Bilirubin metabolism by asogwa innocent kingsley ml 508
ASOGWA INNOCENT KINGSLEY
• Bilirubin is the orange-yellow pigment derived from
senescent red blood cells.
• It is a toxic waste product in the body.
• It is extracted and biotransformed mainly in the liver, and
excreted in bile and urine.
• It is a bile pigment
• Elevations in serum and urine bilirubin levels are normally
associated with Jaundice.
Erythrocytes become “old” as they lose their flexibility
and become pikilocytes (spherical), increasingly rigid
and fragile. Once the cell become fragile, they easily
destruct during passage through tight circulation
spots, especially in spleen, where the intra-capillary
space is about 3 micron as compared to 8 micron of
RBCs useful life span is 100 to 120 days,After
which they become trapped and fragment in smaller
circulatory channels, particularly in those of the spleen.
For this reason, the spleen is sometimes called the “red
blood cell graveyard.”
Dying erythrocytes are engulfed and destroyed by
Formation of Bilirubin
• Primary site of synthesis:-
SPLEEN: The Graveyard
of Red Blood Cells
• Secondary site of synthesis:-
LIVER & BONE MARROW
An average person
produces about 4
mg/kg of bilirubin
The daily bilirubin
production from all
sources in man
averages from 250
to 300 mg.
RBC’S DESTROYED IN
LIVER, SPLEEN &
DESTROYED IN THE
Extravascular Pathway for RBC Destruction
(Liver, Bone marrow,
Amino acid pool
Phagocytosis & Lysis
Within cells of the RE system, heme degraded to bilirubin in a two-step process
• a. The porphyrin ring is opened and the
iron atom is removed by the action of
• heme oxygenase to produce the green-
colored intermediate biliverdin.
• b. Subsequent reduction converts
biliverdin to bilirubin, which has a
• The globin is recycled or converted into amino acids, which
in turn are recycled or catabolized as required.
• Heme is oxidized, with the heme porphyrin ring being
opened by the endoplasmic reticulum enzyme, heme
• The oxidation occurs on a specific carbon producing
equimolar amounts of the biliverdin, iron , and carbon
monoxide (CO). This is the only reaction in the body that is
known to produce CO.
• Most of the CO is excreted through the lungs, with the
result that the CO content of expired air is a direct measure
of the activity of heme oxygenase in an individual.
III IVI II
Oxidation Heme Oxygenase
In the first reaction, a
group is cleaved by
heme oxygenase to
form Linear Biliverdin
from Cyclic Heme
m o l e c u l e .
Fe 2+ is released from
the ring in this process.
• In the next reaction, a second
bridging methylene (between
rings III and IV) is reduced by
Reduction Biliverdin Reductase
• biliverdin causing a change in the color of the molecule from
blue-green (biliverdin) to yellow-red (bilirubin).
• The latter catabolic changes in the structure of tetrapyrroles
are responsible for the progressive changes in color of a
hematoma, or bruise, in which the damaged tissue changes
its color from an initial dark blue to a red-yellow and finally
to a yellow color before all the pigment is transported out of
the affected tissue.
• Peripherally arising bilirubin is transported to the liver in
association with albumin, where the remaining catabolic
reactions take place.
Bilirubin is not very water-soluble, so most of it is carried to the liver bound to
In cells of the liver, bilirubin undergoes modification to
increase its water solubility so that it can be excreted more
a.Bilirubin is conjugated to two molecules
of glucuronic acid, creating bilirubin
b. Bilirubin diglucuronide is transported
out of the hepatocytes into the bile
canaliculi and is thus excreted in bile.
• The bilirubin synthesized in
spleen, liver & bone marrow
is unconjugated bilirubin.
• It is hydrophobic in nature so
it is transported to the liver
as a complex with the
plasma protein, albumin.
– Lipid soluble
– : limits excretion
– 1 gm albumin binds 8.5
– Fatty acids & drugs can
– Indirect positive reaction
in van den Bergh test
Role of Blood Proteins in the
Metabolism of Bilirubin
Dissolved in Blood
Ligandin Prevents bilirubin from
going back to plasma
In Endoplasmic Reticulum
In the microsomes of the endoplasmic reticulum,
unconjugated bilirubin is converted to water soluble
mono- or di- conjugates by sequential covalent
coupling with glucuronic acid.
Bilirubin is conjugated in
a two step process to
form bilirubin mono- &
Conjugation with Glucoronates
In the Intestine
• In the small intestine, conjugated bilirubins are poorly
reabsorbed, but are partly hydrolyzed back to unconjugated
bilirubin by catalytic action of bacterial ß-glucuronidases.
• In the distal ileum and colon, anaerobic flora mediate further
catabolism of bile pigments:
a) hydrolysis of conjugated bilirubin to unconjugated bilirubin by
b) multistep hydrogenation (reduction) of unconjugated bilirubin to
form colorless urobilinogens; and
c) oxidation of unconjugated bilirubin to brown colored
• Urobilinogens is a collective
term for a group of 3
– Stercobilinogen (6H)
– Mesobilinogen (8H)&,
– Urobilinogen (12H)
• Upto 20 % of urobilinogen
produced daily is reabsorbed
from the intestine & enters the
• Most of the reabsorbed urobilinogen is taken up by the liver
& is re-excreted in the bile.
• A small fraction (2 % - 5 %) enters the general circulation &
appears in the urine.
• In the lower intestinal tract, the 3 urobilinogens
spontaneously oxidize to produce the corresponding bile
– Mesobilin &
which are orange-brown in color and are the major
pigments of stool.