*CLINICAL CHEMISTRY-2 (MLT 302)LIVER FUNCTION AND THE BILIARY TRACT

LECTURE THREEDr. Essam H. Aljiffri

*JaundiceBilirubin is a yellow pigment which causes discolorationof the skin and when serum levels exceed 35-40 mol/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).

*Pathogenesis of Jaundice

*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.

*Prehepatic JaundiceIneffective 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.

*Prehepatic JaundiceJaundice 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.

*KEY POINTSPrehepatic jaundice is most commonly Caused by haemolytic disease Bilirubin (unconjugated) is not excreted in urineUrinary urobilinogen concentration is increased

*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).

*Hepatic JaundiceThe pathogenesis of jaundice in these conditions is complex,

- reduced hepatic uptake, - decreased conjugation and,- impaired intracellular transport of bilirubin, all contributing.

*Hepatic JaundiceWhen 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.

*Hepatic JaundiceSerum 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.

*KEY POINTSJaundice due to hepatocyte dysfunction may be caused by selective transport defectsof generalized cell dysfunctionBoth conjugated and unconjugated hyperbilrubinaemiamay occur in hepatocellular jaundice Bilirubin and excess urobilinogen may be found in urine

*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.

*Cholestatic JaundiceIntra- 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.

*Cholestatic JaundiceSome 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.

*Cholestatic JaundiceJaundice 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.

*KEY POINTSCholestasis may be caused by lesions within or outside the liverJaundice is due to conjugated bilirubinBilirubin is found in urine

*Summary in liver function tests in the differential diagnosis of jaundice

TestPrehepaticHepatic Cholestatic

Serum bilirubinUncojugatedMixedConjugated

Urine bilirubinAbsent//PresentPresentPresent

Urine UrobilinogenIncreasedIncreasedDecreased

ALT & ASTNormalMarkedSlight increaseincrease

ALPNormalSlight Marked increaseincrease