AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

First described in 1954, Dubin-Johnson syndrome (DJS) is an autosomal recessive disease characterized by conjugated hyperbilirubinemia and deposition of melaninlike pigment in hepatocytes. Although urinary excretion of coproporphyrin I is increased, liver function remains normal. Long-term follow-up is indicated for neonatal DJS because of possible recurrence and second attacks of jaundice in later life. Disruption of functionally important ATP–binding cassette (ABC) domains in multidrug resistant protein 2 (MRP2) may be related to earlier onset of the disease.

Onset occurs most often in early adulthood; onset during infancy is rare. DJS is caused by mutations of the ABC transporter encoding gene (MRP2/cMOAT/ABCC2), which is mapped to band 10q24. Recently, the genomic DNA sequence of a Caucasian female patient with DJS was analyzed using DNA sequencing. The analysis identified a homozygous missense mutation, C2302T (Materna, 2003). This DJS-causing alteration results in the amino acid exchange Arg768Trp.

Pathophysiology

The conjugated hyperbilirubinemia observed in DJS results from a defect in the transfer of endogenous and exogenous anionic conjugates from hepatocytes into the bile. Lysosomal storage of pigment causes the liver to turn black. A hallmark of DJS is the unusual ratio between the byproducts of heme biosynthesis, urinary coproporphyrin I and coproporphyrin III. In unaffected individuals, the ratio of coproporphyrin III to coproporphyrin I is approximately 3-4:1. This ratio is inverted in patients with DJS.

The molecular basis for DJS is related to defects in the multispecific anion transporter (cMOAT) gene, which belongs to the ABC transporter superfamily. Identified mutations rest in the cytoplasmic domain where binding occurs; thus, disruption of this region probably results in a loss of function.

Frequency

United States

Overall prevalence of DJS is extremely low.

International

DJS occurs in 1 case per 1300 persons of Iranian Jewish descent, primarily because of inbreeding.

Mortality/Morbidity

For the most part, patients are asymptomatic and have normal life spans. Jaundice is the most consistent finding in patients with DJS. Some neonates present with cholestasis.

Race

In persons of Iranian Jewish descent, prevalence is increased to 1 case per 1300 people, primarily because of inbreeding.

Sex

DJS occurs in both sexes but has a tendency to predominate in males. In women with DJS, pregnancy or oral contraceptive use can cause overt jaundice.

Age

DJS is rarely detected before puberty, although neonatal cases have been reported. Onset during infancy is rare; onset occurs most often in early adulthood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Symptoms can include vague abdominal pains and weakness. Patients are usually asymptomatic.

Physical

• For most patients, examination findings are normal.
• Jaundice is the most striking clinical feature.
• Hepatosplenomegaly may be present.

Causes

• Dubin-Johnson syndrome (DJS) is an autosomal recessive disease and is observed most commonly in persons of Iranian Jewish descent.
• DJS is caused by mutations in the MRP2/cMOAT/ABCC2 gene on band 10q24.
• A genotype/phenotype correlation has not been reported.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Rotor syndrome

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Routine laboratory tests reveal a CBC count, serum albumin level, cholesterol level, transaminases, alkaline phosphatase level, and prothrombin time within the reference range.
• The serum bilirubin level usually ranges from 2-5 mg/dL but can be as much as 25 mg/dL.
• Urinary excretion of coproporphyrin is altered in patients with Dubin-Johnson syndrome (DJS). Urinary coproporphyrin III levels measure as much as 80% and are considered diagnostic. The ratio of urinary coproporphyrin III to coproporphyrin I in patients with DJS is approximately 3-4:1.
• Urinalysis may reveal bilirubinuria.
• Serum bromsulfophthalein testing has an increased level at 90 minutes than at 45 minutes.

Imaging Studies

• Cholescintigraphy using disofenin labeled with technetium-99m shows homogenous uptake by the liver but delayed excretion, which suggests altered canalicular transport. The gallbladder is not visualized.

Procedures

• Upon laparoscopy, the liver is found to be black because of a melaninlike pigment concentrated in the hepatocytes.

Histologic Findings

Hepatic biopsy shows a coarsely granulated pigment in hepatocytes in the centrilobular regions. The nature of the pigment remains uncharacterized.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Evaluation can usually be conducted on an outpatient basis. Treatment is generally not required.

Consultations

• Gastroenterologist
• Geneticist

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug therapy is not currently a component of the standard of care for this syndrome.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

• Oral contraceptive use and pregnancy can cause overt jaundice.

Complications

• Jaundice
• Hepatosplenomegaly

Prognosis

• Life expectancy is normal.

Patient Education

• Oral contraceptives, pregnancy, and intercurrent illness may exacerbate icterus.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to avoid exacerbating agents such as oral contraceptives

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Anonymous. Diagnosis of Dubin-Johnson syndrome. J Pediatr. Sep 1988;113(3):618-9. [Medline].
• Jansen PL, Muller M. Genetic cholestasis: lessons from the molecular physiology of bile formation. Can J Gastroenterol. Mar 2000;14(3):233-8. [Medline].
• Jedlitschky G, Hoffmann U, Kroemer HK. Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin Drug Metab Toxicol. Jun 2006;2(3):351-66. [Medline].
• Lee JH, Chen HL, Chen HL, et al. Neonatal Dubin-Johnson syndrome: long-term follow-up and MRP2 mutations study. Pediatr Res. Apr 2006;59(4 Pt 1):584-9. [Medline].
• Materna V, Lage H. Homozygous mutation Arg768Trp in the ABC-transporter encoding gene MRP2/cMOAT/ABCC2 causes Dubin-Johnson syndrome in a Caucasian patient. J Hum Genet. 2003;48(9):484-6. [Medline].
• Pinos T, Constansa JM, Palacin A, Figueras C. A new diagnostic approach to the Dubin-Johnson syndrome. Am J Gastroenterol. Jan 1990;85(1):91-3. [Medline].
• Rosenthal P. Neonatal Dubin-Johnson syndrome. J Pediatr Gastroenterol Nutr. Aug 1994;19(2):255. [Medline].
• Shieh CC, Chang MH, Chen CL. Dubin-Johnson syndrome presenting with neonatal cholestasis. Arch Dis Child. Aug 1990;65(8):898-9. [Medline].
• Shoda J, Suzuki H, Suzuki H, et al. Novel mutations identified in the human multidrug resistance-associated protein 2 (MRP2/ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome. Hepatol Res. Dec 2003;27(4):323-326. [Medline].
• Teh CP, Nevard CH, Lawson N. Clinical quiz. Dubin-Johnson syndrome or Rotor syndrome. Pediatr Nephrol. Sep 1999;13(7):627-8. [Medline].
• Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion-transporter gene (MRP2/cMOAT) and mutations in the ATP-binding-cassette region in Dubin-Johnson syndrome. Am J Hum Genet. Mar 1999;64(3):739-46. [Medline]. [Full Text].
• Tsai WH, Teng RJ, Chu JS, et al. Neonatal Dubin-Johnson syndrome. J Pediatr Gastroenterol Nutr. Feb 1994;18(2):253-4. [Medline].
• Zimniak P. Dubin-Johnson and Rotor syndromes: molecular basis and pathogenesis. Semin Liver Dis. Aug 1993;13(3):248-60. [Medline].
• Zlotogora J. Hereditary disorders among Iranian Jews. Am J Med Genet. Jul 31 1995;58(1):32-7. [Medline].

Article Last Updated: Jan 9, 2007