eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Dubin-Johnson Syndrome

Simon S Rabinowitz, MD, PhD, Professor of Clinical Pediatrics, New York Medical College; Chairman, Chief and Medical Administrator, Department of Pediatrics, Chief, Pediatric Gastroenterology and Nutrition, Richmond University Medical Center
Hamza Elkhidir, MBBS, Staff Physician, Department of Pediatrics, Richmond University Medical Center; Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine; Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine

Updated: Nov 17, 2008

Introduction

Background

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.

The primary defect in DJS 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

Pathophysiology

The conjugated hyperbilirubinemia observed in DJS 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 DJS, the mechanism of which is not fully understood, 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.^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 DJS.

Frequency

United States

Overall prevalence of DJS is extremely low. Although no accurate prevalence figures are available, DJS 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 DJS. 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

DJS occurs in both sexes, but some authors have reported increased incidence and earlier onset in males.^13,16,17

Age

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

Clinical

History

Patients with Dubin-Johnson syndrome (DJS) are usually asymptomatic. However, vague abdominal symptoms may be reported, although this is not believed to reflect serious pathology. Worsening of jaundice due to pregnancy and oral contraceptives (known to impair organic anion transport themselves) is a well-recognized feature of the syndrome.

Physical

For most patients, physical examination findings are normal. Nonpruritic jaundice is the most striking clinical feature. Hepatomegaly may be observed.

Causes

DJS is a genetic, autosomal recessive condition caused by mutations in the MRP2/cMOAT/ABCC2 gene on band 10q24.¹⁰ A genotype/phenotype correlation has not been reported.

Differential Diagnoses

Other Problems to Be Considered

Initially, patients with jaundice must be determined to have direct hyperbilirubinemia. Other causes of elevated direct hyperbilirubinemia include the following:

• Rotor syndrome, especially with normal liver transaminase levels and normal family history, may be the cause of the jaundice.
• Obstructive cholestasis stones in the cystic duct can demonstrate hepatic uptake but delayed or no visualization of the gallbladder on nuclear medicine studies. These should be distinguishable on clinical grounds.
• Virtually all hepatic diseases that cause elevated direct hyperbilirubin levels (eg, viral hepatitis, autoimmune hepatitis, alcoholism and other hepatotoxic exposures, sepsis, hepatic storage diseases, infiltrative diseases such as hepatoblastoma, hepatocellular carcinoma, and metastatic liver disease) are accompanied by elevated transaminase levels as well.

Workup

Laboratory Studies

The diagnosis of Dubin-Johnson syndrome (DJS) should be considered in all individuals with elevated conjugated bilirubin levels with otherwise normal liver function test findings.

• The serum bilirubin level usually ranges from 2-5 mg/dL but can be as much as 25 mg/dL.
• The urinary excretion of coproporphyrins isomers has a fairly unique pattern in patients with DJS and can be used as a pathognomonic feature of the condition when congenital erythropoietic porphyria and arsenic poisoning have been excluded. 
  • An increase in the urinary excretion of coproporphyrin I and a decrease in the excretion of coproporphyrin III are observed.^8,9 This result in total coproporphyrin excretion (I+III) is nearly normal when compared with unaffected individuals. However, the unique feature is that, in patients with DJS, 80% of the urinary coproporphyrin is type I, whereas, in unaffected individuals, only 25% is type I.
  • In heterozygotes, an intermediate ratio of urinary coproporphyrin I to coproporphyrin III ratio is observed; these levels have been used to create family trees and to establish the recessive nature of the condition.
  • How a defect in an apical transporter creates this variance in urinary isomers remains unexplained, with several possible pathogenic mechanisms.
  • Interestingly, for the first 2 days of life, healthy neonates have ratios of urinary coproporphyrin similar to those seen in patients with DJS; however, by 10 days of life, these levels convert to the normal adult ratio.¹⁸
• Fecal coproporphyrin levels are normal.
• Urine dipstick analysis may reveal bilirubinuria.
• Because cMOAT/MRP2 also transports leukotrienes into the bile, patients with DJS have defective biliary secretion and increased urinary excretion of leukotriene metabolites. This may become a noninvasive diagnostic assay for this condition.¹⁹
• Reduced prothrombin activity resulting from lower levels of clotting factor VII is observed in 60% of patients with DJS.²

Imaging Studies

• Hepatobiliary scanning reveals prolonged, intense visualization of the liver with delayed appearance (£ 90 min) or nonvisualization of the gallbladder. Normal scanning has prompt visualization of the gallbladder (within 30 min). This pattern is unique to DJS compared with other primary liver abnormalities.²⁰
• Oral cholecystography may fail to visualize the gallbladder.
• Ultrasonography reveals a normal biliary tree.
• CT scanning of the liver has shown increased attenuation in one report.²¹

Procedures

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

Histologic Findings

• Hepatic biopsy reveals the coarsely granulated pigment in hepatocyte lysosomes. The heaviest deposition is in the centrilobular regions, known to be the primary region of hepatic waste and drug detoxification.
• The exact chemical composition of the pigment remains uncertain, with conflicting evidence suggesting a relationship to melanin, polymerized epinephrine, or other metabolites that accumulate in the lysosomes.²²
• The pigment has been shown to disappear from the liver during acute viral hepatitis, with subsequent reappearance. 
• Other than this striking pigmentation, the liver histology is normal.

