eMedicine Specialties > Gastroenterology > Liver

Dubin-Johnson Syndrome: Differential Diagnoses & Workup

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

Differential Diagnoses

Hyperbilirubinemia, Conjugated

Other Problems to Be Considered

The differential diagnosis of Dubin-Johnson syndrome (DJS) is that of conjugated hyperbilirubinemia. Disease categories to consider include the following:

  • Other inherited disorders (eg, Rotor syndrome)
  • Hepatocellular diseases (eg, viral hepatitis, drugs, alcohol, sepsis)
  • Infiltrative liver diseases (eg, metastatic cancer, pyogenic abscesses)
  • Extrahepatic causes (eg, gallstone disease, cholangiocarcinoma, pancreatic head tumor)

Workup

Laboratory Studies

  • The diagnosis of Dubin-Johnson syndrome (DJS) can be confirmed by demonstrating an increase in the ratio of urinary coproporphyrin I to coproporphyrin III.
    • Coproporphyrins are byproducts of heme biosynthesis. Normally, coproporphyrin I is preferentially excreted in bile, whereas coproporphyrin III is preferentially excreted in urine.
    • The total urinary coproporphyrin level is within the reference range in patients with Dubin-Johnson syndrome (DJS).
      • Patients with DJS – 80% coproporphyrin I; 20% coproporphyrin III
      • Patients without DJS – 25% coproporphyrin I; 75% coproporphyrin III
  • Laboratory studies reveal conjugated hyperbilirubinemia, with total bilirubin levels in the 2- to 5-mg/dL range.
    • Results of other laboratory tests, including liver enzymes, serum albumin, and hematologic studies (eg, complete blood cell [CBC] count, reticulocyte count), tend to be within reference ranges.
    • Prothrombin time (PTT) is usually within normal limits, but it can be prolonged in Iranian Jewish patients with associated factor VII deficiency.5

Imaging Studies

  • Oral cholecystography fails to visualize the gallbladder in patients with Dubin-Johnson syndrome (DJS).
  • These patients also tend to have unique findings on hepatobiliary scans.
    • Specifically, the liver is visualized immediately following intravenous administration of the radiopharmaceutical dye and remains intensely and homogeneously visualized for up to 120 minutes.
    • Although the gallbladder may be visualized up to 90 minutes after dye injection in some patients, it may not be observed at all in other patients. (Normally, images of the gallbladder should be observed within 30 minutes after dye injection.)
    • This combination of intense and prolonged visualization of the liver with delayed to no visualization of the gallbladder is unique to Dubin-Johnson syndrome (DJS).6
  • These findings can be mistaken for evidence of gallbladder disease if the patient presents with abdominal pain and may result in an unnecessary cholecystectomy.
  • Computed tomographic (CT) findings of patients with Dubin-Johnson syndrome (DJS) show a significantly higher attenuation as compared with that of control subjects.
  • The radiographs below show, respectively, acute cholecystitis and acalculous cholecystitis.

  • 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.

Procedures

  • In general, procedures are not necessary to confirm the diagnosis of Dubin-Johnson syndrome (DJS). If a patient is suspected of having DJS, the diagnosis can be confirmed by the test for urinary coproporphyrins as described above (see Workup, Laboratory Studies).
  • A liver biopsy (see image below) is not necessary for the diagnosis of Dubin-Johnson syndrome (DJS). Patients may be noted to have a dark liver during routine surgeries (eg, cholecystectomy), prompting biopsy. The histologic findings are described below (see Workup, Histologic Findings).

  • 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.

Histologic Findings

Deposition of melaninlike pigment occurs in the livers of patients with Dubin-Johnson syndrome (DJS) but not with Rotor syndrome, which helps to differentiate the 2 diseases.7 Macroscopically, the pigment can cause the liver to appear dark or almost black (see image below).

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.


Microscopically, there is accumulation of coarsely granular pigment, most pronounced in the centrilobular zones (see image below). No associated scarring, hepatocellular necrosis, or distortion of zonal architecture is present. The amount of pigment can vary among patients and within an individual. Certain diseases (eg, viral hepatitis) can cause the pigment to disappear. The pigment reaccumulates slowly once the acute process is resolved. Electron spin resonance spectroscopy suggests that the pigment is composed of polymers of epinephrine metabolites.
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.


The changes in the hepatocytes coexist with marked stimulation and enhanced phagocytic activity of Kupffer cells.8 This manifests in the accumulation of pigment deposits within their cytoplasm that corresponds to those observed in hepatocytes. Hyperactive pericentral Kupffer cells, which are involved in the response to pigmentary material originating from disintegrated hepatocytes, may play an essential role in the development of Dubin-Johnson syndrome (DJS).

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: eMedicine Salary Employment

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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