Conjugation of Bilirubin

Report
Bilirubin Metabolism
&
Jaundice
Formation of Bilirubin from Heme
Heme is degraded in RE system (esp. liver & spleen)
85% from RBCs
15% from turnover of immature RBCs & cytochromes
Heme
heme oxygenase
biliverdin (green)
bilirubin (red-orange)
bile pigments
In Blood with albumin
UNCONJUGATED BILIRUBIN
(or INDIRECT BILITUBIN)
Salicylates & sulfonamides can displace
bilirubin from albumin & so bilirubin
enters CNS causing neural damage
Bilirubin Metabolism in the Liver
• Uptake of Bilirubin by hepatocytes:
Bilirubin dissociates from its carrier albumin & enters hepatocytes
• Conjugation of Bilirubin:
In hepatocytes, bilirubin is conjugated with two molecules of glucuronic
acid by the enzyme glucuronyl transferase
• Excretion of bilirubin into bile:
Conjugated bilirubin (bilirubin diglucuronide) is transported into bile canalculi
& then into bile.
Process is energy dependent & is impaired in liver diseases
Bilirubin Metabolism in the Intestine
Conjugated bilirubin
bacteria
in the intestine
Urobilinogen
Stercobilin
in stool
(brown)
Reabsorbed
Kidney
Urine Urobilin (yellow)
OVERVIEW OF BILIRUBIN METABOLISM
Jaundice
Yellow color of skin, nail beds & sclera caused by deposition of
bilirubin secondary to increased bilirubin levels in blood
(hyperbilirubinemia)
JAUNDICE IS NOT A DISEASE
HOWEVER,
IT IS A SIGN OF
AN UNDERLYING DISEASE
Types of Jaundice
1- Hemolytic Jaundice
2- Obstructive Jaundice
3- Hepatocellular Jaundice
Hemolytic Jaundice
Massive lysis of RBCs in hemolytic anemia
e.g. sickle cell anemia
Bilirubin is produced in a rate faster than rate of
conjugation by the liver
Blood:
Increased blood unconjugated (indirect) bilirubin
Urine:
Urobilinogen is increased
No bilirubin in urine (Color of urine is normal)
as it is bound to albumin
Stool
Dark color
Increased stercobilin (produced from increased urobilinogen)
Obstructive Jaundice
In bile duct obstruction:
Conjugated bilirubin is prevented from passing to the intestine.
Thus, it is regurged to blood increasing conjugated (direct) bilirubin in blood
Excessive conjugated bilirubin is excreted in urine giving the yellowish brown color of urine
Blood:
Increased conjugated (direct) bilirubin
GGT & ALP are markedly elevated (ALT is normal or mildly elevated)
Urine:
Bilirubin appears in urine
Thus, color is yellowish brown
Urobilinogen is reduced
Stool
Pale (low stercobilin)
Hepatocellular Jaundice
First
Liver damage (by hepatitis or hepatitis) causes low conjugation efficiency leading to increased
unconjugated (indirect) bilirubin in blood
Second
Conjugated bilirubin is not efficiently secreted into bile. Instead, diffuses to blood increasing
conjugated (direct) bilirubin in blood
Blood
Increased BOTH unconjugated (indirect) & conjugated (direct) bilirubin
ALT & AST levels are markedly elevated
Urine:
Bilirubin is present in urine
So, urine color is yellowish brown
Stool
Pale (low stercobilin)
LABORATORY INVESTIGATIONS IN TYPES OF JAUNDICE
URINE
BLOOD
UROBILINOGEN
BILIRUBIN
UNCONJUGATED
BILIRUBIN
CONJUGATED
BILIRUBIN
ALT & AST
GGT & ALP
NORMAL
TRACE
NIL
N: 0.2 – 1 mg/dl
N:0 - 0.2 mg/dl
NORMAL
NORMAL
HEMOLYTIC
JAUNDICE
INCREASD
NIL
INCREASED
N:0 - 0.2 mg/dl
NORMAL
NORMAL
OBSTRUCT.
JAUNDICE
Decreased or absent
PRESENT
N:0 - 0.2 mg/dl
INCREASED
Normal
or
mild increase
MARKED
INCREASE
INCREASED
MARKED
INCREASED
HEPATOCEL.
JAUNDICE
Decreased or absent
PRESENT
INCREASED
Normal
or
mild increase
Jaundice in Newborns
•
In newborns (especially premature),
Bilirubin accumulates as the liver enzyme bilirubin glucuronyl transferase
(responsible for conjugation of bilirubin) is low at birth. (The enzymes reaches
adult levels in about 4 weeks)
•
Accordingly, unconjugated bilirubin is increased in blood.
Elevated bilirubin in excess of the binding capacity of albumin can diffuse
into basal ganglia & cause toxic encephalopathy (kernicterus)
•
Treatment
Exposure of the newborn skin to blue fluorescent light which converts
bilirubin to more polar & hence water-soluble isomers
These isomers can be excreted into bile without conjugation to glucuronic
acid.
Congenital hyperbilirubinemia
Bilirubin is elevated in blood due to inherited defects in the bilirubin metabolic pathway
Crigler-Najjar syndrome
Low activity of glucoronyltransferase (conjugating enzyme)
Rare Inherited l disease
Severe hyperbilirubinemia in neonates (unconjugated bilirubin)
Complicated by kernicterus & early death
Gilbert`s syndrome
Decreased production (expression) of glucoronyltransferase
Rare autosomal dominant trait
More common men
Occurs in 2-3 % of men
Usually asymptomatic hyperbilirubinemia
Liver function tests are normal
Dubin-Johnson syndrome
Defect in transfer of conjugated bilirubin into the biliary canalculi
Conjugated hyperbilirubinemia.

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