Dubin-Johnson Syndrome

Etiology

DJS comes from mutations of the ATP binding cassette subfamily C member (ABCC2) gene. The ABCC2 gene provides instructions for producing a protein called multidrug resistance protein 2 (MRP2) that works as a transporter protein. The MRP2 protein is involved in the transport of substances out of cells and is essential for the secretion of conjugated bilirubin out of the hepatocytes into the bile duct system for excretion. Mutation of the ABCC2 gene causes a deficiency of canalicular MRP2 expression and impairs the transport of conjugated bilirubin into the bile duct system. Conjugated bilirubin accumulates in hepatocytes, and conjugated bilirubin levels rise in the blood.[2][4][5]

 A classic feature of DJS is the reversal of the ratio of the byproducts generated during heme synthesis. The levels of urinary coproporphyrin l levels are greater than coproporphyrin lll. In otherwise healthy people, the ratio of coproporphyrin lll to coproporphyrin l is about 3.5:1.

Epidemiology

DJS is rare, occurs equally among men and women, and typically manifests in adolescence or young adulthood. The disorder is found in all races and nationalities but is more frequent in Sephardic Jews.[6][7][8]

The disorder occurs in both genders but has an earlier onset in males. The disorder is rarely detected within the first decade of life.[9]

Histopathology

The liver is grossly black in appearance and on light microscopy; the architecture of the liver is normal, but there is the accumulation of dark, coarsely granular pigment in the centrilobular hepatocytes; this feature is not seen in Rotor syndrome. On electron microscopy, the pigment appears to be within the lysosomes. Based upon the pigment's histochemical staining and physicochemical properties, it appears that it is related to melanin.[2][4]

History and Physical

Most patients with DJS are often young adults and are asymptomatic. Hyperbilirubinemia is found as an incidental finding while undergoing routine testing or being tested for some other unrelated problem. They may rarely present with mild icterus, weakness, and/or upper abdominal pain. Pruritus is not a symptom of DJS since serum total bile acid levels are normal. In women, the condition may be subclinical and discovered because of hyperbilirubinemia or obvious jaundice once started on oral contraceptives or becoming pregnant, at which time development of jaundice may lead to the establishment of the diagnosis. Except for mild icterus, physical examination results are within normal limits.[7][4]

Evaluation

Patients with DJS have hyperbilirubinemia, and it is predominantly conjugated hyperbilirubinemia. Total bilirubin concentrations are typically between 2 and 5 mg/dL but on occasion may rise to 20-25 mg/dL, but this distinctly unusual. Laboratory tests including complete blood count, serum albumin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, cholesterol, and prothrombin time are normal. There is no evidence of hemolysis. Patients with DJS have a diagnostic abnormality in urinary coproporphyrin excretion, and abnormal distribution of the coproporphyrin isomers I and III in the urine is a characteristic feature of DJS. There are two naturally occurring coproporphyrin isomers, I and III. Normally about 75% of the coproporphyrin in urine is isomer III. In patients with DJS, the total coproporphyrin content of the urine is normal, but >80% is isomer I.  

Studies such as the hepatobiliary iminodiacetic acid (HIDA) scan and computerized tomography (CT) of the abdomen are performed in patients with hyperbilirubinemia. In the patients with DJS, the HIDA scan shows a characteristic pattern of delayed visualization or no visualization of the gallbladder and bile ducts in the presence of intense, homogenous, and prolonged visualization of the liver. Similarly, oral cholecystography will fail to visualize the gallbladder- subjecting many patients to unnecessary laparoscopic surgery because of a false positive result suggesting the presence of gallstones. Computed tomography scans in patients with DJS show a significantly higher attenuation than those seen in normal subjects. Therefore, these studies generally are not needed or done if DJS is suspected.[10]

Bromosulphthaleine (BSP) clearance test is no longer used in clinical practice. If done in patients with DJS, DSP clearance is normal at 45 minutes, with a second (biphasic) peak occurring at 90 minutes, indicating an excretory defect. The second rise is related to the reflux of conjugated BSP from the liver to plasma. BSP clearance test is not specific for DJS, and similar findings may present in other cholestatic hepatobiliary disorders.

On liver biopsy in DJS, one can see the accumulation of dark, coarsely granular melanin-like pigment in centrilobular hepatocytes in a liver that otherwise looks normal. However, liver biopsy is not a recommendation for making a diagnosis.

Diagnosis of DJS can be made based on the presence of conjugated hyperbilirubinemia with no other abnormality of liver function tests and elevated urine coproporphyrin I fraction. Invasive diagnostic tests should be avoided. Genotyping of the ABCC2 gene is possible but used for scientific studies and not the clinical purpose.[4][5]

Treatment / Management

DJS is a benign disease, does not progress to fibrosis or development of cirrhosis, and does not require any treatment. The importance of diagnosing DJS is to eliminate the possibility of other hepatobiliary disorders that may cause hepatic injury and diagnose those which may be potentially treatable. Phenobarbital and ursodeoxycholic acid are therapeutic for significant cholestasis that occurs in neonatal DJS.[4]

Differential Diagnosis

Differential diagnosis includes:

• Obstructive bile duct conditions
• intrahepatic cholestasis
• Acute or chronic hepatic injury
• Rotor syndrome
• Hemolysis and other hematological diseases
• Portosystemic shunting
• Gilbert-Meulengracht syndrome
• Crigler-Najjar syndrome
• Breast milk Jaundice[11]

Prognosis

DJS prognosis is often benign with a normal life expectancy.[4]

Complications

DJS has no risk of fibrosis progression or cirrhosis development. However, jaundice and hepatomegaly may occur. Use of oral contraceptives, intercurrent illness, and pregnancy may trigger jaundice.[4]