This document discusses bilirubin metabolism and jaundice. It begins by explaining bilirubin formation from heme and its transport and metabolism in the liver, which involves hepatic uptake, conjugation, and biliary excretion. An enterohepatic circulation is also described. Jaundice occurs when bilirubin levels exceed 2 mg/dL and can be pre-hepatic (hemolytic), hepatic, or obstructive in origin. Specific causes and characteristics of each jaundice type are provided. The document also discusses hyperbilirubinemia conditions like Gilbert's syndrome and Crigler-Najjar syndrome. Testing to differentiate jaundice types and clinical features like symptoms and lab findings are summarized

1. 1
Presented by:
KRJ
Lumbini medical college
Pravas, Tansen, Palpa
BILIRUBIN METABOLISM

2. Formation of Bilirubin

3. Bilirubin Metabolism
Heme
Biliverdin
Bilirubin
Bilirubin Diglucoronide
Urobilinogen
Urobilin
Stercobilin

6. globin globin globin globin
Hemoglobin
heme heme heme heme

7. Bilirubin Metabolism
 Bilirubin formation
 Transport of bilirubin in plasma
 Hepatic bilirubin transport
 Hepatic uptake
 Conjugation
 Biliary excretion
 Enterohepatic circulation

11. 3 Steps of Biliverdin Metabolism
1) Hepatic Uptake
-Unconjugated bilirubin is presented in the
liver cell
-The albumin associated with it is dissociated
-Ligandin is delivered to prevent efflux of
bilirubin back to plasma

12. 2) Conjugation:-
Uncojugated bilirubin ( H2O insoluble ) is
converted to bilirubin diglucuronides ( H2O
soluble).
Takes place in the smooth endoplasmic
reticulum of the liver.
Catalysed by glucoronyl transferase.
3) Excretion:-
Bilirubin which is now H2O soluble can now
be excreted from the liver cells to the biliary
system.

13. Role of Blood Proteins in the
Metabolism of Bilirubin
1. Albumin
Dissolved in Blood
Sparingly soluble in
Blood

14. Blood
Liver
Ligandin
(-) charge
Ligandin
(-) charge
Ligandin Prevents bilirubin from
going back to plasma
own class

15. Fate of Conjugated Bilirubin in
intestine
Intestinal bacteria deconjugate the
conjugated bilirubin
This free bilirubin is further reduced to a
colorless tetrapyrrole urobilinogen (UBG)
Further reduction of the vinyl substituent
groups of UBG leads to formation of
mesobilinogen and stercobilinogen (SBG)
Stercobilinogen is mostly excreted through
feces (250-300mg/day)

16. Enterohepatic Circulation
20% of the UBG is reabsorbed from the
intestine and returned to the liver by portal
blood
The UBG is again re-excreted
Since it is passed through blood, a small
fraction is excreted in urine (<4mg/day)

17. Final Excretion
 UBG and SBG are both colorless
compounds but are oxidized to colored
products, urobilin and stercobilin
respectively by atmospheric oxidation
 Both urobilin and stercobilin are present in
urine as well as in feces

18. Plasma bilirubin
 Normal plasma bilirubin level ranges from
0.2 – 0.8 mg/dl
 Unconjugated bilirubin = 0.2 – 0.6 mg/dl
 Conjugated bilirubin = 0 -0.2 mg/dl
 Hyperbilirubinemia = >1 mg/dl
 Latent jaundice = 1 – 2 mg/dl
 Jaundice = > 2 mg/dl

19. Vanden Berg Reaction:
 Direct Indirect Biophagic
> Conjugated > unconjugated > both
> Purple colour produced
> Immediate Purple > Colour Produced after immediately and colour
Colour appear addition of alcohol only. intensified after addition of
alcohol.
19

20. Jaundice:-
Jaundice is also k/a Icterus.
Defination:
It is yellow colour pigmentation
present in skin, conjuctiva, mucous
membrane and clinically it becomes
apperent when serum bilirubin conc. Excess
more than 2 mg/dl.

23. Pathophysiology of jaundice
 Disturbance in bilirubin production or
clearance.
 It is characterized by yellow color of white
of the eyes (sclera) and skin
 Serum bilirubin levels rise above 2.0 to 2.5
mg/dL; level as high as 30-40mg/dL can
occur with severe disease
 ↑ also called as hyperbilirubinemia.

24. Mechanism of jaundice
 Excessive production of bilirubin
 Reduced hepatic uptake
 Impaired conjugation
 Decreased hepato-cellular excretion
 Impaired bile flow (both intrahepatic and
extrahepatic)

25. Types of jaundice
Jaundice
Pre-hepatic Post-hepatic
Hepatic

26. Classification of jaundice
1) Hemolytic / pre-hepatic
jaundice
 Excessive production of bilirubin due to excessive
destruction of red blood cells.
 It is associated with increased hemolysis of erythrocytes
(e.g incompatible blood transfusion, malaria, sickle cell
anemia).
 This results in overproduction of bilirubin beyond the
capacity of the liver to conjugate and excrete bilirubin.

