# Bilirubin Metabolism and Jaundice

> Bilirubin metabolism — conjugation, enterohepatic circulation, jaundice classification, physiological jaundice and kernicterus for MBBS Biochemistry.

- Canonical URL: https://prepelephant.com/topics/mbbs/biochemistry/bilirubin-metabolism-and-jaundice
- Exam / course: MBBS · Subject: Biochemistry
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-02
- Last updated: 2026-10-02
- How to cite: "Bilirubin Metabolism and Jaundice", PrepElephant, https://prepelephant.com/topics/mbbs/biochemistry/bilirubin-metabolism-and-jaundice

## 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.