Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Dubin-Johnson Syndrome Workup

  • Author: Simon S Rabinowitz, MD, PhD, FAAP; Chief Editor: BS Anand, MD  more...
 
Updated: Jun 24, 2015
 

Approach Considerations

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 diagnosis can be confirmed by demonstrating an increase in the ratio of urinary coproporphyrin I to coproporphyrin III.

A combination of intense and prolonged visualization of the liver following intravenous administration of the radiopharmaceutical dye, with delayed to no visualization of the gallbladder, is unique to Dubin-Johnson syndrome (DJS).

Next

Laboratory Studies

Laboratory studies reveal conjugated hyperbilirubinemia, with total bilirubin serum levels usually in the 2- to 5-mg/dL range (but potentially as high as 25 mg/dL).

Results of other laboratory tests, including liver enzymes, serum albumin, and hematologic studies (eg, complete blood count [CBC], reticulocyte count), tend to be within reference ranges. Urine dipstick analysis may reveal bilirubinuria.

Prothrombin time is usually within normal limits, but it can be prolonged in Iranian Jewish patients with associated factor VII deficiency.[19]

Reduced prothrombin activity resulting from lower levels of clotting factor VII is observed in 60% of patients with Dubin-Johnson syndrome.

Because MRP2 also transports leukotrienes into the bile, patients with Dubin-Johnson syndrome have defective biliary secretion and increased urinary excretion of leukotriene metabolites. This may become a noninvasive diagnostic assay for this condition.[24]

Coproporphyrins

Coproporphyrins are byproducts of heme biosynthesis. Normally, coproporphyrin I is preferentially excreted in bile, whereas coproporphyrin III is preferentially excreted in urine.

The urinary excretion of coproporphyrin isomers, however, has a fairly unique pattern in patients with Dubin-Johnson syndrome 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 in Dubin-Johnson syndrome.[11] This results in total urinary coproporphyrin excretion (I+III) that is nearly normal when compared with unaffected individuals. The unique feature in Dubin-Johnson syndrome, however, is that 80% of the urinary coproporphyrin is type I in patients with Dubin-Johnson syndrome, compared with only 25% in in other persons.[25] (Fecal coproporphyrin levels remain normal.)

In persons who are heterozygous for Dubin-Johnson syndrome, an intermediate ratio of urinary coproporphyrin I to coproporphyrin III 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 Dubin-Johnson syndrome; by 10 days of life, however, these levels convert to the normal adult ratio.[26]

Previous
Next

Imaging Studies

Computed tomography (CT)–scan findings in patients with Dubin-Johnson syndrome reportedly show a significantly higher attenuation than that seen in control subjects.[27] Ultrasonography reveals a normal biliary tree and, in the first image below, demonstrates acalculous cholecystitis. The second image, a radiograph, shows acute cholecystitis.

A 26-year-old man known to be human immunodeficien 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.
Plain abdominal radiograph in a patient with a cli 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 midabdomen secondary to localized ileus.

Scintigraphy

Patients with Dubin-Johnson syndrome 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.

The gallbladder may be visualized after a delay of up to 90 minutes after dye injection in some patients and may not be observed at all in others. (Normally, images of the gallbladder are observed within 30 minutes after dye injection.)

This combination of intense and prolonged visualization of the liver and delayed or failed visualization of the gallbladder is unique to Dubin-Johnson syndrome (DJS) in comparison with other primary liver abnormalities. These findings, however, can be mistaken for evidence of gallbladder disease if the patient presents with abdominal pain and may result in an unnecessary cholecystectomy.

Oral cholecystography fails to visualize the gallbladder in patients with Dubin-Johnson syndrome.

Previous
Next

Procedures

In general, procedures are not necessary to confirm the diagnosis of Dubin-Johnson syndrome. If a patient is suspected of having the disease, the diagnosis can be confirmed by the test for urinary coproporphyrins, as described earlier.

Although a liver biopsy is not necessary for the diagnosis of Dubin-Johnson syndrome, patients may be noted to have a dark liver during routine surgery (eg, cholecystectomy), prompting biopsy.

Previous
Next

Histologic Findings

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

Gross liver specimen from a patient with Dubin-Joh 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, which is most pronounced in the centrilobular zones (see the 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-Johnso 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.[28] 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.

Previous
 
 
Contributor Information and Disclosures
Author

Simon S Rabinowitz, MD, PhD, FAAP Professor of Clinical Pediatrics, Vice Chairman, Clinical Practice Development, Pediatric Gastroenterology, Hepatology, and Nutrition, State University of New York Downstate College of Medicine, The Children's Hospital at Downstate

Simon S Rabinowitz, MD, PhD, FAAP is a member of the following medical societies: American Gastroenterological Association, American Academy of Pediatrics, Phi Beta Kappa, American Association for the Advancement of Science, American College of Gastroenterology, American Medical Association, New York Academy of Sciences, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, Sigma Xi

Disclosure: Nothing to disclose.

Chief 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, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

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.

Miriam K Anand, MD, FAAAAI, FACAAI Consulting Staff, Department of Allergy/Immunology, Allergy Associates and Lab, Ltd; Clinical Assistant Professor, Midwestern School of Osteopathic Medicine

Miriam K Anand, MD, FAAAAI, FACAAI 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: TEVA pharmaceuticals Honoraria Speaking and teaching

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.

