Hemoglobin 04102018

HEMOGLOBIN
Learning Objectives:
1. List the steps in the biosynthesis of Hemoglobin
2.Describle the function of Hemoglobin
3. Describe the fate of Hemoglobin
4. List the Normal and Abnormal Hemoglobin
5. Discuss the types of Jaundice
Structure of Hemoglobin
Figure 17.4
Hemoglobin
• Oxyhemoglobin – hemoglobin bound to
oxygen
– Oxygen loading takes place in the lungs
• Deoxyhemoglobin – hemoglobin after
oxygen diffuses into tissues (reduced Hb)
• Carbaminohemoglobin – hemoglobin
bound to carbon dioxide
– Carbon dioxide loading takes place in the
tissues
Synthesis of Haemoglobin (Hb)
• Haem & globin produced at two different sites in
the cells
• Haem in mitochondria
• Globin in polyribosomes
• Well synchronized
• Normal hemoglobin production is dependent
upon 3 processes: Adequate iron delivery and
supply, adequate synthesis of protoporphyrins
and adequate globin synthesis.
Hemoglobin Structure and
Function
• Hemoglobin occupies 33% of the RBC
volume and 90-95% of the dry weight.
– 65% of the hemoglobin synthesis occurs in
the nucleated stages of RBC maturation and
35% during the reticulocyte stage.
– Normal hemoglobin consists of 4 heme
groups which contain a protoporphyrin ring
plus iron and globin which is a tetramer of 2
pairs of polypeptide chains.
Hemoglobin synthesis
Porphyria
– Since porphyrinogens are readily oxidized to form porphyrins,

excess formation of porphyrins can occur if any of the normal
enzymatic steps in heme synthesis is blocked.
– Inherited
Erythropoietic porphyria - results from
excessive production of porphyrins in the bone
marrow.
Hepatic porphyria - results from excessive
production of porphyrins in the liver.
- Acquired
Lead intoxication - interferes with protoporphyrin
synthesis
Chronic alcoholic liver disease
Synthesis of Haemoglobin
• Globin Synthesis
– In the fetus and the adult 4 types of hemoglobin
chains may be formed: alpha ( ), beta ( ),
gamma ( ), and delta ( ).
– Normal hemoglobin's contain 4 globin chains.
– Hemoglobin (hgb) F= 2 2 and is the
predominant hgb formed during liver and bone
marrow erythropoiesis in the fetus.
– A normal, full term baby has 50-85% hgbF.
– Near the end of the first year of life, normal
adult hgb levels are reached.
Hemoglobin Structure and Function
• Normal adult RBCs contain:

» 95-97% hgb A= 2 2
» 2-3% hgb A2= 2 2
» 1-2% hgb F (fetal hgb)= 2 2
– Each globin chain links with heme to form hgb= 4 globin
+ 4 heme.
– An adequate amount of globin synthesis is also

important. A decreased production in 1 chain results in
thalassemia.
Function
• The primary function of hgb is gas
transport.
• In unloading the space between the chains widens
and 2,3 diphosphoglycerate (DPG) binds. This is
the T (tense) form of hgb and it is called deoxyhgb.
It has a lower affinity for O2, so O2 unloads from the
hbg.
• When hgb loads O2 and becomes oxyhgb the
chains are pulled together, expelling 2,3 DPG. This
is the R (relaxed) form of hgb. It has a higher
affinity for O2, so O2 binds to or loads onto the
hgb.
Oxy & deoxyhaemoglobin
Function
• Acquired abnormal hgbs of clinical importance are
those that have been altered post- translationally
to produce hgbs that are unable to transport or
deliver O2 and they include:
– Carboxyhgb - CO replaces O2 and binds 200X tighter
than O2.
» This may be seen with heavy smokers
– Methgb - occurs when iron is oxidized to the +3 (ferric)
state. In order for hgb to carry O2 the iron must be in the
+2 (ferrous) state. In the body, normally~ 2% is formed
and reducing systems prevent an increase beyond 2%.
» Increases above 2% can occur with the ingestion of
strong oxidant drugs or
» As a result of enzyme deficiency.
Function
» Methgb can be reduced by treatment with methylene
blue or ascorbic acid.
– Sulfhgb - occurs when the sulfur content of the blood
increases due to ingestion of sulfur containing drugs or to
chronic constipation. Unlike 1 and 2 this is an
irreversible change of hgb.
Erythrocyte destruction
• RBC destruction is normally the result of
senescsence.
– Each day ~ 1% of the RBCs are removed and
replaced.
– RBC aging is characterized by decreased glycolytic
enzyme activity which leads to decreased energy
production and subsequent loss of deformability and
membrane integrity.
– 90% of aged RBC destruction is extravascular and
occurs mainly in the phagocytic cells in the spleen,
with a small amount occurring in the liver and bone
marrow.
Function of Haemoglobin
When there is a high concentration of oxygen e.g

