Catabolism of heme to Bile Pigments and Hyperbilirubinemia

Catabolism of heme to Bile Pigments and Hyperbilirubinemia

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Catabolism of heme to Bile Pigments and Hyperbilirubinemia

Catabolism of heme to Bile Pigments and
Hyperbilirubinemia

Content
• Explain Porphyrin
• Explain formation of bile pigments
• Discuss hyperbilirubinemia

 

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Porphyrin
• 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
a

magnesium-containing porphyrin

• Heme and chlorophyll are the classical examples of
metalloporphyrins

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Porphyrin

 

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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

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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.

 

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Degradation of heme to bile pigments

 

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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
circulation
• 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 www.remixeducation.in
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
circulation www.remixeducation.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

 

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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 www.remixeducation.in
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

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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
unconjugated to the liver

Catabolism of hemoglobin www.remixeducation.in
Hyperbilirubinemia

 

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Jaundice
• 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
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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
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Jaundice cont…

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

• 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
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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

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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
stercobilinogen

• The affected individuals experience nausea and anorexia (loss of
appetite)
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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
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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

 

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Summary
• 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
• Urobilinogen is oxidized by intestinal bacteria to the brown
stercobilin
• Jaundice is a clinical condition characterized by yellow colour
of the white of the eyes (sclerae) and skin, due to deposition
of bilirubin www.remixeducation.in
Thank you
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