The document summarizes the process of hemoglobin degradation and bilirubin metabolism. It discusses how hemoglobin is broken down into globin, heme, and iron. Heme is further degraded into biliverdin and then bilirubin by heme oxygenase. Bilirubin is conjugated in the liver and secreted into bile. It is excreted in feces or reabsorbed and appears in urine. Conditions that interfere with bilirubin metabolism can cause jaundice. The document classifies types of jaundice and inherited disorders of bilirubin metabolism.

1. 1 of 58

2. In the human body approx. 100 – 200 million RBCs are
broken down every hour.
Degradation of Hb begins in ER of reticuloendothelial
cells (RE) of the liver, spleen, bone marrow and skin.
Hb is degraded to:
 Globins → AAs → metabolism
 Heme → bilirubin
Fe2+ → transported with transferrin and used in the
next heme biosynthesis
Not only Hb but other hemoproteins also contain heme
groups which are degraded by the same pathway.
Hemoglobin degradation

3. Breakdown of
Hemoglobin
Heme globin
Biliverdin
Biliverdin
Amino acids
Reutilized
O2, NADPH+H+
NADP+,O2
NADPH+H+
NADP+
Heme
oxygenase
Bilirubin
reductase
Fe+++
Hemoglobin

5. I
II
III
IV Fe2+
NADPHC
O2O O2
Heme Oxygenase
O

6. IIIIIIIV
Biliverdin

7. NADPH
H
Bilirubin

8. 250-300mg of bilirubin per day
Bilirubin is much less soluble in aqueous media
than biliverdin.
Potent anti-oxidant properties
The further metabolism (fate) & excretion of
bilirubin occurs in liver & intestine.
It can be divided into following process……
Uptake of bilirubin by liver cells
Conjugation of bilirubin in liver
Secretion of conj. Bilirubin into bile
Excretion of bilirubin (in feces & urine)
Fate of Bilirubin

9. Role of Blood Proteins in
the Metabolism of Bilirubin
1. Albumin
Dissolved in Blood

10. Bilirubin transported to the liver by plasma
albumin.
In liver bilirubin binds to intracellular protein.
Uptake of bilirubin by liver cells

11. Blood
Liver
Ligandin
(-) charge
Ligandin
(-) charge
Ligandin Prevents bilirubin from
going back to plasma

12. Hepatocytes convert sparingly soluble bilirubin
to a more soluble form.
This done by conjugation of two molecules of
glucuronate.
Conjugation of bilirubin in liver
Bilirubin
UDP-Glucuronate
UDP
Bilirubin glucuronyl
transferase
Bilirubin
monoglucuronide
UDP-Glucuronate
UDP
Bilirubin glucuronyl
transferase
Bilirubin
diglucuronide

13.  Two molecules of
glucuronic acid are
attached sequentially
to bilirubin by UDP
glucuronyl transferase
(UGT)
 The product, bilirubin
diglucuronide is
excreted in the bile

14. Most conjugated bilirubin formed in the liver
secretes into bile by an active transport
process.
It is a rate limiting step for the hepatic
bilirubin metabolism.
Unconjugated bilirubin is not secreted into bile.
Secretion of bilirubin into bile

15.  Following secretion conj bilirubin passes through hepatic &
bile duct into intestinal lumen.
 By bacterial enzyme β-glucuronidase bilirubin
diglucuronidase is hydrolyzed.
 Bilirubin is reduced by the fecal flora to colorless
urobilinogen.
 Upto 20 % of urobilinogen produced daily is reabsorbed
from the intestine & enters the entero-hepatic circulation.
 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 as oxidized yellow pigment, urobilin.
 The remaining urobilinogen is reduced to stercobilinogen,
 Which is excreted as oxidized brown pigment, stercobilin.
Excretion of bilirubin into bile

17. HemoglobinHeme globin
120 days
Biliverdin
Bilirubin
Bilirubin
diglucuronide
Urobilinogen
Urobilin
Stercobilin
UDP-glucuronate
Urine
Bile
Bacteria
Feces

