Bilirubin Metabolism & Jaundice. Formation of Bilirubin from Heme in RE system (esp. liver & spleen) Heme is degraded in RE system (esp. liver & spleen)

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 Reabsorbed in stool (brown) 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 DISEASEHOWEVER,

IT IS A SIGN OF AN UNDERLYING DISEASE

Types of Jaundice

1- Hemolytic Jaundice2- Obstructive Jaundice3- Hepatocellular Jaundice

Hemolytic Jaundice

Massive lysis of RBCs in hemolytic anemiae.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 increasedNo bilirubin in urine (Color of urine is normal)as it is bound to albumin

StoolDark colorIncreased 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 bloodExcessive conjugated bilirubin is excreted in urine giving the yellowish brown color of urine

Blood:Increased conjugated (direct) bilirubinGGT & ALP are markedly elevated (ALT is normal or mildly elevated)

Urine:Bilirubin appears in urineThus, color is yellowish brownUrobilinogen is reduced

StoolPale (low stercobilin)

Hepatocellular Jaundice

FirstLiver 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

BloodIncreased BOTH unconjugated (indirect) & conjugated (direct) bilirubinALT & AST levels are markedly elevated

Urine:Bilirubin is present in urineSo, urine color is yellowish brown

StoolPale (low stercobilin)

BLOOD URINE

GGT & ALP ALT & AST CONJUGATEDBILIRUBIN

UNCONJUGATEDBILIRUBIN BILIRUBIN UROBILINOGEN

NORMAL NORMAL N:0 - 0.2 mg/dl N: 0.2 – 1 mg/dl NIL TRACE NORMAL

NORMAL NORMAL N:0 - 0.2 mg/dl INCREASED NIL INCREASD HEMOLYTICJAUNDICE

MARKED INCREASE

Normal or

mild increaseINCREASED N:0 - 0.2 mg/dl PRESENT Decreased or absent OBSTRUCT.

JAUNDICE

Normalor

mild increase

MARKEDINCREASED INCREASED INCREASED PRESENT Decreased or absent HEPATOCEL.

JAUNDICE

LABORATORY INVESTIGATIONS IN TYPES OF JAUNDICE

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 syndromeLow activity of glucoronyltransferase (conjugating enzyme)Rare Inherited l disease Severe hyperbilirubinemia in neonates (unconjugated bilirubin)Complicated by kernicterus & early death

Gilbert`s syndromeDecreased production (expression) of glucoronyltransferaseRare autosomal dominant traitMore common menOccurs in 2-3 % of menUsually asymptomatic hyperbilirubinemia Liver function tests are normal

Dubin-Johnson syndromeDefect in transfer of conjugated bilirubin into the biliary canalculiConjugated hyperbilirubinemia.