27. Causes of haemolytic jaundice:-
a) Inside RBC.( thalessimia, sickle cell
anaemia)
b) RBC cell wall( elliptocytosis,spherocytosis)
c) Outside the RBC (Acquired haemolytic
anaemia).

28. Hemolytic Jaundice
Symptoms
weakness, Dark urine, anemia,
Icterus, splenomegaly
Lab
 UB without bilirubinuria
 fecal and urine urobilinogen
 hemolytic anemia
 hemoglobinuria (in acute intravascular
hemolysis)
 Reticulocyte counts

29. 2) Hepatocellular / Hepatic jaundice
 Defective hepatic uptake
 Abnormal conjugation
 Hepatocellular damage

30. Defective hepatic uptake
 Unconjugated bilirubin in the plasma is carried into the
liver by intracellular transport proteins.
 Absences of these proteins result in failure of bilirubin
uptake, leading to unconjugated hyperbilirubinemia (e.g
Gilbert Syndrome).
 Defective of blood supply to the liver also can cause
abnormality of bilirubin metabolism
 These problems happen in congestive heart failure,
pathway shunt due to surgery and adverse effect from
drug intake.

31.  Abnormal conjugation
- Partial deficiency of glucoronyl transferase
- drugs may interfere with this enzyme
system e.g Novobiocin
 Hepatocellular damage
- Acute or chronic hepatocellular injury

32. Hepatic Jaundice
Symptoms
weakness, loss appetite, hepatomegaly,
palmar erythema
Lab Findings
• liver function tests are abnormal
• both CB and UCB
• Bilirubinuria 

34. Gross specimen of cirrhosis of the
liver

36. 3) Obstructive Jaundice:
> Also k/a post-hepatic jaundice.
Pathogenesis
it is due to intra- and extra hepatic obstruction of
bile ducts
 intrahepatic Jaundice: Hepatitis, Drugs
 Extra Hepatic Biliary Obstruction: Stones,
Stricture, Inflammation, Tumors.

37. Intrahepatic:- Liver cell Damage/Blockage of Bile
Canaliculi.
 Drugs or chemical toxins
 Dubin-Johnson syndrome
 Intrahepatic biliary hypoplasia or atresia
 Primary biliary cirrhosis
Extrahepatic:- Obstructive of bile Ducts
 Compression obstruction from tumors
 Extrahepatic biliary atresia
 Intraluminal gallstones

39. Acholuric Vs. Choluric jaundice
 CHOLURIC – presence of bile derivatives in
the urine
– Occurs in regurgitation hyperbilirubinemia
– Obstructive type
 ACHOLURIC – absence of bile in urine
– Retention hyperbilirubinemia
– Hemolytic type

40. Jaundice- Differential diagnosis
Differential Diagnosis
 UCB or CB
 Exclude UCB (e.g. hemolysis or Gilbert
Synd.)
 Distinguish hepatocellular from obstructive
 Distinguish intrahepatic from extra hepatic
cholestasis

42. Hyperbilirubinemia
1. Gilbert’s Syndrome
2. Dubin’s johnson’s syndrome.
3. Rotor syndrome.
4. Crigler-Najjar Syndrome (Type I)
5. Crigler-Najjar Syndrome (Type II)

43. 1) Gilbert’s syndrome:-
 It is ihherited as an autosomal dominent trait.
 Defect in uptake of bilirubin by the liver.
 Bilirubin level is usually 3mg/dl and patient is
asymptomatic except for the presence of mild
jaundice.
 Defficiency of UDP-glucoronyl transferase
resulting increased unconjugated bilirubin.
 No treatment is necessary

44. 2) Dubin’s johnson’s syndrome:-
 It is a autosomal recessive trait.
 Leading to defective excretion of conjugation
bilirubin and increased conjugation bilirubin in blood.
 The bilirubin gets deposited in the liver and the liver
appears black ( black liver jaundice).
 The patient is asymptomatic except for mild
intermittent jaundice.
 No treatment is required.

45. 3) Rotor syndrome:-
 Bilirubin excretion is defective but there is no deposit
in liver.
4) Crigler-Najjar Syndrome (Type I):-
 Severe deficiency of UDP-glucuronyl transferase.
 The disease is often fatal and the children die before
the age of 2 yr.
 Jaundic e usually appear within the first 24hrs of life.
 Since unconjugated bilirubin level increases to high
levels >20mg/dl lead to kernicterus.

46. 5) Crigler-Najjar Syndrome (Type II):-
Serum bilirubin raises above 15mg/dl.
Hence kernicterus doesnot occurs.
In the bile bilirubin monoglucuronides is
present.
2nd stage of conjugation is deficient.
When barbiturates are given some response is
seen and jaundice improves.

47. Thank you