Pediatric Dubin-Johnson Syndrome Workup

  • Author: Simon S Rabinowitz, MD, PhD; Chief Editor: Carmen Cuffari, MD   more...
 
Updated: May 4, 2010
 

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 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.[8, 9] This results in total urinary coproporphyrin excretion (I+III) which is nearly normal when compared with unaffected individuals. However, the unique feature is that 80% of the urinary coproporphyrin is type I in patients with Dubin-Johnson syndrome, whereas only 25% is type I in patients without Dubin-Johnson syndrome. A new simple and rapid high-performance liquid chromatography (HPLC) method to measure these urinary isomers in fresh and frozen samples has been studied.[18]
    • 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 Dubin-Johnson syndrome; however, by 10 days of life, these levels convert to the normal adult ratio.[19]
  • Fecal coproporphyrin levels are normal.
  • Urine dipstick analysis may reveal bilirubinuria.
  • Because cMOAT/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.[20]
  • Reduced prothrombin activity resulting from lower levels of clotting factor VII is observed in 60% of patients with Dubin-Johnson syndrome.[2]
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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 Dubin-Johnson syndrome compared with other primary liver abnormalities.[21] 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.[22]

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Procedures

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

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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.[23] 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.

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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.

Specialty Editor Board

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.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

Steven M Schwarz, MD, FAAP, FACN, AGAF  Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center

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: Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor; Johnson & Johnson, Inc. Grant/research funds Independent contractor

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.

References

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  2. Habashi SL, Lambiase L R. Dubin-Johnson Syndrome. eMedicine from WebMD [serial online]. October 2006;Available at http://emedicine.medscape.com/article/173517-overview.

  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].

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  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. Respaud R, Benz-de Bretagne I, Blasco H, et al. 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. Nov 15 2009;877(30):3893-8. [Medline].

  19. 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].

  20. 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].

  21. 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].

  22. 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].

  23. 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].

  24. 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].

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

  26. 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].

  27. 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].

 
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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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