Pediatric Dubin-Johnson Syndrome 

First described in 1954,^[1] Dubin-Johnson syndrome (DJS) is an inherited, relapsing, benign disorder of bilirubin metabolism.^[2] This rare autosomal recessive condition is characterized by conjugated hyperbilirubinemia with normal liver transaminases, a unique pattern of urinary excretion of heme metabolites (coproporphyrins), and the deposition of a pigment that gives the liver a characteristic black color (see the image below).

The primary defect in Dubin-Johnson syndrome is a mutation in an apical canalicular membrane protein responsible for excretion of bilirubin, and other nonbile salt organic anions. Originally termed the canalicular multiple organic anion transporter (cMOAT), it is also known as multidrug resistance protein 2 (MRP2) and is a member of the ABC transporter superfamily.^{[3, 4, 5]} The gene that encodes the transporter is ABCC2 and is found on chromosome 10.

Clinical onset is most often seen in early adulthood; however, a neonatal onset has also been rarely described. Because of possible recurrence and second attacks of jaundice in later life, the neonatal form requires closer long term follow-up.^[6]

Four inherited defects in bilirubin metabolism are recognized. Gilbert syndrome and Crigler-Najjar syndrome are associated with indirect hyperbilirubinemia. The other syndromes, Dubin-Johnson syndrome and Rotor syndrome, result in conjugated hyperbilirubinemia. Only Dubin-Johnson syndrome has the melaninlike pigment in the liver cells and increased urinary coproporphyrin I. Both inherited direct hyperbilirubinemias have a relatively benign course. However, diagnosing these conditions allows the physician to exclude other more serious causes of hyperbilirubinemia and, thus, avoid unnecessary investigations and procedures.

The conjugated hyperbilirubinemia observed in Dubin-Johnson syndrome results from defective transport of bilirubin glucuronide across the membrane that separates the hepatocyte from the bile canaliculi. Pigment that is not secreted from the hepatocyte is stored in the lysosome and causes the black liver color.^[7] A hallmark of Dubin-Johnson syndrome, the mechanism of which is not fully understood, is a reversal of the usual ratio between the byproducts of heme biosynthesis: urinary coproporphyrin I levels are higher than coproporphyrin III levels. In unaffected individuals, the ratio of coproporphyrin III to coproporphyrin I is approximately 3-4:1.^{[8, 9]}

The cMOAT/MRP2 protein is encoded by a single-copy gene located on chromosome 10q24.^[10] MRP2 plays an important role in the detoxification of many drugs by transporting a wide range of compounds, especially conjugates of glutathione, glucuronate, and sulfate, which are collectively known as phase II products of biotransformation. Unlike other members of the MRP/ABCC family, MRP2 is only expressed on the apical membrane domain of polarized cells. Besides hepatocytes, it is located in renal proximal tubular cells, enterocytes, and syncytiotrophoblasts of the placenta.^[11] Energy derived from ATP is critical to the secretory function of MRP2. Mutations in the ATP-binding region represent a significant proportion of the recognized genetic defects in Dubin-Johnson syndrome.

An enhanced understanding of the molecular biology of Dubin-Johnson syndrome is derived from investigations of the missense mutation Delta (R,M).^[12] This leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. The mutated MRP2 Delta (R,M) is associated with the absence of the MRP2 glycoprotein from the apical membrane of hepatocytes. In this mutation, only core glycosylation of the protein occurs, which interferes with transport from the endoplasmic reticulum to the canalicular membrane of the hepatocyte. The mutated protein is sensitive to endoglycosidase H digestion in the endoplasmic reticulum. Proteasomes are also involved in the degradation of the mutated protein.

Frequency

United States

Overall prevalence of Dubin-Johnson syndrome is extremely low. Although no accurate prevalence figures are available, Dubin-Johnson syndrome is far more common than Rotor syndrome.

International

The highest recognized prevalence (1 case per 1300 population) is in Iranian Jews and is clustered in the same families.^[13] The prevalence in Moroccan Jews is nearly as high, a reflection of the fact that these populations diverged about 2000–2500 years ago.^[14]

Mortality/Morbidity

For the most part, patients are asymptomatic and have normal life spans. Jaundice is the most consistent finding in patients with Dubin-Johnson syndrome. Some neonates can present with cholestasis, which may be severe. Increased fetal wastage has been reported in one study.^[15]

Race

In persons of Iranian Jewish descent, prevalence is primarily increased because of cultural pressures that support isolation and, therefore, consanguineous marriages and reproduction trends.

Sex

Dubin-Johnson syndrome occurs in both sexes, but some authors have reported increased incidence and earlier onset in males.^{[13, 16, 17]}

Age

Dubin-Johnson syndrome is rarely detected before puberty, although neonatal cases have been reported. It is most often diagnosed in the late teens and early adulthood.