Catabolism of heme to Bile Pigments and Hyperbilirubinemia

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Catabolism of heme to Bile Pigments and

• Explain Porphyrin
• Explain formation of bile pigments
• Discuss hyperbilirubinemia
• Porphyrins are cyclic compounds composed of 4 pyrrole rings
held together by methenyl (=CH-) bridges

• Metal ions can bind with nitrogen atoms of pyrrole rings to
form complexes

• Eg: Heme is an iron-containing porphyrin while chlorophyll is

magnesium-containing porphyrin

• Heme and chlorophyll are the classical examples of
Structure of heme
• The characteristic red color of hemoglobin (ultimately blood) is due
to heme

• Heme contains a porphyrin molecule

namely protoporphyrin lX, with iron

at its center

• Protoporphyrin lX consists of four

pyrrole rings to which four methyl,

two propionyl and two vinyl groups

are attached
Structure of globin
• Globin consists of four polypeptide chains of two different
primary structures( monomeric units)

• The common form of adult hemoglobin (HbA1) is made up of
two α-chains and two β-chains(α2 β2)

• The four subunits of hemoglobin are held together by non-
covalent interactions primarily hydrophobic, ionic and
hydrogen bonds. Each subunit contains a heme group.
Degradation of heme to bile pigments
Degradation of Heme to Bile Pigments
• Erythrocytes have a life span of 120 days
• At the end of this period, they are removed from the
• Erythrocytes are taken up and degraded by the
macrophages of the reticuloendothelial (R E) system in the
spleen and liver
• Hemoglobin is cleaved to the protein part globin and non-
protein heme
• About 6 g of hemoglobin per day is broken down, and
resynthesized in an adult man (70 kg)
• Fate of globin: globin may be reutilized as such for the
formation of hemoglobin or degraded to the individual
amino acids
Formation of Bile Pigments
• Non protein heme: 80% of heme that is subjected for
degradation comes from erythrocytes and 20% from
immature RBC & cytochromes

• Normal concentration in male is 14-16 g/dl, and in female 13-
15 g/dl

• Heme oxygenase is a complex microsomal enzyme utilize
NADPH & O2 to cleaves the methenyl bridge between two
pyrrole ring (A&B) to form biliverdin, simultaneously ferrous
ion (Fe2+) is oxidized to ferric form(Fe3+) and released in
Formation of Bile Pigments

• The product of heme oxygenase is biliverdin, Fe3+ and
carbon monoxide
• Biliverdin reductase reduce biliverdin to bilirubin (yellow
pigment) by reducing methylene group
• 1gm of hemoglobin on degradation finally yields about
35 mg bilirubin
• Approximately 250-350 mg of bilirubin is daily produced
in human adults

Bile pigment Cont…
• Bilirubin is lipophilic and therefore insoluble in aqueous solution
• Bilirubin is transported in the plasma in a bound form to albumin
• Albumin has two binding sites for bilirubin- high affinity site and a
low affinity site

• Albumin-bilirubin complex enters the liver, bilirubin dissociates and is
taken up by hepatocytes by a carrier mediated active transport

• Conjugated bilirubin is excreted into the bile canaliculi against a
concentration gradient which then enters the bile.

• The transport of bilirubin diglucuronide is an active, energy-
dependent and rate limiting process
Bile Pigment cont…
• Bilirubin glucuronides are hydrolysed in the intestine by specific
bacterial enzymes namely B-glucuronidases to liberate bilirubin

• The latter is then converted to urobilinogen (colourles compound), a
small part of which may reabsorbed into the circulation

• Urobilinogen can be converted to urobilin (an yellow colour
compound) in the kidney and excreted

• The characteristic colour of urine is due to urobilin A major part of
urobilinogen is converted to stercobilin which is excreted with feces
The characteristic brown colour of feces is due to stercobilin
CELLS Urobilin
excreted in feces
Hemoglobin excreted in urine

O2 formed by bacteria KIDNEY
Heme oxygenase INTESTINE into blood

Biliverdin IX via bile duct to intestines
Biliverdin Bilirubin diglucuronide
reductase (water-soluble)

NADP+ 2 UDP-glucuronic acid
Bilirubin Bilirubin
(water-insoluble) LIVER
(water-insoluble) via blood
unconjugated to the liver

Catabolism of hemoglobin
• The normal serum total bilirubin concertration is in the
range of 0.2 to 1.0 mg/dl.

