS ↓ ↓ ↓ Hyperventilation
ALKALOSI ↑ ↑ ↑ Hypoventilation
• The principle acid is hydrogen ions, whereas, the S
principle base in the blood is bicarbonate (HCO3-) RESPIRATORY
ACIDOSIS ↓ ↑ ↑ ↑ renal bicarb
• When the pH is altered, compensatory responses reabsorption
by the kidney or respiratory system act to correct ALKALOSI ↑ ↓ ↓ ↓ renal bicarb
this abnormal pH S reabsorption
Henderson-Hasselbalch equation: • In red, are compensatory responses
• Hyper or hypoventilation are immediate
[HCO−3 ] respiratory responses to metabolic alkalosis and
pH = 6.1 + log
0.03 × PCO2 acidosis
• Increased or decreased renal bicarbonate
How to differentiate between simple metabolic acidosis reabsorption are delayed compensatory responses
and metabolic acidosis with concomitant respiratory in respiratory acidosis and alkalosis
acidosis:
Renal Tubular Acidosis Type 1:
• In metabolic acidosis, hyperventilation is the Defect:
immediate compensatory mechanism to correct
• Alpha-intercalated cells are unable to secrete
the acidosis
hydrogen into the lumen
• Hyperventilation clears CO2 → decreases PCO2
• When hydrogen is not secreted, the alpha-
• Winters formula is used to calculate the predicted
intercalated cells are unable to generate new
new PCO2 and it is expected to be equal to the real
HCO3-
measured value
• This results in metabolic acidosis with a urine pH
• When measured PCO2 is higher than predicted above 5.5 because of the inability of acidifying
PCO2 → concomitant respiratory acidosis
the urine

681
 • Serum potassium is decreased
• Patients with RTA type 1 are at an increased risk Acute Interstitial Nephritis
of calcium phosphate kidney stones formation Definition
because these stones form in urine pH above 5.5 Acute interstitial nephritis is an inflammatory condition
and because of increased calcium resorption from characterized by an idiosyncratic delayed hypersensitivity
the bone due to increased bone turnover immune reaction to foreign antigens that is associated with
Causes: acute renal injury. It is classically associated with pyuria and
azotemia. It often occurs after the administration of drugs
• Drug-induced nephropathy as in amphotericin B that act as haptens.
toxicity and analgesic nephropathy
• Congenital anomalies that cause obstruction of
the urinary tract
Note: Acute interstitial nephritis is also known as
• Autoimmune diseases including systemic lupus tubulointerstitial nephritis.
erythematosus
Renal Tubular Acidosis Type 2:
Defect: Epidemiology
• A defect in the proximal convoluted tubule that • Because the diagnosis requires a kidney biopsy,
prevalence is often underestimated
decreases HCO3- reabsorption
• The incidence of AIN in patients with acute renal
• Increased bicarbonate excretion in urine →
injury of unknown etiology is 13.5%
metabolic acidosis
• Most commonly, AIN is caused by drugs such as
• The urine’s pH remains below 5.5 because alpha-
NSAIDs, diuretics, penicillin derivatives, proton
intercalated cells are functioning normally in
pump inhibitors, sulfonamides, and rifampin
RTA type 2 → they can acidify the urine
• However, the action of the alpha-intercalated • Less commonly, it can be secondary to systemic
infections such as mycoplasma, or autoimmune
cells is not enough to produce enough HCO3- to
diseases including Sjogren syndrome, SLE and
correct the metabolic acidosis
sarcoidosis
• Serum potassium is decreased
Causes of AIN: 5 P’s:
• Increased risk of hypophosphatemic rickets
especially in Fanconi syndrome • Pee (diuretics)
Causes: • Penicillins and cephalosporins
• Proton pump inhibitors
• Fanconi syndrome
• Pain-free (NSAIDs)
• Multiple myeloma
• RifamPin
• Carbonic anhydrase inhibitors such as
Pathogenesis
acetazolamide
• AIN is caused by idiosyncratic delayed
Hyperkalemic Tubular Acidosis Type 4: hypersensitivity immune reaction to foreign
Defect: antigens
• Antigen-reactive T-cells play a key role in a
• Hypoaldosteronism or aldosterone resistance in
dysregulated immunologic response that includes
the collecting duct
skin eruptions and eosinophilia
• Hyperkalemia inhibits the synthesis of
• Idiosyncratic means: it occurs in a small number
ammonium in the PCT and this decreases NH4+
of people exposed to an antigen such as NSIADs,
excretion
is not dose-related, is associated with systemic
• Renal tubular acidosis type 4 is the most common manifestations of hypersensitivity and the
form of RTA in adults reaction occurs on re-exposure
Causes:
Histopathology:
• Decreased aldosterone production as in diabetic
• Infiltration of inflammatory cells within the renal
hyporeninism, ACE inhibitors, heparin use,
interstitium associated with edema, and
cyclosporine, or adrenal insufficiency interstitial fibrosis
• Aldosterone resistance due to use of potassium • Sparing of the glomeruli and blood vessels
sparing diuretics
• Cellular infiltrates are T-cells, monocytes, and
• Obstructive nephropathy eosinophils
Use of trimethoprim-sulfamethoxazole.

682
 • Eosinophilic micro-abscesses might be seen • If there is no clinical improvement after
Clinical Findings withdrawal of the offending agent, a biopsy is
• Patients typically present with nonspecific indicated
symptoms of acute renal failure such as oliguria, • Once the diagnosis of AIN is confirmed by renal
malaise, anorexia, nausea and vomiting with biopsy, a trial of prednisone is indicated
acute onset • If the trial was successful, continue with steroid
• A generalized hypersensitivity syndrome therapy. Otherwise, consider other
characterized by the following is seen in patients immunosuppressive treatments.
with AIN: Cyclophosphamide is a good option here
o Fever Acute Renal Injury
o Rash Definition:
o Eosinophilia and pyuria with mainly Acute kidney injury is an abrupt decline in renal function
eosinophils measured by an elevated creatinine, BUN or by the
o Oliguric renal failure presence of oliguria/anuria.
o Rapid decrease in renal function with
rapid elevation in creatinine and BUN AKI is defined as any of the following:
• Patients with AIN could also have hematuria and
• Increase in creatinine by 0.3 mg/dL or more
costovertebral angle tenderness
within 48 hours
• On the other hand, some patients might be
• Increase in creatinine by 1.5 times or more within
asymptomatic
7 days from baseline
Diagnosis
• Urine volume < 0.5 mL/kg/h for 6 hours
• Renal biopsy is the only definitive method of
Epidemiology
establishing the diagnosis of AIN (however, it is
• Main causes of AKI in the developing world in
rarely done in straightforward cases)
urban areas are hospital acquired (ischemia,
sepsis and nephrotoxic drugs)
• Main cause of AKI in the community in the
developing world is dehydration due to diarrhea
or other infections
• In the developed world, 15% of hospitalized
patients have AKI (60% in critically ill patients)
• In the developed world, AKI rarely occurs in non-
hospitalized patients
Prerenal Azotemia
• Renal hypoperfusion → decreased GFR without
damage to renal parenchyma
• The kidneys receive 25% of cardiac output → any
failure of the systemic circulating blood volume
Figure 420: AIN in a patient with polyarteritis nodosa. can lead to a profound impact on renal perfusion
Source: https://en.wikipedia.org/wiki/Interstitial_nephritis Hypovolemia:

• Hemorrhage, volume depletion, renal fluid loss

When can the presumptive diagnosis of AIN be made
due to over-diuresis, and third-space losses such
without a renal biopsy?
as burns and peritonitis
• Patients who have a fever, rash, arthralgia, and Impaired cardiac function:
eosinophiluria after a recent infection or drug
• Congestive heart failure, acute myocardial
exposure who are in acute renal failure can be
infarction and massive PE
presumed to have AIN
Systemic vasodilatation:
Treatment
• The management of AIN is step-wise • Anti-hypertensive medications, gram-negative
• If the diagnosis is suspected, a biopsy is not bacteremia (endotoxins), cirrhosis and
mandatory. Instead, it is crucial to withdraw the anaphylaxis
potentially offending medication and wait for Increased vascular resistance:
clinical improvement

683
 • Anesthesia, surgery, hepatorenal syndrome, • Urea reabsorption is impaired → decreased
NSAID medications, and cyclosporine (causes BUN/creatinine ratio
renal vasoconstriction) • Increased FENa
Post-renal AKI
• Occurs after acute obstruction of the urinary flow
Note: In prerenal azotemia, Na, water and urea
are retained by the kidney to conserve volume. → increased intra-tubular pressure → decreased
This elevates the BUN/creatinine ratio because GFR
while urea is reabsorbed, creatinine is not. FE Na is
decreased.
• Can occur if the obstruction occurs at any level
within the urinary collection system: from renal
tubule to urethra
It is important in prerenal azotemia that the cause • Stones, BPH, neoplasia and congenital anomalies
of decreased GFR is only decreased renal
hypoperfusion and not ischemic tubular necrosis are the most common causes of post-renal AKI
(the latter is a cause of intrinsic renal failure). Extrarenal obstruction:

• Prostate hypertrophy, improperly placed catheter,

neoplasia of the bladder, prostate and cervix and
Intrinsic Renal Failure retroperitoneal fibrosis are the main causes of
• Intrinsic causes of acute renal injury imply that extrarenal obstruction post-renal AKI
the cause of renal failure is renal parenchymal Intrarenal obstruction:
injury/damage
• The damage can affect the tubules, glomeruli, • Nephrolithiasis
interstitium, or renal blood vessels • Blood clots
• The most common cause is acute tubular necrosis • Papillary necrosis
due to ischemia or toxins Consequences of Renal Failure
Tubular: • Impaired renal filtration function → retained
nitrogenous waste products and electrolyte
• Renal ischemia due to shock, hemorrhage, disturbances
trauma, bacteremia, pancreatitis or as an obstetric Consequences of renal failure (MAD HUNGER):
complication can lead to tubular necrosis
• Nephrotoxic drugs such as antibiotics, • Metabolic Acidosis
antineoplastic drugs, contrast media, organic • Dyslipidemia – mainly elevated triglycerides
solvents, and heavy metals cause tubular damage • Hyperkalemia
and AKI • Uremia
• Myoglobin, hemoglobin and uric acid • Na/water retention leading to HF, pulmonary
Glomerular: edema and hypertension
• Growth retardation and developmental delay in
• Acute post-infectious glomerulonephritis
children
• Lupus nephritis, IgA glomerulonephritis,
• Erythropoietin deficiency → anemia
infective endocarditis, Goodpasture syndrome an
• Renal osteodystrophy
Wegener disease are less common causes of AKI
Uremia:
due to glomerular damage
Vascular: • Nausea and anorexia
• Bilateral renal artery stenosis or bilateral renal • Asterixis
vein thrombosis can present with intrinsic AKI • Encephalopathy
• Vasculitis, malignant hypertension, • Pericarditis
atherosclerotic and thrombotic emboli, hemolytic • Platelet dysfunction
uremic syndrome, and TTP are possible causes of Renal osteodystrophy:
vasculopathy-induced intrinsic AKI
• Hypocalcemia, hyperphosphatemia and failure of
ATN as a cause of AKI:
vitamin D hydroxylation
• Patchy necrosis is characteristic and is due to • Seen in chronic renal disease
debris obstructing tubules → fluid backflow • Results in secondary hyperparathyroidism
across necrotic tubules • Elevated serum phosphate binds calcium →
• GFR is decreased tissue deposits and decreased serum calcium level
• Urine has epithelial and granular casts

684
 • The impaired vitamin D hydroxylation results in o Caused by damage to the renal vascular
less active vitamin D and decreased intestinal endothelial cell → ischemia of the renal
calcium absorption tubular epithelial cell
o Because of this, patients with renal o GFR further falls
osteodystrophy have hypocalcemia • The maintenance phase is established by cellular
despite having hyperparathyroidism repair, apoptosis, migration and proliferation
• Subperiosteal thinning of bones is the pathologic o The goal of this phase is to maintain
feature of the disease cellular and tubule integrity
Laboratory Findings in Acute Renal Failure o Cellular function improves slowly
Prerenal azotemia: o Blood flow returns to normal range
• Recovery phase is a continuation of the
• Urine osmolality above 500 mOsm/kg maintenance phase. Cellular differentiation
• Urine Na below 20 mEq/L continues, and epithelial polarity is reestablished.
• FENa below 1% Kidney function improves
• Serum BUN/Cr above 20 o While BUN and creatinine levels start to
Intrinsic renal failure: fall, risk of hypokalemia and renal
wasting of other electrolytes is high
• Urine osmolality below 350 mOsm/kg
• Urine Na above 40 mEq/L
• FENa above 2% Note: ATN usually resolves spontaneously,
however, it can be fatal especially during the
• Serum BUN/Cr below 15 initial oliguric phase
Postrenal azotemia:
Etiologies of ATN:
• Urine osmolality below 350 mOsm/kg Ischemic-induced ATN:
• Urine Na excretion, FENa and serum BUN/Cr • Prerenal azotemia can lead to ischemic acute
vary depending on the etiology tubular necrosis
• Common causes include hypovolemia due to
Acute Tubular Necrosis
diarrhea, vomiting, bleeding, dehydration, burns
Definition: or renal losses via diuretics
Acute tubular necrosis is characterized by renal tubular cell
• Systemic vasodilation as seen in sepsis or
damage and death and is caused by intrarenal
anaphylaxis can lead to ischemic ATN
vasoconstriction or a direct effect of drug toxicity.
• Coagulopathy as in DIC can also lead to ischemic
Drug toxicity in ATN is mediated by:
ATN
• Ischemic event
• Necrotic renal tubular cells may slough into
• Nephrotoxic mechanism
tubular lumen
• A mixture of both
• Mainly affects PCT and thick ascending limb
Nephrotoxic-induced ATN:
Epidemiology
• Some drugs that are cleared by the kidneys
• ATN is the most common cause of intrinsic acute
behave as exogenous toxins
kidney injury in hospitalized patients
• They can cause direct renal tubular injury or
• 50% of ATN cases are caused by ischemic injury
crystal-induced AKI
• 25% are mediated by a nephrotoxic mechanism
• Aminoglycosides, amphotericin B, radiocontrast
media, sulfa drugs, acyclovir, cisplatin,
Pathogenesis
calcineurin inhibitors such as tacrolimus,
Stages of ATN:
mammalian target of rapamycin mTOR inhibitors
• The initiation phase is characterized by an acute such as everolimus, foscarnet, ifosfamide,
decrease in GFR and a sudden deterioration in cidofovir and IV immunoglobulins all can cause
kidney function (elevated serum creatinine and ATN
BUN)
• Heme-containing proteins such as hemoglobin
• The extension phase consists of two major events. and myoglobin (released in crush injuries) can
Ongoing hypoxia following the ischemic event
lead to ATN:
and an inflammatory response o These behave like endotoxins
o More pronounced at the o Cause direct proximal tubular injury,
corticomedullary junction of the kidney
obstruction and renal vasoconstriction

685
 o High-cell turnover states → FENa:
hyperuricemia → crystal-induced • This is a good test to differentiate between ATN
nephropathy and AKI due to prerenal azotemia
o Light-chains accumulation in multiple • FENa above 2% favors ATN over prerenal AKI
myeloma is toxic to renal proximal and Urine sodium concentration:
distal tubules • In ATN, you expect urine sodium concentration
Sepsis-induced ATN: to be around 40 to 50 mEq/L
• Systemic hypotension and renal hypoperfusion • In prerenal AKI, urine sodium concentration is
are the main mechanisms of ATN in septic below 20 mEq/L
patients
• Endotoxemia can lead to renal vasoconstriction Treatment:
and release of inflammatory cytokines → release The mainstay of treatment of ATN is to prevent it by
of reactive oxygen species → renal injury and identifying the most common causes.
ATN • Prevent hypotension and hypovolemia in
hospitalized patients
Clinical Findings Renal replacement therapy:
• Look for possible causes of prerenal azotemia • Indicated in patients with hyperkalemia, uremia
such as diarrhea, vomiting, sepsis, dehydration, or and metabolic acidosis
blooding • Critically ill hemodynamically unstable patients
• Look for common causes of ATN in hospitalized
patients such as hypotension, sepsis, use of Chronic Renal Failure
nephrotoxic agents such as radiocontrast media or Definition:
use of a nephrotoxic antibiotic Chronic renal failure or chronic kidney disease (CKD) is
Physical findings: defined as the presence of kidney damage or an estimated
• Tachycardia, dry mucous membranes, decreased GFR less than 60 ml/min/1.73m2 persisting for 3 months or
skin turgor, and cool extremities indicate more irrespective of the cause.
dehydration as a possible cause of ATN End-stage renal failure is defined as a GFR less than 10
• Fever and hypotension → sepsis ml/min or being on dialysis.
• Muscle tenderness → rhabdomyolysis
Epidemiology
Diagnosis • The most common cause of CKD is diabetes
The goal of evaluation in a patient with AKI is to mellitus type 2
differentiate prerenal AKI from other causes of AKI • The second most common cause of CKD is
(mainly ATN). hypertension
Urinalysis: • Other causes of CKD from more common to least
• Microscopy is normal in prerenal AKI. In ATN, common are:
you expect to see muddy brown casts or renal o Primary glomerulonephritis
tubular epithelial cells o Diabetes mellitus type 1
o Cystic diseases
o Interstitial nephritis

Pathogenesis
Sequence of events that lead to scarring and fibrosis in
CKD:
• Infiltration of damaged kidneys by inflammatory
cells
• Activation and proliferation, and loss of intrinsic
renal cells
• Activation and proliferation of extracellular
matrix producing cells such as myofibroblasts
and fibroblasts (scarring and fibrosis)
Figure 421: Muddy brown casts in a patient with hepato- • Replacement of the normal extracellular matrix
renal syndrome. Source: with pathologic one
urine.optmq.connexence.com/Imdoceng/d21d002.html • Development of focal segmental
glomerulosclerosis, regardless of the cause
686
Mechanisms of accelerated progression of CKD: Treatment:
• Some diseases are characterized by rapid General management:
progression of AKI to CKD • Adjust patient’s current medications’ doses for
• These include systemic and intraglomerular the level of estimated GFR
hypertension • Placement of an arteriovenous fistula or graft to
• Glomerular hypertrophy prepare the patient for renal replacement therapy
• Intrarenal deposition of calcium phosphate Treatment of reversible causes of renal failure:
• Altered prostanoid metabolism • Infections and drugs can reduce GFR, treat
accordingly
Clinical Findings • Hypotension needs to be corrected
Symptoms and signs of CKD manifest in later stages of the • Avoid contrast media, NSAIDs, aminoglycosides,
disease. and other nephrotoxic agents
• Nausea and vomiting Decreasing the progression of CKD:
• Loss of appetite • Treat hypertension, proteinuria, metabolic
• Fatigue and weakness acidosis and hyperlipidemia
• Sleep disturbances • Smoking cessation
• Oliguria • Protein restriction
• Decreased mental sharpness • Bicarbonate supplementation in patients with
• Muscle twitches and cramps chronic metabolic acidosis
• Swelling of feet and ankles • Intensive glucose control in diabetics
• Persistent pruritus • Low potassium, and low phosphate diet
• Chest pain due to uremic pericarditis Treatment of consequences of CKD:
• Hypertension • Vitamin D and calcium supplements
• Pulmonary edema and dyspnea • Erythropoietin for anemia
• Capsaicin and cholestyramine for uremia-induced
Diagnosis pruritus
It is crucial to establish the chronicity of the condition. • Desmopressin for uremia-induced bleeding
• History of long-standing HTN, proteinuria, disorders
diabetes or other predisposing disease • ACE inhibitors
• Skin pigmentation, LVH, and hypertensive fundal Renal replacement therapy:
changes which are signs of chronicity • Hemodialysis
• Low calcium, high phosphate and normal PTH → • Peritoneal dialysis
AKI more likely than CKD • Kidney transplantation is the treatment of choice
• Very high BUN and creatinine in a patient for ESRD – patients become eligible when eGFR
appearing well is likely to have CKD not AKI is less than 20 ml/min
Supporting laboratory tests: Indications for renal replacement therapy:
• CBC, which can show anemia and • Uremic pericarditis or pleuritis → urgent
thrombocytopenia indication
• Serum electrolytes • Progressive uremic encephalopathy → urgent
• Creatinine clearance to estimate GFR indication
Imaging of the kidneys: • Clinically significant bleeding diathesis → urgent
• Ultrasound shows small kidneys, reduced cortical indication
thickness, increased echogenicity, scarring, or • Hypertension unresponsive to antihypertensive
multiple cysts medications
• Other imaging modalities such as renal • Fluid overload refractory to furosemide/diuretics
angiography, CT, and renal nuclear scans • Hyperkalemia, hyponatremia, metabolic acidosis,
Metabolic and electrolyte disturbances in CKD: hypercalcemia, hypocalcemia, or
• Protein C, S and antithrombin III deficiency hyperphosphatemia refractory to medical therapy
• Low vitamin D, hyperphosphatemia, • Persistent nausea and vomiting
hypocalcemia and secondary • Malnutrition
hyperparathyroidism
Note: CKD patients should be referred to a
• Hyperkalemia and hypernatremia nephrologist when the estimated GFR is less than
30 ml/min/1.73m2

687
Analgesic Nephropathy Part of the routine microscopic urine analysis is to look for
Definition casts. Their presence indicates hematuria or pyuria that is
Analgesic nephropathy is a disease caused by the frequent of glomerular or renal tubular origin. Causes of hematuria
use of analgesic medications (NSAIDs and acetaminophen) from a lower level such as kidney stones or bladder cancer
over many years leading to significant impairment of renal will not present with casts. Similarly, acute cystitis
function. presents with pyuria but no casts.

Pathogenesis RBC Casts:

Types of analgesic nephropathy • Erythrocyte casts most commonly indicate
• Classic analgesic nephropathy is caused by the glomerular injury
chronic use of high-dose acetaminophen with or • Less commonly, seen in hypertensive emergency
without NSAIDs • When RBCs pass through the glomerular
• NSAID-induced analgesic nephropathy is a basement membrane gaps “due to glomerular
specific form of analgesic nephropathy that is damage”, they mix with uromodulin which is
discussed here produced in the loop of Henle to form casts
• While specific for glomerular injury, they are
Nephrotoxicity of NSAIDs: difficult to find
• Nonspecific blocking of cyclooxygenase → • Can be associated with WBC casts when the
inhibition of prostaglandin synthesis → etiology of glomerular disease is inflammatory
vasoconstriction and ischemic acute tubular
necrosis → acute renal injury
• Interstitial nephritis and papillary necrosis →
chronic kidney disease
Risk factors for analgesic nephropathy:
• The development of analgesic nephropathy is
seen in a small number of patients receiving
NSAIDs
• Sickle cell disease, diabetes mellitus, urinary
obstruction and chronic pyelonephritis have been
identified as possible risk factors for analgesic
nephropathy Figure 422: RBC Cast. Source:
https://www.ajkd.org/article/S0272-6386(18)30873-4/pdf
Clinical Findings
• The diagnosis of analgesic nephropathy is a WBC Casts:
diagnosis of exclusion in a patient taking NSAIDs
• Leukocyte casts most commonly are due to acute
• Patients can present with symptoms and signs interstitial nephritis
suggestive of chronic pain “the indication for
• Also seen in acute pyelonephritis and in
chronic NSAID use”, and acute or chronic kidney
transplant rejection
failure
• In most cases of drug-induced acute interstitial
nephritis, the only clue is an increase in serum
Treatment:
creatinine level and abnormalities in the urine
• Analgesic nephropathy is usually a non-
Possible urinalysis abnormalities seen in AIN:
progressive disease once the diagnosis is
identified and the etiologic analgesic is • Low grade proteinuria
withdrawn • Positive blood and leukocyte esterase
• Unfortunately, it is not a reversible condition if • Negative urine culture
chronic kidney disease has developed • WBC casts
• Patients with ATN secondary to NSAID • Less specific findings include granular casts and
nephrotoxicity can improve spontaneously renal tubular epithelial cells
• It is very challenging to treat chronic pain in these
patients. Generally, NSAIDs and acetaminophen
need to be avoided

Urine Casts
Urine Casts on Microscopy Analysis:

688
 causes of granular casts include thrombotic
microangiopathy, AIN and other kidney lesions
• It should be also emphasized that not all granular
casts are muddy brown casts. Dense brownish
granular casts are what we call muddy brown
casts
• Presence of muddy brown casts + renal tubular
epithelial cells + history of recent exposure to
nephrotoxic agents known to be associated with
ATN = the diagnosis of ATN can be assumed

Figure 423: WBC cast/ Source:

https://www.ajkd.org/article/S0272-6386(18)30873-4/pdf

Fatty Casts:
• Seen in nephrotic syndrome – other urinalysis
findings include high-grade proteinuria, free lipid
droplets, oval fat bodies, and cholesterol crystals Figure 425: Muddy brown casts in a patient with AKI due
to septic shock. Source:
• Oval fat bodies contain cholesterol esters, which
produce birefringent Maltese crosses under https://www.ajkd.org/article/S0272-6386(18)30873-4/pdf
polarized light
• Oval fat bodies are macrophages or renal tubular Waxy Casts:
epithelial cells engorged with fat droplets • Seen in end-stage renal disease and chronic renal
• Lipid or fatty casts are free lipid droplets, failure
cholesterol crystals and oval fat bodies embedded • Their presence suggests very low urine flow
in a cast matrix which is seen in severe long-standing kidney
disease
• They are cylindrical
• They possess a high refractive index
• They are rigid, and have sharp edges, fractures
and broken-off ends

Figure 424: Lipid cast seen under phase contrast

microscopy with strong positive Maltese cross under
polarized light (picture on right). Source:
https://www.ajkd.org/cms/10.1053/j.ajkd.2018.07.012/attac
hment/a580ca4f-80c3-4407-9e9c-b3697e05a45c/mmc3.pdf Figure 426: Waxy casts. Source:
https://laboratoryinfo.com/types-of-casts-in-urine-and-
Granular or Muddy Brown Casts: their-clinical-significance/
• An important clue for acute tubular necrosis in a
patient with AKI Hyaline Casts:
• When found in a large number in a patient with • Can be a normal finding, especially in
AKI, the diagnosis of ATN is very likely concentrated urine samples
• However, when found in moderate numbers in a • Composed primarily of uromodulin which is
hospitalized patient, it is important to remember produced by loop of Henle
that they are not very specific to ATN. Other

689
 • Can be seen in larger numbers when there is a Membranous:
decline in renal perfusion as in prerenal AKI
which leads to a sluggish urinary flow • Membranous nephropathy is characterized by
• When the main finding in a patient with AKI is thickening of the glomerular basement membrane
hyaline casts + few renal tubular epithelial cells, Etiologic classification of glomerular diseases:
it should be presumed that the patient has a mixed
• The previous descriptors are histopathological
picture of prerenal azotemia and renal tubular
• Another important way to describe glomerular
necrosis
diseases is to determine whether the disease is
primary or secondary
• A primary glomerular disease is a primary disease
of the kidney that specifically impacts the
glomeruli. Minimal change disease, a cause of
nephrotic syndrome, is an example of a primary
glomerular disease
• Systemic diseases can involve multiple organs
including the kidneys causing secondary
glomerular disease such as SLE and diabetic
nephropathy
Figure 427: Hyaline casts in a patient with acute kidney Glomerular hematuria:
injury due to decompensated heart failure "a cause of • Disruption of the glomerular basement membrane
prerenal azotemia". Source: becomes significant enough that red blood cells
https://www.ajkd.org/article/S0272-6386(18)30873-4/pdf can pass while being distorted. You expect 5% or
more acanthocytes in urine in glomerular
hematuria. Intact RBCs in the urine are seen in
Introduction to Glomerular Diseases
lower urinary tract causes of bleeding, not
Important Terminology Related to Glomerular Diseases
glomerular disease
Glomerular diseases typically present with nephritic
Glomerular proteinuria:
syndrome, nephrotic syndrome or a mixed picture.
However, these syndromes are clinical descriptions and are • The most abundant plasma protein is albumin.
not considered as a diagnosis per-se. The diagnosis of a Normally, these are excluded in the glomerular
glomerular disease is largely based on the result of filtrate, however when glomerular disease is
histopathologic examination and whether the disease is present, and the glomerular basement membrane
primary or secondary. Accordingly, it is crucial to is disrupted, you expect to see microalbuminuria
understand the descriptors of glomerular diseases. in early disease, proteinuria in nephritic
syndrome, and macroalbuminuria in nephrotic
Focal:
range in nephrotic syndrome
• A focal glomerular disease involves less than Nephritic Syndrome
50% of glomeruli • Defined as a urine sediment showing red cells
• A classical example is focal segmental more than 5 per high power field and the presence
glomerulosclerosis of one or more of the following:
Diffuse: o Acanthocytes
o Red cell casts
• A diffuse glomerular disease involves more than o Mixed red cell/white cell casts
50% of glomeruli • Due to GBM disruption and is characterized
• Diffuse proliferative glomerulonephritis is a good clinically by the following:
example o Hypertension
Proliferative: o Elevated BUN and creatinine
o Oliguria
• In diffuse proliferative glomerulonephritis, we o Hematuria and proteinuria
used a second descriptor, “proliferative” • Proteinuria is often less than 3.5 grams per day
• A proliferative pathologic glomerular process is “sub-nephrotic range” – can be in nephrotic range
characterized by hypercellular glomeruli in severe cases
• Another example is membranoproliferative Examples of glomerular diseases causing nephritic
glomerulonephritis syndrome:

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 • Acute poststreptococcal glomerulonephritis • Loss of immunoglobulins → increased risk of
• Rapidly progressive glomerulonephritis infections
• Alport syndrome Primary glomerular diseases causing nephrotic syndrome:
• IgA nephropathy (Berger disease)
• Membranoproliferative glomerunephritis • Minimal change disease and focal segmental
Nephrotic Syndrome glomerulosclerosis
Secondary glomerular diseases causing nephrotic
• Characterized by proteinuria above 3.5 grams per
syndrome:
day
• Severe nephrotic syndrome is defined as • Amyloidosis
proteinuria exceeding 10 grams per day, serum • Diabetic glomerulonephropathy
albumin less than 2.5 grams per dL, and severe Epidemiology:
edema
• Due to podocyte disruption → charge barrier • Annual incidence of nephrotic syndrome in adults
impaired → inability to propel negatively- is 3 per 100,000 persons
charged proteins • 90% are idiopathic
• Patients also have hyperlipidemia → increased • Membranous nephropathy is the most common
risk of cardiovascular disease cause of nephrotic syndrome in white adults
• Can be primary or secondary • Focal segmental glomerulosclerosis is the most
Primary or secondary glomerular diseases that can cause common cause of nephrotic syndrome in black
nephrotic syndrome: adults
• Minimal change disease is the most common
• Minimal change disease cause of nephrotic syndrome in children
• Membranous nephropathy Minimal Change Disease
• Focal segmental glomerulosclerosis • Most often a primary disorder
Secondary glomerular diseases that can cause nephrotic • May be triggered by a recent infection,
syndrome: immunization, or an immune stimulus
• Amyloidosis • Secondary to lymphoma in rare cases →
cytokine-mediated damage
• Diabetic glomerulonephropathy
Nephritic-Nephrotic Syndrome • Primary disease has excellent response to
corticosteroids
• Severe nephritic syndrome with profound GBM
Clinical presentation:
damage → damage of glomerular filtration charge
barrier → nephrotic range proteinuria • Nephrotic-range proteinuria, edema, weight gain,
• Most commonly seen in diffuse proliferative and hypoalbuminemia (nephrotic syndrome)
glomerulonephritis, and membranoproliferative • Edema usually starts in the lower half of the
glomerulonephritis but can occur in any cause of body, and periorbital edema
nephritic syndromes • Older adults may present with acute kidney injury
Nephrotic Syndrome and high blood pressure
Definition: Microscopic examination:
Nephrotic syndrome is caused by glomerular diseases that
cause massive proteinuria. Nephrotic-range proteinuria is • On light microscopy, you expect to see no
defined as loss of more than 3.5 grams of protein per day in changes on a kidney biopsy in minimal change
urine. This happens because of the disruption of the disease
glomerular filtration charge barrier, which can be a primary • Sometimes, the mesangium may be expanded on
or a secondary process. light microscopy, or lipid may be seen in PCT
cells
Other laboratory disruptions in nephrotic syndrome:
• Under immunofluorescence, you expect a
• Hypoalbuminemia → plays a role in pathogenesis negative result
of edema in nephrotic syndrome • Electron microscopy shows effacement of
• Hyperlipidemia → increased risk of podocyte foot processes
cardiovascular disease
• Frothy urine with fatty casts
• Loss of antithrombin III, protein C and S →
hypercoagulable state

691
 Figure 429: Focal segmental glomerulosclerosis. Source:
Figure 428: Electron microscopy showing normal podocyte https://en.wikipedia.org/wiki/Focal_segmental_glomerulos
and podocyte with minimal change disease. Source: clerosis#/media/File:Focal_segmental_glomerulosclerosis_
https://unckidneycenter.org/kidneyhealthlibrary/glomerular -_high_mag.jpg
-disease/minimal-change-disease/
Membranous Nephropathy
Treatment: • Can be primary where the cause is antibodies to
phospholipase A2 receptor
• First-line therapy in children is corticosteroids
• Secondary to NSAIDs, penicillamine, gold, HBV,
• Cyclosporine, levamisole, calcineurin inhibitor, HCV, syphilis, SLE, or solid tumors
and mycophenolate mofetil are second-line
• Poor response to corticosteroids and may
treatments
progress to CKD
• The mainstay of treatment in adults is
• Also known as membranous glomerulonephritis
corticosteroids, statins to decrease high levels of
Microscopy:
cholesterol, and ACE inhibitors in adults with
minimal change disease and hypertension • Diffuse capillary and glomerular basement
Focal Segmental Glomerulosclerosis membrane thickening on light microscopy
• Can be primary or secondary • Immunofluorescence microscopy shows granular
• Inconsistent response to corticosteroids and may deposition of immune complexes
progress to CKD • Electron microscopy shows spike and dome
• Clinical presentation is nephrotic syndrome most appearance of subepithelial deposits
commonly in an African American or a Hispanic
Secondary causes of focal segmental glomerulosclerosis:

• HIV infection
• Sickle cell disease
• Massive obesity
• Heroin abuse
• Interferon treatment
• Congenital malformations
Microscopy:

• Segmental sclerosis and hyalinosis on light

microscopy (see figure 2) Figure 430: Membrane thickening and spike formation in
• Immunofluorescence microscopy is often membranous glomerulonephritis. Source:
negative, however nonspecific immune focal https://en.wikipedia.org/wiki/Membranous_glomeruloneph
deposits of IgM, C3 and C1 may be seen ritis#/media/File:Membranous_nephropathy_-_mpas_-
_very_high_mag.jpg
• Effacement of foot processes like minimal change
disease in electron microscopy
Amyloidosis
• Kidneys are the most commonly involved organs
in systemic amyloidosis
• Caused by the deposition of AL amyloid or AA
amyloid in the mesangium which is seen in

692
 chronic conditions that predispose to amyloid Definition:
deposition Nephritic syndrome is caused by an inflammatory process.
• Light microscopy with Congo red stain shows Characterized by hematuria and erythrocyte casts in urine.
green birefringence under polarized light Hypertension is a characteristic feature of nephritic
syndrome and is mainly due to salt retention by the
kidneys.
Other laboratory disruptions in nephritic syndrome:

• Azotemia → elevated BUN and creatinine

• Oliguria
• Proteinuria → usually not in nephrotic range
o Severe disruption of the GBM →
disruption of the glomerular basement
charge barrier → nephrotic-range
proteinuria
Figure 431:Amyloid deposits in the kidneys. Source:
• Hypercellular and inflamed glomeruli on biopsy
https://stanfordhealthcare.org/medical-conditions/blood-
Acute Poststreptococcal Glomerulonephritis
heart-circulation/amyloidosis.html
• Most frequently seen in children
• Occurs two to three weeks after group A
Diabetic Glomerulonephropathy
streptococcal infection of the pharynx, or less
• Most common cause of end-stage renal disease in commonly the skin
the United States
• Good prognosis – resolves spontaneously in most
• Caused by the glycation of tissue proteins due to
children
hyperglycemia
• Worse prognosis in adults → may progress to
• Characterized by mesangial expansion and
renal insufficiency
glomerular basement membrane thickening →
Pathophysiology:
increased permeability and hyperfiltration
(glomerular hypertension and increased GFR) • Type III hypersensitivity reaction → decreased
• Glomerular hypertension → glomerular complement levels especially C3 due to
hypertrophy → glomerular scarring → deposition along the glomerular basement
glomerulosclerosis and further progression of membrane and mesangium
nephropathy • Cola-colored urine due to massive glomerular
• Early finding is microalbuminuria hematuria
• Light microscopy shows mesangial expansion, • Consistent evidence of a recent streptococcus
GBM thickening, and eosinophilic nodular infection (positive strep titers or serology testing)
glomerulosclerosis (Kimmelstiel-Wilson lesions) • Peripheral and periorbital edema due to salt
retention with water → hypertension
Microscopy:

• Light microscopy shows enlarged and

hypercellular glomeruli (see figure 1)
• Immunofluorescence microscopy shows starry
sky granular appearance due to IgG, IgM and C3
deposition along the glomerular basement
membrane and mesangium (known as a lumpy-
bumpy appearance), (see figure 2)
• Electron microscopy reveals subepithelial
immune complex humps
Figure 432: Eosinophilic nodular glomerulosclerosis in
diabetic nephropathy. Source:
https://en.wikipedia.org/wiki/Diabetic_nephropathy#/medi
a/File:Nodular_glomerulosclerosis.jpeg

Nephritic Syndrome

693
Figure 433: Post-streptococcal glomerulonephritis on light Figure 435: Crescentic glomerulonephritis. Source:
microscopy. Source: https://en.wikipedia.org/wiki/Rapidly_progressive_glomer
https://en.wikipedia.org/wiki/Acute_proliferative_glomerul ulonephritis#/media/File:Crescentic_glomerulonephritis_(2
onephritis#/media/File:Post- ).jpg
infectious_glomerulonephritis_-_very_high_mag.jpg
Goodpasture syndrome:

• Linear immunofluorescence appearance due to

antibodies deposition on GBM
• Also involves the alveolar basement membrane
• Because of the involvement of these two
basement membranes, patients present with
hematuria (nephritic syndrome) and hemoptysis
• Type II hypersensitivity reaction
• Treated with plasmapheresis

Figure 434: Immunofluorescence microscopy showing

immune complex deposits in PSGN. Source:
https://unckidneycenter.org/kidneyhealthlibrary/glomerular
-disease/post-infectious-glomerulonephritis-gn/

Rapidly Progressive Glomerulonephritis

• Poor prognosis with most patients ending in end-
stage renal disease rapidly within days to weeks
of onset Figure 436: Linear pattern of IgG deposition on GBM in
• Goodpasture syndrome, Wegener disease, and Goodpasture syndrome. Source:
microscopic polyangiitis are possible causes of https://webpath.med.utah.edu/RENAHTML/RENAL093.ht
rapidly progressive glomerulonephritis ml
(crescentic glomerulonephritis)
• Described as crescentic because of crescent moon Wegener disease (granulomatosis with polyangiitis)
shape due to fibrin and plasma proteins (C3b) • Negative immunofluorescence testing due to no
deposition with hypercellular background of immunoglobulins or C3 deposition
glomerular parietal cells, monocytes and
• C-ANCA (PR3-ANCA) positive
macrophages (see figure 3)
• Presents with nosebleeds, stuffy nose, and
inflammation of the uveal layer of the eye
• Involves the heart, lungs and kidneys → can be
fatal
• Treated with a combination of
immunosuppressive therapy
(rituximab/cyclophosphamide with high-dose

694
 corticosteroids for remission followed by • Poststreptococcal glomerulonephritis or diffuse
azathioprine or methotrexate for maintenance) proliferative glomerulonephritis can cause rapidly
• Plasma exchange in severe cases progressive glomerulonephritis
• Diffuse proliferative glomerulonephritis is often
severe enough to cause nephrotic-nephritic
syndrome
Diffuse Proliferative Glomerulonephritis
• Most commonly due to systemic lupus
erythromatosus
• Characterized by wire-looping of capillaries on
light-microscopy
• Granular appearance on immunofluorescence
• Electron microscopy shows subendothelial and
intramembranous IgG-based immune complexes
Figure 437: C-ANCA. Source: with C3 deposition
https://en.wikipedia.org/wiki/C- • Patients typically present with hematuria,
ANCA#/media/File:C_anca.jpg moderate to severe (nephrotic-range) proteinuria,
hypertension and renal insufficiency
Microscopic polyangiitis: Membrano-proliferative Glomerulonephritis
• Most often presents with nephritic-nephrotic
• An autoimmune disease characterized by a pauci- syndrome
immune necrotizing, small vessel vasculitis
• Mesangial ingrowth results in GBM splitting and
without evidence of necrotizing granulomatous
tram-track appearance on light microscopy with
inflammation
H&E and PAS stains
• Presents with fever, loss of appetite, weight loss,
fatigue and kidney failure
• Rapidly progressive glomerunephritis occurs in
some patients
• Characterized by the deposition of the perinuclear
antineutrophil cytoplasmic antibodies (p-ANCA).
MPO-ANCA positive
• Treated with high-long-term dosage of
prednisone alternated with cyclophosphamide or
azathioprine Figure 439: Tram-like appearance due to mesangial
• Plasmapheresis is indicated in acute setting to hypercellularity. Source:
remove ANCA antibodies https://webpath.med.utah.edu/RENAHTML/RENAL097.ht
ml

Type 1 MPGN:

• Secondary to hepatitis B or C infection

• Can be idiopathic in some patients
• Characterized by subendothelial immune
complex deposits with granular appearance on
immunofluorescence
Type 2 MPGN:
Figure 438: P-ANCA. Source:
https://en.wikipedia.org/wiki/P- • Associated with C3 nephritic factor which is an
ANCA#/media/File:P_anca.jpg IgG antibody that stabilizes C3 convertase →
persistent complement activation and
Causes of rapidly progressive glomerulonephritis with consumption of C3
granular IF appearance: • C3 levels drop in the blood
• Characterized by intramembranous deposits
which give the disease its name “dense deposit
disease”
695
 Overview:
Kidney stones present with symptoms and signs related to
their location whether in the kidney, ureter, or urinary
bladder. The typical signs of a kidney stone occur later,
and they include:

• Renal colic
Figure 440: Dense deposit disease. Source: • Flank pain
https://webpath.med.utah.edu/RENAHTML/RENAL205.ht • Hematuria
ml • Obstructive uropathy
• Urinary tract infections
IgA Nephropathy: • Blockage of urine flow
• Also known as Berger disease • Hydronephrosis
• Presents with episodic hematuria that occurs • Nausea and vomiting
concurrently with GI or respiratory tract Renal colic:
infections
o Infections in the GI or respiratory tracts • Renal colic occurs when there is a stone in the
ureter. It subsides once the stone passes into the
result in the release of secretory IgA
urinary bladder
antibodies which deposit in the kidneys
causing IgA vasculitis • The pain is described as intense cramping
o When involves other blood vessels → • The emergency treatment of a kidney stone is
Henoch-Schonlein purpura often direct to alleviate renal colic, and associated
• Light microscopy reveals mesangial proliferation nausea and vomiting
Obstructive kidney stones:
• Immunofluorescence reveals IgA-based immune
complex deposits in the mesangium • The symptoms and signs of kidney stones become
• Electron microscopy shows mesangial immune evident when the stones are obstructive of the
complex deposition urinary flow
• Therefore, pain will be confined to the ipsilateral
flank side of the stone
• Treated and prevented by encouraging fluid
intake
Most common kidney stone presentation is a calcium
oxalate stone in a patient with hypercalciuria and
normocalcemia.
Epidemiology:
Figure 441: IgA deposits in mesangium in a patient with • Kidney stone disease prevalence and recurrence
Berger disease. Source: rates are increasing
https://webpath.med.utah.edu/RENAHTML/RENAL096.ht • Up to 12% of the world population will suffer
ml from urolithiasis at some stage in their lifetime
• More common in men within the age group of 20
Alport Syndrome: to 49 years
• Most commonly an X-linked dominant disorder • Recurrence rates if the patient does not apply
• Mutation in type IV collagen which affects metaphylaxis range from 10 to 50% within 5
several organs that have this collagen: years
o Kidneys: thinning and splitting of • Kidney stones affect 1 in 11 people in the United
glomerular basement membrane States
resulting in glomerulonephritis Anatomical Locations of Kidney Stones:
o Eyes: retinopathy and lens dislocation • Kidney stones can virtually affect any part of the
o Nerves: sensorineural deafness urinary tract, but they are more commonly seen in
o Hence, the common saying “can’t see, areas of urine stasis
can’t pee and can’t hear a bee” • Within the kidney, stones can be found in the
• Electron microscopy reveals basket-weave minor or major calyces and in the ureter
appearance
Kidney Stones
696
 • Based on the location of the kidney stones, the • Low urine volume due to inadequate water intake
following types are found: which leads to dehydration and supersaturated
o Pelvic stone in the kidney pelvis urine
o Calyx stone in kidney calyx • Recurrent urinary tract infections result in the
o Staghorn stone in kidney pelvis and alkalization of urine which increases the risk of
calyces stone formation
o Mid-ureter stone • Family history of kidney stone disease and renal
o Bladder stones tubular acidosis
• Anatomical defects of the urinary tract such as
medullary sponge kidney, ureteropelvic junction
stenosis, pyeloureteral duplication, polycystic
renal disease, and horseshoe kidney
• Hypertension, obesity, inflammatory bowel
disease and use of broad-spectrum antibiotics
• Lithogenic drugs such as indinavir, sulfonamides,
uricosuric agents and high-dose ceftriaxone
Calcium Stones:
• 80% of all urinary calculi
• 50% are pure calcium oxalate, 5% are calcium
phosphate, and 45% are a mixture of both
Figure 442: Types of kidney stones based on location.
• Calcium oxalate monohydrate and calcium
Source:
oxalate dihydrate are the most commonly
https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_p
identified chemical compositions
mc/tileshop_pmc_inline.html?title=Click%20on%20image
%20to%20zoom&p=PMC3&id=5817324_AU2018- • Hypercalciuria due to resorptive defects,
hyperoxaluria, hypocitraturia, hypomagnesuria,
3068365.001.jpg
and hypercystinuria
Etiology and Risk Factors for Kidney Stones: • Also caused by ingestion of antifreeze, vitamin C
Pathogenesis of kidney stone formation: abuse, and Crohn disease
• Urinary pH of 5.0 to 6.5 for calcium oxalate
• Urinary supersaturation of calcium, oxalate or stones
uric acid and urinary stasis • Calcium phosphate stones form in urinary pH
• Oxidative stress and cell injury above 7.5
• Nucleation of the stone material Radiography:
• Crystal growth
• Crystal aggregation • Calcium stones are radiopaque on x-ray and CT
Microscopy:
• Crystal retention and adhesion
• Stone formation • Calcium oxalate crystals are shaped like envelope
Causes of kidney stones: or dumbbell
• Lifestyle habits and dietary factors such as
excessive intake of animal proteins and salt and
deficiencies in chelating agents such has citrate,
fiber, and alkali foods increase the risk of kidney
stone disease
• Metabolic disorders including hypercalciuria,
hypocitraturia, hyperoxaluria, hyperuricosuria, Figure 443: Calcium oxalate monohydrate dumbbell
and gout disease shaped. Source:
• Hypercalcemic disorders such as primary https://en.wikipedia.org/wiki/Calcium_oxalate#/media/File
hyperparathyroidism :Calcium_oxalate_crystals_(urine)_-
• Excessive excretion of promoters of urinary _kalsiyum_oksalat_kristalleri_(idrar)_-_01.png
crystallization and reduction in inhibitors
excretion • Calcium phosphate crystals are wedge-shaped
prisms
Treatment:

697
 • Thiazides, citrate, and low-sodium diet for Radiology:
calcium oxalate stones
• Thiazides and low-sodium diet for calcium • Radiolucent on x-ray and minimally visible on
phosphate stones CT
Struvite Stones: Microscopy:
• 10 to 15% of urinary stones are struvite or • Uric acid crystals are rhomboid or rosettes in
magnesium ammonium phosphate stones shape
• Occurs among patients with chronic urinary tract
infections that produce urease
• The most common cause is proteus mirabilis,
however other pathogens can also cause struvite
stones such as Klebsiella pneumonia,
pseudomonas aeruginosa and Enterobacter
• Escherichia coli is not capable of splitting urea
and is not associated with struvite stones:
o Remember, the most common cause of
UTI is Escherichia coli
Pathogenesis:

• Urease cleaves urea into ammonia and CO2 which Figure 445: Uric acid crystals in urine. Source:
makes the urine more alkaline https://www.google.com/url?sa=i&rct=j&q=&esrc=s&sour
• Urinary pH is above 7 ce=images&cd=&ved=2ahUKEwiA04bDpP3iAhWQAGM
• Commonly form staghorn calculi BHQWiB2kQjRx6BAgBEAU&url=https%3A%2F%2Fw
Radiology: ww.123rf.com%2Fphoto_57740676_uric-acid-crystal-in-
urine-sediment-.html&psig=AOvV
• Radiopaque on x-ray and CT
Microscopy: Treatment:

• Coffin lid crystals • Alkalization of urine

• Allopurinol
Cystine Stones:
• Caused by a genetic disorder of the transport of
cystine which results in excess of cystine in urine
• Autosomal recessive disorder caused by a defect
in the rBAT gene on chromosome 2
• Impaired renal tubular absorption of cystine or
leaking of cystine into urine
o Loss of function of cystine-reabsorbing
Figure 444: Struvite crystals. Source: PCT transporter
https://en.wikipedia.org/wiki/Kidney_stone_disease#/medi o Same transporter of ornithine, lysine,
a/File:Struvite_crystals_dog_with_scale_1.JPG and arginine which results in increased
urinary concentration of COLA:
Treatment: Cystine, Ornithine, Lysine and Arginine
• Eradication of underlying infection, and surgical • Cystine is poorly soluble in urine
removal of the stone • Usually begins in childhood
Uric Acid Stones: • Can form staghorn calculi
• Represent about 5% of all stone types • Sodium cyanide nitroprusside test positive
• More common in people on diets that are rich in • Cystine “SIXtine” stones have SIX sides
purines such as meat and fish which results in “hexagonal crystals on microscopy”
hyperuricosuria • Associated with a low urinary pH
• Associated with low urine volume and a pH less
than 5.05
• Associated with gouty arthritis, but is most
commonly idiopathic
• More common in men

698
 • Damage to the renal pelvis and calyces →
infection, stone formation and loss of function
Grading:

• Ultrasound is the imaging modality of choice for

grading of hydronephrosis
Grade 0:

• No renal pelvis dilation

Figure 446: Cystine stone crystals in urine are hexagonal. Grade 1:
Source:
https://www.google.com/url?sa=i&rct=j&q=&esrc=s&sour • Mild renal pelvis dilation without dilation of the
ce=images&cd=&ved=2ahUKEwiJ1rLppP3iAhWE2uAK calyces nor parenchymal atrophy
HcrqCbkQjRx6BAgBEAU&url=https%3A%2F%2Fwww. Grade 2:
kidneystoners.org%2Finformation%2Fcystine-kidney-
• Moderate renal pelvis dilation with dilation of a
stones%2F&p
few calyces
Grade 3:
Radiology:

• Faintly radiopaque on x-ray • Renal pelvis dilation with all calyces uniformly
dilated but with normal renal parenchyma
• Moderately radiopaque on CT
Grade 4:
Treatment:
Low sodium diet, alkalization of urine and use of chelating agents • Severe hydronephrosis with same features as
when refractory. grade 3 in addition to thinning of the renal
parenchyma
Hydronephrosis
Definition:
Hydronephrosis is urine-filled dilation of the renal pelvis
and/or calyces as a result of obstruction.
Pathology:

• Hydronephrosis can be caused by structural

abnormalities at the junctions between the kidney,
ureter and bladder which can occur during fetal
development
• Trauma, surgery and radiation therapy can also
cause structural abnormalities in the urinary tract Figure 447: Hydronephrosis grading. Source:
that can lead to obstruction and subsequent https://en.wikipedia.org/wiki/Hydronephrosis#/media/File:
hydronephrosis Society_for_Fetal_Urology_(SFU)_grading_of_hydroneph
• External compression of one or both ureters can rosis.jpg
lead to hydronephrosis. Pregnancy is a possible
cause of bilateral ureter compression Clinical Findings:
• Kidney stones, blood clots and retroperitoneal
fibrosis can cause hydronephrosis • The symptoms and signs of hydronephrosis
• Severe benign prostate hypertrophy, cervical depend on whether the obstruction is partial or
cancer and vesicoureteral reflux are possible complete, unilateral or bilateral, and acute or
causes of hydronephrosis, however, they are less chronic
common than the above-mentioned causes Acute hydronephrosis:
Pathophysiology:
• Caused by a sudden cause of obstruction as a
• Obstruction of the urinary tract flow leads to kidney stone or trauma
increased pressure within the kidney pelvis and • Intense pain in the flank area
calyces → inability to pass urine → dilation of • Described as Dietl’s crisis
the renal pelvis and calyces Chronic hydronephrosis:

699
 • Attacks of dull discomfort or no pain at all • Lower urinary tract obstruction is treated by the
• Nausea and vomiting insertion of a urinary catheter or a suprapubic
• Recurrent urinary tract infections, especially if catheter
the level of obstruction is in the lower urinary Urinary Tract Tumors
tract Renal Cell Carcinoma:
• Complete obstruction → renal failure Histopathology and pathology:
Physical examination:
• Polygonal clear cells filled with accumulated
• Palpable abdominal or flank mass caused by an lipids and carbohydrates, see figure 1
enlarged kidney • Gold-yellow due to high lipid content
Diagnosis: • Originates from PCT and invades renal vein quite
early → spread through the inferior vena cava
Laboratory tests: with metastasis to the lung and bone
• If on the left side → patient may develop
• Usually become useful in the case of bilateral
varicocele
hydronephrosis
• Elevated urea and creatinine
• Hyponatremia and other electrolyte disturbances
due to renal failure
• Hyperchloremic metabolic acidosis
• Urinalysis might reveal hematuria from stones,
pyuria from UTI, and an elevated urine pH due to
destruction of nephrons
Imaging:

• Renal ultrasonography is the imaging modality of Figure 449: RCC. Source:

choice because it has excellent sensitivity and https://en.wikipedia.org/wiki/Renal_cell_carcinoma#/medi
specificity a/File:Clear_cell_renal_cell_carcinoma_high_mag.jpg
• CT is useful in identifying the cause of
hydronephrosis Epidemiology:
• Intravenous urogram and MRI are helpful
• Most common primary renal malignancy
• Most common in men aged between 50 and 70
years
• Smoking and obesity are possible risk factors
• Associated with gene deletion on chromosome 3
which can be sporadic or inherited as in von
Hippel-Lindau syndrome
Clinical findings:

• Manifests with hematuria, palpable mass,

Figure 448: Renal ultrasonography of hydronephrosis. secondary polycythemia, flank pain, fever and
https://en.wikipedia.org/wiki/Hydronephrosis#/media/File: weight loss
Hydro.jpg • Paraneoplastic syndromes including: PTHrP
(hypercalcemia), ectopic EPO (polycythemia),
Treatment
ACTH and renin (hypertension)
• The goal of treatment is to remove the obstruction Treatment:
and to drain the accumulated urine
• Surgery and ablation for localized disease
• Acute obstruction of the upper urinary tract is
• Aldesleukin or targeted therapy for metastatic
treated by the insertion of a nephrostomy tube
disease
• Chronic obstruction of the upper urinary tract is
• Treatment is rarely curative
treated by the insertion of a ureteric stent or a
• RCC is usually resistant to chemotherapy and
pyeloplasty
radiation therapy
Renal Oncocytoma
Pathology:

700
 • Renal oncocytoma is a benign epithelial cell o Beckwith-Wiedemann syndrome is
tumor arising from collecting ducts characterized by Wilms tumor,
• It presents as a well-circumscribed mass with macroglossia, organomegaly, and
central scar hemihyperplasia and is caused by WT 2
• The cells appear eosinophilic with abundant mutation
mitochondria without perinuclear clearing Clinical findings:
Clinical findings:
• Presents with a large, palpable unilateral flank
• Painless hematuria and an abdominal mass mass with or without hematuria
• Flank pain in some patients Treatment:
Treatment:
• Surgery with or without
• While benign, the distinction from renal cell chemotherapy/radiotherapy
carcinoma is often difficult • Can be curative in early stages
• Therefore, the tumor is often resected Transitional Cell Carcinoma
Pathology:

• Most common tumor of the urinary tract system

• Can occur in renal calyces, pelvis, ureters, and
bladder
• Can be suggested by painless hematuria without
casts (lower urinary tract source of hematuria)
• Possible risk factors include exposure to
phenacetin, smoking, aniline dyes, and
cyclophosphamide
• Also known as urothelial carcinoma
Treatment:

• Localized and early transitional cell carcinoma of

Figure 450: Renal oncocytoma. Source: the bladder is treated by surgical resection of the
https://en.wikipedia.org/wiki/Renal_oncocytoma#/media/F tumor – recurrence is common
ile:Renal_oncocytoma.jpg • Mitomycin can be given into the bladder as a one-
off dose in the immediate post-operative period
Nephroblastoma • BCG infusions into the bladder can be used to
Pathology: treat localized tumors as well
• Chemotherapy is used for advanced and
• Also known as Wilms’ tumor, it contains metastatic disease
embryonic glomerular structures Squamous Cell Carcinoma of the Bladder
• Caused by loss of function mutations of tumor Pathology:
suppressor genes WT1 and WT2 on chromosome
11 • For squamous cell carcinoma to arise in the
• The most common pediatric renal malignancy in bladder, squamous metaplasia followed by
children aged between 2 and 4 years dysplasia are prerequisites
• Maybe a part of different syndromes: • The main cause of squamous metaplasia is
o WAGR complex: Wilms tumor, chronic irritation of the urinary bladder
aniridia, genitourinary malformations, • Possible risk factors include Schistosoma
and mental retardation. Caused by WT1 haematobium, chronic cystitis, smoking, and
deletion chronic nephrolithiasis
o Denys-Drash syndrome is characterized Treatment:
by Wilms tumor, diffuse mesangial
necrosis which leads to early-onset • Radical cystectomy is the standard treatment
nephrotic syndrome, dysgenesis of • SCC of the bladder is chemotherapy-resistant
gonads which leads to male pseudo- • Neoadjuvant or adjuvant radiotherapy might be
hermaphroditism and is caused by WT1 helpful
mutation Urinary Incontinence

701
Stress Incontinence difficult to defer. Most people with urgency incontinence
Definition: also have overactive bladder syndrome.
Stress incontinence is the complaint of urine leakage in Overactive bladder syndrome:
association with coughing, sneezing, or physical exertion.
• Urinary urgency with or without incontinence
Epidemiology: associated with urinary frequency and nocturia in
the absence of a UTI or any other pathology
• Isolated stress incontinence is estimated to have a • The presence of urgency incontinence is
prevalence of 10 to 15% in women aged between sufficient, but not necessary, for the diagnosis of
40 to 64 years overactive bladder syndrome
• Mixed incontinence with urgency and stress • Current therapies for urgency incontinence are
components is more common than stress also effective for overactive bladder syndrome
incontinence. The estimated prevalence of mixed Epidemiology:
incontinence is 30%
Pathology: • The most common type of urinary incontinence
• Its presence is enough for the diagnosis of
• Urethral hypermobility due to loss of support of overactive bladder syndrome
the bladder neck and urethra Pathology:
• Weakness of the urinary sphincter
o If this is the main pathology, the term • Overactive bladder with detrusor instability leads
intrinsic stress incontinence is preferred to leak with urge to void immediately
o Can be caused by trauma, repeated • Can be associated with chronic or recurrent UTI
urogynecological surgeries, Clinical Findings:
neurological disease, ageing, or any
other disease associated with systemic • In addition to incontinence, the patient can also
muscular atrophy complain of symptoms of urgency, nocturia, and
• Leakage of urine with increased intra-abdominal frequency
pressure as in sneezing, coughing, or lifting • Variable volume loss on voiding diary
• Obesity, vaginal delivery, and prostate surgery • Negative cough stress test
are possible risk factors Diagnosis and Management:
Clinical Findings:
• Post-void residual volume of less than 50 ml
• The patient presents to the outpatient clinic • No symptoms and signs of stress incontinence
complaining of urine leakage in associated with • Treatments include Kegel exercises, bladder
coughing, sneezing or physical exertion training, and antimuscarinics
• This is often associated with urgency o Bladder training includes timed voiding,
incontinence in most women distraction and relaxation techniques
• When isolated, patients are expected to have no o Antimuscarinics include oxybutynin.
nocturia Often poor compliance due to side
• Small-volume leakage on voiding diary between effects
5 to 10 ml Mixed Incontinence
Diagnosis and Management: A mixed picture with urgency in addition to stress
incontinence. The patient typically has history of nocturia
• Positive bladder stress test (directly observed and frequency, in addition to a positive cough-stress test.
leakage from urethra upon coughing or Valsalva Most patients with stress incontinence actually have mixed
maneuver) incontinence.
• Post-void residual volume is less than 50 ml
• Pelvic floor muscle strengthening (Kegel) Overflow Incontinence
exercises, weight loss and pessaries are the Definition:
mainstay of treatment
Incomplete emptying of the urinary bladder results in
Urgency Incontinence
overfilling and leakage of urine.
Definition:
Epidemiology:
Urgency incontinence is the complaint of urine leakage
associated with a sudden compelling desire to void that is Rare, as compared to other types of incontinence.