in the alveoli haemoglobin combines with oxygen to
form oxyhaemoglobin. When the blood reaches the
tissue which have a low concentration of oxygen
the haemoglobin dissociates with the oxygen and
the oxygen is released into body tissues
Heme Degradation
Heme Catabolism
HEME
NADPH O2
(opens the porphyrin ring)
Fe+3 NADP+
BILIVERDIN
NADPH
NADP+
BILIRUBIN
BILIRUBIN diglucuronide
BILE
BLOOD
Stercobilin
CELLS Urobilin
excreted in feces
Hemoglobin excreted in urine
Globin
Urobilinogen
Heme
O2 formed by bacteria KIDNEY
reabsorbed
Heme oxygenase INTESTINE into blood
CO
Biliverdin IX via bile duct to intestines

NADPH
Biliverdin Bilirubin diglucuronide
reductase (water-soluble)
NADP+ 2 UDP-glucuronic acid

Bilirubin Bilirubin
(water-insoluble) LIVER
(water-insoluble) via blood
to the liver
Catabolism of hemoglobin
Jaundice (icterus)
hyperbilirubinemia
- causes yellow color of skin, nail beds and sclerae
- not a disease, but symptom of underlying disorders

Jaundice
Hyperbilirubinemia:
Two forms:
Direct bilirubin: Conjugated with
glucoronic acid
Indirect bilirubin: unconjugated,
insoluble in water.
Types of Jaundice
hemolytic jaundice
- liver can handle 3000 mg bilirubin/day - normal is 300
- massive hemolysis causes more than can be processed
- can’t be conjugated
- increased bilirubin excreted into bile, urobilinogen
is increased in blood, urine
- unconjugated bilirubin in blood increases = jaundice
obstructive jaundice
- obstruction of the bile duct
- tumor or bile stones
- gastrointestinal pain - nausea
- pale, clay-colored stools
- can lead to liver damage and increased
unconjugated bilirubin
Types of Jaundice
Hepatocellular Jaundice
- liver damage (cirrhosis or hepatitis) cause increased
bilirubin levels in blood due to decreased conjugation
- conjugated bilirubin not efficiently exported to bile
so diffuses into blood
- increased urobilinogen in enterohepatic circulation
- so urine is darker and stool is pale, clay-colored
- Serum Aminotransferases (AST and ALT levels)
are elevated
- nausea and anorexia
Examples of hyperbilirubinemia
A. Hemolytic anemia B. Hepatitis C. Biliary duct stone
excess
hemolysis
 unconjugated bilirubin
 unconjugated bilirubin  unconjugated bilirubin
(in blood)
(in blood)
 conjugated bilirubin (in blood)
 conjugated bilirubin  conjugated bilirubin
(released to bile duct)
(in blood) (in blood)
Jaundice in Newborns
premature babies often accumulate bilirubin due to

late onset of expression of bilirubin glucuronyltransferase
- maximum expression (adult level) at ~ 4 weeks
- excess bilirubin can cause toxic encephalopathy
(kernicterus)
- treated with blue fluorescent light
- converts bilirubin to more polar compound
- can be excreted in bile without conjugation
- Crigler - Najjar syndrome is deficiency in bilirubin
glucuronyltransferase

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HEMOGLOBIN

– Since porphyrinogens are readily oxidized to form porphyrins,

• Normal adult RBCs contain:

– An adequate amount of globin synthesis is also

When there is a high concentration of oxygen e.g

Biliverdin IX via bile duct to intestines

NADP+ 2 UDP-glucuronic acid

- not a disease, but symptom of underlying disorders

A. Hemolytic anemia B. Hepatitis C. Biliary duct stone

premature babies often accumulate bilirubin due to

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