PATHOLOGY

Pathology is the study of the causes and effects of

disease or injury.

Pathos (suffering)
Logos
Appendix
Normal lungs Lungs with tuberculosis
Liver anatomy
Symmers' pipe stem periportal fibrosis,
Symmers' pipe stem periportal fibrosis, egg’s granuloma
 PATHOLOGY
• Divisions
• Histopathology, cytology
• Haematology
• Chemical Pathology
• Microbiology, Immunology
• Genetics
 PATHOLOGY
• GENERAL
• SYSTEMIC
 PATHOLOGY
• ETIOLOGY (“Cause”)
• PATHOGENESIS (“Insidious
development”)
• MORPHOLOGY
(ABNORMAL ANATOMY)
• CLINICAL EXPRESSION
 Cellular Injury,
Necrosis, Apoptosis
“Cell Injury”
 Cell Injury
• If the cells fail to adapt under stress, they undergo
certain changes called cell injury. The affected cells
may recover from the injury (reversible) or may die
(irreversible).
• Causes of Cell Injury
– oxygen deprivation (anoxia)
– physical agents
– chemical agents
– infections agents
– immunologic reactions
– genetic defects
– nutritional imbalances
 Causes of hypoxia or anoxia
• Oligemia
• Ischemia
• Atherosclerosis
= hard: hardened lumpy plaque of lipid,
lymphocytes and foam cells
• Thrombosis
– thrombus = lump: clot of coagulated blood that
forms within a blood vessel or heart chamber and
remains at the site of its formation, impeding blood
flow
• Embolism
– embolos = stopper: clot or gas bubble that travels
from site of formation to block a small vessel
 Reversible or Irreversible
• Reversible cell injury
Irreversible cell injury
 Reversible ischemic injury
Reduced oxygen tension inhibits ATP production and
increases glycolysis, anaerobic respiration
Increased glycolysis decreases pH, denatures proteins,
activates acid proteases and phosphatases
ATP depletion inhibits active transport of ions across
membranes
Decreased ion transport flattens ion gradients and disrupts
osmotic gradients
Disrupted osmosis results in swelling
Swelling smoothes endoplasmic reticular membranes,
decreases protein synthesis, disperses cytoskeletal ultra
structure
Nuclei remain intact and cells may restore integrity
Depends on time elapsed and tissue type
Reversible: Hydropic Degeneration
Reversible damage –
cellular swelling

Cellular swelling (synonyms: hydropic change, vacuolar degeneration,

cellular edema) is an acute reversible change resulting as a response to
nonlethal injuries. It is an intracytoplasmic accumulation of water due to
incapacity of the cells to maintain the ionic and fluid homeostasis. It is
easy to be observed in parenchymal organs : liver (hepatitis, hypoxia),
kidney (shock), myocardium (hypoxia, phosphate intoxication). It may
be local or diffuse, affecting the whole organ.
Swollen kidney tubules
• Increased eosinophili
staining
• Decreased basophilic
staining (RNA)
• Plasma membrane
rounding, blebbing,
loss of cilia, due to
loss of connections
with cytoskeleton
• Integrity of tubules
degrading, but
basement membranes
intact
Necrotic kidney tubules
• Cellular
fragmentation
• Loss and fading of
nuclei--karyolysis
• Burst membranes
• Loss of tissue
architecture
Blebs in cells
Nuclear chromatin clumping
Mitochondrial swelling
 Morphology of Cell Injury
• Irreversible/Necrosis
– The changes are produced by enzymatic digestion
of dead cellular elements, denatunation of
proteins and autolysis (by lysosomal enzymes)
– Cytoplasm - increased eosinophilia
– Nucleus - nonspecific breakdown of DNA leading
to
• pyknosis (shrinkage),
• karyolysis (fading) and
• karyorrhexis (fragmentation).
 Irreversible cell injury
• Nuclear pyknosis
• “ “ karrhyrexis
Pyknotic /necrotic cell
Karyolysis
 Tissue necrosis
• Coagulative necrosis
– Proteins denature and aggregate rather than degrade
– Dry gangrene
• Liquefactive necrosis
– Enzymatic digestion of cellular components
– Wet gangrene
• Caseous necrosis
– End result of tuberculous infections, granuloma
• Fatty necrosis
– End result of pancreatic lipases digesting fat cells
resulting in calcium soaps
• Fibrinoid necrosis
– Ag-Ab complexes and fibrin accumulate in arteries or
other vessels
Coagulative necrosis—kidney infarction

