Hereditary Hyperbilirubinaemias
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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.