Review Question - QID 217316

This patient with conjugated (direct) hyperbilirubinemia, mild scleral icterus (triggered by starting oral contraceptives), and evidence of accumulated dark pigment in hepatocytes has Dubin-Johnson syndrome, which is caused by a deficiency of multidrug resistance protein 2 (MRP2) expression.

Dubin-Johnson syndrome is an autosomal recessive condition marked by conjugated hyperbilirubinemia. Normally, the ATP binding cassette subfamily C member (ABCC2) gene leads to the production of the MRP2 protein, which is responsible for the secretion of conjugated bilirubin into the bile duct. With mutations in the ABCC2 gene and the resultant decrease in MRP2 levels, there is an increase in conjugated bilirubin levels in hepatocytes and the blood. Patients are mostly asymptomatic but can present with mild icterus or jaundice, especially with oral contraceptive use or pregnancy. A key characteristic finding in Dubin-Johnson syndrome is an elevated urine coproporphyrin I fraction. In normal individuals, 75% of the urine fraction is coproporphyrin III while >80% is coproporphyrin I in Dubin-Johnson syndrome patients. Additionally, the liver would appear grossly black (due to pigment accumulation) if observed. Diagnosis is made with these urine findings, conjugated hyperbilirubinemia, and no other liver abnormalities; invasive procedures are normally avoided. As patients are normally unaffected and do not have long-term complications, Dubin-Johnson syndrome does not need further treatment.

Strassburg reviews some characteristics of Dubin-Johnson syndrome. From the epidemiology perspective, Dubin-Johnson syndrome is found equally in men and women and is more frequently seen in Sephardic Jews. The specific underlying mechanism is a deficiency of non-bile acid organic anions. In comparison to Rotor syndrome, there is a greater unconjugated proportion of hyperbilirubinemia.

Incorrect Answers:
Answer 1: Abnormal production of organic anion transporting polypeptide 1B1 and 1B3 is the underlying mechanism of Rotor syndrome, which is also an autosomal recessive, hereditary conjugated hyperbilirubinemia. There are a few key differences compared to Dubin-Johnson syndrome: the gallbladder can be visualized by oral cholecystography, normal gross liver appearance, and elevated total urine coproporphyrin levels. The finding of pigment accumulation in the hepatocytes would not be found in Rotor syndrome.

Answer 2: Absence of UDP-glucuronosyltransferase is the underlying mechanism of Crigler-Najjar syndrome type I, which is a hereditary unconjugated hyperbilirubinemia that affects neonates. It is marked by high serum bilirubin levels (20-50 mg/dL). Patients can present with severe neonatal jaundice with a high kernicterus risk and hypotonia. Phototherapy and plasmapheresis can manage bilirubin levels, but liver transplantations are the definitive treatment. This patient has conjugated hyperbilirubinemia.

Answer 3: Decreased activity of UDP-glucuronosyltransferase is the underlying mechanism of Crigler-Najjar syndrome type II, which is a hereditary unconjugated hyperbilirubinemia that affects neonates. Compared to type I, Crigler-Najjar syndrome type II has lower serum bilirubin levels (<20 mg/dL) and generally a better prognosis. Patients present with similar but milder presentations compared to type I. Medical treatment with phenobarbital, which induces UDP-glucuronosyltransferase activity, is sufficient for bilirubin level reduction. This patient does not have significant unconjugated hyperbilirubinemia.

Answer 5: Elevated levels of ß-glucuronidase is the underlying mechanism of breast milk jaundice, which is a cause of neonatal unconjugated hyperbilirubinemia. The combination of the immature liver and the presence of ß-glucuronidase (which deconjugates bilirubin) in breast milk leads to an elevation of unconjugated bilirubin in the blood. It usually presents within the first week of life. Per the American Academy of Pediatrics, no treatment is necessary and breastfeeding can continue if total bilirubin levels are <20 mg/dL. Pigment-accumulated hepatocytes would not be observed.

Bullet Summary:
Dubin-Johnson syndrome is due to a deficiency of multidrug resistance protein 2 expression.