Question

A 5-month-old infant presents with prolonged jaundice. Liver function tests show conjugated hyperbilirubinemia. Liver biopsy reveals dark melanin-like pigment in hepatocytes, especially in the centrilobular region. What is the most likely diagnosis?

• A. Gilbert syndrome
• B. Dubin-Johnson syndrome
• C. Rotor syndrome
• D. Biliary atresia

Hint:

Dubin-Johnson vs Rotor Differentiating Rules:
$\bullet$ Dubin-Johnson: Mutation in MRP2/ABCC2 $\rightarrow$ Black Liver (dense lysosomal pigment) + Urinary Coproporphyrin I $>80\%$.
$\bullet$ Rotor Syndrome: Mutation in OATP1B1/OATP1B3 $\rightarrow$ Normal liver color (NO pigment) + High total urinary coproporphyrin.

Answer 1

The Correct Option is B

Concept:
Hereditary conjugated hyperbilirubinemias are benign autosomal recessive metabolic liver disorders presenting with persistent or fluctuating direct hyperbilirubinemia and normal routine serum transaminases and alkaline phosphatase.
The classic differential rests between Dubin-Johnson syndrome and Rotor syndrome.
Explanation:
• Dubin-Johnson Syndrome: Caused by homozygous loss-of-function mutations in the ABCC2 gene on chromosome 10q24, which encodes the canalicular Multidrug Resistance-Associated Protein 2 (MRP2).

• Defective MRP2 abolishes ATP-dependent canalicular excretion of conjugated bilirubin and certain organic anions into the bile canaliculi.

• As a result, polymeric epinephrine and catecholamine metabolite derivatives cannot be transported into bile; they accumulate within secondary lysosomes of hepatocytes, turning the liver grossly black.

• Histopathological examination reveals coarse, dark brown/black, melanin-like, dense pigment accumulation predominantly in the centrilobular (perivenular) hepatocytes.

• Urinary coproporphyrin analysis shows a normal total excretion but a pathognomonic reversal of isomers, where coproporphyrin I accounts for $>80\%$ of total urinary coproporphyrin (normal is predominantly coproporphyrin III).

• Rotor Syndrome: Caused by mutations in SLCO1B1 and SLCO1B3 (OATP1B1/OATP1B3); the liver biopsy shows completely normal histology with no pigment accumulation.

• Gilbert and Crigler-Najjar syndromes cause unconjugated hyperbilirubinemia due to UDP-glucuronosyltransferase deficiency.
Final Answer:
Centrilobular dark melanin-like pigmentation on liver biopsy in a patient with conjugated hyperbilirubinemia is pathognomonic of Dubin-Johnson syndrome.