# Hereditary Hyperbilirubinaemias

> Hereditary hyperbilirubinaemias for NEET-PG Paediatrics covering Gilbert, Crigler-Najjar, Dubin-Johnson and Rotor syndromes by conjugation and liver pigment.

- Canonical URL: https://prepelephant.com/topics/neet-pg/paediatrics/hereditary-hyperbilirubinaemias
- Exam / course: NEET-PG · Subject: Paediatrics
- Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team
- First published: 2026-10-14
- Last updated: 2026-10-14
- Reference basis: Harrison's Principles of Internal Medicine; Sherlock's Diseases of the Liver and Biliary System
- How to cite: "Hereditary Hyperbilirubinaemias", PrepElephant, https://prepelephant.com/topics/neet-pg/paediatrics/hereditary-hyperbilirubinaemias

## Direct answer

Hereditary hyperbilirubinaemias are inherited disorders of bilirubin handling, and the first step is to ask whether the raised bilirubin is unconjugated or conjugated. Gilbert and Crigler-Najjar syndromes are unconjugated defects of glucuronidation, while Dubin-Johnson and Rotor syndromes are conjugated defects of hepatic transport, and liver pigment plus gallbladder imaging separate those two.

## What you must remember

- **Gilbert syndrome:** a UGT1A1 promoter variant with extra TA repeats reduces glucuronidation, causing a mild unconjugated rise that worsens with fasting, illness or stress.
- **Crigler-Najjar type 1:** complete absence of UGT1A1 activity causes very high unconjugated bilirubin and kernicterus risk, treated with intensive phototherapy and liver transplantation.
- **Crigler-Najjar type 2:** partial enzyme activity gives lower bilirubin levels that respond to phenobarbitone, an enzyme inducer.
- **Dubin-Johnson syndrome:** an MRP2 export defect causes conjugated hyperbilirubinaemia with dark pigment in hepatocytes and a non-visualised gallbladder on oral cholecystography.
- **Rotor syndrome:** a combined OATP1B1 and OATP1B3 uptake defect causes conjugated hyperbilirubinaemia without liver pigment, with the gallbladder visualised.
- **Haemolysis check:** a normal haemoglobin, reticulocyte count and blood smear exclude haemolysis, which also raises unconjugated bilirubin and can mimic Gilbert syndrome.
- **Prognosis:** Gilbert and Dubin-Johnson syndromes are benign, while untreated Crigler-Najjar type 1 is life-threatening in infancy.

## Sorting the syndromes by conjugation and clues

A fourteen-year-old is noticed to be mildly yellow during an examination, with normal haemoglobin and no symptoms. A newborn has jaundice on day two that keeps rising despite phototherapy, and the two problems are separated by the same first question.

| Syndrome | Defect and bilirubin type | Key clue |
|---|---|---|
| Gilbert | UGT1A1 promoter, unconjugated | Mild, rises with fasting or illness |
| Crigler-Najjar type 1 | Absent UGT1A1, unconjugated | Very high levels, kernicterus risk |
| Crigler-Najjar type 2 | Partial UGT1A1, unconjugated | Falls with phenobarbitone |
| Dubin-Johnson | MRP2 export, conjugated | Dark liver pigment, gallbladder not seen |
| Rotor | OATP1B1 and OATP1B3 uptake, conjugated | No liver pigment, gallbladder seen |

Fractionating the bilirubin comes first, because the unconjugated group points to glucuronidation and the conjugated group to transport. Within conjugated jaundice, liver histology and the cholecystogram then separate Dubin-Johnson from Rotor.

The fractionated bilirubin is checked in every infant, and the same split applies to an older child found to be incidentally jaundiced.

## Where the exam sets its traps

Most errors come from mixing up the unconjugated and conjugated groups, and the two conjugated syndromes.

- **Trap:** attributing a rising unconjugated jaundice in a newborn to Gilbert syndrome. — **Correct:** Gilbert is a benign adolescent or adult diagnosis; newborn unconjugated jaundice needs haemolysis excluded and Crigler-Najjar considered.
- **Trap:** treating Crigler-Najjar type 1 with phenobarbitone. — **Correct:** phenobarbitone works only when some enzyme remains, as in type 2; in type 1 the enzyme is absent, so liver transplantation is definitive.
- **Trap:** confusing Dubin-Johnson with Rotor because both are conjugated. — **Correct:** Dubin-Johnson shows hepatic pigment and a non-visualised gallbladder, whereas Rotor shows neither.

## Frequently asked questions

### What causes Gilbert syndrome at the molecular level?

Gilbert syndrome results from a UGT1A1 promoter variant with extra TA repeats, which reduces bilirubin glucuronidation. The enzyme is only partly reduced, so the bilirubin rise stays mild and benign.

### Why does phenobarbitone help Crigler-Najjar type 2 but not type 1?

Phenobarbitone induces residual UGT1A1 activity, lowering bilirubin in type 2 where some enzyme remains. In type 1 the enzyme is absent, so enzyme induction cannot work and transplantation is needed.

### Which test separates Dubin-Johnson from Rotor syndrome?

Oral cholecystography shows a non-visualised gallbladder in Dubin-Johnson syndrome, whereas Rotor syndrome shows a visualised gallbladder. Liver histology showing dark pigment further supports Dubin-Johnson syndrome.

### Why must haemolysis be excluded before diagnosing a hereditary hyperbilirubinaemia?

Haemolysis raises unconjugated bilirubin and can mimic Gilbert syndrome. A normal haemoglobin, reticulocyte count and blood smear help confirm that the cause is a hereditary defect.