This is the typical pattern with ischemia and infarction (loss of

blood supply and resultant tissue anoxia). Here, there is a wedge-
shaped pale area of coagulative necrosis (infarction) in the renal
cortex of the kidney. Microscopically, the renal cortex has
undergone anoxic injury at the left so that the cells appear pale
and ghost-like. There is a hemorrhagic zone in the middle where
the cells are dying or have not quite died, and then normal renal
parenchyma at the far right.
 Coagulative necrosis—myocardial infarction

Gross, cross section: A pale, whitish infarct is surrounded by a zone of

hyperemia (vascular dilatation).
Very low power glass slide: The area of coagulative necrosis is bright
pink compared to the lighter pink viable myocardium. The bluish areas
on each side of the necrotic zone represent the granulation tissue
response to the necrosis.
Coagulative Necrosis
• When there is marked
cellular injury, there is cell
death. This microscopic
appearance of myocardium
is a mess because so many
cells have died that the
tissue is not recognizable.
Many nuclei have become
pyknotic (shrunken and
dark) and have then
undergone karorrhexis
(fragmentation) and
karyolysis (dissolution).
The cytoplasm and cell
borders are not
recognizable.
 Liquefactive necrosis
 This is liquefactive necrosis
in the brain in a patient who
suffered a "stroke" with
focal loss of blood supply to
a portion of cerebrum. This
type of infarction is marked
by loss of neurons and
neuroglial cells and the
formation of a clear space at
the centre left.
Liquefactive necrosis
• Caseous necrosis:
– specific form of coagulation necrosis typically
caused by mycobacteria (e.g. tuberculosis).
– a form of coagulative necrosis (cheese-like).
– Example: tuberculosis lesions.
• Fat necrosis:
– enzymatic digestion of fat.
– Example: necrosis of fat by pancreatic enzymes.
• Gangrenous necrosis:
– Necrosis (secondary to ischemia)
– usually with superimposed infection.
– Example: necrosis of distal limbs, usually foot
and toes in diabetes.
 Caseous Necrosis
• Microscopically,
caseous necrosis is
characterized by
acellular pink areas
of necrosis, as seen
here at the upper
right, surrounded by
a granulomatous
inflammatory
process.
• Caseous necrosis
hilar lymph node
lung
Caseous necrosis of lung
 Fat Necrosis
• This is fat necrosis of the
pancreas. Cellular injury to
the pancreatic acini leads
to release of powerful
enzymes which damage fat
by the production of soaps,
and these appear grossly as
the soft, chalky white areas
seen here on the cut
surfaces.
 Gangrenous Necrosis
• In this case, the toes
were involved in a
frostbite injury. This
is an example of
"dry" gangrene in
which there is
mainly coagulative
necrosis from the
anoxic injury.
Dry gangrene
 Fate of necrosis
• Complete restoration of tissue, rare
• Inflammation
• Fibrosis
• Calcification
 Apoptosis
• Programmed cell death
– Especially during fetal development
– In response to hormonal cycles (e.g.
endometrium)
– Normal turnover in proliferating tissues (e.g.
intestinal epithelium)
• Cells shrink, not swell
• Nuclei condense and DNA fragments
• Cells fragment into membrane-bound bits
• Bits are phagocytosed by macrophages
 Apoptosis
• In the human body ~ 100,000 cells are
produced every second by mitosis and a
similar number die by apoptosis.
• Development and morphogenesis
– During limb formation separate digits
evolve
– Ablation of cells no longer needed
(tadpole)
• Homeostasis
– Immune system
– >95% T and B cells die during
maturation (negative selection)
• Deletion of damaged/ dangerous cells
 Mechanisms of Apoptosis
• Apoptosis can be induced by various
factors under both physiological and
pathological conditions:
• It is an energy-dependent cascade of
molecular events which include protein
cleavage by a group of enzymes
(caspases), protein cross-linking, DNA
breakdown.
• Apoptosis is regulated by a large family
of genes some of which are inhibitory
(bcl-2) and some are stimulatory (bax).
 Morphology of Apoptosis
• Shrinkage of cells
• Condensation of nuclear chromatin peripherally
under nuclear membrane
• Formation of apoptotic bodies by fragmentation of