702
Pathology: Clinical Findings:
Associated with polyuria as in diabetes, bladder outlet • History taking is the most important tool for the
obstruction as in benign prostate hyperplasia, or diagnosis of acute uncomplicated cystitis
neurogenic bladder as in multiple sclerosis • The main symptoms of acute cystitis include
frequency, urgency, dysuria, suprapubic pain,
Clinical Findings: cloudy urine, nausea, vomiting, and hematuria
• Recurrent UTIs due to urinary stasis • Systemic symptoms such as high fever and chills
• Increased post-void residual volume (urinary are usually absent
retention) on catheterization or ultrasound • Physical examination is typically normal except
Diagnosis and Management: for suprapubic tenderness in 10% of women with
cystitis
• Treatment is to relieve outlet obstruction (alpha- Diagnosis and Management:
blockers for BPH) or catheterization to drain the
bladder • Urinalysis with microscopy of a mid-stream catch
Urinary Tract Infections or catheter oriented to avoid contamination
Acute Bacterial Cystitis: • Nitrites are found in the urine of patients with
Definition: gram-negative UTI
• Presence of intact or broken neutrophils result in
Acute inflammation of the urinary bladder. Urinary tract leukocyte esterase positivity
infection (UTI) is defined as significant bacteriuria in the • Pyuria is the finding of more than 5 WBCs per
setting of symptoms of cystitis or pyelonephritis. HPF
o Sterile pyuria and negative urine
Epidemiology: cultures suggest urethritis by Neisseria
• UTIs including acute bacterial cystitis are the gonorrhoeae or chlamydia trachomatis
most common bacterial infection in women • Treatment of acute cystitis include nitrofurantoin,
trimethoprim-sulfamethoxazole, ciprofloxacin,
• 40% of women experiencing a UTI at some point
in their lives levofloxacin, or beta-lactams such as amoxicillin-
clavulanate
• Within a year of infection, 27 to 46% of women
Pyelonephritis
will have another UTI
Definition:
• Risk factors include female gender due to a short
urethra, sexual intercourse (honeymoon cystitis), Acute pyelonephritis is a bacterial infection of the kidneys
indwelling catheter, diabetes mellitus, and and is one of the most common diseases of the kidney.
impaired bladder emptying as in overflow urinary Pyelonephritis results as a complication of an ascending
incontinence urinary tract infection that spreads from the bladder to the
Pathology: kidneys.
• Most UTIs in females are caused by Escherichia Epidemiology:
coli (86%), staphylococcus saprophyticus (4%)
and Klebsiella species (3%) • More common in females
• Proteus species and Enterobacter species account • 15 to 17 new cases per 10,000 females and 3 to 4
for the remainder of the cases new cases per 10,000 males annually
• Urethral catheterization accounts for 80% of • Main risk factors are indwelling urinary catheters,
nosocomial UTIs urinary tract obstruction, vesicoureteral reflux,
Pathophysiology: diabetes mellitus and pregnancy
• Complications include chronic pyelonephritis,
• Bacteria migrate from the rectum, perineum and renal papillary necrosis and perinephric abscess
vagina to the urethra or urosepsis
o Because of the smaller length of urethra Pathology:
in females, the distance required for
pathogens to migrate is shorter and the • Neutrophilic infiltrate of renal interstitium that
risk of UTI is higher in females mainly affects the cortex and spares the glomeruli
• Gram-negative enteric organisms thrive in and vessels, see figure 1
females with an elevated vaginal pH which • The most common causative organism is
happens as they age, and estrogen levels diminish Escherichia coli

703
 • While the most common mechanism is ascending • Associated with proteus infection
UTI, hematogenous spread of pathogens to the
kidneys is another possible mechanism

Figure 452: Foamy macrophages in xanthogranulomatous

Figure 451: Neutrophils infiltrate the tubules and pyelonephritis. Source:
interstitium in acute pyelonephritis. Source: https://en.wikipedia.org/wiki/Pyelonephritis#/media/File:X
https://webpath.med.utah.edu/RENAHTML/RENAL019.ht anthogranulomatous_pyelonephritis_cd68.jpg
ml
Kidney Cystic Diseases
Clinical Findings: Autosomal Dominant Polycystic Kidney Disease
Definition:
• Patients present with systemic features such as
fever, chills, nausea and vomiting Autosomal dominant polycystic kidney disease (ADPKD)
is one of the most common inherited diseases in humans. It
• Flank pain with costovertebral angle tenderness
has a prevalence of 1 in 400 to 1000. The most common
Diagnosis and Management:
etiology is a mutation in PKD1 gene (85%) located on the
• Pyuria with leukocyte casts (the latter is not short arm of chromosome 16. The rest have mutations in
mandatory for the diagnosis of pyelonephritis) PKD2 gene found on the long arm of chromosome 4.
• CT shows striated parenchymal enhancement These genes encode for polycystin 1 and polycystin 2
• The mainstay of treatment is antibiotics, respectively.
analgesics and antipyretics PKD1 vs PKD2 mutations:
o Oral cephalosporins or trimethoprim-
sulfamethoxazole for 14 days • Patients with PKD2 mutations present later and
o Complicated acute pyelonephritis is progress slower to ESRD than those with PKD1
treated with IV antibiotics such as mutations
piperacillin-tazobactam, meropenem, • Patients with mutations in both PKD1 and PKD2
cefepime, or fluoroquinolones gene have a more severe phenotype than those
Chronic pyelonephritis: with PKD1 or PKD2 mutations only
Pathophysiology and histopathology:
Recurrent episodes of acute pyelonephritis can result in
chronic pyelonephritis. Usually, the patient has • Polycystin 1 and 2 form a functional receptor-
vesicoureteral reflux or chronically obstructing kidney channel complex. Defects in this complex lead to
stones as predisposing factors. renal cyst formation
Thyroidization of the kidney: • These proteins are also found in cilia, hence
ADPKD can be seen as a disease of cilia defect
• In patients with chronic pyelonephritis, the • Cysts can arise from any part of the nephron
calyces become blunt, and there is asymmetric including the cortex and medulla, see figure 1
corticomedullary scarring • Cysts arise as outpouchings connected to the
• The tubules contain eosinophilic casts tubular lumen and they eventually disconnect
• The picture resembles thyroid tissue • Overtime, the cysts enlarge and destroy the
Xanthogranulomatous pyelonephritis: normal renal parenchyma. This results in bilateral
kidney enlargement
• Grossly orange nodules that can mimic tumor
nodules
• Wide-spread kidney damage due to
granulomatous tissue infiltration with foamy
macrophages
704
 Treatment:

• The mainstay of treatment is to control

hypertension and reduce proteinuria
• This is met by the administration of ACE
inhibitors or ARBs
Autosomal Recessive Polycystic Kidney Disease
Definition:
Autosomal recessive polycystic kidney disease (ARPKD)
Figure 453: An autopsy here shows markedly bilaterally is caused by a mutation in PKHD1 gene which is located
enlarged kidneys because of ADPKD. Source: on chromosome 16p12 and encodes for the protein
https://webpath.med.utah.edu/RENAHTML/RENAL048.ht fibrocystin/polyductin. The estimated incidence is 1 in
ml 20,000 live births. Over 300 mutations have been
identified.
Clinical presentation:
Pathophysiology and histopathology:
• Most patients present between 20 and 40 years of
age • The exact function of fibrocystin is unknown
• Abdominal pain, polyuria, recurrent UTIs, • Again, this protein is found on primary cilia
hematuria, and hypertension are the main clinical similar to polycystin
features • Cystogenesis might be caused by aberrant cell
o Death can occur secondary to proliferation and apoptosis. Down-regulation of
complications of chronic kidney disease PKHD1 results in increased cell apoptosis
or hypertension • Diffuse dilatation and elongation of the renal
o Hypertension is caused by increased collecting ducts not the whole nephron
renin production • The cysts are usually small less than 3 mm in
• Extra-renal manifestations are rare in children diameter
and they include hepatic, pancreatic, ovarian, • All patients with ARPKD have congenital hepatic
splenic and intestinal cysts fibrosis or Caroli disease → portal hypertension
• Increased incidence of mitral valve prolapse, Clinical presentation:
aortic aneurysms and intracranial aneurysms
Diagnosis: • Often presents in infancy
• Severe oliguric renal failure in utero can lead to
• Ultrasonography Potter sequence
• CT and MRI are more sensitive than • Systemic hypertension, portal hypertension,
ultrasonography, see figure 2 congenital hepatic fibrosis, and progressive renal
• Direct DNA sequencing of PKD1 and PKD2 is insufficiency in the post-natal period
now readily available Treatment:

• In the neonatal period, mechanical ventilation

may be required for pulmonary hypoplasia or
respiratory compromise due to enlarged kidneys
• Bilateral nephrectomy in severe enlarged kidneys
• Treatment of hypertension and urinary tract
infections in those who survive the neonatal
period
Autosomal Dominant Tubulointerstitial Kidney Disease
Also known as medullary cystic kidney disease, is a rare
autosomal dominant condition that leads to ESRD.
Presents in adulthood but can occur in children.
Figure 454: Abdominal CT scan of an adult with ADPKD.
Source: • Caused by mutations in several genes
https://en.wikipedia.org/wiki/Autosomal_dominant_polycy • MCKD1 locus found on chromosome 1q21 and
stic_kidney_disease#/media/File:CT_scan_autosomal_dom MCKD2 locus found on chromosome 16p12 are
inant_polycystic_kidney_disease.jpg

705
 the main loci associated with medullary cystic
kidney disease
• This inherited disease causes tubulointerstitial
fibrosis which leads to progressive renal
insufficiency with inability to concentrate the
urine
• The kidneys are small in size when visualized by
ultrasound
• The medullary cysts are usually not visualized
• Poor prognosis
Simple vs Complex Kidney Cysts
Figure 456: Sites of action of diuretics. Source:
Simple cysts are filled with ultrafiltrate fluid and appear as
https://www.cvpharmacology.com/diuretic/diuretics
anechoic on ultrasound. They are very common and
account for the majority of all renal masses. Most often,
Mannitol
they are an incidental finding on imaging because they are
Mechanism of action:
asymptomatic.
Mannitol works primarily in the proximal convoluted
Complex cysts are renal cysts that are septated or have tubule and thick ascending limp of the loop of Henle. It
solid components. They could also show enhancement. results in diuresis primarily by its osmotic effects. This
These complex cysts need follow-up or removal due to the increases urine flow and decreases intracranial/intraocular
risk of renal cell carcinoma. pressure.

Clinical use:
• Elevated intracranial or intraocular pressure
• Cerebral edema
• Drug overdose

Side effects:
• Dehydration
• Hypo or hypernatremia
• Pulmonary edema
• Heart failure
• Contraindicated in anuric patients

Figure 455: Simple renal cyst on ultrasonography. Source: Acetazolamide

https://en.wikipedia.org/wiki/Renal_cyst#/media/File:Simp Mechanism of action:
le_cyst_with_posterior_enhancement.jpg Acetazolamide is a carbonic anhydrase inhibitor. It acts on
the proximal convoluted tubule. It causes self-limited
Diuretics NaHCO3 which decreases total body bicarbonate stores →
Overview: can cause acidosis.
• Diuretic compounds are used for the treatment of
various medical disorders Clinical use:
• All diuretics act primarily by impairing sodium • Glaucoma
reabsorption in the renal tubules, however, the • Metabolic alkalosis
mechanism of action of each category of diuretics • Altitude sickness
differ considerably • Pseudotumor cerebri
• Diuretics are used in the treatment of eye • Alkalization of the urine
disorders such as glaucoma, cerebral edema,
edematous disorders, and hypertension among Side effects:
other clinical indications • Proximal renal tubular acidosis
• Paresthesia
• NH3 toxicity
• Sulfa allergy
• Hypokalemia

706
 • Calcium phosphate stone formation because it • Heart failure
increases urine’s pH • Osteoporosis (because they decrease calcium
excretion)
Loop Diuretics
Mechanism of action: Side effects: (HyperGLUC)
They act on the thick ascending limb of the loop of Henle • HyperGlycemia
by inhibiting the co-transporter Na-K-2Cl. They belong to • HyperLipidemia
the chemical group of sulfonamides and they abolish • HyperUricemia
hypertonicity of the medulla. They result in a diluted urine • HyperCalcemia
and they stimulate the release of PGE which has a • Sulfa allergies
vasodilatory effect on the afferent arteriole. They increase
• Hypokalemic metabolic alkalosis
calcium excretion in urine. They include furosemide, Thiazide-related agents:
torsemide, bumetanide, and ethacrynic acid. Same mechanism of action and clinical uses of thiazides.
Ethacrynic acid:
Examples include chlorthalidone, indapamide, metolazone
• It is a non-sulfonamide loop diuretic and quinethazone.
• Used for diuresis in patients allergic to sulfa
drugs Potassium-Sparing Diuretics
• More ototoxic than other loop diuretics Mechanism of action:
They can be pteridine derivatives (amiloride and
Clinical uses: triamterene) or aldosterone antagonists (spironolactone and
• Edematous disorders including congestive heart eplerenone). Both work on the cortical collecting duct.
failure, hepatic cirrhosis, and nephrotic syndrome Amiloride and triamterene inhibit the epithelial Na
• Renal insufficiency channel, whereas, spironolactone and eplerenone block
• Hypertension in kidney disease aldosterone receptors.
• Hypercalcemia (because they increase calcium
excretion) Clinical uses:
• Hyponatremia Amiloride and triamterene:
• SIADH • Hypertension with potassium or magnesium loss
• Renal tubular acidosis • Liddle’s syndrome
Spironolactone and eplerenone:
Side effects: (OHH DAANG!) • Primary aldosteronism
• Ototoxicity • Hypertension with potassium or magnesium loss
• Hypokalemia • Secondary hyperaldosteronism as in congestive
• Hypomagnesemia heart failure, hepatic cirrhosis and nephrotic
• Dehydration syndrome
• Allergy to sulfa component • Resistant hypertension
• Alkalosis
• Nephritis (interstitial) Side effects:
• Gout • Hyperkalemia which can lead to arrhythmias
• Spironolactone can cause endocrine disturbances
Thiazide Diuretics which can result in gynecomastia and other
Thiazides: antiandrogenic effects
Mechanism of action:
Inhibit NaCl co-transporter in the distal convoluted tubule Diuretics and Electrolyte Disturbances
Diuretic class Urine Urine K Blood pH Urine Ca
which decreases NaCl reabsorption. Examples include NaCl
hydrochlorothiazide, chlorothiazide, Bendroflumethiazide, Mannitol Increases Slightly --- ---
and trichlormethiazide. They decrease the diluting capacity increase
of the nephron and decrease calcium excretion in urine. Acetazolamide Increases Slightly Acidemia ---
increase
Loop Increases High loss Alkalemia Increases
Clinical uses: Thiazides Increases High loss Alkalemia Decreases
K-sparing Increases --- Acidemia ---
• Hypertension
• Hypercalciuria • Acetazolamide results in acidemia by inhibiting
carbonic anhydrase and decreasing bicarbonate
• Nephrogenic diabetes insipidus
reabsorption
• Mild edema

707
 • Potassium-sparing diuretics that block Angiotensin II receptor blockers such as losartan,
aldosterone receptors prevent potassium and candesartan and valsartan selectively block the binding of
hydrogen secretion angiotensin II to AT1 receptors. They have similar effects
• Loop and thiazide diuretics result alkalemia by to ACE inhibitors, but they do not inhibit the inactivation
the following mechanisms: of bradykinin, hence do not increase bradykinin.
o Volume contraction which increases
angiotensin II → increases Na/H Clinical uses:
exchange in PCT → increases • Same as ACE inhibitors in patients who are
bicarbonate reabsorption intolerant to ACE inhibitors because of cough or
o They induce hypokalemia which angioedema
activates H/K exchanger in all cells and Side effects:
hydrogen enters cells
• Hyperkalemia
ACE Inhibitors, ARBs and Renin Inhibitors • Decrease GFR (better to be avoided in bilateral
ACE Inhibitors: renal artery stenosis)
Mechanism of action: • Hypotension
Angiotensin converting enzyme (ACE) inhibitors produce • Teratogenic
vasodilation by inhibiting the formation of angiotensin II. Renin Inhibitors:
Mechanism of action:
Angiotensin I is formed from angiotensinogen in the
presence of renin. Angiotensin I is converted to angiotensin Aliskiren is a direct renin inhibitor that blocks the
II by ACE. ACEis inhibit this latter step. conversion of angiotensinogen to angiotensin I.

ACE inhibitors decrease GFR by preventing constriction of Clinical uses:

efferent arterioles. Renin level increases because of the loss
• Hypertension
of negative feedback. Inhibition of ACE also prevents the
Side effects:
inactivation of bradykinin, a potent vasodilator.
• Hyperkalemia
Examples include captopril, enalapril, lisinopril, ramipril
and perindopril. • Decrease GFR
• Hypotension
Clinical uses: • Angioedema
• Relatively contraindicated in patients taking ACE
• Hypertension inhibitors or ARBs
• Heart failure (decrease mortality, prevent heart • Contraindicated in pregnancy
remodeling and hypertrophy due to hypertension)
• Proteinuria (helpful in diabetic nephropathy
because it decreases intraglomerular pressure
which slows GBM thickening)
Side effects: (CATCHH)

• Cough and Angioedema due to increased

bradykinin (contraindicated in C1 esterase
inhibitor deficiency because of the inherited risk
of angioedema)
• Teratogenic and can cause fetal renal
malformations
• Elevate Creatinine
• Hyperkalemia
• Hypotension
• Used with caution in bilateral renal artery stenosis
→ further decrease GFR → renal failure

ARBs
Mechanism of action:

708
 Chapter 15:

Fluids and Electrolytes

709
Fluid and electrolytes introduction 10% is the citrate/phosphate bound
Normal body fluid compartments
Male total body water = 60% of the body weight Causes
Female total body water = 50% of the body weight Hyperparathyroidism is the most common cause
The body fluid is divided into two compartments: Neoplasms are second most common cause e.g. small cell
1. Intracellular fluid compartment (2/3 of total body carcinoma of lung
water) Calcium intake
2. Extracellular fluid compartment (1/3 of total body Hyperparathyroidism/ hyperthyroidism
water) Iatrogenic i.e. thiazide diuretic
Extra cellular fluid compartment is further divided into Mumps
interstitial compartment (3/4 of extracellular fluid) and Paget’s disease of the bone
blood vessels (1/4 of extracellular fluid) Acidosis
Neoplasm
Zollinger-Ellison syndrome
Total body fluids
plasma
Excess vitamin D
Excess vitamin A
8% Sarcoidosis
Interstitial
25%
Intracellul Clinical features
ar CNS: Altered mental status, lethargic and confusion
67% Renal: Nephrolithiasis, diabetes insipidus
GI: Constipation, pancreatitis
Intracellular Interstitial plasma CVS: tachycardia, decreased QT interval

Treatment and management

Normal input of water IV fluids
Total average input of water = 2000ml Diuretics i.e. furosemide
1500ml oral intake + 500ml solids = 2000ml Bisphosphonates
Calcitonin
Normal output of water
Urine output = 800-1500ml Hyperkalemia
Stool output = 250ml Definition
Minimum urine output should be 500-600 ml per day. Increase serum potassium levels i.e. more than normal 3.5-
5.0 mEq/L is hyperkalemia.
Insensible water loss
Total insensible water loss is 600-900 ml. Etiology
Sweating (varies according to external environment and Acute/chronic renal failure
occupation) Spurious causes:
Fever (for every 1 degree raise in temperature above 37 Lab errors
degree Celcius there is 100ml/day water loss.) Hemolysis in the test tube
Hyperventilation (carbon dioxide and water are excreted) Thrombocytosis
Leukocytosis
Assessment of fluid volume Prolong tourniquet
Dry mucous membranes and poor skin turgor Redistribution of potassium:
Input/output Metabolic acidosis results in exchange of hydrogen ions
Urine output (normal output 1ml/kg/hour) with potassium
Insulin deficiency especially in diabetes mellitus
Hypercalcemia Drugs i.e. digitalis, beta blockers, succinylcholine
Definition Rhabdomyolysis
Hypercalcemia is the elevated calcium level in the blood. GI bleed
Normal metabolism of calcium Conditions causing low aldosterone level
80% of ingested calcium is removed in the feces Hyporennin hypoaldosteronism syndrome
2% of calcium is reabsorbed Addison’s disease
Out of all the calcium levels in the blood: ACE inhibitors
50% is free calcium ion in the plasma
40% is the protein bound calcium Clinical features
710
The clinical features start appearing when potassium levels
are more than 6 mEq/L and include Hypernatremia
Arrhythmia Definition
Muscle weakness, paralysis, Elevated amount of sodium inside blood i.e. more than
Decreased deep tendon reflex normal 135-145 mEq/L is called hypernatremia.
Respiratory failure
Diarrhea Causes
Nausea Too much infusion containing sodium ions
Vomiting
Eating too much salty food
Treatment Underlying pathology
Calcium gluconate, calcium chlodride are given. But it
increases digitoxin toxicity Types of hypernatremia
Beta agonist i.e. albuterol There are three types of hypernatremia:
Insulin with glucose
Kayexalak, a sodium-potassium resin 1. Hypovolemic hypernatremia
Dialysis 2. Isovolemic hypernatremia
3. Hypervolemic hypernatremia
Hypovolemic Isovolemic Hypervolemic
Hypokalemia hypernatremia hypernatremia hypernatremia
Definition
Potassium levels of less than normal 3.5-5.5 mEq/L is There is water loss Normal water level There is gain of water
Renal loss i.e. Diabetes insipidus is Iatrogenic cause i.e.
termed as hypokalemia. diuretics, diabetes common cause infusion of sodium
bicarbonate
Causes of hypokalemia Extrarenal loss i.e. Insensible respiratory Cushing syndrome
diarrhea, diaphoresis loss i.e. tachypnea
Renal losses: Exogenic steroids
Normally, 90% of potassium is excreted through kidneys. Primary
The excess potassium is excreted by the kidneys in cases of hyperaldosteronism
diuretics (furosemide, thiazide), renal tubular acidosis,
hyper aldosteronism, hypomagnesemia, Batter’s syndrome
Clinical features
Extra renal losses (GI loss):
CNS effects are altered mental status, focal neurologic
Diarrhea
deficits, seizures, confusion leading to coma
Vomiting
Laxatives Tissue effects are dry, thick mucus membranes, thick
Other causes saliva
Poor diet intake
Insulin Diagnosis
Profuse sweating Urine output should be monitored for renal functions
Antibiotics I.e. gentamicin, cisplatin, penicillin,
theophylline and epinephrine Urine osmolality may be greater than 380 mOsm/L
Desmopressin test for differentiating between central and
Clinical features
nephrogenic diabetes
Arrhythmia
Muscle weakness, fatigue, paralysis or cramps Treatment and management
Worsen digitalis toxicity Hypovolemic Isovolemic Hypervolemic
hypernatremia hypernatremia hypernatremia
Diagnosis
Serum electrolytes
Urine potassium concentration Give isotonic NS Give vasopressin Give diuretics i.e.
furosemide

Treatment Stop diuretics Diabetes insipidus 5% dextrose water

Treating the original cause of hypokalemia will cure the patients are treated by
this drug
patient
Oral KCl is given in patients with moderately low Control diabetes Oral fluids
potassium level
5% dextrose water
IV KCl is given in severely hypokalemic patients with
great care
711
Complication Renal symptoms include oliguria, anuria
Rapid correction of hypernatremia will lead to cerebral
edema. Rate of sodium correction should not exceed > 12
mEq/L or less than 8 mEq/L. Diagnosis
Calculate plasma osmolality by using formula:
Hyponatremia 2 Na + glucose/18 + BUN/2.8 (normal range 280-295)
Definition If plasma osmolality is normal or greater than 295 then the
Low sodium level in the blood is hyponatremia i.e. less patient must have elevated glucose or BUN.
than 135 mEq/L If plasma osmolality is less than 280 then the patient is
Symptoms of hyponatremia appear when sodium level is truly hyponatremic hypo osmolar
less than 120 mEq/L Urine osmolality
If urine osmolality is less than normal, then person is
Approach to hyponatremia having primary polydipsia.
Before going in detail of hyponatremia, one should be well If urine osmolality is greater than normal, then the person
aware of plasma osmolality. is suffering from SIADH, dehydration, hypothyroidism or
Plasma osmolality = 2(Na) + Glucose/18 + BUN/1.8 CVS failure.
(Normal = 280-295 mOsm/L)
According to the above formula, the plasma osmolality can Treatment and management
be affected by sodium, glucose or blood urea nitrogen In isotonic hyponatremia (pseudohyponatremia), just treat
levels the underlying cause i.e. multiple myeloma and
triglyceridemia
If the person is suffering from hyponatremia, then he may In hypertonic hyponatremia, there is elevated glucose level.
have normal, high or low osmolality depending on the So giving insulin along with fluids and potassium should
aggregate of all the three basic factors. treat the patient.
In hypertonic hyponatremia (plasma osmolality greater In true hyponatremia, there are three cases:
than 295), there is increased level of glucose, sorbitol or If sodium levels are between 120-130, then holding the
mannitol in the blood and they attract greater amount of free water will cure the patient
water. Thus hyponatremia ensues. If sodium levels are between 110-120, then normal saline
with loop diuretic will cure the patient
In pseudo hyponatremia (normal plasma osmolality If sodium levels are below 110, then IV hypertonic
between 280-295), there are elevated plasma proteins solution will cure the patient. The hypertonic solution
(multiple myeloma), hypertriglyceridemia i.e. more than should be given at the rate of 1-2 mEq per hour. If IV fluid
1000 mg/dl or excess of D5W i.e. 5% Dextrose water. rate is much faster than recommended dose, the brain will
suffer from a condition called “central pontine
In true hyponatremia (plasma osmolality less than 280), demyelination”.
this low level of sodium may be associated with
hypervolemia, hypovolemia or normal volume. The causes Hyponatremia
of hypervolemia are congestive heart failure, Definition
nephrolithiasis and cirrhosis. The cause of hypovolemia is Low sodium level in the blood is hyponatremia i.e. less
mainly renal excretion of sodium as in diuretics, poisoning than 135 mEq/L
and acute tubular necrosis. There are conditions, in which Symptoms of hyponatremia appear when sodium level is
urine secretion of sodium is low i.e. less than 10, like less than 120 mEq/L
diarrhea, vomiting and third spacing. In patients with
normal plasma volume, there can be SIADH, Symptoms and signs
hypothyroidism, psychogenic polydipsia or post operation. CNS symptoms are predominant due to cerebral swelling,
edema which manifest themselves in the form of headache,
Symptoms and signs delirium, irritability, hyperactive deep tendon reflex,
CNS symptoms are predominant due to cerebral swelling, weakness, muscle twitching and raised intra cranial
edema which manifest themselves in the form of headache, pressure culminating into seizures and coma.
delirium, irritability, hyperactive deep tendon reflex, CVS symptoms include hypertension due to raised intra
weakness, muscle twitching and raised intra cranial cranial pressure
pressure culminating into seizures and coma. GI symptoms may include nausea, vomiting
CVS symptoms include hypertension due to raised intra Renal symptoms include oliguria, anuria
cranial pressure
GI symptoms may include nausea, vomiting

