Old red cells are broken down in macrophages: haem becomes biliverdin, then unconjugated bilirubin, which travels in blood bound to albumin. The liver takes it up, conjugates it with glucuronic acid using UGT1A1, and pumps the water-soluble product into bile through MRP2. Gut bacteria turn it into urobilinogen, most of which leaves as stercobilin in the stool. Jaundice is what you see when any step in that chain is overwhelmed or blocked.
The pathway in five steps
- Production. About 80% of bilirubin comes from the haem of senescent red cells, broken down in macrophages of the spleen and liver. Haem oxygenase makes biliverdin; biliverdin reductase makes bilirubin. An adult produces roughly 250–300 mg a day.
- Transport. This unconjugated bilirubin is fat-soluble, so it travels tightly bound to albumin. Because it is bound, it cannot be filtered by the kidney and never appears in the urine.
- Conjugation. Hepatocytes take it up through OATP transporters, and UGT1A1 attaches glucuronic acid. The product is water-soluble.
- Excretion. MRP2 pumps conjugated bilirubin into the bile canaliculus. This is the rate-limiting step, which is why it is the first to fail in cholestasis.
- Gut and recycling. Bacteria deconjugate and reduce it to urobilinogen. Around 80–90% leaves as stercobilin and gives stool its brown colour; 10–20% is reabsorbed, mostly re-excreted by the liver, and a little is excreted by the kidney as urobilin — the yellow of normal urine.
Four places it fails
| Failure | Example | Result |
|---|---|---|
| Overproduction | Haemolysis | Unconjugated hyperbilirubinaemia, normal urine |
| Uptake or conjugation | Gilbert, Crigler–Najjar | Unconjugated, enzymes normal |
| Excretion into bile | Dubin–Johnson, drug cholestasis | Conjugated, dark urine |
| Drainage of bile | CBD stone, tumour | Conjugated, dark urine, pale stool, itch |
Numbers to know
- Normal total bilirubin: up to about 1.1 mg/dL (≈21 µmol/L); direct up to 0.3 mg/dL.
- Conversion: 1 mg/dL = 17.1 µmol/L.
- Scleral jaundice becomes visible at about 2.5–3 mg/dL, roughly three times the upper limit.
- Look at the sclera in natural light. Carotenaemia yellows the palms but spares the sclera.
The inherited hyperbilirubinaemias
| Condition | Defect | Bilirubin | Course |
|---|---|---|---|
| Gilbert syndrome | UGT1A1 reduced (≈30% activity) | Unconjugated | Benign; worse with fasting or illness |
| Crigler–Najjar type I | UGT1A1 absent | Unconjugated | Neonatal kernicterus |
| Crigler–Najjar type II | UGT1A1 much reduced | Unconjugated | Responds to phenobarbital |
| Dubin–Johnson | MRP2 (excretion) | Conjugated | Benign; black liver |
| Rotor syndrome | OATP1B1/1B3 (uptake) | Conjugated | Benign |
The Ramadan patient
Gilbert syndrome affects perhaps 5–10% of people and often declares itself during fasting. A young adult with mildly yellow eyes during Ramadan, normal enzymes, a normal blood count and a negative urine bilirubin needs a fractionated bilirubin and reassurance — not an ultrasound and a surgical referral.
Why it matters in the newborn
Unconjugated bilirubin is fat-soluble and crosses the immature blood–brain barrier, where it can cause kernicterus. This is why neonatal jaundice is taken seriously and why phototherapy — which converts bilirubin into water-soluble isomers that can be excreted without conjugation — works.