Bilirubin Metabolism and Jaundice
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Direct answer
Every hour the body degrades haem from aged erythrocytes — haem oxygenase opens the ring, releasing carbon monoxide and iron while forming biliverdin, which is reduced to bilirubin — about 250–300 mg of bilirubin daily in an adult (roughly 4 mg per kg). Unconjugated bilirubin travels tightly bound to albumin (therefore absent from urine), is conjugated in the liver's endoplasmic reticulum by UDP-glucuronosyltransferase to a water-soluble diglucuronide, and is excreted in bile; gut bacteria then convert it to urobilinogen, giving stool its colour. Jaundice classification — pre-hepatic, hepatic, post-hepatic — falls straight out of which step fails.
What you must remember
- Normal serum total bilirubin is 0.3–1.2 mg/dL, nearly all unconjugated; jaundice becomes visible above 2–3 mg/dL, first in the sclerae.
- Unconjugated bilirubin is lipid-soluble, albumin-bound and indirect-reacting in the van den Bergh diazo test; conjugated bilirubin is water-soluble, direct-reacting and appears in urine (dark urine) when it regurgitates into plasma.
- Conjugation is by UGT1A1 in the hepatic smooth ER, and canalicular excretion is by MRP2 — two separate steps, two separate diseases (Gilbert/Crigler–Najjar versus Dubin–Johnson).
- Enterohepatic leg: gut bacteria deconjugate and reduce bilirubin to urobilinogen; part is reabsorbed and re-excreted in urine (normal up to about 4 mg/day), the rest oxidises to stercobilin, colouring stool brown.
- Pre-hepatic (haemolytic) jaundice: unconjugated fraction raised, stool normal or dark, urinary urobilinogen raised with absent bilirubin.
- Hepatic jaundice: mixed fractions, raised aminotransferases (ALT above AST in viral hepatitis; AST:ALT above 2 in alcoholic injury), varying cholestasis.
- Post-hepatic (obstructive) jaundice: conjugated hyperbilirubinaemia, pale stools, dark bilirubin-positive urine, absent urobilinogen, pruritus from retained bile salts, disproportionately raised alkaline phosphatase and gamma-glutamyl transferase.
- Inherited hyperbilirubinaemias: Gilbert (mild UGT1A1 deficiency, 3–7 per cent of people, jaundice with fasting or stress, benign), Crigler–Najjar type I (absent enzyme, kernicterus risk), type II (partial, phenobarbitone-responsive), Dubin–Johnson (MRP2 defect, conjugated, black pigmented liver) and Rotor (conjugated, no pigment).
- Neonatal physiology: UDPGT is immature at birth, so physiological jaundice appears on day 2–3, peaks around day 3–5 (below about 12–13 mg/dL in term babies) and resolves by two weeks; jaundice within the first 24 hours is always pathological (haemolysis — Rh, ABO, G6PD).
- Kernicterus: unconjugated bilirubin crosses the immature blood-brain barrier and stains basal ganglia; sulphonamides and aspirin displace bilirubin from albumin and must be avoided in neonates; treatment is phototherapy and, at critical thresholds, exchange transfusion.
Working through three yellow patients
A 22-year-old notices mild scleral icterus after an overnight fast; bilirubin 2.4 mg/dL, almost entirely indirect, enzymes normal: Gilbert syndrome — reassure and explain. A neonate of an Rh-incompatible pregnancy turns yellow within 24 hours, indirect fraction 18 mg/dL, direct Coombs positive: haemolytic disease needing immediate phototherapy and exchange transfusion if that fails — the under-24-hour timeline is itself the alarm. A 55-year-old with painless jaundice, bilirubin 15 mg/dL mostly direct, clay-coloured stool, itching and alkaline phosphatase thrice normal has obstruction — imaging comes next, and painless progression at this age demands exclusion of pancreatic carcinoma. The urine and stool told the story before the enzymes did: bilirubin in urine means conjugated; absent urobilinogen means obstruction.
Where students slip
Students say "unconjugated bilirubin is excreted in urine" — never, it is albumin-bound and not filtered; only the conjugated fraction is water-soluble enough to appear. Second, they forget urobilinogen needs gut bacteria, so in complete obstruction (or a sterile newborn gut) urobilinogen falls and stool pales. Third, the physiological-versus-pathological neonatal line is drawn on time: first 24 hours pathological, day 2–3 physiological, persistence beyond two weeks needs evaluation — breast milk jaundice and hypothyroidism among the causes. And remember phototherapy does not conjugate bilirubin; it photo-isomerises it into water-soluble forms excreted without conjugation — the phrasing examiners reward.
Frequently asked questions
How is bilirubin formed from haem?
Haem oxygenase opens the porphyrin ring, releasing carbon monoxide and iron and forming biliverdin, which biliverdin reductase converts to bilirubin; about 80 per cent comes from haemoglobin of senescent erythrocytes.
Why is urine dark but stool pale in obstructive jaundice?
Conjugated bilirubin regurgitates from bile into blood (dark, bilirubin-positive urine) while bile fails to reach the gut, so less urobilinogen and stercobilin form — producing pale, clay-coloured stools with absent urinary urobilinogen.
What distinguishes Gilbert syndrome from Crigler–Najjar syndrome?
Both cause unconjugated hyperbilirubinaemia from UDP-glucuronosyltransferase deficiency: Gilbert is common and mild (fasting jaundice under about 4 mg/dL, entirely benign), Crigler–Najjar type I has absent enzyme with kernicterus risk, and type II is intermediate and phenobarbitone-responsive.
Why does physiological jaundice occur in newborns?
Hepatic UDP-glucuronosyltransferase activity at birth is low while neonatal red-cell turnover is high, so unconjugated bilirubin rises on days 2–3 and falls as the enzyme matures; appearance within 24 hours, a rise over 5 mg/dL per day, or persistence beyond two weeks is pathological.
How does phototherapy work and what drugs must be avoided in a jaundiced neonate?
Phototherapy converts bilirubin into water-soluble photoisomers (including lumirubin) excreted in bile and urine without conjugation; sulphonamides and aspirin are avoided because they displace bilirubin from albumin and raise the risk of kernicterus.