20. The normal conc of serum bilirubin is…
Total bilirubin 0.1 to 1.0 mg/dl
Conjugated (direct) 0.1 to 0.4 mg/dl
Unconjugated (indirect) 0.2 to 0.7 mg/dl
Serum Bilirubin

21. Any conditions that interfere with bilirubin
metabolism may cause a rise in its serum conc.
If bilirubin in the blood exceeds 3mg/dl, that
condition is called hyperbilirubinaemia.
Disorders of heme catabolism

22. Hyperbilirubinaemia
 It may be due to ……
Production of bilirubin
Hepatic uptake
 Hepatic conjugation
 Excretion of bilirubin into bile
 These leads to accumulation of bilirubin
in the blood, this will leads to diffusion
into the tissue.
 The skin & sclera appear yellowish due to
deposition of bilirubin.
 This condition is called jaundice or
icterus.

24. Classification of
Hyperbilirubinaemia
Hyperbilirubinaemia may be……
Acquired
Inherited
Acquired Hyperbilirubinaemia, examples…
Hemolytic or prehepatic jaundice
Hepatocellular or Hepatic jaundice
Obstructive or posthepatic jaundice
Neonatal or physiological jaundice.
Inherited Hyperbilirubinaemia, examples…
Gilbert’s syndrome
Crigler Najjar syndrome
Dubin Johnson syndrome
Rotor syndrome

25. Classification of Jaundice
Hemolytic or prehepatic jaundice
Hepatocellular or Hepatic jaundice
Obstructive or posthepatic jaundice
Neonatal or physiological jaundice.

26. In this there is breakdown of hemoglobin to
bilirubin takes place.
The rate of bilirubin formation is more than the
ability of liver cell to conjugate bilirubin.
So, the levels of unconjugated bilirubin .
Excess hemolysis may be due to……
Sickle hemoglobin (Sickle cell anaemia)
Deficiency of G6-P dehydrogenase.
Incompatible blood transfusion.
Hemolytic or pre-hepatic Jaundice

27. Since the excess bilirubin is unconjugated, it is not
excretable in the urine.
The urine color is normal.
As more than normal amounts of bilirubin are
excreted into the intestine, resulting in amount
of urobilinogen in urine and faeces.
Biochemical picture in hemolytic jundice….
 serum unconjugated bilirubin
 amount of urobilinogen in urine and faeces
Absence of bilirubin in the urine.
Hemolytic or pre-hepatic Jaundice

29. In this kind of jaundice, there is some disorder of
the liver cells or bile passages within the liver.
Hepatic cells damage impairs conjugation of bilirubin
and results in  serum unconjugated bilirubin.
Patients with jaundice due to hepatocellular damage
commonly have obstruction of the biliary tree within
the liver that results in the  serum conjugated
bilirubin.
The causes of hepatocellular damage are….
Infection (viral hepatitis)
Toxic chemicals (alcohol, chloroform,CCl4 etc)
Drugs
Cirrhosis.
Hepatocellular or Hepatic jaundice

30. Biochemical picture in hepatic jaundice….
 serum unconjugated & conjugated bilirubin
 amount of urobilinogen in urine and faeces
Presence of bilirubin in the urine.
 level of the SGPT (ALT).
Hepatocellular or Hepatic jaundice

32. This occurs when there is an obstruction to the flow
of conjugated bilirubin from liver cells to intestine.
The condition is also called cholestasis.
This obstruction may be intrahepatic or extrahepatic.
Extrahepatic cholestasis occurs due to…
Blockage to the common bile duct by gallstone.
Carcinoma of the head of pancreas.
Carcinoma of duct itself.
Biochemical picture in obstructive jaundice….
 serum conjugated bilirubin
Absence of urobilinogen in urine and faeces.
Presence of bilirubin and bile salts in the urine.
 level of the SGPT (ALP).
Obstructive or posthepatic jaundice