712
Diagnosis Pulmonary edema
Calculate plasma osmolality by using formula: Peripheral edema
2 Na + glucose/18 + BUN/2.8 (normal range 280-295)
If plasma osmolality is normal or greater than 295 then the Physical examination
patient must have elevated glucose or BUN. Pulmonary rales
If plasma osmolality is less than 280 then the patient is Elevated central venous pressure and pulmonary capillary
truly hyponatremic hypo osmolar wedge pressure
Urine osmolality Diagnosis
If urine osmolality is less than normal, then person is Decreased hematocrit
having primary polydipsia. Low albumin especially in cirrhosis and nephrotic
If urine osmolality is greater than normal, then the person syndrome
is suffering from SIADH, dehydration, hypothyroidism or
CVS failure. Treatment and management
Fluid restriction
Treatment and management Loop diuretic i.e. furosemide
In isotonic hyponatremia (pseudohyponatremia), just treat Monitor urine output and weight of the patient till complete
the underlying cause i.e. multiple myeloma and recovery
triglyceridemia
In hypertonic hyponatremia, there is elevated glucose level. Hypovolemia
So giving insulin along with fluids and potassium should Definition
treat the patient. Less than normal body fluid volume of 60% is called
In true hyponatremia, there are three cases: hypovolemia.
If sodium levels are between 120-130, then holding the
free water will cure the patient Causes
If sodium levels are between 110-120, then normal saline • Inadequate drinking
with loop diuretic will cure the patient • Vomiting
If sodium levels are below 110, then IV hypertonic • Diarrhea
solution will cure the patient. The hypertonic solution • Small bowel obstruction
should be given at the rate of 1-2 mEq per hour. If IV fluid • NG tube suction
rate is much faster than recommended dose, the brain will • Diabetic ketoacidosis
suffer from a condition called “central pontine
• Third spacing i.e. effusions, ascites and burns
demyelination”.
• Skin (75% water)
• Lungs (25% water)
Hypervolemia
Definition • Trauma i.e. hemorrhage, open wounds
Increased total body volume i.e. more than 60% is called
hypervolemia. Clinical presentation
• Central nervous system effects
Causes • Cardio vascular effects i.e. Low blood pressure,
Parenteral over hydration tachycardia, feeble but rapid pulse, orthostatic
Cirrhosis hypotension
Renal failure • Poor skin turgor i.e. dry skin
Congestive heart failure • Oliguria i.e. low urine output
• Acute renal failure
Pathophysiology
The pathophysiology behind congestive heart failure, Diagnosis
cirrhosis and renal failure is the decreased renal perfusion • Urinary output measurement
which activates the rennin-angiotensin-aldosterone • Daily weight
pathway. Aldosterone reserves the sodium which attracts • Central venous pressure
water into the extra cellular fluid compartment and thus • Pulmonary capillary wedge pressure
makes the serum hypervolemic. • Serum sodium level (elevated)
• Urinary sodium level (decreased)
Clinical features • Hematocrit is usually raised up to 3%
Weight gain
Jugular venous distention Treatment
Ascites
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 • Correct volume of blood using normal saline, • The intracellular concentration of potassium is
ringer lactate very high but we are concerned with extracellular
• Maintain urine output 0.5-1 ml/kg/hr potassium i.e. 3.5-5 mEq/dL
• Maintenance fluid should be given comprising of
Dextrose 50g, 0.45% normal saline and add 20 Functions of potassium
mEq potassium chloride. • Cardiac rhythm i.e. SA node, Purkinje fibers, AV
node
Osmolality and tonicity • Cellular function
Osmolality • Neurovascular transmission
The total amount of solute in fluid compartment is called
osmolality. Sources
• Diet
The important solutes are sodium, glucose and urea.
• Skeletal muscles (lysis of muscles)
According to formula: • RBCs (lysis of RBC)
• GI bleed
Osmolality = 2(Na) + Glu/18 = BUN/2.8 • KCl injection
The normal serum osmolality ranges from 280-295.
Potassium excretion
From the above equation it is quite clear that sodium is the • 90% potassium is excreted through kidneys
main component which determines plasma osmolality. • 10% potassium is excreted in feces
Glucose also affects the osmolality e.g. in hyperglycemia,
the excess glucose draws more and more blood into the Potassium regulation
extracellular fluid from intracellular fluid. The intracellular • Thick ascending loop of Henle bears NaK2Cl
fluid moves out of the cell and is responsible for transporter that reabsorb most of the sodium,
polydipsia. Urea, on the other hand, has ability to move potassium and chloride.
freely inside and outside of the cell. So it has less effect on • Collecting tubules are acted upon by aldosterone.
the plasma osmolality. Aldosterone helps in reabsorption of sodium
while excreting potassium into the lumen of
Tonicity tubules.
The combined effect of solutes in extra cellular
compartment to cause water to move from one Factors increasing potassium excretion
compartment to another compartment across the semi • Increased aldosterone i.e. hyperaldosteronism
permeable membrane. • Increased delivery of sodium to collecting ducts
For example, if sodium concentration in the blood is i.e. diuretics furosemide, hydrochlorothiazide
increased then plasma osmolality is also raised and the • Metabolic alkalosis i.e. greater amount of
solution is hypertonic. This solution has tendency to draw bicarbonates draw more sodium with it delivers
more and more water from the intracellular fluid the excess of sodium to the collecting ducts
compartment into the extracellular fluid compartment.
DKA diabetic ketoacidosis patients have polyuria. As more
In contrast, if sodium concentration is decreased then and more water is excreted out, there is dehydration and
plasma osmolality is also decreased and the solution if decreased perfusion of the glomerulus. Thus, rennin-
hypo tonic. This solution has tendency to move into the angiotensin system is activated, and aldosterone
intracellular compartment and causing swelling of the cell. concentration is increased which act on collecting tubule.
Sodium and Water regulation
Isotonic solution has equal concentration of solutes in the Role of kidneys
intracellular and extracellular fluid compartment. • Glomerulus has afferent and efferent capillaries
producing GFR (glomerular filtration rate).
Potassium regulation
Location • Proximal convoluted tubules reabsorb most of the
sodium.
• Potassium is present inside the cells. It is most
common cation present in human cells. Sodium- • Thick ascending loop of Henle absorb sodium
potassium ATPase pump is responsible for actively.
maintaining the high quantities of potassium • Distal convoluted tubule reabsorb remaining
within the cell. sodium.

714
 • Collecting tubules are under direct influence of
aldosterone which reabsorb more amount of
sodium in the ECF.

Water reabsorption
• Water moves according to the levels of sodium.
Where sodium is present in higher quantities, it
draws more and more water. Thus, sodium
determines the extracellular fluid compartment.

Sodium reabsorption
• Sodium determines the amount of extracellular
fluid.
• When there is hypervolemia, there is increased
sodium levels in the extracellular fluid. The
causes are parenteral over hydration, cirrhosis,
renal failure and congestive heart failure
• When there is hypovolemia, there is decreased
sodium levels in the extracellular fluid. The
causes are inadequate drinking, vomiting,
diarrhea, small bowel obstruction, NG tube
suction, diabetic ketoacidosis, third spacing i.e.
effusions, ascites and burns.

Sodium regulation
• Juxtaglomerular apparatus
• Volume receptors
• Sympathetic nervous system

Water regulation
• The water is regulated by the factors that are
shown in the following equation
• Osmolality = 2 Na + Glucose/18 + BUN/2.8
• When plasma osmolality is >295, then
hypothalamus stimulates the thirst center.

715
 Chapter 16:

Reproductive system

716
Male reproductive anatomy • Epididymis
Major component of male reproductive system • Vas deferens
• Ejaculatory ducts
• Urethra
• Penis
Erection
• Erection is caused by dilation of the blood vessels
(a parasympathetic response) in the erectile tissue
of the penis (the corpora- and ischiocavernous
sinuses).
A. Testis
B. Epididymis, Release of Nitric
C. Ductus deferens oxide (NO)
D. Ejaculatory duct on each side
E. Urethra cGMP
F. penis in the midline
Smooth muscle
• Three types of accessory glands are associated relaxation
with the system:
A. A single prostate
Vasodilation
B. A pair of seminal vesicles
C. A pair of bulbourethral glands
Piloerection
How the sperm is ejected
Testis
• After ejaculation, the penis returns back to its
normal state through NE release

Release of NE

Increase
• Testis has ellipsoid-shaped intracelleular Ca+2
• Testis develop in the abdomen and move before
birth into the scrotum
• Covered by a closed sac of peritoneum called Contraction of
smooth muscle
tunica vaginalis
• The testis is also surrounded by a dense fibrous
capsule called the tunica albuginea. Back to normal
• The tunica albuginea is continuous with many of state
the interlobular septa that Emission
• divide the testis into approximately 250 • Emission is the movement of semen from the
pyramidal compartments (testicular epididymis, vas deferens, seminal vesicles, and
• lobules). prostate to the ejaculatory ducts.
• Within each lobule are 1-4 tubes, seminiferous • The movement is mediated by sympathetic
tubules, where spermatozoa are produced. adrenergic transmitters and hypogastric nerve
• The tubules open into a network of channels • During emission, smooth muscle contractions by
called rete testis the vas deferens and ejaculatory ducts push sperm
• The seminiferous tubules contain spermatogenic into the prostatic urethra.
cells, Sertoli cells, and a well-defined basal Ejaculation
lamina. • Ejaculation is caused by the rhythmic contraction
of the bulbospongiosus and the ischiocavernous
• Pathway of sperm during ejaculation (Seven up): muscles, which surround the base of the penis.
• Seminiferous tubules

717
 • Contraction of these striated muscles that are
innervated by somatic motor nerves causes the
semen to exit rapidly in the direction of least
resistance, i.e., outwardly through the urethra.
• Pundendal nerve is responsible for ejaculation
Seminiferous tubules
Spermatogonia

• Endocrine interstitial cells responsible for

testosterone production under the control of LH

Spermatogenesis
Spermatogenesis
• Production of sperm
• spermatogonia differentiate into primary • Take place in testis (Seminiferous tubules)
spermatocytes that enter meiosis.
• Begins at puberty (age 11 to 15)
• Location: The stem cells (spermatogonia) are
adjacent to the basement membrane. As the cells
develop, they move from the basal to the luminal
side of the tubule.

Sertoli Cells
• Non dividing cells, irregular in shape
• Secrete androgen-binding protein that binds • At week 4, primordial germ cells arrive in the
testosterone and dihydrotestosterone. indifferent gonad and remain dormant until
• The production of androgen-binding protein is puberty.
stimulated by follicle-stimulating hormone (FSH • When a boy reaches puberty, primordial germ
receptors are on Sertoli cells). cells differentiate into type A spermatogonia
• These hormones are essential for normal germ- (Diploid, 2 N.), which serve as stem cells
cell maturation. throughout adult life.
• Secrete inhibin, which suppresses FSH synthesis. • Some type A spermatogonia differentiate into
• Produce anti-Müllerian hormone during fetal life type B spermatogonia.
that suppresses the development of female • Type B spermatogonia enter meiosis I to form
internal reproductive structures. primary spermatocytes (Diploid, 4 N.)
• Provide nutrition to the developing spermatozoa. Note: Failure of meiosis I results in primary
• Sertoli cells are tall columnar epithelial cells. spermatocyte accumulation.
Most common cells in seminiferous tubules • Primary spermatocytes form 2 secondary
before puberty spermatocytes (Haploid, 2 N.).
• At puberty, Sertoli cells form tight junctions with • Secondary spermatocytes enter meiosis II to
each other, creating the basal and adluminal form 2 spermatids.
compartment and the blood-testis barrier. • Spermatids undergo spermiogenesis, which is a
• The blood testis barrier protects the maturing series of morphological changes resulting in the
sperms from autoimmune attack mature spermatozoa.
• Temperature sensitive: Increase temperature Meiosis
decreases sperm production and decreases release • Cell division that produces the male and female
of inhibin gametes during spermatogenesis and oogenesis,
Leydig cells respectively.
• Meiosis consists of 2 cell divisions: meiosis I and
meiosis II.
A. In meiosis I, the events include synapsis,
exchange of DNA, and disjunction, resulting in a
reduction from 46 to 23 chromosomes.

718
 B. In meiosis II, there is a reduction of DNA from
2n to 1n.

Sperm structure

Types of androgens
• Spermatids undergo spermiogenesis, which is a
series of morphological changes resulting in the
mature spermatozoa.
• Differentiation process involves formation of the
acrosome, condensation, and elongation of the
nucleus; development of the flagellum; and loss 1. Testosterone (produced by testis)
of much of the cytoplasm 2. Dihydrotestosterone (produced by testis)
• The head of a mature sperm contains chromatin 3. Androstenedione (produced by adrenal gland)
and acrosomal enzymes needed for penetration of
the ovum’s outer zona pellucida. • Potency: Dihydrotestosterone>Testosterone>
• The midpart of the sperm contains Mitochondria Androstenedione
for ATP production • Testosterone is further converted by 5-α-
• The tail contains specialized cilia for efficient reductase into dihydrotestosterone and inhibited
transport. by Finasteride
• Impaired tail mobility leads to male infertility
(Common in Kartagener syndrome/ ciliary Finasteride
dyskinesia) • 5-Alpha reductase inhibitor, preventing
• Kartagener syndrome is characterized by conversion of testosterone dihydrotestosterone
immotile spermatozoa and infertility. It is due to (DHT)
an absence of dynein that is required for flagellar Clinical uses:
mobility. It is usually associated with chronic • Benign prostate hyperplasia (BPH)
respiratory infections because of similar defects • Male pattern baldness
in cilia of respiratory epithelium Benign prostatic hyperplasia (BPH) characterized by:
• Decreased caliber and force of stream
Hormonal control of testicular function • Trouble starting (hesitancy)/stopping the stream
• Hypothalamus release FSH, LH • Postvoid dribbling
• LH stimulate Leydig cells to release testosterone • Urinary retention
• Testosterone diffuses into Sertoli cells (high • Incontinence
concentration) and into the blood • Urgency/frequency
• Circulating testosterone provides negative • Nocturia/dysuria
feedback to regulate LH secretion • Possible elevation in prostate specific antigen
• FSH will stimulate FSH receptors on Sertoli cell (PSA) but usually <10 ng/mL
to release androgen binding protein that binds
testosterone and dihydrotestosterone. TESTOSTERONE DHT
• Sertoli cells secrete inhibin B, which produces FUNCTION -Deepening of voice -Sexual differentiation:
-Libido differentiation to form male
feedback regulation on FSH -Bone mass external genitalia
-Fat distribution -Growth of the prostate
-Muscle size and -Male-pattern baldness
strength -Increased activity of sebaceous
-Red blood cell glands
production -Synthesis of NO synthase in
-Differentiation of penile tissue
epidermis, vas
deferens, seminal
vesicles

719
 -Closing of • The cycle is divided into a follicular phase
epiphyseal plates
(via estrogen (before ovulation) and a luteal phase (after
converted from ovulation)
testosterone). Follicular phase (Day1-14)

• Leydig cells express aromatase, which aromatizes

testosterone into estradiol, an important hormone
for growth and maturation of the sperm.
• Aadministration of exogenous testosterone
decreases LH, FSH, and testicular synthesis of
testosterone due to inhibition of hypothalamic-
pituitary gonadal axis (Azoospermia)

Female reproductive cycle

Overview

• This phase of the menstrual cycle occurs from

approximately day 1-14
• Day 1 is the first day of bright red bleeding (last
for 5 days om average), and the end of this phase
is marked by ovulation
• Once the bleeding stops, the endometrium begins
to prepare for the possibility of a pregnancy
• The uterine lining becomes thicker and enriched
in blood and nutrients
• During the follicular phase, FSH secretion is
Oogenesis slightly elevated, several follicles to rise on the
• Growth process in which the primary egg cell (or surface of the ovary
ovum) becomes a mature ovum. • The maturing follicle produces the hormone
• The primary ova remain dormant until just prior estrogen, which increases over the follicular
to ovulation, when an egg is released from the phase and peaks in the day or two prior to
ovary ovulation (Estrogen levels gradually increases
and maximize at 12thday)
• Estrogen stimulate endometrium repair and
proliferation. It also stimulates Ovulation
• High estrogen levels stimulate the release of LH
• On about day 12, surges in LH and FSH cause the
egg to be released from the follicle.
Ovulatory phase (Day 14)
• Around day 14, an egg is released from one of the
ovaries (Due to surge in LH and FSH over the
previous day) and begins its journey down the
fallopian tubes to the uterus.
Ovarian cycle (Menstrual cycle) • Fertilization can occur If sperm are present in the
• It is a series of cyclic changes occurring in the fallopian tube
reproductive tract of female with the periodicity • In this case the fertilized egg is released, the
of 28 days follicle seals over and this is called the
• It occurs from puberty to menopause corpus luteum.
• The first day of bleeding (menses) is called day 1 Luteal phase (Days 14-28)
of the menstrual cycle. • The luteal phase refers to the corpus luteum,
• It is characterized by loss of vaginal blood which forms from the follicle once the oocyte has
(breaking of endometrium wall of uterus) been expelled.
• The cycle is under Influenced of hormones • The corpus Luteum secretes Progesterone to
secreted by pituitary gland (FSH and LH), and stimulate thickening of endometrium wall
ovary (progesterone and estrogen).
720
 • Corpus luteum secrete high level of progesterone
to inhibit maturation of any other follicles
• If fertilization has not occurred, the corpus
luteum disintegrates, which causes progesterone
levels to drop and signals the endometrial lining
to begin shedding

Klinefelter syndrome (47, XXY)

Pathophysiology
• Klinefelter syndrome (XXY aneuploidy) is the
most common human sex chromosome disorder
• Neonates develop normal phenotype; signs occur
• Approximately 1 in 80 males is born with an at puberty:
extra X chromosome.
• Testicular atrophy
• Male with extra X chromosome
• Tall, long extremities
• The extra chromosome is retained because of a
• Infertility
nondisjunction even during meiosis I
• Gynecomastia
(Gametogenesis)
• Female distribution of hair
• Nondisjunction occurs when homologous
chromosomes fail to separate • Low testosterone
• Elevated FSH and LH
• Hyalinization and dysgenesis of the seminiferous
tubules leads to: • High-pitched voice
• Presence of inactivated chromosome
Decreased inhibin
Turner Syndrome (45, XO)
Overview
Decrease FSH

Testicular atrophy firm rubbery

testicles

Oligospermia
• The common cause of female hypogonadism.
Infertility • Primary cause of amenorrhea is turner syndrome
• Develop abnormal Leydig cell function leads to: • Females with 45, X/46,XY mosaicism are at risk
for Gonadoblastoma, microdeletions
Decreased Testosterone
Pathophysiology
• The second missing X chromosome is necessary
for oogenesis and normal development of the
Increase LH ovary
• Lack paternal X chromosome loss of follicles by
Clinical presentations age of 2
• Mitotic error in early development, Mosaicism
• Loss of follicles decreases estrogen levels that
lead to increase FSH and LH levels
• Decrease estrogen levels negatively affect
ovulation and eventually lead to infertility

Functions of estrogen:
• In fallopian tubes: estrogen is responsible for the
growth of a thick, muscular wall in the fallopian

721
 tubes, and for the contractions that transport the Androgen insensitivity syndrome
egg and sperm cells. Overview
• In uterus: estrogen enhances and maintains the
mucous membrane that lines the uterus.

Lack of estrogen

No endometrial proliferation no shading /amenorrhea

(absence of menstruation)

• Note: Genetic mosaicism is defined as a condition

in which there are cells of different genotypes or • Testosterone is the main androgen hormone
chromosome constitutions within a single responsible for male sexual development
individual. • In men, LH stimulates production of:
• Some women with Turner syndrome have A. Testosterone by the Leydig cells in the testis
somatic cells that are 45, X and others that are 46, B. Androgen-binding protein (ABP) by the Sertoli
XX or 47, XXX cells of the testis
Pathophysiology
Clinical presentations • Occurs when a fetus with a 46, XY genotype
• Short stature • Known as testicular feminization syndrome
• Ovarian dysgenesis (“streak” gonads, which are
nonfunctional, causing sterility and lack of Complete absence of testosterone receptors in
estrogen and sexual infantilism). the target tissue in the body (may be due to a
• Edema of wrists and ankles in newborn mutation)
• Cystic hygroma in utero resulting in excess
nuchal skin and “webbed” neck
Increase LH (Lack of negative feedback inhibition to HPA
• Primary amenorrhea
axis)
• Congenital heart disease (preductal coarctation
of the aorta and bicuspid aortic valve)
• Infertility Increase testosterone
• Newborn girls showed swollen hands and feet • Increase peripheral conversion of testosterone to
because of lymphedema estrogen lead to development of a normal-
• Horseshoe kidney appearing female with female external genitalia
• No barr body detected • Normal FSH levels
• Normal conditions Clinical presentations
• Male = No barr bodies are seen.
• Female = Barr body is positive.

• Individuals present as normal-appearing females,

and their psychosocial orientation is female
despite their genotype.
• Male develops testes and female external
genitalia with a rudimentary vagina; the uterus
and uterine tubes are generally absent
• Testis may be found in the labia majora and are
surgically removed to circumvent malignant
tumor formation.
• Scant axillary and pubic hair

722
 • Tests in abdominal wall produce testosterone but • Due to normal testosterone levels during
no spermatogenesis childhood, meanwhile, the body unable to convert
testosterone to DHT which is important in
5α-reductase deficiency (46, XO) developing male external genitalia and
Overview masculinization
• During puberty, the high level of testosterone
enhances the masculinization and restore of male
appearing phenotype

Clinical presentations
• Internal genitalia are normal (The epididymis,
ductus deferens, seminal vesicle, and ejaculatory
duct
• Underdevelopment of external genitalia (the penis
Functional comparison between testosterone and and emission of sperm and prostate)
dihydrotestosterone (DHT) • Testosterone/estrogen levels are normal; LH is
normal or increase
TESTOSTERONE DIHYDROTESTOSTERONE (DHT)
DEVELOPMENT OF Development of External genital
INTERNAL GENITAL organs: Kallmann´s Syndrome
ORGANS (Penis, scrotum and prostate) Overview
(DIFFERENTIATION OF
EPIDIDYMIS, VAS
• Congenital hormonal condition characterized by
DEFERENS AND SEMINAL the failure of an individual to enter puberty
VESICLES) • Form of hypogonadotropic hypogonadism
EMBRYOGENESIS Later in puberty, enhances hair growth,
prostate enlargement and hair Other names for this condition:
recession
SPERMATOGENESIS
• Anosmic hypogonadism
INCREASE MUSCLE MASS • Anosmic idiopathic hypogonadotropic
AND RBC PRODUCTION hypogonadism
LIBIDO
DEEPENING OF VOICE • Hypogonadism with anosmia
• Hypogonadotropic hypogonadism-anosmia
Types of 5α-reductase enzymes: syndrome
• Type 1: postpubescent
• Type 2: genital organs Pathophysiology
• Several gene mutations associated with
Pathophysiology Kallmann´s syndrome result in disruption of the
migration of olfactory nerve cells and GnRH-
producing nerve cells in the developing brain

Decrease synthesis of GnRH in the hypothalamus;

hyposmia/anosmia

Decrease GnRH, FSH, LH, testosterone

• Autosomal recessive disorder affects male 46,

XY • Hyposmia: diminished the sense of smell
• Mutation in the 5α-reductase 2 gene that renders • Anosmia: complete absent of the sense of smell
5α-reductase 2 enzyme unable to convert
testosterone to dihydrotestosterone
• Deficiency in DHT production leads to:
o Phenotypically female-appearing males until
puberty, Why?

723
 • Results in a triploid cell 69, XXY, 69, XXY; 69,
XYY
Expect fetal parts (The embryo may develop for a
few weeks)
• High hcg levels
• Rare incidence of choriocarcinoma
• Risk less than 5%

Clinical presentations General clinical presentations

• Males born with hypogonadotropic 1. Excessive uterine enlargement (“size greater than
hypogonadism often have an unusually small dates”)
penis and undescended testes (cryptorchidism) 2. Vaginal bleeding
• Infertility due to low sperm count 3. Passage of edematous, grape-like soft tissue
• Amenorrhea in females 4. Elevated beta-human chorionic gonadotropin (β-
• At puberty, delayed development secondary sex hCG)
characteristics, such as the growth of facial hair
and deepening of the voice in males, and breast Treatment
development in females, and a growth spurt in • Evacuation of the uterus by uterine suction or by
both sexes. surgical curettage
• To avoid the risks of choriocarcinoma, patients
Hydatidiform mole are followed up until their (hCG) level has fallen
Overview to an undetectable level.
• Known as molar pregnancy = tumor of
gestational trophoblastic tissue (GTD) Partial Mole VS Complete Mole
• Rare mass or growth that forms inside the womb
(uterus) at the beginning of a pregnancy
• Women ages <15 and >40 are at increased risk.
• Results from abnormal fertilization of the oocyte
(egg)
• Molar pregnancy divided into 2 subtypes:
1. Partial molar pregnancy: There is an abnormal
placenta and some fetal development.
2. Complete molar pregnancy: There is an abnormal
placenta and no fetus.

Complete mole
• Results from fertilization of an ovum that lost all
of its Chromosomal material (2 sperms fertilize Pregnancy complications
an empty egg) Abruptio placentae
• All chromosomal material is derived from sperm, Pathophysiology
No chromosome from the mother • partial premature detachment of the placenta
• 90% of the time, the molar karyotype is 46, XX away from the endometrium, with resulting
• 10% of the time, the molar karyotype includes a hemorrhage and clot formation
Y chromosome 46XY Clinical presentations
• The embryo does not develop (No fetal parts)
• On ultrasound, there are grapelike vesicles and a
“snowstorm” appearance
• 20% chance of progressing to malignancy and 2%
risk of choriocarcinoma
• hCG will be elevated

Partial mole
• Results from fertilization of an ovum by 2 sperms
(2 sperms with one egg)
• Abrupt, painful bleeding in third trimester
724
 • Tetanic contractions
• Fetal distress
• The mother predisposed to disseminated
intravascular coagulation (DIC)
• Life threatening for mother and fetus.
Risk factors
• Trauma
• Smoking
• Hypertension
• Cocaine abuse
Placenta previa
Pathophysiology Retained placenta
• Occurs when a baby's placenta partially or totally • Commonly a cause of postpartum hemorrhage
covers the mother's cervix • Occurs when the placenta remains in the womb
and isn't delivered on its own naturally
• Attachment of placenta to lower uterine segment,
where the placenta overlies the cervical os
Ectopic pregnancy
Definition
• The implantation of a fertilized ovum outside of
the endometrial cavity,
• The most common site of ectopic pregnancy is
the fallopian tube, which accounts for 98.3% of
all ectopic gestations
• Tubal (most common form) usually occurs when
the blastocyst implants within the ampulla of the
fallopian tube because of delayed transport.

