eMedicine Specialties > Gastroenterology > Liver

Dubin-Johnson Syndrome

Author: Samir L Habashi, MD, Assistant Professor of Medicine, Department of Medicine, Division of Gastroenterology, University of Florida at Jacksonville
Coauthor(s): Louis R Lambiase, MD, Associate Professor of Medicine, University of Florida College of Medicine; Chief, Division of Gastroenterology, Department of Internal Medicine, University of Florida Health Science Center/Jacksonville; Miriam K Anand, MD, Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd; Kenneth J Mishark, MD, Instructor, Department of Internal Medicine, Mayo Clinic Scottsdale, Mayo Medical School; Cuong Nguyen, MD, Instructor, Department of Internal Medicine, Section of Gastroenterology, Mayo Clinic Scottsdale
Contributor Information and Disclosures

Updated: May 19, 2009

Introduction

Background

Dubin-Johnson syndrome (DJS) is a type of hereditary hyperbilirubinemia that was first described independently in 1954 by Dubin and Johnson and by Sprinz and Nelson.

Hereditary hyperbilirubinemias can be divided into conjugated forms and unconjugated forms. Although Gilbert syndrome and Crigler-Najjar syndrome are examples of the unconjugated hyperbilirubinemias, Dubin-Johnson syndrome (DJS) and Rotor syndrome represent the 2 types of familial conjugated hyperbilirubinemias.

Dubin-Johnson syndrome (DJS) and Rotor syndrome have a relatively benign course, but establishing the diagnosis is important to spare patients from undergoing multiple unnecessary procedures and to exclude other more serious causes of hyperbilirubinemia.

For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Children's Health Center. Also, see eMedicine's patient education articles Jaundice and Newborn Jaundice.

Gross liver specimen from a patient with Dubin-Jo...

Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.

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Gross liver specimen from a patient with Dubin-Jo...

Gross liver specimen from a patient with Dubin-Johnson syndrome showing multiple areas of dark pigmentation. Image courtesy of Cirilo Sotelo-Avila, MD.



Microscopic histology of the liver in Dubin-Johns...

Microscopic histology of the liver in Dubin-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.

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Microscopic histology of the liver in Dubin-Johns...

Microscopic histology of the liver in Dubin-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.

Pathophysiology

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder that is caused by a mutation in the gene responsible for the human canalicular multispecific organic anion transporter (cMOAT) protein. It is also called the multidrug resistance protein 2 (MRP2).1,2,3 This protein mediates adenosine triphosphate (ATP)-dependent transport of certain organic anions across the canalicular membrane of the hepatocyte.

The human MRP2 gene has been localized to band 10q23-10q24. A defect in the cMOAT (MRP2) protein results in the impaired hepatobiliary transport of non–bile salt organic anions and is thought to be responsible for the conjugated hyperbilirubinemia and for the accumulation of hepatocellular pigment.

Several different mutations in the MRP2 gene have been identified in patients with Dubin-Johnson syndrome (DJS). Mutations in the ATP-binding region, which is critical for the functioning of the protein, form a significant proportion of the genetic lesions identified to date. One mutation causes impaired transcription and mislocalization of the protein.

Frequency

United States

Dubin-Johnson syndrome (DJS) is rare.

International

Dubin-Johnson syndrome (DJS) is rare, except in Iranian Jews, in whom the prevalence is about 1:1300.4,5

Mortality/Morbidity

Life expectancy is normal in Dubin-Johnson syndrome (DJS). Reduced prothrombin activity, resulting from lower levels of clotting factor VII, is found in 60% of patients with DJS.

Race

Dubin-Johnson syndrome (DJS) has been described in all nationalities, ethnic backgrounds, and races. Prevalence reportedly is highest among Iranian Jews (1:1300). This group may have an associated deficiency in clotting factor VII that is not observed in other populations.5

Sex

Both sexes are affected equally in Dubin-Johnson syndrome (DJS).

