1. 1 CLINICAL CHEMISTRY-2 (MLT 302) LIVER FUNCTION AND THE BILIARY TRACT LECTURE THREE Dr. Essam H. Aljiffri

2. 2 Jaundice Bilirubin is a yellow pigment which causes discoloration of the skin and when serum levels exceed 35-40 µmol/L. Concentrations may increase for three reasons: - the production rate of bilirubin is increased, exceeding the excretory capacity of the liver (prehepatic jaundice); - conjugating and / or excretory functions are reduced, (hepatic or hepatocellular jaundice); - biliary obstruction interferes with the flow of bile and thus bilirubin excretion (posthepatic, obstructive or cholestatic jaundice).

3. 3 Pathogenesis of Jaundice

4. 4 Prehepatic Jaundice Prehepatic jaundice is caused by increased destruction of erythrocytes either: - mature cells or - precursors (ineffective erythropoiesis). The breakdown of mature cells can be caused by: - haemolysis, or - as a result of the metabolism of blood following internal haemorrhage, e.g. into a soft tissue injury or fracture.

5. 5 Prehepatic Jaundice Ineffective erythropoiesis occurs in conditions such as: - pernicious anaemia, where the maturation of red cells is impaired, or - thalassaemia, where the structure of haemoglobin is abnormal. Hyperbilirubinaemia in prehepatic jaundice results from the accumulation of unconjugated bilirubin; this is not excreted by the kidney.

6. 6 Prehepatic Jaundice Jaundice occurs because the conjugating capacity of the liver is saturated, - the capacity of the liver for conjugation is greater than the normal rate of bilirubin production. Increased fluxes of bilirubin through the liver into the gut Greater amounts of urobilinogen are produced, with - increased urobilinogen excretion in urine.

7. 7 KEY POINTS Prehepatic jaundice is most commonly Caused by haemolytic disease Bilirubin (unconjugated) is not excreted in urine Urinary urobilinogen concentration is increased

8. 8 Hepatic Jaundice Congenital disorders of bilirubin transport lead to jaundice because of: - defective uptake, reduced conjugation or impaired excretion of bilirubin. Generalized hepatocellular dysfunction may occur in hepatitis and hepatic cirrhosis. Drugs may cause hepatocellular damage, either due to dose-dependent hepatoxicity (e.g. paracetamol).

9. 9 Hepatic Jaundice The pathogenesis of jaundice in these conditions is complex, - reduced hepatic uptake, - decreased conjugation and, - impaired intracellular transport of bilirubin, all contributing.

10. 10 Hepatic Jaundice When hyperbilirubinaemia is caused by impaired conjugation of bilirubin; - unconjugated bilirubin, and no increased fluxes of bilirubin through the liver, - bilirubinuria does not occur and - urinary urobilinogen is not increased.

11. 11 Hepatic Jaundice Serum bilirubin may be unconjugated or conjugated, as UDP glucuronyl transferase and intracellular transport may be defective. If the rate of conjugation exceeds excretory capacity; - conjugated hyperbilirubinaemia will occur and bilirubin may be excreted,in urine, - this is sometimes seen in recovery from acute viral hepatitis.

12. 12 KEY POINTS Jaundice due to hepatocyte dysfunction may be caused by selective transport defects of generalized cell dysfunction Both conjugated and unconjugated hyperbilrubinaemia may occur in hepatocellular jaundice Bilirubin and excess urobilinogen may be found in urine

13. 13 Cholestatic Jaundice Cholestatic jaundice results from interference to biliary flow between the sites of secretion by the hepatocyte and drainage into the duodenum. It may be caused by lesions; - within the liver (intrahepatic cholestasis), or in the biliary tree or head of the pancreas (extrahepatic cholestasis); - the term cholestatic is preferable to post-hepatic to describe this pattern of jaundice.

14. 14 Cholestatic Jaundice Intra- and extra-hepatic cholestasis can be differentiated by; - ultrasound examination or - liver biopsy, but not by liver function tests. Intrahepatic cholestasis may result from generalized hepatocellular dysfunction, such as occurs in; - Hepatitis, - Hepatic cirrhosis Hepatic malignancies may block branches of the biliary tree.

15. 15 Cholestatic Jaundice Some drugs may cause intrahepatic cholestasis such as: - anabolic steroids, and - phenothiazines Extrahepatic obstruction may be due to tumours in: - major branches of the biliary tract, - head of pancreas. Gallstones may obstruct biliary flow.

16. 16 Cholestatic Jaundice Jaundice is due to impaired excretion and accumulation of conjugated bilirubin which can be filtered by the kidney and appear in urine. If obstruction is complete bilirubin does not reach the gut, therefore urobilinogen: - is not produced, and - is absent in urine. Under such circumstances the stools are pale.

17. 17 KEY POINTS Cholestasis may be caused by lesions within or outside the liver Jaundice is due to conjugated bilirubin Bilirubin is found in urine

18. 18 Summary in liver function tests in the differential diagnosis of jaundice TestPrehepaticHepatic Cholestatic Serum bilirubinUncojugatedMixedConjugated Urine bilirubinAbsent//PresentPresentPresent Urine UrobilinogenIncreasedIncreasedDecreased ALT & ASTNormalMarkedSlightincrease ALPNormalSlight Marked increaseincrease