Bilirubin metabolism Major metabolite of heme Heme is found in hemoglobin, myoglobin and cytocrome. Most of daily production (0.2 to 0.3g/dL) is derived from breakdown of senescent erythrocytes Rate of systemic bilirubin production is equal to the rates of hepatic uptakes, conjugation, and biliary excretion.
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.
Mechanism of jaundice Excessive production of bilirubin Reduced hepatic uptake Impaired conjugation Decreased hepato-cellular excretion Impaired bile flow (both intrahepatic and extrahepatic)
Aetiology of jaundice Jaundice Pre-hepaticPost-hepatic Hepatic
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.
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 or congenital and adverse effect from drug intake.
Abnormal conjugation - Partial deficiency of glucoronyl transferase - drugs may interfere with this enzyme system e.g Novobiocin Hepatocellular damage - Acute or chronic hepatocellular injury
Post hepatic jaundice a)Obstruction or impaired excretion of bilirubin Failure of transfer of bilirubin glucuronide from the liver cell into the canaliculus (e.g Dubin-Johnson syndrome and Rotor’s syndrome) b) Obstruction at the intra-hepatic level (cholestasis) Obtruction to the flow of bile in the intralobular biliary canaliculli
Post hepatic jaundice: cont; Intra-hepatic cholestasis occurs in: - in viral hepatitis - alcoholic liver disease - as a toxic reaction to drugs, including andrigens (methyltestosterone), anabolic steroids, oral contraceptives, and phenothiazines - in benign familial cholestatic jaundice, a rare familial disease in which recurrent attacks of cholestatic jaundice represent the only abnormality
Extra-hepatic obstruction Obtruction involve main hepatic ducts, the common hepatic duct, or common bile duct. Complete obstructive jaundice prevents entry of bilirubin into the intestine, producing pale clay-colored or chalky stools Absence of fecal and urinary urobilinogen dark brown (tea colored) urine containing bilirubin.
Laboratory investigation Usually, the following examinations are taken: - FBC (hemolysis) -serum aminotransferase (AST,ALT) - Serology for hepatitis including HCAb,HBsAg, HBcAb - ALP: if elevated or if an obstruction is suspected, images of the bile ducts should be obtained. - GGT - Fractionated bilirubin
Laboratory differential diagnosis of jaundice HemolyticCholestaticHepatocellular Features Bilirubin usually <75 µ mol/L No bilirubin in urine Reticulocytosis Hemoglobin ↓ Haptoglobin ↓ LDH may ↑ Bilirubin ↑ ↑ ↑ Bilirubin in urine ALP more than 3x normal range AST, ALT,LDH usually modestly ↑ AST, ALT ↑ ↑ Bilirubin ↑later Bilirubin in urine ALP ↑ later
Neonatal jaundice Jaundice is the most common condition that requires medical attention in newborns. In most infants, unconjugated hyperbilirubinemia reflects a normal transitional phenomenon. However, in some infants, serum bilirubin levels may excessively rise, cause death in newborns and lifelong neurologic sequelae in infants who survive (kernicterus). For these reasons, the presence of neonatal jaundice frequently results in diagnostic evaluation.
Pathophysiology of neonatal jaundice Neonatal jaundice results the following phenomena: Increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates. Hepatic excretory capacity is low both because of low concentrations of the binding protein ligandin in the hepatocytes and because of low activity of glucuronyl transferase, the enzyme responsible for binding bilirubin to glucuronic acid.
Pathophysiology of neonatal jaundice:cont; Certain factors present in the breast milk of some mothers may contribute to increased enterohepatic circulation of bilirubin (breast milk jaundice). Blood group incompatibilities (eg, Rh, ABO) may increase bilirubin production through increased hemolysis. Nonimmune hemolytic disorders (spherocytosis, G-6-PD deficiency) may also cause increased jaundice
Laboratory investigation A total serum bilirubin level is the only testing required in an infant with moderately jaundice. Blood type and Rh determination in mother and infant Direct Coombs testing in the infant Hemoglobin and hematocrit values. Peripheral blood film for erythrocyte morphology Reticulocyte count Tests for viral and/or parasitic infection: These may be indicated in infants with hepatosplenomegaly or other evidence of hepatocellular disease.
Example The liver function tests shown below were those of a 77 year old man with an advanced carcinoma of the colon. The physical examination revealed an enlarged, hard, non-tender liver but there was no evidence of jaundice.
Plasma Tprot 64 g/L (60-80) Alb 35 g/L (30-50) ALP 725 U/L (30-120) ALT 78 U/L (<35) Bili 72 µmol (<20) -characteristic of cholestatic nature. -space occupying lesion due to secondary carcinoma
characteristic of cholestatic nature. -space occupying lesion due to secondary carcinoma Very high plasma ALP- obstruction of intrahepatic bile ducts Modest increase in the plasma ALT-lesion slowly expanding and destroying hepatocytes