the cells and nuclei. The fragments remain
membrane-bound and contain cell organelles with or
without nuclear fragments.
• Phagocytosis of apoptotic  bodies by adjacent
healthy cells or phagocytes.
• Unlike necrosis, apoptosis is not accompanied by
inflammatory reaction
 Apoptosis
In this fetal thymus there is
involution of thymic lymphocytes
by the mechanism of apoptosis.
Individual cells fragment and are
consumed by phagocytes to give
the appearance of clear spaces
filled with cellular debris.
Apoptosis is controlled by many
mechanisms. Genes such as Bcl-2
are turned off and Bax genes
turned on. Proteolytic enzymes
called caspases produce much
cellular breakdown.
 Apoptosis
Apoptosis is a more orderly
process of cell death in which
there is individual cell
necrosis, not necrosis of large
numbers of cells.
In this example, liver cells are
dying individually (arrows)
from injury by viral hepatitis.
The cells are pink and without
nuclei.
 Free radicals
Free radicals are normally produced during cellular respiration
Free radical generation occurs by….
– Absorption of irradiation
• E.g. OH•, and H•
– Endogenous normal metabolic reactions
• E.g. O2-•, and H2O2
– Transition metals
• E.g. Fe+++
– nitrous oxide
• an important paracrine-type mediator that helps regulate
vascular pressure
– Toxins
• e.g. carbon tetrachloride
• Free radicals are removed by….
– Spontaneous decay
– Anti-oxidants
• E.g. Vitamin E, vitamin A, ascorbic
acid, glutathione
– Storage proteins
• E.g. transferrin, ferritin,
ceruloplasmin
– Enzymes
• Catalase, SOD, glutathione
peroxidase
• Injure cells by…..
–Membrane lipid peroxidation
• Autocatalytic chain reaction
–Interaction with proteins
• Protein fragmentation and
protein-protein cross-linkage
–DNA damage
• Single strand breaks (genomic
and mitochondrial)
• Heat shock response genes
– comprise a large group of genes
– expression is up-regulated in the face of cell
stressors and
– serve to protect proteins from stress-related
damage
– "clean up" damaged proteins from the cell.
• Many tissues and organs can survive significant
injury if they are "pre-stressed"
– Ways to exploit this phenomenon to improve
organ transplantation and tissue repairs are
being tested in clinical trials.
 ISCHAEMIA/REPERFUSION INJURY
• If cells are reversibly injured due to ischaemia, complete
recovery occurs following restoration of blood flow.
• However, reperfusion can result in more damage including
cell death.
• This is due to incompletely metabolised products producing
reactive oxygen species on re-introduction of oxygen
– (especially damaging to mitochondria;
– loss of anti-oxidants during ischaemia;
– inflow of calcium with the renewed blood flow;
– recruitment of leukocytes to the injured area.
• Reperfusion injury is especially important in ischaemic
damage to the heart and brain and in organ transplantation.
• Various therapies and preventive measures are in use.
 Cellular adaptation.
• Cells are the structural and functional units of tissues
and organs. They are capable of adjusting their
structure and functions in response to various
physiological and pathological conditions. This
capability is called cellular adaptation.
• Cellular adaptations include:
– Atrophy--shrinkage of cells
– Hypertrophy--increase in the size of cells which
results in enlargement of the organs
– Hyperplasia--increased number of cells in an
organ or tissue
– Metaplasia--transformation or replacement of one
adult cell type with another
 Atrophy
• There are some muscle fibres
here that show atrophy.
• The number of cells is the
same as before the atrophy
occurred, but the size of
some fibres is reduced.
• This is a response to injury
by "downsizing" to conserve
the cell.
• In this case, innervation of
the small fibres in the centre
was lost.
• This is a trichrome stain.
 Atrophy-
-shrinkage of cells; classified as:
–Physiologic--due to decreased work load
(e.g., decreased size of uterus following
child birth, or disease)
–Pathologic--primarily due to denervation
of muscle, diminished blood supply,
nutritional deficiency
 Hypertrophy
• This is cardiac