Clinical presentations
• Painless vaginal bleeding
Risk factors
• Prior caesarean section
• Multiparity
Placenta accrete
• The placenta implants directly in the myometrium
Pathophysiology
• Massive bleeding after delivery Implantation sites for ectopic pregnancy
• No separation of placenta after birth Risk factors
Risk factors • Prior ectopic pregnancy
• C-section • Endometriosis
• Inflammation • Pelvic inflammatory disease
• Previous Placenta previa • History of infertility
• Salpingitis (PID)
Note: Hysterectomy is required after delivery to remove • Ruptured appendix
the rest of the placenta. • Prior tubal surgery
• Smoking
• Advanced maternal age
• Intrauterine devices (IUDs) have been associated
with ectopic pregnancy

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Clinical presentations Other symptoms include
• Vaginal bleeding • Sudden and new swelling in your face, hands,
• Pelvic pain and eyes
• Adnexal mass. • Blood pressure greater than 140/90.
• Sudden onset of abdominal pain that may be • Sudden weight gain over 1 or 2 days
confused with appendicitis • Abdominal pain, especially in the upper right side
• Positive human chorionic gonadotropin test(hCG) • Severe headache
• Missed menstrual period (e.g., LMP 60 days ago) • Blurry vision
= amenorrhea Risk factors
• The mother is at risk for potentially fatal intra- • Preexisting hypertension
abdominal haemorrhage • Diabetes
• Intraperitoneal blood, and positive sonogram. • Chronic renal disease
• Autoimmune disorders
Note: Human chorionic gonadotropin (hCG): Can be Complications
assayed in maternal blood or urine and is the basis for early • Placental abruption
pregnancy testing • Coagulopathy
• Renal failure
Diagnosis • Pulmonary edema
• Serial measurements of β-hCG Clinical case
• Ultrasonography • G1P1 39 weeks week pregnant, 2 weeks
Treatment postpartum showed the following symptoms:
• Methotrexate o Severe onset headache
• Surgical intervention when rupture causes o Blurry vision
intraperitoneal hemorrhage o Abdominal pain
o Altered mental status
Hypertension in pregnancy o Facial edema and Lower extremities
Gestational hypertension o Hyperreflexia
• Known as pregnancy-induced hypertension o Mortality due to either acute respiratory distress
• No previous history of high blood pressure syndrome (ARDS)
• Blood pressure >140/90 mm Hg o Lab diagnosis reveals hyperuricemia
• Absence of proteinuria Treatment
• Are ≥20 weeks pregnant • Urgent delivery
Treatment • Treatment of hypertension
• Hydralazine • I.V Magnesium sulfate is given to prevent
• α-Methyldopa progression to eclampsia (Seizures)
• Labetalol • Note: untreated preeclampsia might predispose
• Nifedipine the patient to HELP syndrome or Eclampsia
Preeclampsia Eclampsia
• Preeclampsia (pregnancy induced hypertension) • Preeclampsia + maternal seizures
• The hypertension is defined as more than 140/90 • Treated by Magnesium sulfate to prevent seizures
mm Hg HELP syndrome
• Affects 7% of pregnant women • Help syndrome characterized by triad of
• Usually occurs after 20 weeks gestation and after symptoms:
6 weeks postpartum 1. Hemolysis
Pathophysiology 2. Elevated LFT
• Due to impaired vasodilation of spiral arteries 3. Low platelets
that lead to ↑ TPR and eventually ↑ BP Complications:
• Endothelial damage in glomeruli → GFR • Seizures
impaired→ renal failure • Stroke
Clinical presentations • Liver rupture
• Preeclampsia characterized by triad of symptoms: • Placental abruption (separation of the placenta
1. Hypertension from the wall of the uterus before the baby is
2. Proteinuria born)
3. Edema

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Cervical Pathology • Smoking
Cervical Carcinoma • STDs (including human papilloma virus)
• Most commonly squamous cell carcinoma • Immunosuppression
• Least common gynecologic malignancy.
• With peak incidence at ages 35–44. Ovarian tumor
• Complications: might progress to renal failure Types of Ovarian tumors
due to lateral diffusion
1. Ovarian germ cell tumors
Pap smear is an early detection method before 2. Epithelial (non-germ cell) tumors
progression to invasive carcinoma
Ovarian germ cell tumors
Cervical dysplasia Teratoma
• Cervical intraepithelial neoplasia (CIN) is • Most common cause 90% of ovarian teratomas
premalignant transformation of the normal • Benign tumor
columnar epithelium to squamous epithelium, and • commonly occurs in early reproductive years 10-
occurs commonly at the squamocolumnar 30 years old
junction • Include elements from all 3 germ cell layers:
• Cervical intraepithelial lesions show a ectoderm (skin, hair, adnexa, neural tissue),
progression of changes on histologic mesoderm (bone, cartilage), and endoderm
examination: (thyroid, bronchial tissue)
1. Low grade SIL (squamous intraepithelial lesion) • Struma ovarii is an ovarian tumor defined by the
2. High grade SIL presence of thyroid tissue comprising >50% of
3. Carcinoma in situ the overall mass
4. Superficially invasive squamous cell carcinoma • Differentiate easily
5. Invasive squamous cell carcinoma • Contain teeth, hair, sebum
• Immature teratomas are more likely to develop
into a malignant cancer, diagnosed before the age
20
• Increase T3, T4 hyperthyroidism
Choriocarcinoma
• Rare- Malignant
• It can happen after a miscarriage, abortion,
ectopic pregnancy, or molar pregnancy (when an
egg is fertilized, but the placenta develops into a
mass of cysts instead of a fetus)
• Type of gestational trophoblastic disease.
• Associated with IL-6
Clinical presentations • Metastasis to the lungs
• Typically, asymptomatic or may present with • High hCG levels
postcoital vaginal bleeding, dyspareunia, and/or Yolk sac tumor
malodorous discharge. • Malignant tumor of cells that line the yolk sac of
Diagnosis the embryo
• The Papanicolaou (Pap) test is useful for early • known as ovarian endodermal sinus tumor
detection, and colposcopy with biopsy for • Found in the ovary, testes, or the sacrococcygeal
microscopic evaluation. area
• More common in male infants
Risk factors • Characterized by Schiller-Duval body (distinctive
• HPV 16 and 18 (the highest risk of the HPV perivascular structure seen in the endodermal
types), which inactivate p53 and Rb tumor sinus pattern of yolk sac tumor)
suppressor genes • On gross pathology, these tumors have
• Early age of first intercourse a yellow, friable appearance, and hemorrhage is
• Multiple sexual partners common
• Multiple pregnancies • Associated with high levels of alpha-fetoprotein
• Oral contraceptive use (AFP) and human chorionic gonadotropin (HCG)

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Dysgerminoma Granulosa cell tumor
• Malignant tumor
• 1% in females and 30% males
• Risk factors: Turner syndrome
• High hCG and LDH levels

Epithelial (non-germ cell) tumors

Serous cystadenoma
• Most common benign ovarian tumor
• Bilateral
• Diagnosed microscopically as cyst with simple
epithelia with cilia
Serous cystadenocarcinoma
• The most common malignant ovarian tumor • Malignant tumor
• Shows psammoma bodies and a lining similar to • Defined as estrogen-producing tumor that can
that of the fallopian tube cause endometrial hyperplasia
• Bilateral • Characterized by Call-Exner bodies
Mucinous cystadenoma • Clinical presentation varies through the age:
• Large benign ovarian mass lined by mucous- 1. Prepuberal patients with juvenile granulosa cell
secreting cells tumor present with precocious puberty
2. Reproductive age patients present with irregular
• Tumor markers: CA-125, CEA
Mucinous cystadenocarcinoma menses
3. Postmenopausal patients present with vaginal
• Large malignant mass with pseudomyxoma
bleeding
peritonei (mucinous material in the peritoneal
space from seeding)
Krukenberg tumor
• Occur both in ovary and breast
• GIT tumor that metastasized to the ovary
• The tumor is multilocular and the cyst contains
• Commonly presents as bilateral ovarian masses
hemorrhagic or cellular debris
Risk factor for Epithelial tumors:
Brenner tumor • BRCA1/2
• Benign tumor • HNPCC mutation
• Characterised by coffee bean nuclei
• Note: No screening test for ovarian cancer,
• Resembles bladder epithelium
however, Pap test reduce the incidence for
• Pale yellow in colour
cervical cancer

Polycystic ovarian syndrome (PCOS)

Pathophysiology
• Complex endocrine disorder that affects 5-20% of
reproductive age women
• Due to abnormal production of metabolism of
androgens and estrogen in females lead to
elevated LH/FSH ratio.
• PCOS involves increase LH release
→↑Testosterone, but FSH is not enough to
stimulate conversion of testosterone to estrogen
H&E staining showing coffee bean nuclei (by aromatase enzyme)
• Low FSH levels suppresses aromatase activity
Fibroma tumor and thus a diminished capacity to convert
• Most common stromal tumor that form bundles of androgen into estrogen, but the adrenals may also
spindle-shaped fibroblasts contribute to the excess androgens as well
• Meigs syndrome refers to the combination of (↑androgens ↓estrogen)
fibroma, ascites, and pleural effusion. • High androgens promote atresia in developing
follicles and disrupt feedback relationships.

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 • Low FSH levels results in follicular degeneration Endometrium hyperplasia
and bilateral cystic ovaries Pathophysiology

• Increase proliferation of endometrial gland due to

excess exposure to estrogen
• Classified into 2 categories:
1. Simple (Benign endometrial hyperplasia)
2. Complex (Endometrial intraepithelial neoplasia):
• Patients are at high risk for endometrial
adenocarcinoma
• Treatment: hysterectomy or hormonal therapy

Clinical presentations
• Postmenopausal vaginal bleeding
Risk Factors
Clinical presentations • Anovulatory cycle
• Amenorrhea (Low FSH) • Hormone replacement therapy
• Infertility (atresia of follicles) • PCDS
• Obesity • Granulosa cell tumor
• Hirsutism (High LH) • Polycystic ovarian syndrome
• Insulin resistance & Dyslipidemia • Endometrial hyperplasia (vaginal bleeding) +
• Risk of endometrial cancer secondary to women > 35 years old might predisposed to
unopposed estrogen from fat cells endometrial cancer
Treatment Endometrium carcinoma
• Weight loss to regulate menstrual cycle • Most common gynecological malignancy
• Oral contraceptives prevent endometrial worldwide
hyperplasia due to unopposed estrogen • Affect women 55-65 years old
• Clomiphene and Metformin to induce ovulation • Associated with abnormal uterine bleeding
• Spironolactone, ketoconazole (antiandrogens) to • Endometrial adenocarcinoma commonly affects
treat hirsutism postmenopausal women who present with
abnormal uterine bleeding
Endometrium Pathology Risk factors
Overview • Early menarche and late menopause
• Endometrium is the innermost lining layer of the • Nulliparity
uterus. • Hypertension and diabetes
• The endometrium grows to a thick, blood vessel- • Obesity
rich, glandular tissue layer during the menstrual • Chronic anovulation
cycle • Estrogen-producing ovarian tumors (granulosa
cell tumors)
• HRT and tamoxifen
• Endometrial hyperplasia (Complex atypical
hyperplasia)
• Lynch syndrome (colorectal, endometrial, and
ovarian cancers)

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 • Highly common among African American
• Note: Endometroid adenocarcinoma associated • Grossly, the tumor is fleshy and white with
with PTEN mutation haemorrhage and necrosis.
• Can protrude into the cervix and cause abnormal
Myometrial tumors bleeding
Leiomyoma (fibroid)
Endometriosis
Overview
• The endometrium changes throughout the
menstrual cycle in response to hormones.
• With each monthly cycle, the endometrium
prepares itself to nourish a fetus.
• During the first part of the cycle, the hormone
estrogen is made by the ovaries.
• Estrogen increases the thickness of endometrium
to prepare the uterus for pregnancy.
• Most common tumor in female genital tract • If fertilization does not occur, the endometrium,
• More common in African American along with blood and mucus from the vagina and
• Occur in woman between 20-40 years old cervix make up the menstrual flow that leaves the
• Their growth is estrogen dependant body through the vagina during the period
• Benign tumor and development into the
malignant variant (Leiomyosarcoma) is rare

Clinical presentations
• Asymptomatic but the patient might present the
following signs:
o Heavy menstrual bleeding which might lead to
miscarriage
o Menorrhagia predispose the patient to iron
deficiency
o Constipation
o Urinary frequency or urgency
o Abdominal mass
o Pelvic/back pain
o Suprapubic discomfort
o Infertility and spontaneous abortion
o Tumor size↑with pregnancy and ↓with Definitions
menopause • Presence of endometrial tissue (both glands &
o Microscopically characterized by: stroma) outside the uterus (menstrual period
o Whorled pattern of smooth muscle bundles with outside uterine cavity)
well-demarcated borders • Tissue is morphologically and functionally
similar to endometrial tissue and responds to
hormones in cyclical manners
Pathophysiology
• Endometriosis subjected to 4 different theories:
1. Retrograde menstrual flow through the fallopian
tubes
2. Coelemic metaplasia into endometrial cells
3. Vascular or lymphatic metastasis

Leiomyosarcoma Possible sites of endometriosis

• Highly aggressive uterine malignancy associated
with a high risk of recurrence and death
• Irregular in shape

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 Breast pathology

• Ligaments that support the uterus (uterosacral

ligaments)
• The posterior cul-de-sac, i.e., the space between
the uterus and rectum
• The anterior cul-de-sac, i.e., the space between
the uterus and bladder

Clinical presentations
• Chronic pelvic pain
• Dysmenorrhea
• Dyspareunia (Painful sexual intercourse)
• Rectal pain and constipation
• Abnormal uterine bleeding
• Infertility
• Retrograde menstrual flow Common breast conditions
• Chocolate cysts (Hemolyzed blood) red-brown Fibrocystic changes
serosal nodules • Affect women in their reproductive years
• Dyschezia (pain with defecation) (premenopausal women < 35 years old)
Treatment • Associated with palpable mass or nodularity with
• Nonsteroidal anti-inflammatory drugs (NSAIDs) premenstrual breast pain
are often the first-line treatment for endometriosis • Often bilateral and multifocal
• Combined contraceptive pills • Benign
• Progestins (Medroxyprogesterone) • Divided into proliferative and non-proliferative
• Levonorgestrel-releasing intrauterine system lesions.
(Mirena) • They differ in the risk degree to develop breast
• GnRH agonists cancer
• Gonadotropin-releasing hormone analogue
• Danazol
• Laparoscopic removal

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 • Prior surgery or due to injury to the breast
NONPROLIFERATIVE PROLIFERATIVE • Painless
NO INCREASE IN RISK CHANGES
RELATIVE HIGH RISK • May produce palpable mass
FIBROSIS Ductal hyperplasia • Microscopic examinations revealed fat necrosis,
CYSTS Sclerosis adenosis
APOCRINE METAPLASIA Atypical lobular hyperplasia
chronic inflammation, hemosiderin deposits and
MICROCALCIFICATIONS fibrosis with calcification

Subtypes include: Gynecomastia

• Fibrosis • Unilateral or bilateral benign breast enlargement
• Cysts (fluid-filled duct dilation, blue dome) in a male due to excessive production of estrogen
• Apocrine metaplasia is often seen in cyst walls. • Clinical causes of gynecomastia can be:
• Microcalcifications occur in benign and 1.Physiologic
malignant processes. • New-born infants, pubescent adolescents, and
• Ductal hyperplasia elderly
• Atypical lobular hyperplasia 2.Pathologic
• Sclerosing adenosis • Liver cirrhosis due to increase estrogen levels
• Epithelial hyperplasia (increased risk of cancer) • Klinefelter syndrome
• pituitary tumors such as prolactinomas
RELATIVE FIBROCYSTIC CHANGE • Testicular cancer (choriocarcinoma and leyding
RISK cell tumor)
NO INCREASE Fibrosis, cysts, adenosis 3.Side effect of drugs
1.5-2X Sclerosing ductal hyperplasia • Endogenous estrogen
4-5X Epithelial hyperplasia (Atypical • Drug abuse marijuana,
ductal or lobular hyperplasia) • Spironolactone
• Digitalis
Acute mastitis • Cimetidine
• Alcohol
• Ketoconazole
Benign breast tumors
Fibroadenoma

• Mastitis: infection of the breast

• Pathophysiology: Staphylococcus aureus
infection
• Characterized by erythema, Purulent nipple
discharge and firmness in the breast, commonly
during lactation that can lead to breast abscess.
Fat necrosis
• The most common benign breast tumor in you
women Age <35
• Characterized by a palpable, round, movable,
firm, with well-defined edges in the breast stroma
• Fibroadenoma does not commonly progress to
breast cancer

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 • Tend to increase in size because it feed on • Age, women 45 years old
estrogen, especially during pregnancy and • Ethnicity, African American are with high risk to
menstruation
develop triple ⊝ breast cancer
Intraductal papilloma
• Family history (First-degree relative with breast
cancer)
• Hereditary risk factor genes, such as:
o BRCA1
o BRCA2
o TP53
• Overproduction/ exposure to estrogen, in cases of
o long length of reproductive life
o Nulliparity
o Obesity as adipose tissue converts
androstenedione to estrone
o Exogenous estrogens
• Presence of proliferative fibrocystic changes,
especially atypical hyperplasia

Invasive and non-invasive breast cancer

Non-invasive breast cancer

• Associated with a bloody nipple discharge

• Causes benign papillary growth within lactiferous
ducts (beneath areola)
• Benign but increase the risk of cancer
Phyllodes tumor
• Affect older populations (60 years old women) 1. Ductal carcinoma in situ (DCIS)
• Might become malignant • Don´t penetrate the basement membrane
• Large bulky tumor with “leaf-like” lobulations (Preservation of the myoepithelial cell layer) that
Malignant breast tumors usually distinguish from invasive types
• The most common cancer in women and affects 1 • Mammography revealed microcalcifications
in 9 women
• The second most common cause of cancer death 2. Comedocarcinoma
• Usually affect the upper right quadrant of the • Characterized by central necrosis
breast which might drain into auxiliary lymph • Usually non-infiltrating and intraductal tumors
node • Considered as ductal carcinoma in situ
• Liver, bone, ovary and lung are common target
organs for breast metastasis Invasive breast cancer
• Breast cancer is classified according to presence 1. Invasive ductal carcinoma
of absence of hormonal receptors that affect the • About 70% of cases are ER/PR positive and 30%
prognosis and future treatment, such as: overexpress HER2.
1. Estrogen receptor (ER) • Firm, fibrosis, rock-hard, sharp edges
2. Progesterone receptor (PR) • Worst prognosis
3. Human epidermal growth factor receptor 2 • The most common form (>80% of cases)
(HER2/neu) • Classic morphology “stellate” infiltration.
• ER-positive cancers → Better prognosis 2. Invasive lobular
→Treated with estrogen blockers such as • Bilateral and multifocal
tamoxifen • Multiple lesions
• HER27new positive cancer → Worse prognosis • Indian file
→Treated with monoclonal antibody trastuzumab • Bilateral bloody discharge
• Triple negative (ER ⊝, PR ⊝, and Her2/Neu ⊝) • Characterized by inactivation of E-cadherin
→ More aggressive • About 50% are ER/PR-positive; these tumors do
Risk factors not overexpress HER2
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 3. Medullary carcinoma (lymphocytic infiltrate)
• Pleomorphic tumor cells forming syncytial
groups surrounded by a dense lymphocytic host
response
• It has a better prognosis
• Related to BRCA1 mutation, hormone receptors
are negative; the tumors do not overexpress
HER2
• Soft fleshy tumor
4. Inflammatory breast cancer
• Inflammatory carcinoma is related to tumor
invasion into the dermal lymphatics with
resulting lymphatic edema
• Known as called nodular hyperplasia; glandular
• Lymphatic drainage is blocked by cancer cells
and stromal hyperplasia
• Associated with poor prognosis
• Common among men around 50-60 years old
• Patient commonly present with red, warm,
• Not considered premalignant
edematous skin (Peau d’orange)
• Risk factors: Obese patients, metabolic disorders,
erectile dysfunction and family history

Pathophysiology
• Enlargement of the transitional and periurethral
lobes results in compression of the prostatic
urethra
• BPH might cause renal azotemia due to urinary
tract obstruction
• Microscopically, the lesion shows glandular and
stromal hyperplasia resulting in the characteristic
prostate enlargement
Advanced Breast Cancer with Peau d’Orange Skin
Involvement

5. Paget disease
• Commonly associated with an underlying
invasive or in situ ductal carcinoma
• It may present with ulceration, oozing, crusting,
and fissuring of the nipple and areola.
• large cells in the epidermis with halos.

Benign prostate hyperplasia (BPH

Overview Azotemia is an elevation of blood urea nitrogen (BUN) and
serum creatinine levels.

Clinical presentations
• Increase frequency of urination
• Dysuria

734
 • Nocturia (nocturnal urination), when we wake up • Chemotherapy
in the night to urinate
• Difficulty starting and stopping urine stream Note: Erectile dysfunction and urinary incontinence are
• Urinary retention considered side effects of the surgery
• Incontinence
• Hydronephrosis Leuprolide
• UTI Mechanism of action
• GnRH analogue
Diagnosis • When used in pulsatile mood, increases FSH, LH
• Possible elevation in prostate specific antigen • When used in continuous fashion, inhibits FSH,
(PSA) but usually <10 ng/mL LH

Treatment Clinical uses

Terazosin, Tamsulosin are selective for alpha-1-
adrenoceptors
• MOA: Inhibition of these alpha-1-adrenoceptors
results in relaxation of smooth muscle in blood
vessels and the prostate, lowering blood pressure
and improving urinary flow
• Finasteride that block the conversion of
testosterone to DHT
• Surgical treatment is most commonly
transurethral resection of the prostate (TURP).

Prostate cancer
Overview
• Common among males over 50 years old
• Affect the peripheral of posterior lobe of the
prostate
• Risk factors: Age, family history and African
American more susceptible to prostate cancer

Pathophysiology
• Enlarge firm mass commonly arises in the
posterior aspect of the peripheral zone
• Tumor can be detected by digital rectal exam

Clinical presentations
• Clinically silent but may present with lower back
pain secondary to metastasis
• Osteoblastic bone metastasis to lumbar spine can
occur, and can be associated with elevated • Infertility (Pulsatile)
alkaline phosphatase • Prostate cancer (Continuous use)
• Uterine fibroid
Diagnosis • Precocious puberty
• Needle Biopsy • Endometriosis
• Increased total PSA, with decreased fraction of
free PSA Side effects
• Hypogonadism
Treatment • ↓libido
• For local tumor: prostatectomy and/or external • Erectile dysfunction
beam radiation • Nausea
• For metastatic cases: Orchiectomy, estrogen, or • Vomiting
LHRH agonists and anti-androgens
• Testicular atrophy

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 • Menopausal symptoms Tamoxifen
• Target different tissues such as:
Estrogen • E-receptor agonist (bone), antagonist (breast), and
Overview partial agonist (endometrium)
• Examples: Ethinyl estradiol, DES, mestranol • Competitively bind to estrogen in breast tissue
• Synthetic estrogen is used to increase feedback • Bone agonist, increase bone density
inhibition of FSH and LH Side effects
• It may risk of endometrial cancer
Clinical uses • Causes flushing and hot flashes
• Female hypogonadism • Possible ↑ risk of endometrial cancer
• Hormone replacement therapy (HRT) in Clinical uses
menopause →↓ bone resorption (↓ PTH) • Used in estrogen-dependent breast cancer
• Contraception—feedback ↓ of gonadotropins
• Dysmenorrhea Raloxifene
• Uterine bleeding • E-receptor agonist (bone), antagonist breast and
• Acne uterus
• Prostate cancer (palliative) • Prevent proliferation of endometrium
Clinical uses
Side effects • Breast cancer
• ↑ blood coagulation, via ↓ antithrombin III and ↑ • Treatment of osteoporosis in postmenopausal
factors II, VII, IX, and X (only at high dose) women
• ↑ endometrial cancer (unless progestins are Side effects
added) • Decrease LDL
• Bleeding in postmenopausal women • ↑risk of thromboembolic events but no increased
• Other general symptoms: risk of endometrial cancer (vs tamoxifen)
• Nausea • Hot flashes
• Breast tenderness • Weight again
• Endometrial hyperplasia
• ↑ gallbladder disease, cholestasis
• Migraine
• Bloating

Contraindications
• Estrogen induced breast cancer
• Smokers > 35 years old. Anastrozole
• History of deep vein thrombosis Mechanism of action

Selective estrogen receptor modulators

Clomiphene
• Selective estrogen receptor modulator (SERM)
• Bind to estrogen receptors in pituitary gland
• Has both estrogenic and anti-estrogenic properties
• MOA: Inhibit feedback inhibition → stimulate • Aromatase inhibitor decreases estrogen synthesis,
the release of FSH and (LH) → maturation of hence, prevent binding of estrogen to cancer cells
ovarian follicle, ovulation →pregnancy
Clinical uses Clinical uses
• Used mainly in female infertility due to • Estrogen-dependent, postmenopausal breast
anovulation (e.g. due to polycystic ovary cancer
syndrome) to induce ovulation • Endometriosis
Side effects
• Multiple gestation (Multi-birth) Side effects
• Ovarian enlargement • Hot flashes
• Hot flashes • Nausea
• Visual disturbances
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 • Vomiting Misoprostol
• Abdominal pain • PGE1 analogue
• Heavy bleeding • Blocks glucocorticoid and progestin receptors
• Stimulation of prostaglandin receptors in the
Progesterone stomach reduces gastric acid secretion
Overview (Cytoprotective effect)
• Examples: Medroxyprogesterone, • Stimulating these receptors in the uterus and
Levonorgestrel, Norethindrone, Desogestrel cervix can increase the strength and frequency of
• Synthetic progesterone used to increase feedback contractions and decrease cervical tone
inhibition of luteinizing hormone LH
• Through binding to progesterone receptors, it Clinical uses
decreases the growth and vascularization of • Used as a cervical ripening agent for induction of
endometrium labor
• Reduce the risk of NSAID related ulcers
Clinical uses • prevent post-partum hemorrhage
• Contraception such as: • Used for termination of pregnancy for first
1. Combined oral contraceptive pills (oral with trimester abortions.
estrogens)
2. depot contraception (medroxyprogesterone Oral contraceptives
IM every 3 months) Definition
3. Intrauterine device • Combinations of estrogens (ethinyl estradiol,
4. Implant mestranol) with progestins (norgestrel,
• Hormone replacement therapy (HRT)with norethindrone)
estrogen to ↓ endometrial cancer • Oral contraceptives available as pills, patch and
• Abnormal uterine bleeding vaginal ring

Progestin challenge, or progesterone withdrawal test Mechanism of action

• Used to evaluate a patient who presents • Prevent estrogen surge →↓Midcycle LH surge→
amenorrhea by measuring serum estradiol levels Estrogen and progesterone at basal levels → NO
• Positive test indicated that the patient's ovulation
amenorrhea is due to anovulation • Progestins cause thickening of cervical mucus →
Limiting access of sperm to uterus.
Side effects • Progestins inhibit endometrial proliferation
• ↓ HDL and ↑ LDL →Endometrium is less suitable to the
• Glucose intolerance implantation of an embryo
• Breakthrough bleeding • Administration of exogenous progesterone → ↑
• Androgenic (hirsutism and acne) oral bioavailability and ↑ feedback inhibition of
• Antiestrogenic (block lipid changes) luteinizing hormone (LH)
• Weight gain • Note: Progesterone is the major natural progestin
• Depression

Mifepristone and Misoprostol

Mifepristone
• Synthetic steroid with antiprogestational
• MOA: competitive interaction with progesterone
at progesterone-receptor sites

Clinical uses
• Medical termination of intrauterine pregnancy
through 49 days' pregnancy.
• Treatment of Cushing's syndrome, Mifepristone
blocks the binding of cortisol to its receptor.

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 • Endometriosis
Toxicity
• Weight gain
• Hirsutism
• Decrease HDL
• Hepatotoxicity
• Edema
• Masculinization

Advantages Terbutaline
• ↓ Risk of endometrial and ovarian cancer • β2-agonist action uses as bronchodilator
• ↓ Dysmenorrhea • Inhibit uterine contractions in preterm labor
• ↓ Endometriosis (tocolysis) and prolong gestation when beneficial
• ↓ Pelvic inflammatory disease (PID) (Premature labor)
• ↓ Osteoporosis
Testosterone and Methyltestosterone
Contraindications • Steroid sex hormone
• Liver disease or liver tumor • Exogenous testosterone decreases LH, FSH and
• Migraine endogenous testosterone production by negative
• Heavy smokers because it increases the risk of feedback
cardiovascular events
• Severe hypertension Clinical uses
• History of cardiovascular diseases (history of • Indicated to treat primary hypogonadism
venous thromboembolism, coronary artery • Delayed puberty
disease, stroke) • Metastatic Breast cancer
• Breast cancer (Estrogen dependent tumors) • Development of masculine sex organs and
secondary sexual characteristics facial and body
Hormonal replacement therapy (HRT) hair, enlargement of the larynx, thickening of the
Indication vocal cords, and changes in muscle and fat
• Menopause distribution
• Osteoporosis
• Vasomotor symptoms Side effects
• Prevention of skin and connective tissue atrophy • Masculinization in females
• Testicular atrophy
Menopause signs and symptoms • Premature closure of epiphyseal plates
PSYCHOLOGICAL PHYSICAL • ↑LDL↓HDL
DEPRESSION Hot flashes
LOSS OF CONCENTRATION Irregular period
ANXIETY Weight gain
SLEEP DISTURBANCE Headache Antiandrogenic drugs
LOSS OF LIBIDO Night sweats
Osteoporosis
Overview

Side effects of HRT

• Increase risk of stroke (makes of
hypercoagulation)
• Increase risk of cervical carcinoma

Danazol
• Synthetic steroid with:
1. Antigonadotropic and anti-estrogenic activities
2. Partial agonist for androgen receptors

Clinical uses:
• Heredity angioedema

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 Mechanism of action:
• 5-Alpha reductase inhibitor, preventing
conversion of testosterone to dihydrotestosterone
(DHT)
Clinical uses:
• Benign prostate hyperplasia
• Males with pattern boldness
Side effects
• Sexual dysfunction (↓Libido, ↓ ejaculation)
• Gynecomastia
Flutamide
• Antiandrogen non-steroidal drug (Competitive
inhibitor at testosterone receptor)
• Used for treatment of prostate cancer
Ketoconazole
• Antifungal agent for fungal infection
• Androgen synthesis inhibitors
• Inhibits gonadal and adrenal steroid synthesis by
inhibiting cholesterol side chain cleavage

Clinical uses
• Used for treatment of prostate cancer
• Used in PCOS to reduce androgenic symptoms
• Used to suppress glucocorticoid synthesis in the
treatment of Cushing´s syndrome.

