🧠 Core idea: inherited hyperbilirubinaemia syndromes are usually disorders of bilirubin conjugation, biliary excretion, or hepatic bilirubin transport. 🔍 First decide whether the bilirubin is mainly unconjugated or conjugated, then interpret the LFT pattern and clinical context.

🧪 Bilirubin Metabolism — Simple Pathway

🩸 Old red cells are broken down → haem → biliverdin → unconjugated bilirubin.
🚕 Unconjugated bilirubin is water-insoluble and travels in blood bound to albumin.
🏭 The liver takes up bilirubin and conjugates it using UGT1A1, making it water-soluble.
🚪 Conjugated bilirubin is exported into bile by canalicular transporters, especially MRP2.
💩 It then enters the gut and is converted into urobilinogen and stercobilin, giving stool its brown colour.

🔀 First Split: Unconjugated vs Conjugated

🧪 Pattern	⚙️ Mechanism	🧬 Inherited Causes	🚩 Other Important Causes
🟡 Unconjugated hyperbilirubinaemia	Too much bilirubin production or impaired hepatic conjugation	Gilbert’s syndrome Crigler–Najjar syndrome	Haemolysis, neonatal jaundice, large haematoma, ineffective erythropoiesis
🟤 Conjugated hyperbilirubinaemia	Impaired excretion or hepatic handling of conjugated bilirubin	Dubin–Johnson syndrome Rotor syndrome	Hepatitis, cholestasis, gallstones, biliary obstruction, drug-induced liver injury

🧬 Inherited Hyperbilirubinaemia Syndromes — Comparison Table

🏷️ Condition	🧬 Gene / Protein	👨‍👩‍👧 Inheritance	⚙️ Main Defect	🧪 Bilirubin Pattern	🔑 Key Features
🟡 Gilbert’s syndrome	UGT1A1 ↓ UDP-glucuronosyltransferase activity	Usually autosomal recessive / polygenic tendency	Reduced bilirubin conjugation in the liver	Mild unconjugated hyperbilirubinaemia	🌤️ Mild intermittent jaundice, often triggered by fasting, illness, stress, dehydration, menstruation or exertion. LFTs otherwise normal. Benign.
🚨 Crigler–Najjar syndrome type I	UGT1A1 Absent UDP-glucuronosyltransferase activity	Autosomal recessive	Absent bilirubin conjugation	Severe unconjugated hyperbilirubinaemia	👶 Neonatal severe jaundice. Very high risk of kernicterus. Does not respond to phenobarbital. Requires specialist management.
⚠️ Crigler–Najjar syndrome type II	UGT1A1 Reduced UDP-glucuronosyltransferase activity	Autosomal recessive	Markedly reduced bilirubin conjugation	Unconjugated hyperbilirubinaemia	📉 Less severe than type I. Lower risk of kernicterus. Often responds to phenobarbital.
⚫ Dubin–Johnson syndrome	ABCC2 MRP2 transporter defect	Autosomal recessive	Impaired canalicular excretion of conjugated bilirubin into bile	Conjugated hyperbilirubinaemia	🟤 Benign recurrent jaundice. Liver may appear dark/black due to pigment deposition. LFTs usually otherwise normal.
🟠 Rotor syndrome	SLCO1B1 / SLCO1B3 OATP1B1 / OATP1B3 transporter defect	Autosomal recessive	Impaired hepatic uptake and storage of conjugated bilirubin	Predominantly conjugated hyperbilirubinaemia	✅ Benign recurrent jaundice. No black liver pigmentation, unlike Dubin–Johnson syndrome.

🧠 Memory aid: 🟡 UGT1A1 problems impair conjugation → unconjugated hyperbilirubinaemia: Gilbert’s and Crigler–Najjar.
🟤 MRP2 / ABCC2 problems affect excretion of already conjugated bilirubin into bile → conjugated hyperbilirubinaemia: Dubin–Johnson.
🟠 SLCO1B1 / SLCO1B3 problems affect hepatic reuptake/storage → Rotor syndrome.

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Inherited Hyperbilirubinaemia Syndromes

🧬 Inherited Hyperbilirubinaemia Syndromes

🧪 Bilirubin Metabolism — Simple Pathway

🔀 First Split: Unconjugated vs Conjugated

🧬 Inherited Hyperbilirubinaemia Syndromes — Comparison Table

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