hypertrophy involving the
left ventricle.
• The number of myocardial
fibres does not increase,
but their size can increase
in response to an increased
workload, leading to the
marked thickening of the
left ventricle in this patient
with systemic
hypertension.
 Hypertrophy-
• Increase in the size of cells which results
in enlargement of the organs.
• It is mostly seen in cells that cannot
divide, such as:
– skeletal muscle (pumping iron),
– cardiac muscle (hypertension).
• These changes usually revert to normal if
the cause is removed.
• Hypertrophy is mediated by different
mechanisms.
Hyperplasia
• The prominent folds of
endometrium in this uterus
opened to reveal the
endometrial cavity are an
example of hyperplasia.
• Cells forming both the
endometrial glands and the
stroma have increased in
number.
• As a result, the size of the
endometrium has increased.
• This increase is physiologic
with a normal menstrual cycle.
 Hyperplasia-
Increased number of cells in an organ or tissue.
Hyperplasia may sometimes co-exist with
hypertrophy. Hyperplasia can be classified as:
– physiologic--hormonal (e.g., breast and uterus
during pregnancy)
– compensatory--regeneration of liver following
partial hepatectomy. Various growth factors and
interluekins are important in such hyperplasia.
– pathologic--excessive hormonal stimulation, viral
infection (papilloma viruses); neoplasms
• Hypoplasia is underdevelopment or incomplete
development of a tissue or organ. Although the term
is not always used precisely, it properly refers to an
inadequate or below-normal number of cells.
Hypoplasia is a congenital condition, while
hyperplasia generally refers to excessive cell growth
later in life. (Atrophy, the wasting away of already
existing cells, is technically the direct opposite of
both hyperplasia and hypertrophy.)
• Hypoplasia can be present in any tissue or organ. It
is descriptive of many medical conditions, such as:
• Breasts during puberty,
• Testes in Klinefelter's syndrome
Metaplasia
• Metaplasia of laryngeal
respiratory epithelium has
occurred here in a smoker.
• The chronic irritation has led
to an exchanging of one type
of epithelium (the normal
respiratory epithelium at the
right) for another (the more
resilient squamous
epithelium at the left).
• Metaplasia is not a normal
physiologic process and may
be the first step toward
neoplasia.
 Metaplasia-
Transformation or replacement of one adult cell type
to another adult cell type
– (e.g., the change from columnar to squamous cells
in respiratory tract, from squamous to columnar in
Barrett esophagitis).
– Metaplasia also occurs in mesenchymal tissue (e.g.,
formation of bone in skeletal muscle).
Metaplastic changes usually result from chronic
irritation.
Metaplastic changes seem to precede the development
of cancer, in some instances.
Metaplasia is thought to arise from reprogramming of
stem or undifferentiated cells that are present in adult
tissue.
Dysplasia
• This is dysplasia. The
normal cervical squamous
epithelium has become
transformed to a more
disorderly growth pattern,
or dysplastic epithelium.
• This is farther down the
road toward neoplasia, but
dysplasia is still a
potentially reversible
process.
 Cellular inclusions
• Fatty change
• Iron overload
• Carbon in tissues, anthracosis
• Occupational diseases
 Reversible damage – fatty change

Intracellular accumulations of a variety of materials can occur in

response to cellular injury. Here is fatty metamorphosis (fatty change) of
the liver in which deranged lipoprotein transport from injury (most often
alcoholism) leads to accumulation of lipid in the cytoplasm of
hepatocytes.
• Causes
• Fatty liver is commonly
associated with alcohol or
metabolic syndrome (diabetes,
hypertension, obesity, and
dyslipidemia), but can also be due
to any one of many causes
 Calcification
• Dystrophic calcification
• Metastatic calcification
• Dystrophic calcification, without a systemic
mineral imbalance.
• Metastatic calcification, a systemic elevation
of calcium levels in the blood and all tissues
such as malignancy and hyperprathyroidism.
•
Dystrophic calcification
Metastatic calcification lung