Age

Patients with Dubin-Johnson syndrome (DJS) tend to develop nonpruritic jaundice during their teenaged years.

Clinical

History

  • Patients with Dubin-Johnson syndrome (DJS) tend to develop nonpruritic jaundice during their teenaged years.
  • Although most patients are asymptomatic, some patients complain of nonspecific right upper quadrant pain, which has been attributed to the anxiety associated with prolonged diagnostic testing.
  • Subclinical cases can become evident during pregnancy or following the initiation of oral contraceptives.
  • A thorough family history can reveal a history of jaundice in an autosomal recessive pattern.
  • Associated findings include the presence of hepatitis B virus (HBV) -related chronic hepatitis, history of tubercular lymphadenitis, chronic cholecystitis, coronary heart disease, and also exacerbation during pregnancy.
    Liver biopsy specimen showing ground-glass appear...

    Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.

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    Liver biopsy specimen showing ground-glass appear...

    Liver biopsy specimen showing ground-glass appearance of hepatocytes in a patient with hepatitis B.


    Plain abdominal radiograph in a patient with a cl...

    Plain abdominal radiograph in a patient with a clinical diagnosis of acute cholecystitis. The diagnosis was confirmed by means of abdominal ultrasonography. The radiograph shows faint opacities in the region of the gallbladder fossa and dilated loops of small bowel in the epigastrium and mid abdomen secondary to localized ileus.

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    Plain abdominal radiograph in a patient with a cl...

    Plain abdominal radiograph in a patient with a clinical diagnosis of acute cholecystitis. The diagnosis was confirmed by means of abdominal ultrasonography. The radiograph shows faint opacities in the region of the gallbladder fossa and dilated loops of small bowel in the epigastrium and mid abdomen secondary to localized ileus.


    A 26-year-old man known to be human immunodeficie...

    A 26-year-old man known to be human immunodeficiency virus (HIV) positive presented with pain in the right upper quadrant and mild jaundice. Axial sonogram through the gallbladder (GB) and pancreas (P) shows sludge within the gallbladder and the lower common bile duct (CBD) (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.

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    A 26-year-old man known to be human immunodeficie...

    A 26-year-old man known to be human immunodeficiency virus (HIV) positive presented with pain in the right upper quadrant and mild jaundice. Axial sonogram through the gallbladder (GB) and pancreas (P) shows sludge within the gallbladder and the lower common bile duct (CBD) (arrow). A diagnosis of acalculous cholecystitis was confirmed. A = aorta; IVC = inferior vena cava; S = splenic vein.

Physical

  • Aside from the presence of jaundice, physical examination findings patients with Dubin-Johnson syndrome (DJS) are generally normal, with the exception of possible hepatosplenomegaly.
  • Hyperbilirubinemia and clinical icterus can be worsened by intercurrent illnesses, by drugs that can decrease hepatic excretion of organic anions (eg, oral contraceptives), and by pregnancy.

Causes

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder that is caused by a mutation in the gene responsible for the cMOAT protein.

More on Dubin-Johnson Syndrome

Overview: Dubin-Johnson Syndrome
Differential Diagnoses & Workup: Dubin-Johnson Syndrome
Treatment & Medication: Dubin-Johnson Syndrome
Follow-up: Dubin-Johnson Syndrome
Multimedia: Dubin-Johnson Syndrome
References
Further Reading
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References

  1. 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]. [Full Text].

  2. 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].

  3. Nisa AU, Ahmad Z. Dubin-Johnson syndrome. J Coll Physicians Surg Pak. Mar 2008;18(3):188-9. [Medline].

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

  5. Mor-Cohen R, Zivelin A, Fromovich-Amit Y, et al. 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].

  6. Bar-Meir S, Baron J, Seligson U, et al. 99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes. Radiology. Mar 1982;142(3):743-6. [Medline]. [Full Text].

  7. Zimniak P. Dubin-Johnson and Rotor syndromes: molecular basis and pathogenesis. Semin Liver Dis. Aug 1993;13(3):248-60. [Medline].

