Catabolism of heme to bile pigments and hyperbilirubinemia

Catabolism of heme to bile pigments and hyperbilirubinemia


       At the end of this lecture, student
will be able to

      Explain Porphyrin

formation of bile pigments



       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

Structure of heme

characteristic red color of hemoglobin (ultimately blood) is due to heme

contains a porphyrin molecule namely protoporphyrin lX, with iron at its center

lX consists of four pyrrole rings to which four methyl, two propionyl and two
vinyl groups are attached

Structure of globin

consists of four polypeptide chains of two different primary structures(
monomeric units)

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

four subunits of hemoglobin are held together by non-covalent interactions
primarily hydrophobic, ionic and hydrogen bonds. Each subunit contains a heme


Degradation of heme to bile pigments

Degradation of heme to bile pigments

       Erythrocytes have a life span of 120

       At the end of this period, they are
removed from the circulation

       Erythrocytes are taken up and
degraded by the macrophages of the r
eticuloendothelial (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

protein heme: 80% of heme that is subjected for degradation comes from
erythrocytes and 20% from immature RBC & cytochromes

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

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

product of heme oxygenase is biliverdin, Fe3+ and carbon monoxide

reductase reduce biliverdin to bilirubin (yellow pigment) by reducing methylene

       1gm of hemoglobin on degradation
finally yields about 35 mg bilirubin

        Approximately 250-350 mg of bilirubin is daily
produced in human adults

of Bilirubin in Plasma

Bilirubin on release from macrophages circulates
as unconjugated bilirubin in plasma tightly bound to albumin.

Albumin + free Bilirubin ó Bilirubin ~ Albumin
à unconjugated bilirubin

Why bound to albumin?


Increase the solubility of
whole molecule

Prevent unconjugated bilirubin
freely come into other tissue, cause damage.

       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

       The transport of bilirubin diglucuronide
is an active, energy-dependent and rate limiting process

       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

Formation of urobilins in the intestine

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

       Classification of jaundice : Jaundice is classified into three major types-
hemolytic, hepatic and obstructive

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

       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

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.)
of liver,
cardiac failure etc

       Damage to the liver adversely
affects the bilirubin uptake and its conjugation by liver cells

       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)

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

       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


are the cyclic compounds composed of 4 pyrrole ring held together by methlenyl (=CH-) bridges

        Biliverdin & Bilirubin are bile pigments

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 stercobilin

       Jaundice is a clinical condition
characterized by yellow colour of the white of the eyes (sclerae) and skin, due
to deposition of bilirubin

       The term hyperbilirubinemia is often
used to represent the increase 
concentration of serum bilirubin

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