Side effects
• Nausea
• Vomiting
• Diarrhea
• Gynecomastia
• Amenorrhea
• Hepatotoxicity
• Low platelet count
• Inhibit CYTP450

Spironolactone
Finasteride • Inhibit steroid synthesis
• Potassium-sparing medication with anti-
androgenic properties.
• Spironolactone works by
blocking androgen receptors
Clinical uses
• Hirsutism
• Female pattern hair loss

739
 • Adult acne vulgaris
• Used for its antiandrogenic effects in transgender
female patients due to its low cost and reducing
male-pattern hair growth
• Hyperaldosteronism
• Hypertension
• Edema
• CHF
Side effects
• Gynecomastia
• breast pain
• Hyperkalemia
• Impotence

Phosphodiesterase type 5 inhibitors

Overview
• Phosphodiesterase 5 (PDE5) is found in blood
vessels supplying the corpora cavernosa.
Scientific and trade names
• Sildenafil (Viagra)
• Vardenafil (Levitra)
• Tadalafil (Cialis)
Mechanism of action
• Inhibits PDE 5 →↑cGMP → vasodilation →↑
Blood flow in corpus cavernosum of penis→
Erectile response
Clinical uses

• Erectile dysfunction
• Sildenafil (a PDE5 inhibitor) is used for erectile
dysfunction but has been recently approved for
use in pulmonary hypertension
• Benign prostate hyperplasia (Tadalafil)
Side effects
• Flushing
• Headache
• Persistent penile erection (Priapism)
• Cyanopia (Blue-tinted vision)
• Dyspepsia
Contraindications
• Patients undergoing nitrates treatment due to
excessive fall in blood pressure→ Death
• Patients with myocardial infarction
Note: Priapism might occur secondary to sickle cell disease

740
 Chapter 17:

Pulmonary system

741
Rhinosinusitis, Epistaxis and Head and Neck Cancer o Severe disease presents with severe
Rhinosinusitis facial pain and a temperature above 38
Definition: C. Irrespective of the duration of the
symptoms, these patients should be
Rhinosinusitis is the inflammation of the sinuses due to given antibiotics and topical
obstruction of sinus drainage into nasal cavity. This is corticosteroids. Improvement is
characterized by pain over the affected area. The maxillary expected within 48 hours, otherwise
sinuses are the most commonly affected ones, because they reconsider the diagnosis
drain against gravity. Complications of rhinosinusitis:
Clinical findings: • Infection of the sphenoid or ethmoid sinuses can
extend to the cavernous sinus
• Inflammation of the nose and paranasal sinuses
• This can lead to cavernous sinus syndrome
• Presents with two or more of the following:
o Nasal blockage or obstruction
o Nasal congestion
o Nasal discharge
o Anterior or posterior nasal drip
o Facial pain/pressure
o Reduction or loss of sense of smell
• The patient must have one of the symptoms in red
Presumed acute viral rhinosinusitis: most cases

• Duration of symptoms less than 10 days

• While nasal congestion and discharge can last up
to 10 days, fever usually subsides on the 3rd or 4th
day in most patients Figure 457: CT scan showing ethmoid sinus infection.
Presumed acute bacterial rhinosinusitis: Source:
https://en.wikipedia.org/wiki/Sinusitis#/media/File:Ethmoi
• Worsening of symptoms after the 5th day dinfection.png
• Duration of symptoms more than 10 days
• Most commonly caused by S pneumoniae, H Epistaxis
influenzae and M catarrhalis Definition:
Treatment:
Epistaxis (nosebleeds) is one of the most common ear,
• Most patients benefit from intranasal nose and throat emergencies that are encountered in the
corticosteroids. Oral corticosteroids are reserved emergency room and primary care. Nosebleeds can be
for patients with severe disease and they can anterior (more common) or posterior (less common, but
reduce pain more severe and often require medical attention). 90% of
• Specific treatment based on the severity of the nosebleeds occur from the Kiesselbach plexus.
disease
o Mild disease is defined as symptoms Etiology:
lasting than 5 days or improving after 5 Local causes of nosebleeds include:
days. Treated with decongestants, saline
and analgesics • Digital manipulation
o Moderately severe disease is defined as • A deviated septum
symptoms persisting for 5 days or more. • Inhaled corticosteroids
Corticosteroids are helpful. • Trauma
▪ If symptoms last more than 10 • Chronic nasal cannulation
days, consider nasal Systemic causes include:
endoscopy, culture and
imaging • Alcoholism
▪ Imaging can show fluid filled • Hypertension
sinuses, a sign of sinusitis • Vascular malformations
▪ Prescribe oral antibiotics if
needed

742
 • Coagulopathies such as Willebrand disease or Clinical Findings
hemophilia or caused by medications such as DVT:
NSAIDs, or clopidogrel
Environmental causes include: • Unilateral leg pain
• Redness
• Allergies • Swelling
• Dryness in winter months • Edema
Other causes: • Warmth
• Tenderness
• Nasal angiofibroma, more common in males PE:
• Drug use such as cocaine
Clinically relevant anatomy: • Sudden-onset dyspnea and tachypnea →
respiratory alkalosis
Kiesselbach drives his Lexus with his LEGS: o Despite tachypnea, the patient can be
• Labial artery hypoxemic
• Anterior and posterior Ethmoidal arteries • Pleuritic chest pain
• Greater palatine artery • Hemoptysis
• Sphenopalatine artery • Syncope, tachycardia and hypotension →
Head and Neck Cancer massive PE and possibly hemodynamic instability
• Risk factors include cigarette smoking, alcohol, • Massive or saddle emboli may cause sudden
and exposure to HPV-16 which causes death → electromechanical dissociation and a
oropharyngeal squamous cell carcinoma possible cause of pulseless electrical activity
• EBV is associated with squamous cell carcinoma
of the nasopharynx Note: Pulmonary emboli typically
• These carcinogens damage wide mucosal area arise from proximal deep veins of
which results in multiple tumors that develop lower extremity.
independently after exposure
• This phenomenon is known as field cancerization
DVT and PE
Definition The step-wise diagnostic approach for VTE:
Venous thromboembolism (VTE) includes deep vein
thrombosis (DVT) and pulmonary embolism (PE). These 1. Symptoms and signs suggestive of DVT or PET
conditions are common and potentially fatal. Deep vein 2. Pretest Probability or Clinical Decision Rule
thrombosis is a blood clot within a deep vein that is a. VTE unlikely → D-dimer testing → if
predisposed by Virchow triad: positive, consider as VTE likely and
continue with the step-wise approach
• Stasis: post-op state, long-drive or a long flight meaning perform imaging as
predispose to blood stasis appropriate
• Hypercoagulability: an inherited or acquired b. VTE likely → if DVT is in question,
defect in the coagulation cascade or use of oral perform compression ultrasonography |
contraceptives if PE is in question, perform computed
• Endothelial damage: because exposed collagen tomography pulmonary angiography
triggers clotting cascade 3. If imaging is positive, DVT or PE is confirmed. If
negative, then DVT or PE can be excluded
Epidemiology What should be done if d-dimer is positive in a patient
• Estimated annual incidence of a first acute VTE suspected to have DVT but compression ultrasonography is
is 0.7 to 1.4 per 1000 negative?
• Hospital admissions for PE in the United States
doubled over the last decades because of the Repeat compression ultrasonography 1 week later.
availability of sensitive imaging techniques →
detection of potentially insignificant emboli Clinical Decision Rules
• PE is more common in Europe than in the United Pulmonary Embolism Rule-Out Criteria (PERC):
States → the value of clinical decision rule in
Europe is questionable “if you suspect PE in Suitable for emergency departments in the United States:
Europe, consider the patient as high-risk”
1. Age 50 years or older

743
 2. Pulse rate at least 100/min Compression ultrasound with Doppler for DVT:
3. Pulse oximetry oxygen saturation less than 95%
4. Unilateral leg swelling • Can be performed by emergency physicians
5. Hemoptysis within 15 minutes
6. Recent surgery or trauma • Good overall diagnostic accuracy with sensitivity
7. Prior PE or DVT of 96% and specificity of 97% for the diagnosis
8. Exogenous estrogen use of DVT
When none of these are present in a patient with suspected • Unfortunately, the diagnostic accuracy is operator
PE, the diagnosis of PE can be safely excluded without dependent
further imaging. • Perform MRI venography when ultrasonography
results are nonconclusive
Wells Score System for DVT: Computed tomography pulmonary angiography:
-2 – 0 points mean low probability, 1 – 2 points = moderate • Good diagnostic accuracy for PE
probability, 3 – 8 points high probability of DVT. • Look for filling defects
• Widely available, easy to perform and is not
operator dependent
CRITERION POINTS • Replaced ventilation/perfusion scintigraphy (VQ)
Paralysis, paresis or recent orthopedic casting of lower 1
extremity • Contraindicated in patients with severe renal
Recently bedridden > 3 days or major surgery within past 4 1 impairment because of the use of contrast
weeks medium
Localized tenderness in deep vein system 1
Calf swelling > 3 cm in affected leg at 10 cm below the 1 V/Q scintigraphy and V/Q single-photon emission
tibial tuberosity computed tomography:
Swelling of entire leg 1
Pitting edema more in the symptomatic leg 1
Collateral non-varicose superficial veins 1
• Ventilation/perfusion single photon emission
Active cancer or cancer treated within 6 months 1 computed tomography employs less radiation
Alternative diagnosis more likely than DVT like Baker’s -2 than CTPA and avoids the need for intravenous
cyst, cellulitis, muscle damage, post-phlebitic syndrome,
superficial venous thrombosis, inguinal lymphadenopathy contrast
or external venous compression • Superior to conventional planar V/Q scintigraphy,
but same accuracy as CTPA
• Shows V/Q mismatch: ventilated areas without
Pulmonary embolism Wells score:
perfusion
PERC criteria are superior in terms of sensitivity and Other diagnostic tests:
specificity for the exclusion of PE than Wells score,
• May have S1Q3T3 abnormality on ECG,
however, we still mention Wells score because of its
however most common finding in PE is sinus
historic value.
tachycardia
Score < 2 points: low probability, 2 to 6 points moderate • At autopsy, the presence of lines of Zahn which
probability and > 6 points is highly probability for PE. are interdigitating areas of pink (platelets and
fibrin) with red (RBCs) mean that the thrombus
CRITERION POINTS formed before death
Symptoms of DVT 3
No alternative diagnosis better explains the illness 3 Other types of pulmonary emboli:
Tachycardia with pulse > 100 1.5
Immobilization for 3 days or more, or surgery within 1.5 • Fat emboli are associated with long-bone
previous 4 weeks
Prior history of DVT or PE 1.5
fractures, liposuction and present with triad of
Presence of hemoptysis 1 hypoxemia, neurologic abnormalities and
Presence of malignancy 1 petechial rash
• Air emboli are nitrogen bubbles that precipitate in
Diagnosis ascending divers. It is treated with hyperbaric
D-Dimer: oxygen
• Amniotic fluid emboli occur during labor or
• A sensitive marker for DVT and can exclude postpartum and can be due to uterine trauma.
VTE without need for further testing in low-risk
They can lead to DIC and are often fatal.
patients (high sensitivity, low specificity)
Fortunately, they are rare
• Levels > 500 ng/mL → PE is likely
• Bacteria and tumor tissue can also embolize and
• D-dimer levels normally increase with age occlude pulmonary vessels

744
Treatment Inflammation of the tissues in the mediastinum. It is
Initial treatment of VTE (first 5 to 10 days): usually bacterial and is due to rupture of organs in the
mediastinum. It can also be chemical as in the case of
• Unfractionated heparin or low-molecular weight esophageal rupture and acid irritation of the mediastinal
heparins structures.
• Start oral anticoagulation with warfarin or Causes:
rivaroxaban • Postoperative complication typically within first
Long-term (end of acute treatment to 3 or 6 months): 14 days of cardiothoracic surgery
• Esophageal perforation
• Isolated DVT without PE → continue oral
• Contiguous spread of an odontogenic or
anticoagulation for 3 months
retropharyngeal infection
• Unprovoked in women at low-risk of recurrent
Chronic mediastinitis:
VTE or men and women at high risk of bleeding
• Also known as fibrosing mediastinitis
complications → continue oral anticoagulation
for 3 to 6 months • Increased connective tissue formation in the
mediastinum
• Provoked by a transient risk factor such as a
recent major surgery → 3 months of oral • Most commonly caused by histoplasma
anticoagulation therapy capsulatum
Clinical findings:
• Cancer associated, but malignancy is treated → 6
months of oral anticoagulation • Fever
Extended (beyond 6 months and usually for life): oral • Tachycardia
anticoagulants • Chest pain
• Sternal wound drainage in the case of post-op
• Unprovoked in women at high-risk of recurrent mediastinitis
VTE and low risk of bleeding complications • Leukocytosis
• Unprovoked in men at low risk of bleeding Diagnosis:
complications • Contrast-enhanced plain radiography can confirm
• Cancer associated and cancer is still active → the diagnosis in most cases because the most
continue oral anticoagulants as long as cancer is common cause is esophageal perforation
active • Chest CT with oral and intravenous contrast is
Mediastinal Pathology helpful in more difficult cases
Definition Treatment:
The mediastinum is the central compartment of the thoracic • Aggressive intravenous antibiotic therapy and IV
cavity. It contains the heart and major blood vessels, the fluids for adequate rehydration
esophagus, trachea, phrenic nerve, cardiac nerves, thoracic • Abscesses need to be surgically drained and
duct, thymus and the lymph nodes of the central chest. The grossly infected tissues must be debrided
mediastinum is a frequently involved site by various tumors. • Chronic mediastinitis might respond to steroids.
Surgical decompression of affected blood vessels
Mediastinal Masses might be required
Anterior mediastinum:
• Substernal thyroid goiters, lymphoma, thymoma Pneumomediastinum
and teratoma are the most common tumors of the Definition:
anterior mediastinum Pneumomediastinum or mediastinal emphysema is the
Middle mediastinum: abnormal presence of air or other gas in the mediastinum.
• Lymphadenopathy, metastatic disease such as It can result from physical trauma to the lungs, airways, or
from small cell carcinoma of the lung presence of bowels into the chest cavity which leads to air
Posterior mediastinum: escaping into the mediastinum. Can be spontaneous due to
• Neurogenic tumors from the nerve sheath rupture of a pulmonary bleb.
(benign) or elsewhere (malignant) Boerhaave syndrome:
Any compartment: Esophageal perforation due to repeated vomiting. It results
• Lymphoma, lung cancer and abscesses can occur from a full-thickness tear in the esophageal wall due to a
in any compartment sudden increase in intraesophageal pressure combined with
negative intrathoracic pressure (which occurs when
Mediastinitis straining or vomiting). It accounts for 10% of esophageal
Definition: perforations. Boerhaave syndrome is a possible cause of
pneumomediastinum.
745
 Pulmonary function pathology:
Clinical findings:
• Chest pain • Obstruction of air flow → air trapping in lungs
• Dyspnea due to premature closure of airways at high lung
• Voice change volumes. This results in elevated FRC, RV, and
TLC.
• Subcutaneous emphysema
• Crepitus on cardiac auscultation (+ Hamman • Pulmonary function tests show a markedly
decreased FEV1, and a decreased FVC. The
sign)
FEV1/FVC ratio is decreased in COPD which is a
• Can be seen in patients with pneumothorax
hallmark of COPD
Diagnosis:
• V/Q mismatch is seen in patients with COPD
• The diagnosis can be confirmed by a chest plain
radiograph showing a radiolucent outline around • Chronic hypoxic pulmonary vasoconstriction can
result in pulmonary hypertension and cor
the heart, mediastinum and major blood vessels
pulmonale
• CT scan of the chest is helpful in difficult cases
Chronic bronchitis:
Treatment:
• Because the tissues in the mediastinum will • One form of COPD that is characterized by
slowly resorb the air in the cavity, conservative productive cough for more than 3 months in a
treatment is recommended year for more than 2 consecutive years
• High-flow oxygen increases the rate of absorption • Caused by hypertrophy and hyperplasia of
of the air mucus-secreting glands in bronchi. The thickness
• A needle may be inserted into the mediastinum to of mucosal gland layer to thickness of wall
release the air when the heart is under between epithelium and cartilage in bronchi is
compression increased (Reid index) to more than 50%. DLCO is
• If the cause is a ruptured esophagus or trachea, usually normal
surgical repair is needed • Patients present with wheezing, crackles,
cyanosis, dyspnea, CO2 retention and secondary
Obstructive Lung Diseases polycythemia
Chronic Obstructive Pulmonary Disease • Because of the cyanosis, patients with COPD
Definition: who suffer from chronic bronchitis are known as
blue bloaters
COPD is defined as chronic airflow obstruction because of
Emphysema:
chronic lung inflammation due to two main processes:
• The second form of COPD that is seen in smokers
• Small airways disease: obstructive bronchiolitis,
• Centriacinar pattern affects the upper lobes more
airway remodeling, narrowing and loss of the
often and is seen in smokers
peripheral airways
• Panacinar affects the lower lobes more often and
• Emphysema: parenchymal destruction that causes
is seen in patients with alpha-1 antitrypsin
loss of alveolar units, gas trapping and
deficiency
hyperinflation which are characteristic of COPD
patients • The destruction of the parenchyma of the lung
Pathophysiology: results in enlargement of air spaces. The air
spaces have decreased recoil, increased
• Lung inflammation is most commonly caused by compliance and decreased DLCO
cigarette smoking • DLCO which is the diffusion of CO across the
• Can be also caused by other harmful particles alveoli is decreased because of the destruction of
such as smoke from biomass fuels alveolar walls in emphysema
• An inflammatory response that is mediated by • Patients present with a barrel-shaped chest, and
macrophages, neutrophils, and T and B they tend to purse their lips when exhale to
lymphocytes. Genetic predisposition plays an increase airway pressure and prevent airway
important role collapse → hence the common name of pink
o A minority of the patients have puffers
eosinophil-mediated inflammation. • In patients with alpha-1 antitrypsin deficiency,
They respond better to corticosteroids as the pathology is an imbalance between proteases
compared to the general COPD and antiproteases → increased elastase activity →
population

746
 loss of elastic fibers → increased lung • Increased Th2 cells and down-regulation of Treg
compliance cells → increased production of IL-4, IL-5 and
Diagnosis: IL-13
• Increased production of IgE-producing plasma
• Spirometry is necessary for the diagnosis of cells in allergic asthma → Type 1
COPD and should be the initial test of choice hypersensitivity reaction
• The diagnosis is established in patients with a • Accumulation of eosinophils which is IL-5
forced expiratory volume in 1 second (FEV1) to mediated
forced vital capacity (FVC) < 70% • Increased production of IgE → binding to mast
• Plain radiography reveals increased AP diameter, cells and basophils and release of histamine →
a flattened diaphragm and increased lung field bronchospasm and reversible airflow obstruction
lucency in emphysema • Intrinsic asthma is caused by infections such as
Treatment: viruses or by exposure to drugs including aspirin
• Short-acting bronchodilators should be used in all • Extrinsic asthma is an immune-mediated disease
patients with COPD regardless of severity as and is what is being referred to here when we talk
rescue treatment “during an exacerbation” about type 1 hypersensitivity reaction and IgE
• Long-acting muscarinic antagonists, inhaled mediated asthma
corticosteroids, and long-acting beta-agonists are Histopathological changes in asthma:
the mainstay symptomatic treatment of COPD • Smooth muscle hypertrophy and hyperplasia in
Treatments that improve mortality rates in COPD: bronchi
• Lung volume reduction surgery which is reserved • Goblet cell hyperplasia
for severe upper lobe emphysema because of the • Hypertrophy of submucosal mucus glands
high morbidity of the procedure • Subepithelial fibrosis and collagen deposition
• Smoking cessation is the most important • Inflammatory cellular infiltrate and submucosal
treatment of COPD that is known to decrease edema
mortality, alter the natural history of the disease, • Curschmann spirals (shed epithelium forms
and improve long-term outcome mucous plugs in bronchi)
Asthma • Charcot-Leyden crystals which are eosinophilic
Definition: hexagonal double-pointed crystals formed from
the breakdown of eosinophils in the sputum
Asthma is a chronic inflammatory disorder of the airways Aspirin-induced asthma:
in which mast cells, eosinophils, T-lymphocytes,
macrophages, neutrophils and epithelial cells play a role. • Inhibition of COX → leukotriene overproduction
This inflammation, in susceptible patients, causes recurrent → airway constriction
episodes of wheezing, chest tightness, breathlessness, and • Characterized by chronic sinusitis, nasal polyps
cough. The symptoms typically occur at night or in early and asthma symptoms
morning. These episodes are associated with widespread Clinical findings:
but reversible airflow obstruction.
• The cardinal symptoms of asthma are wheezing,
Pathophysiology: shortness of breath, coughing and chest tightness
• These symptoms are typically worse or occur at
• Hyperresponsive bronchi → reversible night or early morning
bronchoconstriction
• Tachypnea, hypoxemia, increased
• Type 1 hypersensitivity reaction inspiratory/expiratory ratio, pulses paradoxus and
• Many cells are involved including mast cells, mucous plugging are the main clinical findings on
eosinophils, T-lymphocytes, macrophages, examination
neutrophils and epithelial cells Diagnosis:
• DLCO is normal or increased
• Endogenous cortisol levels are at minimum at • PFTs show a FEV1/FVC ratio of 0.75 or less
night and early morning → worse symptoms • Methacholine challenge test causes
Inflammatory cellular changes in asthma: bronchoconstriction and reduces the above-
mentioned ratio → confirming the diagnosis
• Increased expression of IL-33 by epithelial cells when the patient has a normal FEV1/FVC ratio
• Metaplasia and increased mucin stores in goblet
cells
747
 • The use of a bronchodilator in an asthmatic with a • Chronic necrotizing infection of the bronchi that
decreased FEV1/FVC ratio shows normalization results in permanently dilated airways
→ reversibility • Bronchi obstruction → infection → necrosis →
• Peak expiratory rate is helpful in classifying permanent dilation of airways
asthma Causes:
Peak expiratory rate:
• Any cause of bronchial obstruction can lead to
PEEK EXPIRATORY bronchiectasis (e.g. tumor)
FLOW RATE IN L/MIN • Poor ciliary motility secondary to smoking or
Normal: males 450 – 650 Kartagener syndrome
Normal: females 350 – 500 • Cystic fibrosis
Moderate asthma 180 – 300 • Allergic bronchopulmonary aspergillosis
Severe asthma < 100 Clinical findings:
Treatment:
• Purulent sputum production
• Short-acting beta2 agonists such as albuterol for • Recurrent infections
acute asthmatic attack “abortive therapy” • Hemoptysis
• Long-acting beta2 agonists such as salmeterol • Digital clubbing
• Inhaled corticosteroids for moderate to severe Restrictive Lung Diseases
asthma Primary Restrictive Lung Disease
• Montelukast which is a leukotriene inhibitor → Restrictive lung diseases are characterized by limited lung
helpful in intrinsic asthma expansion and a decrease in lung volumes (FVC and TLC).
• Cromolyn-sodium is a mast cell stabilizer Because FEV1 is not markedly changed, RLDs are
characterized by an elevated FEV1/FVC ratio. Patients
typically present with short, shallow breaths.
Note: Avoid beta-blockers in asthma
patients because they can cause Primary restrictive lung disease is a condition that is
bronchoconstriction. primarily of the lung parenchyma and interstitium where
chronic inflammation and fibrosis are the main finding. The
fibrosis of the interstitium space interferes with carbon
dioxide diffusion across the alveoli, decreasing the DLCO.
Emergency treatment of acute asthma attack:
The most studied example of a primary restrictive disease is
• A SABA such as albuterol is administered via a idiopathic pulmonary fibrosis (IPF).
metered-dose inhaler
• Intravenous corticosteroids might be needed Secondary Restrictive Lung Diseases
• Third-line treatments include theophylline and Many systemic diseases can result in interstitial lung
magnesium disease and a restrictive lung disease pattern on pulmonary
o Theophylline is a potent bronchodilator function tests. However, these diseases are not primary
o It has a very narrow therapeutic index disorders of the lungs. Examples include:
→ third line only if other treatments fail
• Supplemental oxygen can be administered • Sarcoidosis
• Antibiotics are needed when the cause of asthma • Pneumoconiosis
execration is infection • Asbestosis
• Mechanical ventilation is needed for those who • Silicosis
develop acute respiratory failure • Drug-induced (busulfan, methotrexate,
Complications of severe acute asthma attack: bleomycin, amiodarone, neomycin and gold)
• Radiation pneumonitis
• Status asthmaticus • Wegener’s granulomatosis (granulomatosis with
• Respiratory failure polyangiitis)
• Pneumothorax • Churg-Strauss syndrome
• Pneumomediastinum • Goodpasture’s syndrome
Bronchiectasis • Hypersensitivity pneumonitis
Pathology: • Pulmonary Langerhans cell histiocytosis
(eosinophilic granuloma)

748
Extrapulmonary causes of restrictive lung diseases are • Bilateral inspiratory crackles
characterized by a restrictive pattern on PFTs, but normal • Digital clubbing
DLCO and A-a gradient. Examples include: • Eventually, pulmonary hypertension → cor
pulmonale
• Poor respiratory muscle function as in polio, Diagnosis:
myasthenia gravis and Guillain-Barre syndrome
• Poor structural apparatus as in scoliosis and • Chest radiography shows reticular, reticulo-
morbid obesity nodular, and ground glass appearance (not
Hypersensitivity pneumonitis: recommended because the diagnosis can be
missed)
• Type III and IV hypersensitivity reaction to • Honeycomb lung appearance on high-resolution
environmental antigens computed tomography scans
• Causes inflammation and a restrictive lung • Elevated FEV1/FVC ratio and low DLCO
disease pattern on PFTs
• Biopsy is not recommended when imaging
• Presents with dyspnea, cough, chest tightness, studies confirm the diagnosis. If in doubt, a
and headache biopsy can be taken. It should show usual
• Seen in farmers who are exposed to birds interstitial pneumonia histologic pattern
• If the stimulus is removed in early stages, the • Tractional bronchiectasis
disease is reversible HRCT features of usual interstitial pneumonia:
Idiopathic Pulmonary Fibrosis
Definition: • Subpleural and basal predominant distribution of
honeycombing
Chronic, progressive, fibrosing interstitial pneumonia of
• Peripheral traction bronchiectasis or
unknown cause occurring primarily in older adults and
bronchiolectasis
limited to the lungs. The histologic pattern is known as
Histopathologic features of usual interstitial pneumonia:
usual interstitial pneumonia. It should be considered in all
adults with unexplained chronic exertional dyspnea, cough, • Dense fibrosis with destruction and scarring or
bibasilar inspiratory crackles and/or digital clubbing that honeycombing
occur without constitutional or other symptoms suggestive • Predominant subpleural and/or paraseptal
of a systemic disease. distribution of fibrosis
Epidemiology: • Patchy involvement of lung parenchyma by
fibrosis
• Incidence increases with older age • Fibroblast foci
• Typically has an insidious onset of dyspnea in the • Absence of features suggestive of an alternative
6th or 7th decades diagnosis
• When diagnosed in patients younger than 50 Diagnostic criteria for IPF:
years of age, the possibility of an early connective
tissue disease must be excluded • Exclusion of other known causes of restrictive
lung diseases such as pneumoconiosis,
• More common in men
sarcoidosis or drug-induced lung fibrosis
• Positive history of cigarette smoking in most
patients • Presence of the HRCT pattern of usual interstitial
pneumonia
• Gastroesophageal reflux, chronic viral infections
such as EBV or hepatitis C and family history of • If HRCT results are inconclusive, histopathologic
idiopathic pulmonary fibrosis are other risk examination should show usual interstitial
factors pneumonia
Pathology: Treatment:
Recommended treatments:
• Repeated cycles of lung injury and healing
• Increased collagen deposition in the interstitial • Tyrosine-kinase inhibitor nintedanib can be used
space in some patients
Clinical findings: • Pirfenidone
• Exertional dyspnea. Later on, dyspnea at rest • Treatment of pulmonary hypertension if present
• Non-productive cough • Lung transplantation (single versus bilateral lung
transplantation)
• Fatigue
Treatments no longer recommended:

749
 • Because of the poor understanding of the Chest radiography stages of pulmonary sarcoidosis:
pathophysiology of IPF, treatment
recommendations keep changing • Stage 1: bilateral hilar adenopathy
• Anticoagulation, corticosteroids, selective • Stage 2: bilateral hilar adenopathy and diffuse
endothelin receptor antagonist (ambrisentan), and reticulonodular opacities
sildenafil should NOT be used in the treatment of • Stage 3: reticulonodular pattern
IPF according to the most recent guidelines • Stage 4: fibrosis
Sarcoidosis Imaging in pulmonary sarcoidosis:
Definition:
• HRCT is superior to plain radiography in
Sarcoidosis is a systemic inflammatory disease of unknown identifying the patterns of pulmonary fibrosis and
etiology that can affect the eyes, liver, heart and central confirming the diagnosis
nervous system in addition to the pulmonary system. • Bronchial distortion, linear scarring and
honeycombing are the main identified patterns on
Pathology: HRCT
• The extent and type of fibrosis in sarcoidosis is
• An immune-mediated disease characterized by
highly variable, unlike the well-defined pattern
widespread noncaseating granulomas
seen in IPF
• More common in African-American females
Pulmonary function tests:
• Fibrosis extends from granulomas and occurs in
the same lymphatic distribution as active • Restriction and reduction in diffusing capacity
inflammation (DLCO) in stage 4 pulmonary fibrosis
• Fibrosis results in bronchial distortion, large • FEV1/FVC ratio is slightly increased in
cystic changes, and interlobular fibrosis → linear comparison to IPF
scarring Complications:
• Alveolar interstitial inflammation and fibrosis are
uncommon in sarcoidosis as compared to other • Pulmonary hypertension
interstitial lung diseases • Aspergillus disease
Clinical findings: • Pneumothorax and pleural thickening
• Pulmonary embolism
Pulmonary disease: Treatment:
• Dyspnea Systemic corticosteroids for active disease:
• Cough
• Wheezing – more common in fibrosing • Can cause weight gain, hypertension, DM,
pulmonary sarcoidosis osteoporosis and increases the risk of infection
• Exertional hypoxemia and decreased exercise Methotrexate, TNF-alpha blockers, mycophenolate mofetil
tolerance and azathioprine:
• Unlike IPF, pulmonary sarcoidosis does not result
in acute decline in pulmonary function after an • Increases the risk of infection
acute exacerbation • Bone marrow suppression
Extrapulmonary disease: • Fetal toxicity
• Increases the risk of malignancy
• Bell palsy
• Uveitis
• Lupus pernio (skin lesions on face resembling Note: Lung transplantation is an
lupus) important treatment option for
• Interstitial fibrosis (only in fibrosing pulmonary fibrotic pulmonary sarcoidosis due
sarcoidosis) to high mortality rates.
• Erythema nodosum
• Rheumatoid-arthritis-like arthropathy
• Increased activity of 1alpha-hydroxylase in Inhalational InjuryDefinition
macrophages → increased activation of vitamin D Inhalation injury causes localized damage via direct cellular
→ hypercalcemia damage, changes in blood flow and perfusion, airway
Diagnosis: obstruction, and toxin and inflammatory cytokines release.
It is caused by the inhalation of noxious stimuli. The injury

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can be attributed to the heat of the inhaled smoke, Treatment:
particulates less than 1 micrometer in diameter found in the • The cornerstone of the treatment of inhalation
inhaled air or irritants. injury is providing adequate supportive care
• Pulmonary toilet, chest physiotherapy, airway
Epidemiology suctioning, therapeutic serial bronchoscopies and
• Present in one-third of all burn injuries early aggressive ambulation are extremely
• Account for 90% of all burn-related mortality important
• Main causes are major burns, CO inhalation, • Beta2 adrenergic agonists such as albuterol and
cyanide poisoning and arsenic poisoning salbutamol are helpful
Pathogenesis • Respiratory support in the form of mechanical
Inhalation injury can cause four types of illnesses: ventilation might be needed in selected patients
Resolution typically occurs after 11 days
• Upper airway injury Pneumoconioses
• Lower airway injury Overview:
• Pulmonary parenchymal injury Pneumoconioses are a group of lung diseases that are
• Systemic toxicity characterized by interstitial lung fibrosis post-exposure to
The main determinants of the extent of inhalation injury coal, asbestos, beryllium, silica or other occupational
are: hazards. Pneumoconioses are seen in patients with
occupational lung diseases or in victims of disasters: e.g.
• The source of injury tsunami lung disease and asbestosis lung disease in disaster
• Temperature of the injuring substance survivors.
• Concentration
• Asbestos affects the lower lobes
• Solubility of the toxic gases inhaled
• Silica and coal affect the upper lobes
• The body’s response to that injury
Inhalation injury causes the following pulmonary changes: Asbestosis:
Exposure to naturally occurring minerals that form long
• Formation of casts that can obstruct the airways thin particles known as asbestos. Classified as amphibole
• Reduction of available surfactant → can cause asbestos (more pathogenic) and serpentine asbestos.
ARDS and acute lung injury
• Increased airway resistance • Associated with shipbuilding, roofing, plumbing,
• Decreased pulmonary compliance and in those who survive natural disasters
• Chemical tracheobronchitis • Affects lower lobes
• Edema • Asbestos can cause pleural and parenchymal
disease and is a carcinogenic
• Pneumonia
• Asbestos-related disease has a very long (> 25
Clinical Findings: years) latency from exposure to onset of disease
• History is important as it can give clues about the Asbestos-related pulmonary disease:
mechanism of injury, exposure duration, location
and degree of disability before and after the • Interstitial pulmonary fibrosis (usual interstitial
injury pneumonia pattern on HRCT)
• Physical examination reveals facial burns, singed • Pleural disease: effusions, calcified
nasal or facial hair, carbonaceous sputum, soot, supradiaphragmatic and pleural plaques, and
stridor and possibly edema diffuse thickening
Diagnosis: • Increased risk of bronchogenic carcinoma and
• Fiberoptic bronchoscopy is the standard mesothelioma
technique for the diagnosis of inhalation injury • Increased risk of Caplan syndrome (rheumatoid
• It is readily available and provides longitudinal arthritis with pneumoconiosis and intrapulmonary
evaluation data for the individual patient nodules)
Histopathologic examination:
• Hyperemia, edema and soot on fiberoptic
bronchoscopy are diagnostic of inhalation injury • Asbestos (ferruginous) bodies which are golden-
• Fiberoptic bronchoscopy cannot examine the brown fusiform rods resembling dumbbells
distal airways, however, if the above-mentioned • Found in alveolar sputum sample and
findings of hyperemia, edema and soot are found, bronchoalveolar lavage
involvement of the distal airways must be • Visualized by Prussian blue stain
assumed
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Berylliosis: Silicosis:
• Chronic beryllium disease occurs in up to 10% of Silicosis has a presentation that is similar to coal workers’
those exposed to beryllium in the workplace. pneumoconiosis, however it is seen in people exposed to
Industries that use beryllium include aerospace, silica dust. Sandblasting, foundries and mines are
automotive, electronics, jewelry, military, nuclear occupational sources of silica dust exposure.
energy, recycling and telecommunications
manufacturers. • Macrophages response to silica dust by releasing
• The risk of chronic beryllium disease (CBD) is fibrogenic factors → fibrosis
increased in patients with sarcoidosis or other • Silicosis disrupts phagolysosomes in
granulomatous disease macrophages → increased susceptibility to TB
• Affects the upper lobes • Increased risk of cancer, cor pulmonale and
• Histology reveals non-caseating granulomas → Caplan syndrome
can be responsive to corticosteroids in selected • Affects upper lobes
patients Diagnosis:
• Increased risk of cancer and cor pulmonale
• Eggshell calcification of hilar lymph nodes on
• The diagnosis is confirmed by demonstrating a plain radiography
positive beryllium-specific immune response or
• Nodular infiltrates on HRCT
beryllium sensitization wit ha beryllium
Mesothelioma
lymphocyte proliferation test
Definition:
o This test is usually obtained on blood
Malignant mesothelioma is a cancer of serosal surfaces most
cells
commonly of the pleura and peritoneum. It carries a poor
o Bronchoalveolar lavage cells can be
prognosis and it is strongly associated with exposure to
also used as a sample for this test
amphibole asbestos, particularly in males. The exact
• HRCT shows nodular infiltrates or ground-glass mechanism by how asbestos causes mesothelioma is largely
infiltrates unknown.
Coal Workers’ Pneumoconiosis
Most cases of pneumoconioses are attributed to coal Epidemiology:
workers’ disease or exposure to silica dust (silicosis). The Up to one quarter of lung cancer and mesothelioma occur in
presentation of coal workers’ pneumoconiosis and silicosis nonsmokers
is similar.
It is hypothesized that the majority of these cases are
• Exposure to coal dust causes lung opacities (small secondary to occupational hazards exposure
nodules) which can coalesce
Clinical Findings:
• The disease is progressive and can result in
• While the mechanism of mesothelioma in
massive fibrosis
asbestosis is unknown, it is known that this
• May present with nodular infiltrates on chest malignancy is quite aggressive
radiographs and HRCT or in some patients might
• Hemorrhagic pleural effusion (exudative effusion)
mimic usual interstitial pneumonia radiographic is seen
pattern
• Patients typically have pleural thickening
• There is no proven therapy for dust-induced
• Histopathologic examination reveals psammoma
pneumoconioses
bodies
Pathology:
• Almost all mesotheliomas are calretinin positive,
• Prolonged exposure to coal dust → macrophages unlike lung carcinomas
engalf carbon particulates → inflammation and • Smoking is not a risk factor for mesothelioma
fibrosis Acute Respiratory Distress Syndrome
• Also known as black lung disease Definition
• Increased risk of Caplan syndrome (similar to Acute respiratory distress syndrome is objectively defined
asbestosis) as per the most recently Kigali criteria as follows:
• Affects upper lobes 1. Respiratory failure within 1 week of a known
Anthracosis: insult or new and/or worsening respiratory
symptoms
Prolonged exposure to sooty air among urban dwellers can 2. Respiratory failure cannot be attributed to cardiac
result in an asymptomatic form of pneumoconiosis known dysfunction, or volume overload
as anthracosis.

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 3. Imaging shows bilateral opacities on chest • Patients are usually critically ill before they
radiography or CT that cannot be considered as develop ARDS
effusion, collapse or nodules • Worsening in their hypoxemia or new onset of
4. Acute hypoxemia defined as PaO2/FiO2 < 300 respiratory failure is evident
mmHg • Patients have bilateral lung opacities and
pulmonary edema
Epidemiology • The onset of these symptoms is within 1 week of
• An annual incidence of 190,000 cases of ARDS the alveolar insult
in the United States
• Mortality rate in adults is 38% Diagnosis:
• Prevalence of ARDS in intensive care unit Based on the objective definition of ARDS, one can
patients is estimated to be around 10% conclude the following as the most important diagnostic
• Up to 23% of ventilated ICU patients have ARDS clues for ARDS:
Risk factors: • Abnormal imaging that shows bilateral lung
• Alcohol abuse opacities and cannot be assumed to be pleural
• Cigarette smoking effusion or lung collapse
• Air pollution • Hypoxemia must be objectively confirmed by
• Hypoalbunemia demonstrating a decreased PaO2/FiO2 ratio < 300
• Possibly higher mortality for black and Hispanic • Heart failure and volume overload are excluded
patients than white patients as possible causes of pulmonary edema
• Men with ARDS are more likely to die than
women “possibly, ARDS is often more severe in
males than in females” Note: In the past, the diagnosis of
ARDS could have not been made
Pathogenesis unless PaO2/FiO2 is less than 300
Etiology: despite the patient being on PEEP.
• ARDS is caused by a known alveolar insult This is no longer required for the
• Common causes include sepsis (most common), diagnosis of ARDS in the most
aspiration, pneumonia, trauma and pancreatitis recent definition.
• The end-result of alveolar insult is loss of
surfactant → leads to alveolar collapse and
Treatment:
impaired gas exchange
Pathophysiology: • Treat the underlying cause
• Alveolar insult leads to release of pro- • Mechanical ventilation with the following
inflammatory cytokines settings is recommended:
o Low tidal volumes
• Neutrophils are recruited to the site of injury and
o High PEEP is beneficial in ARDS
activated → release of reactive oxygen species
and proteases → capillary endothelial damage
Sleep Apnea
and increased permeability
Overview:
• Protein-rich fluid leakage into alveoli and
An apnea is the absence of inspiratory airflow for at least
formation of intra-alveolar hyaline membranes →
10 seconds. Hypopnea is a lesser decrease in airflow
noncardiogenic pulmonary edema with normal
lasting 10 seconds or longer and associated with a drop in
PCWP
arterial oxyhemoglobin saturation or an
Hypoxemia in ARDS:
electroencephalographic (EEG) arousal pattern. Apneas are
• Alveolar collapse and loss of surface area generally classified as central or obstructive.
available for gas exchange → intrapulmonary
shunting and diffusion abnormalities Regardless of the cause of sleep apnea, the following
• Decreased lung compliance and pulmonary pathologic consequences occur:
hypertension
• Increased sympathetic nerve activity
Clinical Findings • Metabolic dysregulation
Based on the objective definition of ARDS, one can • Inflammation
conclude the following main clinical features: • Oxidative stress
• Vascular endothelial dysfunction

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 • Intermittent hypoxia → increased release of afterload is increased and possibly
erythropoietin → erythropoiesis pulmonary hypertension
These pathologies eventually lead to three main • Repeated arousals:
cardiovascular abnormalities: o Sympathetic system activation →
hypertension, atrial fibrillation/flutter,
• Heart disease and myocyte toxicity
• Hypertension o Parasympathetic withdrawal →
• Atrial fibrillation tachycardia
Eventually, patients with sleep apnea are at an increased • Decreased pleural pressure:
risk of heart failure and cardiac-related death. o Increased transmural pressure of all
cardiac chambers → R and L ventricular
Sleep apnea results in disrupted sleep and daytime afterload increased → atrial dilation →
somnolence. The diagnosis is confirmed by sleep study. atrial arrhythmias
Patients typically have normal PaO2 during the day but o Aortic dilation
nocturnal hypoxia. Clinical findings:
Obstructive Sleep Apnea
• Obesity, loud snoring and daytime sleepiness are
Occurs when complete upper airway occlusion occurs:
the main clinical features of OSA
• Absent airflow • However, sleep studies are required to confirm
• Tongue falling backward the diagnosis
The activity of inspiratory thoracic pump muscles is not Treatment:
interrupted in obstructive sleep apnea.
• Weight loss
Risk factors: • CPAP
• Surgery
• Obesity (responsible for up to 80% of the cases) Central Sleep Apnea
• Abnormal anatomy of craniofacial structures The main pathology in central sleep apnea, regardless of
• Enlarged tonsils the etiology, is impaired respiratory effort due to CNS
• Upper airway edema “medullary” injury or toxicity. This can be caused by direct
• Non-anatomic causes include upper airway CNS injury, HF or opioids.
dilator muscle dysfunction, heightened
chemosensitivity, and low-arousal threshold Central sleep apnea can be associated with Cheyne-Stokes
respirations which are oscillations between apnea and
(waking up from sleep prematurely)
hyperpnea.
The link between obstructive sleep apnea and obesity:
Why do we see Cheyne-Stokes respirations in CSA?
• Obesity is associated with increased fat deposits
within the upper airway and a reduction in lung • The apneic threshold in patients with CSA is set
volume → caudal traction on the upper airway → at a higher level
upper airway is more amenable to close during • Therefore, medullary input withdrawal to
sleep respiratory effort occurs at a low PCO2
Pathophysiological consequences of sleep apnea and • PCO2 starts building up and the patient becomes
hypopnea: hypercapnic
• Obstructive sleep apnea is associated with • Only then, the medullary input is back, and this
repeated cycles of sleep apnea and recovering results in an episode of hyperpnea
during sleep • Eventually, the patient ends up with fluctuations
• This results in three main derangements: between apnea and hyperpnea, a respiratory
abnormal PO2 and PCO2, repeated arousals, and pattern known as Cheyne-Stokes respirations
decreased pleural pressure Treatment: Positive airway pressure.
• Abnormal PO2 and PCO2: Obesity Hypoventilation Syndrome
o Decreased oxygen delivery to peripheral • Also known as Pickwickian syndrome
tissues → end-organ dysfunction
• Seen in patients with a BMI of 30 kg/m2 or more
o Oxidative stress and inflammation →
• Characterized by hypoventilation, not apnea
endothelial dysfunction
o Hypoxic and hypercapnic pulmonary • PaCO2 is increased (CO2 retention) during the
vasoconstriction → right ventricular day because hypoventilation occurs during day

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 waking hours (unlike OSA which is also linked to • Hereditary pulmonary arterial hypertension
obesity but presents with episodes of apnea and (HPAH) (inactivating mutation in BMPR2 gene)
CO2 retention during sleep) • Drug-related pulmonary arterial hypertension
• Hypoxemia and hypercapnia are also seen in (DPAH)
patients with obesity hypoventilation syndrome o Amphetamines and cocaine
Pulmonary Hypertension • Associated with connective tissue disease, portal
Definition: hypertension, congenital cardiac malformations,
Pulmonary hypertension is defined as a resting mean schistosomiasis or HIV infection
pulmonary artery pressure of 25 mmHg or more. Normal What is the function of BMPR2 encoded protein and how
mean pulmonary artery pressure is from 10 to 14 mmHg. inactivating this gene results in PAH?
Pulmonary arterial hypertension: • The protein encoded by this gene inhibits
vascular smooth muscle proliferation
There are five major types of pulmonary hypertension.
• When inactivated, vascular smooth muscle
Pulmonary arterial hypertension is defined as a mean artery
proliferation is uncontrolled → arteriosclerosis,
pressure of > 25 mmHg, pulmonary arterial wedge pressure
medial hypertrophy and intimal fibrosis of
< 15 mmHg and pulmonary vascular resistance > 240
pulmonary arteries → PAH
dyn×s×cm-5. This discussion is mainly about pulmonary
arterial hypertension. • Carries a poor prognosis as compared to other
causes of PAH
Left heart disease as a cause of pulmonary hypertension: What is the main pathology in idiopathic pulmonary
arterial hypertension?
Systolic or diastolic dysfunction and valvular disease can
elevate left atrial pressure which can in turn result in • Pulmonary vasculature endothelial dysfunction
pulmonary hypertension. → vasoconstriction and loss of vasodilators such
as NO and prostacyclins
Pulmonary hypertension secondary to lung disease or • A vicious cycle occurs where PAH results in
chronic hypoxia: more arteriosclerosis → medial hypertrophy of
pulmonary arteries and fibrosis → worsening of
COPD, ILD and alveolar hypoventilation syndromes (sleep
PAH
apnea) can result in pulmonary hypertension.
What are the pathologic consequences of PAH?
Chronic thromboembolic disease:
• If not treated → severe respiratory distress →
Recurrent microthrombi decrease the cross-sectional area cyanosis and right ventricular hypertrophy → cor
of pulmonary vascular bed and can lead to pulmonary pulmonale → decompensated right heart failure
hypertension. and death
Clinical Findings
Other causes of pulmonary hypertension: Cardinal symptoms of pulmonary hypertension:
Hematologic, systemic, or metabolic disorders can result in • Progressive exercise dyspnea
pulmonary hypertension in a multifactorial way. • Fatigue and exhaustion
• Because the symptoms are nonspecific →
Epidemiology
diagnosis is often delayed
• Pulmonary hypertension is common, and it
affects around 1% of the global population • When the disease or worsens → dyspnea on
bending down (bendopnea) and syncope.
• Up to 10% of those aged above 65 years are
Syncope with slight exertion in PAH is indicative
expected to have pulmonary hypertension
of high mortality and severe disease
• The annual incidence of pulmonary arterial Triad of cardiac decompensation in PAH: (right heart
hypertension is around 3 to 10 new cases per 1 failure)
million adults
• The most common causes of pulmonary • Cervical venous congestion
hypertension are left heart disease and lung • Ascites
disease • Edema
Pathogenesis: Physical examination:
Causes of pulmonary arterial hypertension:
• Often unremarkable except for slight peripheral
• Idiopathic (unknown cause) or central cyanosis that is worse on exertion

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Diagnosis • This is based on the recent understanding of the
Echocardiography pathophysiology of pulmonary arterial
hypertension (endothelial dysfunction and
• Gives important clues about the possibility of unopposed vasoconstriction)
PAH • Treatment for high risk patients is a triple
• Estimated RV pressure, right heart overload, left combination of an endothelial receptor
heart function, and evidence of heart or lung antagonist, a PDE5 inhibitor and an intravenous
disease can be assessed prostacyclin analog
What to do if echocardiography along with the symptoms Treatment goals:
and signs of the patient support the diagnosis of PAH?
• PAH is incurable
If the patient has pre-existing heart or lung disease and no • The goal of treatment is to stabilize the patient,
significant right heart overload: and achieve satisfactory clinical state without
• Further diagnostic workup for PAH is not signs of right heart failure
indicated • Ideally, we should aim for halting disease
If there is evidence of right heart overload: progression
Pulmonary Acute Diseases
• Right heart catheterization is needed to confirm Pleural Effusion
PAH Definition:
• VQ scintigraphy is indicated to look for signs of
Pleural effusion is the excessive accumulation of fluid in
chronic thromboembolic disease
the pleural space. It indicates an imbalance between pleural
Treatment
fluid formation and removal.
General treatment of pulmonary hypertension:
Pathology:
• Rehabilitation measures and active physiotherapy
are important • Pleural effusion is not a disease, but a reflection
• The aim is to improve exercise capacity, quality of underlying pathology
of life, and cardiac function • Lung, pleural and systemic disorders can cause
Specific treatments of pulmonary hypertension: pleural effusions
• Excess accumulation of fluid → restricted lung
• Currently, there are now 10 treatments available
expansion during inspiration
for pulmonary arterial hypertension
Exudative pleural effusion:
Endothelial receptor antagonists:
• Pleural fluid protein divided by serum protein >
• Ambrisentan
0.5, pleural LDH divided by serum LDH > 0.6
• Bosentan
and pleural fluid LDH more than two thirds of the
• Macitentan upper limit of normal serum LDH
PDE5 inhibitors: o Elevated protein content
• Sildenafil o Cloudy
o Must be drained due to risk of infection
• Tadalafil
Stimulator of soluble guanylate cyclase: • Pleural effusions that do not meet these criteria
are transudate
• Riociguat • Simple exudative pleural effusion can be caused
Prostacyclin analogs: by TB, bacterial, viral or parasitic infections,
malignancy, connective tissue disorders such as
• Epoprostenol RA and SLE, immunological disorders such as
• Iloprost sarcoidosis and Wegener’s granulomatosis,
• Treprostinil pancreatitis, hepatitis-related, pulmonary
Prostacyclin receptor agonist: embolism, uremia, and postpartum
• Pyothorax (pus) is caused by bacterial, TB,
• Selexipag amebic and fungal infections
So how these specific treatments work? • Hemothorax (blood) can be seen in trauma,
surgery, or bleeding disorders
• These treatments target endothelial receptors, or
prostacyclin receptors in addition to other targets • Chylothorax (lymph fluid) can be seen post-
surgery, malignancy, idiopathic, congenital,

756
 filariasis, or associated with LAM. Trauma can Alveolar collapse which can occur secondary to any of the
also cause chylothorax following causes:
o Milky-appearing fluid
o Elevated triglycerides • Obstructive: airway obstruction → air cannot
Transudate: reach distal airways and old air is resorbed →
alveolar collapse. Possible causes of obstruction
• Common causes include cirrhosis, congestive include foreign body, mucous plug and tumor
heart failure, ascites, nephrotic syndrome, an • Compressive: external compression on lung →
peritoneal dialysis decreased lung volume and alveolar obstruction.
• Low protein content Possible causes include space-occupying lesion
• Due to low hydrostatic pressure as in HF, or low and pleural effusion
oncotic pressure as in nephrotic syndrome or • Contraction: scarring of lung parenchyma →
cirrhosis distortion of alveoli. Possible causes include
Clinical findings: sarcoidosis. Also known as cicatrisation.
• Adhesive: the alveoli collapse, and the surfaces
• Decreased breath sounds on the affected area adhere → due to lack of surfactant. Possible
• Dull percussion note causes include NRDS in premature babies
• Decreased fremitus Clinical findings:
• If large, tracheal deviation away from side of
lesion • Decreased breath sounds and decreased fremitus
• Symptoms and signs suggestive of the etiology on the affected side
Diagnosis: • Dull percussion note
• Tracheal deviation toward the side of lesion
• Chest radiography shows whitening of the (tracheal traction)
affected region. Ellis S-shaped curve in the case Treatment:
of massive pleural effusion
• Subpulmonic effusion shows blunting of the • Treatment is tailored against the etiology
costo-diaphragmatic angle Simple Pneumothorax
• Ultrasonography can detect small amounts of Definition:
pleural effusions accurately, which may be
Pneumothorax is the accumulation of air in the pleural
missed by plain radiography
fluid. It can be classified into:
• CT is useful in the evaluation of complex
situations in which the anatomy cannot be fully • Primary spontaneous pneumothorax
assessed by plain radiography or ultrasonography • Secondary spontaneous pneumothorax
• Thoracentesis is useful in classifying pleural • Traumatic pneumothorax
effusion into exudative vs transudative, and in Pathology:
identifying the most likely cause. It can be also
therapeutic in the case of massive pleural effusion • Primary spontaneous pneumothorax is more
common in thin, tall young males who are
smokers
• It occurs when an apical subpleural bleb or cyst
spontaneously ruptures
• Air accumulates in the pleural space, which limits
lung expansion and interferes with air filling of
alveoli during inspiration
• Secondary spontaneous pneumothorax occurs in
patients with diseased lungs due to bullae in
emphysema or infections. Mechanical ventilation
Figure 458: Massive pleural effusion with contralateral with the use of high pressures can result in
mediastinal shift. Source: barotrauma and pneumothorax
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4753987/ • Traumatic spontaneous pneumothorax is caused
by blunt trauma (rib fracture), penetrating injury
Atelectasis (knife stab or gunshot), or iatrogenic (e.g. central
Definition: line placement, lung biopsy)
Clinical findings:

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 • Dyspnea and chest pain
• Uneven chest expansion
• Decreased tactile fremitus and breath sounds on
the affected side
• Hyperresonance percussion note on the affected
side
• Tracheal deviation to the contralateral side if
massive “tension pneumothorax”
• In the case of trauma, evidence for trauma to the
chest such as abrasions, puncture wounds, or
fractured ribs
Chest radiography:

• Jet black appearance with loss of bronchial

markings on the affected side Figure 460: Tension pneumothorax on the left side
• CT is helpful in the case of small pneumothorax
Pneumonia and Lung Abscess
Lobar Pneumonia
Definition:
Lobar pneumonia is diffuse consolidation involving the
entire lobe of the lung. Sometimes, it can involve the
whole lung.
Pathology:

• Congestion is the first stage of lobar pneumonia

(1 to 2 days)
Figure 459: CT scan of a pneumothorax on the left side o Characterized by grossly heavy and
boggy appearing lung tissue, diffuse
Treatment: congestion, vascular engorgement and
accumulation of alveolar fluid rich in
• Emergency treatment is often not needed in the infection organisms
case of spontaneous simple pneumothorax o Few RBCs and neutrophils
• Placement of a chest tube is recommended in • Red hepatization is characterized by marked
patients with large symptomatic pneumothoraxes infiltration of red blood cells, neutrophils, and
Tension Pneumothorax fibrin into alveolar fluid (3 to 4 days)
• Any of the causes of simple pneumothorax can o The lungs appear red and firm
result in tension pneumothorax o The tissue looks like a liver → hence,
• In tension pneumothorax, air can enter the pleural the name hepatization
space but cannot exit • Gray hepatization is characterized by
• Increased trapped air in the pleural space → transformation of the red exudate to gray color
increased intrapleural pressure → tension due to RBC breakdown. Fibrinopurulent exudates
pneumothorax are seen at this stage (5 to 7 days)
• Intrathoracic pressure if increased can lead to • Resolution is the final stage and is characterized
mediastinal displacement and kinking of the by clearing of the exudates by resident
inferior vena cava → decreased venous return and macrophages. It happens with or without residual
decreased cardiac output → hemodynamic scar tissue formation (8+ days)
compromise. These conditions can prove fatal if • Possible organisms involved with lobar
not treated immediately pneumonia include streptococcus pneumoniae
• The trachea is deviated away from the affected and less commonly, legionella and klebsiella
lung on chest radiography Clinical findings:
• Immediate needle decompression followed by
chest tube placement is the treatment of choice in • Fever with chills
tension pneumothorax • Malaise
• Loss of appetite

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 • Myalgias • B: blood pressure less than 90 mmHg for systolic
• Pulmonary findings: cough with or without and 60 mmHg for diastolic
sputum production. Bacterial pneumonia is • Age above 65 years
associated with purulent or rarely blood-tinged • One point is awarded for each point of this scale
sputum Treatment:
• In a small number of patients, altered mental
status, abdominal pain, chest pain and other Score 0 to 1 on CURB-65:
systemic findings may be present
• Outpatient management
• Physical examination reveals tachypnea,
• Fluoroquinolones or beta-lactams + macrolides if
tachycardia, fever, decreased or bronchial breath
adverse comorbidities are present
sounds, tactile fremitus, crackles on auscultation
of affected region of the lung, and dullness on • Macrolides or doxycycline alone if no
percussion comorbidities are present
Diagnosis: Score 2 to 3 on CURB-65:

• Clinical evaluation • Inpatient management in a general medicine ward

• Radiological evaluation demonstrates infiltrates • Fluoroquinolones or macrolides + beta-lactams
on chest radiography. The pattern of infiltrate is Score 4 or more on CURB-65:
lobar in the case of lobar pneumonia • ICU management
• Blood culture, sputum culture and microscopy. • Empiric regimen with a combination of a beta-
Routine blood counts, and lymphocyte count lactam + fluoroquinolone or a beta-lactam +
• Procalcitonin and CRP differentiate bacterial macrolide
from viral pneumonia Bronchopneumonia
• Antibiotics should not be delayed, and the Definition:
laboratory investigations are rarely needed in
straightforward cases with typical clinical and Bronchopneumonia is characterized by suppurative
radiographic findings inflammation localized in patches around the bronchi
which may or may not be localized to a single lobe of the
lung.