Treatment

Medical Care

Evaluation for Dubin-Johnson syndrome (DJS) can usually be conducted on an outpatient, noninvasive basis. Treatment is generally not required.

Consultations

• Gastroenterologist
• Geneticist

Medication

Drug therapy is not currently a component of the standard of care for Dubin-Johnson syndrome (DJS) because it is a benign syndrome.

• In one case report of neonatal DJS with severe cholestasis, phenobarbital significantly decreased serum levels of bilirubin and bile acids.⁶ Because of adverse effects, long-term phenobarbital therapy cannot be recommended.
• Rifampicin (RIF) and ursodeoxycholic acid (UDCA) therapy have beneficial effects in chronic cholestatic diseases. These may result, in part, from the induction of MRP2 expression in the liver and kidney. However, neither an indication nor a general role for these agents in DJS has been defined.²³

Follow-up

Deterrence/Prevention

• Oral contraceptive use and pregnancy can cause overt jaundice.

Complications

• Jaundice
• Hepatomegaly

Prognosis

• Life expectancy is normal.

Patient Education

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

Miscellaneous

Medicolegal Pitfalls

• Failure to explain that avoidance of exacerbating agents may increase symptoms could lead to unnecessary investigations and anxiety.
• Failure to diagnose nongenetic, more significant, progressive causes of direct hyperbilirubinemia.

References

1. Dubin IN, Johnson FB. Chronic idiopathic jaundice with unidentified pigment in liver cells; a new clinicopathologic entity with a report of 12 cases. Medicine (Baltimore). Sep 1954;33(3):155-97. [Medline].

2. Habashi SL, Lambiase L R. Dubin-Johnson Syndrome. E medicine [serial online]. October 2006;Available at http://www.emedicine.com/med/topic588.htm.

3. Paulusma CC, Kool M, Bosma PJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome. Hepatology. Jun 1997;25(6):1539-42. [Medline].

4. 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].

5. Kruh GD, Zeng H, Rea PA, Liu G, Chen ZS, Lee K, et al. MRP subfamily transporters and resistance to anticancer agents. J Bioenerg Biomembr. Dec 2001;33(6):493-501. [Medline].

6. Kimura A, Ushijima K, Kage M, et al. Neonatal Dubin-Johnson syndrome with severe cholestasis: effective phenobarbital therapy. Acta Paediatr Scand. Mar 1991;80(3):381-5. [Medline].

7. Muscatello U, Mussini I, Agnolucci MT. The Dubin-Johnson syndrome: an electron microscopic study of the liver cell. Acta Hepatosplenol. May-Jun 1967;14(3):162-70. [Medline].

8. Koskelo P, Toivonen I, Adlercreutz H. Urinary coproporphyrin isomer distribution in the Dubin-Johnson syndrome. Clin Chem. Nov 1967;13(11):1006-9. [Medline].

9. Frank M, Doss M, de Carvalho DG. Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome. Hepatogastroenterology. Feb 1990;37(1):147-51. [Medline].

10. van Kuijck MA, Kool M, Merkx GF, et al. Assignment of the canalicular multispecific organic anion transporter gene (CMOAT) to human chromosome 10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization. Cytogenet Cell Genet. 1997;77(3-4):285-7. [Medline].

11. 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].

12. Keitel V, Kartenbeck J, Nies AT, Spring H, Brom M, Keppler D. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. Dec 2000;32(6):1317-28. [Medline].

13. Zlotogora J. Hereditary disorders among Iranian Jews. Am J Med Genet. Jul 31 1995;58(1):32-7. [Medline].

14. Mor-Cohen R, Zivelin A, Fromovich-Amit Y, Kovalski V, Rosenberg N, Seligsohn U. Age estimates of ancestral mutations causing factor VII deficiency and Dubin-Johnson syndrome in Iranian and Moroccan Jews are consistent with ancient Jewish migrations. Blood Coagul Fibrinolysis. Mar 2007;18(2):139-44. [Medline].

15. Di Zoglio JD, Cardillo E. The Dubin-Johnson syndrome and pregnancy. Obstet Gynecol. Oct 1973;42(4):560-3. [Medline].

16. Dubin IN. Chronic idiopathic jaundice; a review of fifty cases. Am J Med. Feb 1958;24(2):268-92. [Medline].

17. Shani M, Seligsohn U, Gilon E, Sheba C, Adam A. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Q J Med. Oct 1970;39(156):549-67. [Medline].