  8. Sobaniec-Lotowska ME, Lebensztejn DM. Ultrastructure of Kupffer cells and hepatocytes in the Dubin-Johnson syndrome: a case report. World J Gastroenterol. Feb 14 2006;12(6):987-9. [Medline]. [Full Text].

  9. Corpechot C, Ping C, Wendum D, et al. Identification of a novel 974C-->G nonsense mutation of the MRP2/ABCC2 gene in a patient with Dubin-Johnson syndrome and analysis of the effects of rifampicin and ursodeoxycholic acid on serum bilirubin and bile acids. Am J Gastroenterol. Oct 2006;101(10):2427-32. [Medline].

  10. Bosia JD, D'Ascenzo MV, Borzi S, et al. [The Dubin-Johnson syndrome: case report and review of literature] [Spanish]. Acta Gastroenterol Latinoam. Sep 2008;38(3):194-8. [Medline].

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

  12. Fretzayas A, Kitsiou S, Papadopoulou A, Nicolaidou P. Clinical expression of co-inherited Dubin-Johnson and thalassaemic heterozygous states. Dig Liver Dis. Apr 2007;39(4):369-74. [Medline].

  13. Jung MK, Bae MH, Kim DJ, et al. [A case with Rotor syndrome in hyperbilirubinemic family] [Korean]. Korean J Gastroenterol. Apr 2007;49(4):251-5. [Medline]. [Full Text].

  14. Nowicki MJ, Poley JR. The hereditary hyperbilirubinaemias. Baillieres Clin Gastroenterol. Jun 1998;12(2):355-67. [Medline].

  15. Rastogi A, Krishnani N, Pandey R. Dubin-Johnson syndrome--a clinicopathologic study of twenty cases. Indian J Pathol Microbiol. Oct 2006;49(4):500-4. [Medline].

  16. 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].

  17. Sotelo-Avila C, Danis RK, Krafcik J, Malik M, Schwarz KB. Cholecystitis in a 17-year-old boy with recurrent jaundice since childhood. J Pediatr. Apr 1988;112(4):668-74. [Medline].

  18. The familial conjugated hyperbilirubinemias. Semin Liver Dis. Nov 1994;14(4):386-94. [Medline].

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Further Reading

Related eMedicine Topics

Clinical Trials
National Guideline Clearinghouse

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Keywords

Dubin-Johnson syndrome, DJS, hyperbilirubinemia, chronic idiopathic jaundice, neonatal jaundice, Gilbert syndrome, Crigler-Najjar syndrome, CNS, Rotor syndrome, Sprinz-Nelson syndrome

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Contributor Information and Disclosures

Author

Samir L Habashi, MD, Assistant Professor of Medicine, Department of Medicine, Division of Gastroenterology, University of Florida at Jacksonville
Samir L Habashi, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians-American Society of Internal Medicine, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Coauthor(s)

Louis R Lambiase, MD, Associate Professor of Medicine, University of Florida College of Medicine; Chief, Division of Gastroenterology, Department of Internal Medicine, University of Florida Health Science Center/Jacksonville
Louis R Lambiase, MD is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Miriam K Anand, MD, Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd
Miriam K Anand, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians-American Society of Internal Medicine, and American Medical Association
Disclosure: Nothing to disclose.

Kenneth J Mishark, MD, Instructor, Department of Internal Medicine, Mayo Clinic Scottsdale, Mayo Medical School
Kenneth J Mishark, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Cuong Nguyen, MD, Instructor, Department of Internal Medicine, Section of Gastroenterology, Mayo Clinic Scottsdale
Disclosure: Nothing to disclose.

Medical Editor

Waqar A Qureshi, MD, Associate Professor of Medicine, Chief of Endoscopy, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine and Veterans Affairs Medical Center
Waqar A Qureshi, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine
BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy
Disclosure: Nothing to disclose.

CME Editor

Alex J Mechaber, MD, FACP, Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine
Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law Medicine and Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

 
 
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