• The inflammatory infiltrates may infiltrate

adjacent alveoli
• Caused by streptococcus pneumoniae,
staphylococcus aureus, H influenzae and
Klebsiella
• The distinction between lobar and
bronchopneumonia is not important because the
clinical findings, diagnostic workup, and
treatment is not based on this but is based on the
CURB-65 scale score
Interstitial Pneumonia: (not usual interstitial pneumonia
Figure 461: Lobar pneumonia of the right middle lobe. which is the radiologic and histologic feature of idiopathic
Source: interstitial fibrosis)
https://en.wikipedia.org/wiki/Lobar_pneumonia#/media/Fil
• Characterized by patchy inflammation localized
e:X-ray_of_lobar_pneumonia.jpg to interstitial areas at alveolar ways
CURB-65: • Plain radiography of the chest shows bilateral
multifocal opacities
• This scale is used in community acquired • Follows a more indolent course, hence the name
pneumonia to determine whether the patient can “walking pneumonia”
be managed on outpatient basis, in a general • Caused by mycoplasma, Chlamydophila
medicine ward, or in an intensive care unit pneumoniae, Chlamydophila psittaci, legionella,
• C: confusion and viruses such as respiratory syncytial virus,
• U: uremia or BUN above 20 mg/dL cytomegalovirus, influenza and adenovirus
• R: respiratory rate above 30 per minute Cryptogenic Organizing Pneumonia
Definition:

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Formerly known as bronchiolitis obliterans organizing Clinical findings:
pneumonia. It is a noninfectious pneumonia characterized
by inflammation of the bronchioles and surrounding •The tumor is central in location
structure caused by chronic inflammatory diseases such as •May produce ACTH → Cushing syndrome
rheumatoid arthritis or as a side effect to medications such •SIADH is another endocrine paraneoplastic
as amiodarone. syndrome seen in patients with SCLC
• Autoimmune-mediated neurologic diseases
• Sputum and blood cultures need to be negative Autoimmune-mediated neurologic diseases in SCLC:
• No response to antibiotics
Lung Cancer, Pancoast Tumor and SVCS • Antibodies against presynaptic Ca2+ channels →
Lung Cancer Lambert-Eaton myasthenic syndrome
Overview: • Antibodies against neurons → encephalitis,
myelitis, and subacute cerebellar degeneration
• Lung cancer is the leading cause of cancer death Histology:
• The general presentation of lung cancer is cough,
hemoptysis, bronchial obstruction, wheezing, and • Small dark blue cells
a pneumonic lesion on chest radiography or a • Chromogranin A positive
noncalcified nodule on CT • Neuron-specific enolase positive
• Lung cancer may metastasize to the adrenals, • Synaptophysin positive
brain, bone (causing pathologic fractures), or
liver (causing jaundice and hepatomegaly)
• A malignancy found in the lung is more likely to
be metastatic rather than primary. Most common
primary malignancies that metastasize to the
lungs are breast cancer, colonic carcinoma,
prostate cancer and bladder cancer
Risk factors:

• Smoking. Squamous and small cell lung

carcinomas are centrally located and caused by
tobacco smoking Figure 462: FNA of small cell lung cancer. Source:
• Secondhand smoke https://en.wikipedia.org/wiki/Small-
• Exposure to radon or asbestos (asbestos exposure cell_carcinoma#/media/File:Small_cell_lung_cancer_-
is also associated with an increased risk of _cytology.jpg
mesothelioma)
• Family history Treatment:
Complications of lung cancer:
• Chemotherapy with or without radiation
• Superior vena cava or thoracic outlet syndromes • Treatment is mostly palliative
• Horner syndrome Adenocarcinoma
• Pancoast tumor Definition:
• Endocrine (paraneoplastic) syndromes
• Recurrent laryngeal nerve compression → This lung cancer affects the peripheral regions of the lungs
hoarseness and is characterized by a glandular pattern on histology
that stains positive for mucin, hence the name
• Pleural or pericardial effusions
adenocarcinoma. These tumors are more commonly seen in
Small Cell Lung Carcinoma
women and usually arise in nonsmokers. They are caused
Definition:
by mutations in KRAS, EGFR or ALK genes.
SCLC is an undifferentiated form of very aggressive lung
cancer. It is often associated with paraneoplastic Clinical findings:
syndromes and is associated with poor prognosis. It is a • Adenocarcinoma of the lung is the most common
neoplasm of neuroendocrine origin (Kulchitsky cells), type of lung cancer
hence the small dark blue cells that are characteristic of • Associated with hypertrophic osteoarthropathy
this cancer. Oncogenesis occurs due to the amplification of
• Bronchioalveolar subtype also known as
the myc oncogenes.
adenocarcinoma in situ is characterized by hazy

760
 infiltrates on plain radiography that resemble Bronchial Carcinoid Tumor
pneumonia. It carriers a better prognosis • Carcinoid tumors of the lungs can be centrally or
o Tumor cells grow along alveolar septa peripherally located
o Characterized by thickening of the • They carry an excellent prognosis
alveolar walls • Rarely metastasize
o Histology shows columnar cells filled • If symptoms occur, they are either due to the
with mucus mass effect of the tumor or because of carcinoid
Squamous Cell Lung Carcinoma syndrome
Definition: Carcinoid syndrome:
Squamous cell lung carcinoma is the second lung cancer •Serotonin is produced which results in flushing,
that is clearly associated with tobacco smoking and is diarrhea and wheezing
located in the central regions of the lungs. It usually • Unlike carcinoid tumors of the GI tract, bronchial
presents as a hilar mass arising from a bronchus. carcinoid tumor can result in carcinoid syndrome
Clinical findings: without needing to metastasize to the liver
Histology:
• Squamous cell lung carcinoma is characterized by
cavitation • Neuroendocrine cells that are chromogranin A
positive
• This type of malignancy can produce PTHrP →
leading to hypercalcemia
• Histology reveals keratin pearls and intercellular
bridges

Figure 465: Bronchial carcinoid. Source:

https://en.wikipedia.org/wiki/Typical_pulmonary_carcinoi
d_tumour#/media/File:Lung_carcinoid_-_high_mag.jpg

Figure 463: Squamous cell lung cancer. Pancoast Tumor

• Also known as superior sulcus tumor
Large Cell Lung Carcinoma • A carcinoma that occurs in the apex of the lung
• A highly anaplastic, undifferentiated tumor that • Pancoast tumor that compresses or invades local
carries a poor prognosis. It is less responsive to structures such as the recurrent laryngeal nerve or
chemotherapy in comparison to other types of stellate ganglion cause Pancoast syndrome
lung cancer. There is a strong association with Pancoast syndrome:
smoking.
• Histology reveals pleomorphic huge cells •Recurrent laryngeal nerve invasion/compression
→ hoarseness
• Stellate ganglion compression/invasion → Horner
syndrome
• Superior vena cava compression/invasion →
superior vena cava syndrome
• Brachiocephalic vein → brachiocephalic
syndrome (unilateral symptoms)
• Brachial plexus compression/invasion →
sensorimotor deficits
Horner syndrome:
Figure 464: Large cell lung carcinoma. Source:
https://en.wikipedia.org/wiki/Large- • Ipsilateral ptosis
cell_lung_carcinoma#/media/File:Large_cell_carcinoma_o • Miosis
f_the_lung_.jpg • Anhidrosis

761
 Definition
Acute respiratory failure occurs when the respiratory
system fails to properly transfer oxygen from the
atmosphere to the blood or remove CO2 from the blood to
eliminate it into the atmosphere.
Hypoxic respiratory failure is defined as a partial pressure
of arterial oxygen less than 60 mmHg on room air at sea
level. Hypercapnic respiratory failure occurs when the
partial pressure of CO2 is greater than 50 mmHg on room
air at sea level. Hypercapnic respiratory failure is
Figure 466: Pancoast tumor. Source: associated with respiratory acidosis.
https://en.wikipedia.org/wiki/Pancoast_tumor#/media/File:
Hypoxia is defined as decreased delivery of oxygen to
Pancoast_Tumor_1.jpg
peripheral tissues. Hypoxemia is low oxygen partial
pressure in blood. Oxygen saturation is the percentage of
Superior Vena Cava Syndrome
oxygen-bound hemoglobin.
Definition:
Obstruction of the superior vena cava by a lung carcinoma A-a gradient:
→ impairment in blood drainage from the head which A-a gradient = PaO2 – PaCO2
leads to facial plethora, jugular venous distension, and
upper extremities edema. Normal PaO2 is 100 mmHg at room air at sea level

• Commonly caused by mediastinal masses or Normal PaCO2 is 40 mmHg at room air at sea level
Pancoast tumors
• Thrombosis of an indwelling catheter can also Causes of Acute Respiratory Failure
cause superior vena cava syndrome Hypoxic respiratory failure:
• It is considered as a medical emergency • Hypoventilation or shunting (V/Q mismatch)
• If the obstruction is severe → elevated • Ventilation-perfusion inequality
intracranial pressure
• Limited diffusion
CNS consequences of SVCS:
• Pulmonary edema
• Elevated intracranial pressure can cause headache • ARDS
or dizziness • Pneumonia
• Increases the risk of aneurysmal rupture of Hypercapnic respiratory failure:
intracranial arteries
• Decreased tidal volume:
o Sedative overdose:
▪ Opioid
▪ Benzodiazepines
o Neuromuscular weakness:
▪ CNS disease
▪ Spinal cord disease
▪ Peripheral nerve disease
▪ Neuromuscular junction
disease
▪ Myopathy
▪ Metabolic derangements
o Flail chest
• Increased dead space:
Figure 467: SVCS shows facial swelling early in the
o Hyperinflation
morning, on the left which resolves by the end of the day.
▪ Obstructive airway disease as
Source:
in asthma, bronchiolitis and
https://en.wikipedia.org/wiki/Superior_vena_cava_syndro
cystic fibrosis
me#/media/File:SVCcombo.JPG
▪ Excessive PEEP on
Acute Respiratory Failure mechanical ventilation

762
 o Decreased cardiac output direct spreading from an adjacent source of
▪ Dehydration infection such as the mediastinum
▪ Dysrhythmia According to way of spreading:
▪ Myocarditis or
cardiomyopathy • Bronchogenic as is the case with aspiration of
o Increased pulmonary vascular resistance oropharyngeal secretions, or obstruction of a
o Pulmonary embolism bronchus by a tumor
Treatment of Acute Respiratory Failure • Hematogenic as is the case with abdominal sepsis
Initial management steps: and infection endocarditis for instance
Causes
• Ensure airway patency and clearance Aspiration of oropharyngeal secretions:
• Supplemental oxygen via facemask or nasal
cannula • Dental and peridental infection
• Noninvasive positive pressure ventilation such as • Paranasal sinusitis
CPAP or BiPAP • Disturbance of state of consciousness
ARDS: • GERD
• Frequent vomiting
• ARF in ARDS is treated by treating the etiology • Intubated patients
in addition to mechanical ventilation • Patients with a tracheostomy
Asthma: • Alcoholism
Hematogenic spread:
• Bilevel positive airway pressure (BiPAP) is
helpful • Abdominal sepsis
• Anti-inflammatory therapy with steroids, • Infective endocarditis
bronchodilation with inhaled or intravenous beta-
• Intravenous drug abuse
agonists and the use of magnesium,
• Infected cannula or central venous catheter →
anticholinergics or methylxanthines take priority
septic thromboembolisms
in the treatment of ARF in asthmatic patients
Coexisting lung diseases:
Bronchiolitis:
• Bronchiectasis
• This is a viral infection seen in infants
• Cystic fibrosis
• There is no specific therapy and treatment is
supportive • Bullous emphysema
• Bronchial obstruction
• Beta2-agonists, racemic epinephrine and
corticosteroids play an important role • Congenital malformations such as pulmonary
sequestration or cystitis
• Nasal CPAP is helpful
Lung Abscess • Infected pulmonary infarcts
Definition • Pulmonary contusion
Lung abscess is defined as a circumscribed area of pus or • Broncho-esophageal fistula
necrotic debris in lung parenchyma that leads to a cavity and Pathology
after the formation of a bronchopulmonary fistula, an air- Acute lung abscess:
fluid level inside the cavity.
• Circumscribed, but with not so well-defined
surrounding
Classification:
According to duration: • Filled with thick necrotic debris
• On histology: central part of the abscess is filled
• Acute lung abscess is less than 6 weeks with necrotic tissue with necrotic granulocytes
• Chronic lung abscess is more than 6 weeks and bacteria. On the periphery, preserved
According to etiology: neutrophilic granulocytes with dilated blood
vessels and inflammatory edema
• A primary lung abscess is one that occurs due to Chronic lung abscess:
aspiration of oropharyngeal secretions (more
commonly affecting the right lung), necrotizing • Irregular start-like shaped with well-defined
pneumonia or immunodeficiency surrounding to lung parenchyma
• Secondary lung abscesses occur due to bronchial • Filled with grayish light or thick material
obstructions, hematogenic dissemination, or • In the center, there is pus with or without bacteria

763
 • Has a pyogenic membrane through which white Overview:
blood cells migrate to abscess cavitation Role of Histamine release in allergies
• Around the membrane, you will find
lymphocytes, plasma cells and histiocytes
Clinical Findings
• Difficult to differentiate from pneumonia
• Symptoms include fever with shivering, cough,
night sweats, dyspnea and fatigue
• Weight loss is seen more common in patients
with abscess and not pneumonia
• Productive cough is a typical sign
• Chronic lung abscess can result in clubbing of
fingers
Diagnosis • Antihistamines are used to treat histamine-
• Air-fluid level on plain chest radiography mediated conditions such as allergic rhinitis and
• CT scan is helpful in complicated cases urticaria
• Histamine-1 blockers are used in the treatment of
allergies, whereas, histamine-2 blockers are used
to treat upper gastrointestinal conditions related
to excessive stomach acid production such as
peptic ulcer disease

FDA-approved indications for histamine-1 blockers:

• Allergic rhinitis
• Allergic conjunctivitis
• Allergic dermatological reactions
• Sinusitis
• Urticaria
• Atopic dermatitis
Figure 468: Chest radiograph shows a right lung abscess
with air-fluid level. Source: • Angioedema
https://dx.doi.org/10.3978%2Fj.issn.2305-5839.2015.07.08 • Bronchitis
• Motion sickness
Treatment: • Nausea
• Standard conservative therapy for lung abscess is • Vomiting
clindamycin (to cover anaerobic bacteria)
• A combination of a beta-lactam with beta- General characteristics of histamine-1 blockers:
lactamase inhibitors (ticarcillin-clavulanate) for • First and second generation histamine-1 blockers,
example is also effective as the name imply, act as antagonists at H-1
• Chloramphenicol, imipenem, meropenem, second receptors to prevent fluid moving from capillaries
generation cephalosporins, and newer generation into surrounding tissues and allergic reactions
fluoroquinolones are also possible choices • They are both reversible inhibitors of H1
• Macrolides are helpful in polymicrobial lung histamine receptors
abscesses • First-generation antihistamines cross the Blood
• Vancomycin is very effective for gram-positive brain barrier → while helpful in motion sickness,
anaerobic bacteria sleepiness is more pronounced as compared to
Suggested treatment protocol for lung abscess based on the second-generation antihistamines
above points: • The duration of action of first-generation
antihistamines is about 4 to 6 hours. Second-
• Clindamycin 600 mg IV every 8 hours followed generation antihistamines work for 12 to 24 hours
by 300 mg orally every 8 hours in combination • Both are metabolized by the liver using P450
with ampicillin/sulbactam 1.5 to 3 grams IV cytochrome system
every 6 hours • Antihistamines are available as oral pills,
• Vancomycin or linezolid are reserved for MRSA intravenous and intramuscular injections
Histamine-1 Blockers

764
 • Antihistamines are potentially cardiotoxic → • Used as an expectorant
contraindicated in patients with QT prolongation • Can be combined with the antitussive,
• Antihistamines should be avoided in pregnant and dextromethorphan, to control cough
lactating women • Cab ne combined with ephedrine for the
• Hypertension, cardiovascular disease, urinary symptomatic treatment of asthma-related cough
retention, and increased ocular pressure are Adverse effects:
relative contraindications for antihistamines
• Severe antihistamine toxicity → delirium due to • Nausea and vomiting
anticholinergic effects → physostigmine can be • Formation of kidney stones
used as an antidote for the anticholinergic effects • Diarrhea or constipation
N-acetylcysteine
First Generation Histamine-1 Blockers Mechanism of action:
Examples:
• Diphenhydramine • Inhaled N-acetylcysteine (NAC) is a mucolytic. It
liquifies mucus in chronic bronchopulmonary
• Dimenhydrinate
diseases by disrupting disulfide bonds
• Chlorpheniramine
• It is used in the treatment of cystic fibrosis and
• Doxylamine
COPD
Indications:
• Also used as an antidote for acetaminophen
• Allergic rhinitis and other allergic conditions
overdose
• Motion sickness Clinical indications:
• Sleep aid
Adverse effects: • Mucolytic therapy for chronic bronchopulmonary
• Anti-alpha-adrenergic effects diseases
• Anticholinergic → toxicity can cause delirium • Paracetamol overdose treatment
• Sedation → due to high BBB permeability. Can • Prevention of radiocontrast induced kidney
be also an indication when used as a sleeping aid disease
• Might be helpful in bipolar disorder, major
Second Generation Histamine-1 Blockers depressive disorder, obsessive-compulsive
Examples: disorder, schizophrenia, cocaine addiction, and
• Fexofenadine progressive myoclonic epilepsy
• Desloratadine Adverse effects:
• Loratadine
• Cetirizine • IV NAC may cause rash, urticaria, and itchiness
Indications: • Inhaled NAC might cause nausea, vomiting,
• Allergic reactions stomatitis, fever, rhinorrhea, drowsiness,
Adverse effects: clamminess, chest tightness, and
• Less BBB permeability than 1st generation bronchoconstriction
antihistamines → less sedating side effects Dextromethorphan
Mechanism of action:
Guaifenesin, N-acetylcysteine, and Dextromethorphan • Antitussive (cough suppressant)
Guaifenesin
• NMDA-receptor glutamate antagonist. It is a
Mechanism of action:
synthetic codeine analog. It has mild opioid effect
• Acts as an expectorant most likely by increasing when used in excess
the volume and reducing the viscosity of Clinical indications:
secretions in the trachea and bronchi
• Antitussive therapy that can be used in
• Aids in the flow of respiratory tract secretions combination with guaifenesin
• May increase the efficiency of the cough reflex Adverse effects:
and facilitate removal of the secretions
• Has CNS effects such as: muscle relaxant, • Mild opioid effects when used in excess → mild
anticonvulsant properties and NMDA receptor abuse potential
antagonist • May cause serotonin syndrome if combined with
Clinical indications: other serotonergic agents
• Naloxone can be given for overdose

765
Pseudoephedrine and Phenylephrine • cGMP, which is important for vasodilation and
Mechanism of Action vascular smooth muscle relaxation, is degraded
• Decongestants are a group of pharmaceutical by the action of phosphodiesterase type 5
drugs that relieve nasal congestion in the upper • PDE-5 inhibitors inhibit this enzyme, hence
respiratory tract increasing the pool of cGMP
• The most commonly used active ingredients in Clinical indications:
decongestants are either pseudoephedrine or • Sildenafil and tadalafil are helpful in pulmonary
phenylephrine, however, the efficacy of hypertension
phenylephrine is a little inferior • Sildenafil, tadalafil and vardenafil are helpful in
• They work by enhancing norepinephrine and erectile dysfunction
epinephrine activity by stimulating alpha-1 Adverse effects:
adrenergic receptors → vasoconstriction and • PDE5 inhibitors are contraindicated in those
constricting nasal vasculature → decongestion of taking nitrate medications
nasal mucosa • Headache is very common
• The vasoconstriction of the blood vessels in the • Dizziness, flushing, dyspepsia and nasal
nose, throat and paranasal sinuses reduces congestion have been reported as possible
inflammation, swelling and mucus formation adverse effects
• Pseudoephedrine acts indirectly on alpha-1
adrenergic receptors, whereas phenylephrine is a Prostacyclin Analogs and Prostacyclin Receptor Agonists
direct agonist Mechanism of action:
Clinical Use • Prostacyclin has direct vasodilatory effects on
• Helpful in relieving congestion in patients with pulmonary and systemic arterial vascular beds
upper respiratory tract infections • Prostacyclin analogs and prostacyclin receptor
• Open obstructed eustachian tubes agonists have similar effects
Adverse Effects • They also inhibit platelet aggregation
• Because they act on alpha-adrenergic receptors, • Examples include epoprostenol and iloprost
they may cause hypertension (better avoided in Clinical indications:
patients with hypertension) • Pulmonary hypertension
• Rebound congestion if used for more than 4 to 6 Adverse effects:
days • Flushing
• Pseudoephedrine is more controlled in some • Jaw pain
countries (not available as over the counter)
because it can cause CNS stimulation and anxiety Stimulator of Soluble Guanylate Cyclase
Pulmonary Hypertension Drugs Mechanism of action:
• Treatment Goals • In healthy individuals, NO induces vasodilation
in the pulmonary vascular bed
Endothelin Receptor Antagonists • NO binds to guanylate cyclase and mediate the
Mechanism of action: synthesis of cGMP which is important for
• In patients with pulmonary arterial hypertension, vascular smooth muscle relaxation and
one of the pathologies is endothelial dysfunction vasodilation
• Ambrisentan, bosentan and Macitentan are • NO synthesis is decreased in patients with
endothelin-1 receptor competitive antagonists pulmonary hypertension due to decreased activity
• They decrease pulmonary vascular resistance of endothelial nitric oxide synthetase
Clinical indications: • Riociguat directly stimulates soluble guanylate
• They are mainly used in the treatment of cyclase, causing vasodilation
pulmonary arterial hypertension Clinical indications:
• Atrasentan, a new endothelin receptor antagonist, • Chronic thromboembolic pulmonary hypertension
is being investigated as an anti-cancer drug • Pulmonary arterial hypertension
Adverse effects: Adverse effects:
• Hepatotoxic (monitor liver function tests) • Bleeding
• Hypotension
PDE-5 Inhibitors: • Headache
Mechanism of action: • Gastrointestinal disturbances

766
Treatment Goals • Low dose inhaled corticosteroids markedly
• Pulmonary arterial hypertension is incurable reduces asthma hospitalizations and death
• The goal of treatment is to stabilize the patient • Low dose inhaled corticosteroids (ICS) very
and achieve satisfactory clinical state without effectively prevents severe exacerbations, reduces
signs of right heart failure symptoms, and improves lung function in mild
• We should aim for halting disease progression asthma
• In addition to these specific treatments, general • Most patients do not need more than a low dose
non-specific treatments are also recommended: inhaled corticosteroid
o Rehabilitation and active physiotherapy • From 2019, short-acting beta-blocker agents are
are important no longer to be used alone in the treatment of
o Aim to improve exercise capacity, asthma
quality of life and cardiac function • Bronchoconstriction in asthma is mediated by
• High-risk patients should receive triple therapy: inflammatory processes and parasympathetic
o Endothelin receptor antagonist + tone. Therapy targets these two pathways of
o PDE-5 inhibitor + pathogenesis
o Intravenous prostacyclin analog Step-wise treatment of asthma:

Asthma Drugs Preferred reliever:

Overview
• As needed low dose ICS formoterol in all patients
• Asthma is mediated by IGE in response to
• As needed short-acting beta2 agonists
external factors such as dust, pollen
Controller treatment:
• Asthma characterized by:
Step 1:
1. Shortness of breath
2. Wheezing • As needed low dose ICS formoterol to be started
3. Cough as early as possible
4. Chronic air way inflammation (late • When SABA is taken, the patient should also take
phase) low dose ICS formoterol (i.e. do not take SABA
5. Chest tightness (Early phase) alone)
Step 2:

• Daily low dose ICS

• If you prefer to give SABA, then combine with
low dose ICS or leukotriene receptor antagonist
(i.e. do not give SABA alone)
Step 3:

• Low dose ICS plus lung-acting beta2-agonist

• Or, medium dose ICS
• Or, low dose ICS + leukotriene receptor
antagonist
Step 4:

• Medium dose ICS plus lung-acting beta2-agonist

• Or, high dose ICS with addon tiotropium
• Or, whatever is the patient is taking in step 3 +
leukotriene receptor antagonist
Principles of Treatment of Asthma: Step 5:
• The aim of treatment of asthma is to reduce the
burden to the patient and to reduce the risk of • High-dose ICS plus long-acting beta2-agonist
asthma-related death, exacerbations, airway • Consider addon therapies such as tiotropium,
damage, and medication side effects anti-IgE, anti-interleukin5/5R, or anti-
• Patients with mild asthma can still have severe interleukin4-receptor
exacerbations, which should be taken into • Refer the patient for phenotypic assessment
consideration • Consider low dose oral corticosteroid therapy

767
Beta2-Agonists: • Inhibits NK-KB, the transcription factor that
SABA: induces the production of TNF-alpha and other
inflammatory cytokines
• Short-acting beta2-agonists such as albuterol act Examples:
by causing relaxation of the bronchial smooth
muscle • Fluticasone (inhaled).
• They are helpful in the treatment of acute • Beclomethasone (inhaled)
exacerbations of asthma • Prednisone (oral corticosteroid).
• The most recent guidelines suggest they should Clinical indications:
not be used alone in the treatment of asthma
• They may cause tremors and arrhythmias • ICS are now considered as first-line therapy in all
LABA: steps of the management of asthma
• It is recommended to use a spacer or to rinse the
• Long-acting beta2-agonists such as salmeterol or mouth properly after the use of an ICS to prevent
formoterol act in the same way as SABA but for oral thrush, a fungal infection
longer periods of time Muscarinic Antagonists:
• They are helpful in the prophylaxis and in
• Examples include tiotropium and ipratropium
controller therapy of asthma
• They competitively block muscarinic receptors,
• They are typically used in step 3 in the step-wise and this prevents bronchoconstriction
approach for the treatment of asthma in
• Tiotropium is long acting
combination with ICS
• They are considered in step 4 and step 5 in the
• They may cause tremors and arrhythmias
treatment of asthma
• Also helpful in COPD
Antileukotrienes:
Albuterol Salmeterol/ Formoterol • Examples include zafirlukast and montelukast
• They block leukotriene receptors
(Short acting) (Long acting)
• They are considered in step 3 and upwards in the
treatment of asthma, usually as an addon therapy
MOA Selective β2 agonist β2 agonist • They are very effective in aspirin-induced and
Suitable for emergency use
exercise-induced asthma
• Zileuton is a 5-lipoxygenase pathway inhibitor
that blocks the conversion of arachidonic acid to
Side Tachycardia Arrhythmia Tremors
effects leukotrienes. Its use is limited because of the
potential of hepatotoxicity
Anti-IgE Monoclonal Therapy:
• Omalizumab is the main example here
Inhaled Corticosteroids: • Omalizumab binds to unbound serum IgE and
blocks binding to its receptors on mast cells
Mechanism of action:
• Useful in allergic asthmatic patients with elevated
IgE levels who fail to respond to ICS and LABA
• Usually used in step 5 as addon therapy
Methylxanthines:
• Theophylline is drug of choice
• Causes bronchodilation by inhibiting
phosphodiesterase → increasing cAMP
• Limited use nowadays because of the narrow
therapeutic index
• At low dose act as Adenosine receptor
antagonists
N.B: Adenosine is known to cause smooth
muscle contraction and histamine release
• May cause cardiotoxicity and neurotoxicity
• They inhibit the synthesis of all cytokines

768
 • Metabolized by cytochrome P450 (many drug- Chromones:
drug interactions) • Cromolyn is the main example in this class
• Blocks the action of adenosine (may explain in • It prevents mast cell degranulation
part its cardiotoxicity) • Limited efficacy in acute exacerbations
• Rarely used nowadays
Use activated charcoal is used to treat overdose toxicity
Methacholine:
• Helpful in confirming the diagnosis of asthma
• Theophylline is metabolized in the liver and
levels are sensitive to stimulation or inhibition of • Used in bronchial challenge test to demonstrate a
reduction in FEV1%
the P450 enzyme system
• It I a nonselective muscarinic receptor agonist

769
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770
 About the author
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He has completed USMLE Step 1, Step 2 CK, COMLEX
Level I, 2CE, 2 PE, 3 and scored highly on all board exams.

He is a board-certified emergency medicine attending

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