7. Bilirubin Metabolism
Bilirubin formation
Transport of bilirubin in plasma
Hepatic bilirubin transport
Hepatic uptake
Conjugation
Biliary excretion
Enterohepatic circulation
8.
9.
10.
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
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
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.
21.
22.
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)
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
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
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
38.
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
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.