• About 0.2-0.6 mg/dl is unconjugated whie 0.2 to 0.4 mg/dl is
conjugated bilirubin

• Jaundice( French: Jaune-yellow) is a clinical condition
characterized by yellow colour of the white of the eyes
(sclerae) and skin, due to deposition of bilirubin and its
elevation levels in the serum

• The term hyperbilirubinemia is often used to represent the
increase concentration of serum bilirubin
Jaundice cont…
• Classification of jaundice : Jaundice is classified into three
major types- hemolytic, hepatic and obstructive

1. Hemolytic jaundice: This condition is associated with
increased hemolysis of erythrocytes (e.g. incompatible blood
transfusion, malaria, sickle-cell anemia).

• This results in the overproduction of bilirubin beyond the
ability of the Liver to conjugate and excrete the same

• lt should, however be noted that liver possesseas large
capacity to conjugate about 3.0 g of bilirubin per day against
the normal bilirubin production is 0.3/day
Jaundice cont…

• In hemolytic jaundice, more bilirubin is excreted into the bile
leading to the increased formation of urobilinogen and

• Hemolytic jaundice is characterized by Elevation in the serum
unconjugated bilirubin

• Increased excretion of urobilinogen in urine
• Dark brown colour of feces due to high content of stercobilinogen
Jaundice cont…
2. Hepatic (hepatocellular) jaundice:

• caused by dysfunction of the Iiver due to damage to the
parenchymal cells

• This may be attributed to viral infection (viral infection,
hepatic poisons and toxins (chloroform, carbon tetrachloride,
phosphorus etc.) cirrhosis of liver, cardiac failure etc

• Damage to the liver adversely affects the bilirubin uptake and
its conjugation by liver cells
Jaundice cont…
• Hepatic jaundice is characterized by increased levels of
conjugated and unconjugated bilirubin in the serum

• Dark coloured urine due to the excessive excretion of bilirubin
and urobilinogen

• lncreased activities of alanine transaminase (SGPT) and
aspartate transaminase (SCOT)

• Released into circulation due to damage to hepatocytes

• The patients pass pale, clay coloured stools due to the absence of

• The affected individuals experience nausea and anorexia (loss of
Jaundice cont…
3. Obstructive (regurgitation) jaundice:

• Due to an obstruction in the bile duct that prevents the
passage of bile into the intestine

• The obstruction may be caused by gall stones, tumors etc
• Due to the blockage in bile duct, the conjugated bilirubin
from the liver enters the circulation

• Obstructive jaundice is characterized by Increased
concentration of conjugated bilirubin in serum

• Serum alkaline phosphatase is elevated as it is released from
the cells of the damaged bile duct
Jaundice cont…

• Dark coloured urine due to elevated excretion of bilirubin and
clay coloured feces due to absence of stercobilinoge

• Feces contain excess fat indicating impairment in fat digestion
and absorption in the absenceo f bile

• The patients experience nausea and gastrointestinal pain
• Porphyrins are the cyclic compounds composed of 4 pyrrole
ring held together by methlenyl (=CH-) bridges
• Biliverdin & Bilirubin are bile pigments
• Bile is secreted into intestine where glucuronic acid is
removed and the resulting bilirubin is converted to
• Urobilinogen is oxidized by intestinal bacteria to the brown
• Jaundice is a clinical condition characterized by yellow colour
of the white of the eyes (sclerae) and skin, due to deposition
of bilirubin
Thank you