34. PRE-HEPATIC HEPATIC POST HEPATIC
cause
Excessive breakdown
of RBC’s, Malaria, HS
Gilbert Syndrome
Infective
Liver Damage
Bile Duct
Obstruction
Sr. Bilirubin unconjugated Both conj +unconj conjugated
Urine bilirubin Absent
Bilirubinemia +
Deep yellow urine
As in hepatic
jaundice (++)
Urine
urobilinogen
Increases
Because of increased
stercobilinogen
Decreases
Because of
decreased
stercobilinogen
Absent(-)
Fecal
stercobilinogen
(20-250mg/day)
Markedly increased
Dark brown stool
Reduced
Pale coloured stool
Absent
clay colored stool
Vonden burg
Indirect+ biphasic Direct+

35. Mild jaundice in the first few days after birth is
common & physiological
It results from  hemolysis & immature liver enzyme
system for conjugation of bilirubin.
 Liver is deficient in enzyme UDP-glucuronyl transferase.
Enzyme deficiency is more serious with increasing
degree of prematurity.
 unconjugated bilirubin capable of crossing BBB
when its conc in plasma exceed 20-25mg/dl.
This results in…
Hyperbilirubinaemic toxic encephalopathy / kernicterus
Which cause mental retardation.
Neonatal or physiological jaundice

36.  If bilirubin levels are judged to be too high, then
phototherapy with UV light is used to convert it to a
water soluble, non-toxic form.
 If necessary, exchange blood transfusion is used to
remove excess bilirubin
 Phenobarbital is oftentimes administered to Mom
prior to an induced labor of a premature infant –
crosses the placenta and induces the synthesis of
UDP glucuronyl transferase
 Jaundice within the first 24 hrs of life or which
takes longer then 10 days to resolve is usually
pathological and needs to be further investigated

37. Phototherapy
•During phototherapy, (the
treatment of choice for
jaundice), babies are placed
under blue lights that convert
the bilirubin into compounds that
can be eliminated from the
body.
Phototherapy is usually not
needed unless the bilirubin
levels rise very quickly or go
above 16-20 mg/dl in healthy,
full term babies.

38. Gilbert’s Syndrome
Crigler-Najjar (Type I)
Crigler-Najjar (Type II)
Dubin-Johnson
Rotor’s Syndrome
Inherited Disorders of
Bilirubin Metabolism

39. Isolated increased serum bilirubin
Ruling out of hemolysis, subsequent
fractionation of the bilirubin
Possibility of the
following syndromes:
• Dublin-Johnson
• Rotor
Possibility of following syndromes
based on the bilirubin conc. :
• Gilbert’s - <3 mg/dl
• Crigler-Najjar (Type I) - >25 mg/dl
• Crigler-Najjar (Type II) - 5to20 mg/dl
Algorithm for differentiating the
familial causes of Hyperbilirubinemia
Conjugated Unconjugated

40.  Autosomal recessive diseases
 Deficiency of hepatic glucuronyl transferase enzyme.
 Significant elevation of unconjugated bilirubin in serum
 Type 1
▪ No bilirubin glucuronidation (complete absence of enzyme)
▪ It causes sever jaundice and early death.
 Type 2 (rare)
▪ Some bilirubin glucuronidation (partial absence of enzyme)
▪ Less sever.

41.  Mild elevation of unconjugated bilirubin in serum.
 Impaired hepatic uptake of bilirubin &
 Reduced activity of UDP-glucuronyl transferase.
 Could cause neonatal jaundice
 Could result in kernicterus, brain damage due to
high bilirubin concentrations, with overt
hemolysis

42.  It is a benign (harmless), autosomal recessive
condition
 Characterized by jaundice with
 predominantly elevated conjugated bilirubin and
 a minor elevation of unconjugated bilirubin.
 Defective hepatic secretion of conjugated
bilirubin into bile.
 The Liver has a characteristic greenish black
pigment in hepatocytes.
 Imparting a dark brown to black colour to the
liver.

43.  It is another form of conjugated
hyperbilirubinemia.
 It is similar to dubin-johnson syndrome but
without pigmentation in liver.

44. ….