18. Rocchi E, Balli F, Gibertini P, Trenti T, et al. Coproporphyrin excretion in healthy newborn babies. J Pediatr Gastroenterol Nutr. Jun 1984;3(3):402-7. [Medline].

19. Mayatepek E, Lehmann WD. Defective hepatobiliary leukotriene elimination in patients with the Dubin-Johnson syndrome. Clin Chim Acta. May 30 1996;249(1-2):37-46. [Medline].

20. Bar-Meir S, Baron J, Seligson U, Gottesfeld F, Levy R, Gilat T. 99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes. Radiology. Mar 1982;142(3):743-6. [Medline].

21. Shimizu T, Tawa T, Maruyama T, Oguchi S, Yamashiro Y, Yabuta K. A case of infantile Dubin-Johnson syndrome with high CT attenuation in the liver. Pediatr Radiol. Apr 1997;27(4):345-7. [Medline].

22. Kitamura T, Alroy J, Gatmaitan Z, et al. Defective biliary excretion of epinephrine metabolites in mutant (TR-) rats: relation to the pathogenesis of black liver in the Dubin-Johnson syndrome and Corriedale sheep with an analogous excretory defect. Hepatology. Jun 1992;15(6):1154-9. [Medline].

23. Regev RH, Stolar O, Raz A, Dolfin T. Treatment of severe cholestasis in neonatal Dubin-Johnson syndrome with ursodeoxycholic acid. J Perinat Med. 2002;30(2):185-7. [Medline].

24. Arias IM, Blumberg W. The pigment in Dubin-Johnson syndrome. Gastroenterology. Oct 1979;77(4 Pt 1):820-1. [Medline].

25. Hashimoto K, Uchiumi T, Konno T, et al. Trafficking and functional defects by mutations of the ATP-binding domains in MRP2 in patients with Dubin-Johnson syndrome. Hepatology. Nov 2002;36(5):1236-45. [Medline].

26. Tate G, Li M, Suzuki T, Mitsuya T. A new mutation of the ATP-binding cassette, sub-family C, member 2 (ABCC2) gene in a Japanese patient with Dubin-Johnson syndrome. Genes Genet Syst. Apr 2002;77(2):117-21. [Medline].

Keywords

Dubin-Johnson syndrome, DJS, conjugated hyperbilirubinemia, multidrug resistant protein 2, MRP2, hyperbilirubinemia II, jaundice, chronic idiopathic jaundice, Sprinz-Nelson syndrome, Gilbert syndrome, Crigler-Najjar syndrome, Rotor syndrome, jaundice, cholestasis, hepatomegaly

Contributor Information and Disclosures

Author

Simon S Rabinowitz, MD, PhD, Professor of Clinical Pediatrics, New York Medical College; Chairman, Chief and Medical Administrator, Department of Pediatrics, Chief, Pediatric Gastroenterology and Nutrition, Richmond University Medical Center
Simon S Rabinowitz, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Gastroenterology, American Gastroenterological Association, American Medical Association, New York Academy of Sciences, North American Society for Pediatric Gastroenterology and Nutrition, Phi Beta Kappa, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Hamza Elkhidir, MBBS, Staff Physician, Department of Pediatrics, Richmond University Medical Center
Hamza Elkhidir, MBBS is a member of the following medical societies: Royal College of Obstetricians and Gynaecologists
Disclosure: Nothing to disclose.

Suzanne M Carter, MS, Senior Genetic Counselor, Associate, Department of Obstetrics and Gynecology, Division of Reproductive Genetics, Montefiore Medical Center, Albert Einstein College of Medicine
Suzanne M Carter, MS is a member of the following medical societies: American Bar Association
Disclosure: Nothing to disclose.

Susan J Gross, MD, FRCS(C), FACOG, FACMG, Codirector, Division of Reproduction Genetics, Associate Professor, Department of Obstetrics and Gynecology, Albert Einstein College of Medicine
Susan J Gross, MD, FRCS(C), FACOG, FACMG is a member of the following medical societies: American College of Medical Genetics, American College of Obstetricians and Gynecologists, American Institute of Ultrasound in Medicine, American Medical Association, American Society of Human Genetics, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Medical Editor

Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan
Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H is a member of the following medical societies: Royal College of Paediatrics and Child Health, Royal College of Physicians, Royal College of Surgeons in Ireland, Royal College of Surgeons of Edinburgh, and Royal Society of Tropical Medicine and Hygiene
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

CME Editor

Steven M Schwarz, MD, FAAP, FACN, AGAF, Professor of Pediatrics, State University of New York, Downstate Medical Center College of Medicine; Distinguished Lecturer, New York Medical College, School of Public Health
Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research
Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership

Chief Editor

Carmen Cuffari, MD, Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine
Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

The authors would like to thank Dori Harasek for assistance in preparation of this article.

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