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: Prometheus Laboratories Honoraria Speaking and teaching; Abbott Nutritionals Honoraria Speaking and teaching

Hamza Elkhidir, MBBS Resident Physician, Department of Pediatrics, Richmond University Medical Center

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.

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.

Louis R Lambiase, MD, MHA Professor of Medicine, University of Tennessee College of Medicine Chattanooga; Chief, Division of Gastroenterology, University of Tennessee Chattanooga Unit; Assistant Dean for Clinical Affairs, University of Tennessee College of Medicine Chattanooga

Louis R Lambiase, MD, MHA is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Kenneth J Mishark, MD Consultant, Division of Hospital Internal Medicine, Department of Internal Medicine, Mayo Clinic, Assistant Professor of Medicine, College of Medicine, Mayo Clinic

Kenneth J Mishark, MD is a member of the following medical societies: American College of Physicians

Disclosure: Nothing to disclose.

Hisham Nazer, MB, BCH, FRCP, FRCPCH, DCH, DTM&H Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, Amman, Jordan

Hisham Nazer, MB, BCH, FRCP, FRCPCH, DCH, DTM&H is a member of the following medical societies: American College of Physician Executives, Royal College of Paediatrics and Child Health, Royal College of Physicians and Surgeons of the United Kingdom, Royal College of Surgeons of Ireland, and Royal Society of Tropical Medicine and Hygiene

Disclosure: Nothing to disclose.

Cuong Nguyen, MD Instructor, Department of Internal Medicine, Section of Gastroenterology, Mayo Clinic Scottsdale

Disclosure: Nothing to disclose.

Kanika Puri, MD Resident Physician, Department of Pediatrics, State University of New York Downstate Medical Center, Brooklyn

Disclosure: Nothing to disclose.

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.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

References
  1. 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].

  2. 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). 1954 Sep. 33(3):155-97. [Medline].

  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. 1997 Jun. 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. 1999 Mar. 64(3):739-46. [Medline]. [Full Text].

  5. Kruh GD, Zeng H, Rea PA, et al. MRP subfamily transporters and resistance to anticancer agents. J Bioenerg Biomembr. 2001 Dec. 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. 1991 Mar. 80(3):381-5. [Medline].

  7. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct. 24(5):555-71. [Medline].

  8. Benz-de Bretagne I, Respaud R, Vourc'h P, et al. Urinary elimination of coproporphyrins is dependent on ABCC2 polymorphisms and represents a potential biomarker of MRP2 activity in humans. J Biomed Biotechnol. 2011. 2011:498757. [Medline]. [Full Text].

  9. Nisa AU, Ahmad Z. Dubin-Johnson syndrome. J Coll Physicians Surg Pak. 2008 Mar. 18(3):188-9. [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. Frank M, Doss M, de Carvalho DG. Diagnostic and pathogenetic implications of urinary coproporphyrin excretion in the Dubin-Johnson syndrome. Hepatogastroenterology. 1990 Feb. 37(1):147-51. [Medline].

  12. 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. 2006 Jun. 2(3):351-66. [Medline].

  13. 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. 2002 Nov. 36(5):1236-45. [Medline].

  14. 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. 2002 Apr. 77(2):117-21. [Medline].

  15. 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. 2000 Dec. 32(6):1317-28. [Medline].

  16. Uchiumi T, Tanamachi H, Kuchiwaki K, et al. Mutation and functional analysis of ABCC2/multidrug resistance protein 2 in a Japanese patient with Dubin-Johnson syndrome. Hepatol Res. 2013 May. 43(5):569-75. [Medline].

  17. Lee JH, Chen HL, Chen HL, Ni YH, Hsu HY, Chang MH. Neonatal Dubin-Johnson syndrome: long-term follow-up and MRP2 mutations study. Pediatr Res. 2006 Apr. 59(4 Pt 1):584-9. [Medline].

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

  19. 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. 2007 Mar. 18(2):139-44. [Medline].

  20. Liu C, Niu DM, Hsia CY, et al. Living donor liver transplantation using a graft from a donor with Dubin-Johnson syndrome. Pediatr Transplant. 2012 Feb. 16(1):E25-9. [Medline].

  21. Zhou L, Liu C, Bai J, Dong S, Wei J. Dubin-Johnson syndrome with cholecystolithiasis and choledocholithiasis. Int J Surg Case Rep. 2013. 4(7):587-8. [Medline]. [Full Text].

  22. Korkmaz U, Duman AE, Ogutmen Koc D, et al. Severe jaundice due to coexistence of Dubin-Johnson syndrome and hereditary spherocytosis: a case report. Turk J Gastroenterol. 2011 Aug. 22(4):422-5. [Medline].

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

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

  25. Respaud R, Benz-de Bretagne I, Blasco H, Hulot JS, Lechat P, Le Guellec C. Quantification of coproporphyrin isomers I and III in urine by HPLC and determination of their ratio for investigations of multidrug resistance protein 2 (MRP2) function in humans. J Chromatogr B Analyt Technol Biomed Life Sci. 2009 Nov 15. 877(30):3893-8. [Medline].

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

  27. 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. 1997 Apr. 27(4):345-7. [Medline].

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

  29. Corpechot C, Ping C, Wendum D, Matsuda F, Barbu V, Poupon R. 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. 2006 Oct. 101(10):2427-32. [Medline].

 
Previous
Next
 
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-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Cirilo Sotelo-Avila, MD.
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 midabdomen secondary to localized ileus.
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.
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.