Dubin-Johnson syndrome

Synonyms: hyperbilirubinaemia II, DJS, Sprinz-Nelson syndrome

What is Dubin-Johnson syndrome?^{1 2}

Dubin-Johnson syndrome (DJS) is a rare benign chronic disorder of bilirubin metabolism, characterised by conjugated hyperbilirubinaemia, darkly pigmented liver and the presence of abnormal pigment in hepatic parenchymal cells.

DJS was first described in 1954 by Dubin et al and Sprinz et al who reported several cases of healthy young adults with chronic low-grade jaundice (mostly conjugated hyperbilirubinaemia) and black livers, with no other features of hepatobiliary disease.

It is an autosomal recessive disorder and genomic studies have shown that DJS results from homozygous or compound heterozygous mutations in ABCC2/MRP2 resulting in either absent or deficient expression of this transporter.

Several different mutations have been described in DJS patients, including exon skipping, missense, nonsense and base deletion. Most mutations result in stop codons and failure of MRP2 transcription.

There is no haemolysis and no elevation of other liver enzymes. There is impaired secretion of conjugated bilirubin and other non-bile salt organic anions from hepatocytes into the bile. It runs a generally benign course.

• It occurs in about 1 in 1,300 people of Iranian ancestry with Jewish faith. However, it is very rare in those without such ancestry. It has also been reported in Japan. It is inherited as an autosomal recessive disorder and consanguinity is a risk factor.²

• A seminal paper examined 101 cases in Israel from 1955 to 1969. Of the 101, there were 64 people of Iranian ancestry with Jewish faith and there was a 46% frequency of consanguineous marriage in the parents, compared with 26% amongst people of Iranian ancestry with Jewish faith generally.³

• DJS usually presents in young adulthood with predominantly conjugated hyperbilirubinaemia and otherwise normal liver studies. The conjugated hyperbilirubinaemia is mild because of urinary excretion of bilirubin glucuronides.

• Most patients are asymptomatic except for occasional abdominal pain.

• There is no risk of fibrosis or cirrhosis.

• Rarely, DJS can present in the neonatal period:

  • Neonatal DJS differs from adult-onset DJS in that it presents with severe cholestasis and hepatomegaly.

  • Bilirubin levels can reach above 200 mg/L. Increased severity in neonates has been attributed to immature bile physiology combined with the MRP2 defect.

  • As the liver matures, infants become asymptomatic until later in life, when they can present with intermittent hyperbilirubinaemia.

Diagnosis is important to eliminate the possibility of other hepatobiliary disorders that may lead to hepatic injury.

• FBC is usually normal as are LFTs with the exception of bilirubin which is elevated.⁴ ت sulfobromophthalein test will show prolonged retention.

• In addition to elevated conjugated bilirubin levels in the setting of normal liver function tests, urine tests are diagnostic:

  • Urine tests reveal normal total coproporphyrin levels but with 80% coproporphyrin I in affected individuals, compared to 75% coproporphyrin III in healthy controls.

  • Coproporphyrin I is a metabolic byproduct of heme synthesis and also an endogenous substrate of MRP2; therefore, serum and urinary levels are increased in the presence of defective MRP2.

• Hepatobiliary iminodiacetic acid (HIDA) scan will show either normal or slightly delayed visualisation of the liver, with absent or delayed gallbladder filling.

• Laparoscopy examination of the liver will show that it is dark in colour with deposition of a pigment that is rather like melanin.

• Liver histology, though not necessary in establishing the diagnosis, characteristically shows the presence of dark lysosomal melanin-like pigment deposits.

• Genotyping of ABCC2 gene is possible, but not usually part of the routine clinical work up.

Another form of familial hyperbilirubinaemia is Rotor's syndrome but that shows no hyperpigmentation of the liver.² The poor or absent imaging of the gallbladder may lead to an erroneous diagnosis of حصوات المرارة.

Hyperbilirubinaemia often indicates severe hepatobiliary disease of different causes.⁵ Primary biliary cirrhosis causes jaundice and hepatosplenomegaly but there is also marked pruritus and usually positive autoantibodies.

DJS in a benign disease and in adolescents and adults it does not require treatment.
Reassurance is required that no treatment or further investigation is necessary once diagnosis is made. There is no reduction in life expectancy.¹