Chem Path 03: Jaundice and Liver Function

Jaundice (icterus) is the yellow discolouration of skin, sclerae, and mucous membranes caused by hyperbilirubinaemia. It becomes clinically visible when plasma bilirubin exceeds approximately 35–50 µmol/L (reference interval <17 µmol/L). Understanding bilirubin metabolism is essential for classifying jaundice and identifying its cause.

Bilirubin is the end-product of haem catabolism. Senescent red cells are engulfed by splenic macrophages. Haemoglobin is broken down: globin chains are recycled for amino acids; haem is converted by haem oxygenase to biliverdin and then by biliverdin reductase to unconjugated (indirect) bilirubin. Unconjugated bilirubin is lipid-soluble, water-insoluble, and tightly bound to albumin in plasma; it cannot be filtered by the glomerulus and does not appear in urine.

In the liver, hepatocytes take up bilirubin via organic anion transporting polypeptides (OATPs), dissociate it from albumin, and conjugate it with glucuronic acid via UDP-glucuronosyltransferase (UGT1A1), rendering it water-soluble. Conjugated (direct) bilirubin is excreted into bile canaliculi via the MRP2 transporter. In the intestine, bacterial enzymes deconjugate bilirubin and reduce it to urobilinogen; most is excreted as stercobilin (brown faecal pigment), while a small fraction is reabsorbed and excreted in urine as urobilin (enterohepatic circulation). Bilirubinuria (conjugated bilirubin in urine, making it dark) is always pathological — it indicates that conjugated bilirubin is regurgitating into blood and being filtered by the kidney.

Jaundice is classified by the site of metabolic defect. Pre-hepatic (haemolytic) jaundice: excessive red cell destruction overwhelms hepatic conjugating capacity → unconjugated bilirubin elevated; urine: no bilirubin (unconjugated cannot be filtered), urobilinogen elevated; stools: normal or dark (excess bile pigment). Hepatic jaundice: hepatocyte dysfunction → impaired uptake, conjugation, and/or excretion → mixed (unconjugated + conjugated) hyperbilirubinaemia; urine: bilirubinuria + urobilinogen. Post-hepatic (cholestatic/obstructive) jaundice: bile duct obstruction (gallstones, cholangiocarcinoma, pancreatic head cancer) → conjugated bilirubin regurgitates into plasma; urine: dark (bilirubinuria), urobilinogen absent (no bile reaching intestine); stools: pale (acholic, no stercobilin).

Gilbert's syndrome is the most common inherited disorder of bilirubin metabolism, affecting approximately 5–10% of the population. A TATAA box promoter repeat polymorphism in UGT1A1 reduces glucuronidation capacity by approximately 70%, causing mild unconjugated hyperbilirubinaemia (typically 20–50 µmol/L) without haemolysis or liver disease. Episodes are precipitated by fasting, intercurrent illness, exercise, or alcohol. No treatment is required; it is clinically benign.

Liver function tests (LFTs) assess synthetic function (albumin, PT/INR), hepatocellular integrity (ALT, AST), and biliary function (ALP, γGT, bilirubin). Albumin reflects synthetic function with a half-life of 21 days — a late marker of decompensation. PT/INR is a more sensitive and rapid marker of synthetic failure, reflecting depletion of short-lived vitamin K-dependent factors (especially FVII, t½ ~6 hours). Cirrhosis — end-stage liver fibrosis — causes portal hypertension (oesophageal varices, haemorrhoids, caput medusae), hepatic encephalopathy (failure to clear ammonia), ascites, coagulopathy, and hepatocellular carcinoma.