Dubin-Johnson Syndrome

Back

Practice Essentials

Dubin-Johnson syndrome is an inherited, relapsing, benign disorder of bilirubin metabolism. Dubin-Johnson syndrome is characterized by defective bilirubin excretion into bile. This results in reduced hepatic bilirubin clearance.[1] 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 (see the image below).



View Image

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

Signs and symptoms

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

Some patients complain of nonspecific right upper quadrant pain, which has been attributed to the anxiety associated with prolonged diagnostic testing. Hepatosplenomegaly also occurs in some patients, but in most cases, Dubin-Johnson syndrome is asymptomatic.

See Clinical Presentation for more detail.

Diagnosis

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).

In patients with elevated conjugated bilirubin levels but otherwise normal liver function findings, the diagnosis of Dubin-Johnson syndrome can be confirmed by demonstrating an increase in the ratio of urinary coproporphyrin I to coproporphyrin III; type I makes up 80%, rather than the usual 25%, of the urinary coproporphyrin content in these patients.

Patients with Dubin-Johnson syndrome tend to have unique findings on hepatobiliary scintigraphy scans, demonstrating a combination of intense and prolonged visualization of the liver and delayed or failed visualization of the gallbladder.

See Workup for more detail.

Management

Dubin-Johnson syndrome is a benign disorder that requires no specific therapy, although patients should be warned that pregnancy, oral contraceptive use, and intercurrent illnesses can exacerbate the associated jaundice.

In the past, patients were treated with phenobarbital, which was used primarily to reduce serum bilirubin levels. This treatment is no longer recommended.

Rifampicin 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 2 agents has been defined in Dubin-Johnson syndrome. Rifampicin and UDCA should, in fact, be used with caution in patients with the disease, since they may actually increase conjugated bilirubinemia and bile acid levels in such cases.[2]

See Treatment and Medication for more detail.

Background

First described in 1954,[3] Dubin-Johnson syndrome is an inherited, relapsing, benign disorder of bilirubin metabolism. 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 (see the image below). (See Presentation and Workup.)



View Image

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

The primary defect in Dubin-Johnson syndrome is a mutation in an apical canalicular membrane protein responsible for the excretion of bilirubin and other nonbile salt organic anions. The protein was originally termed the canalicular multiple organic anion transporter (cMOAT) but is also known as multidrug resistance protein 2 (MRP2); it is a member of the ABC transporter superfamily.[4, 5, 6, 7, 8, 9, 10] (See Pathophysiology and Etiology.)

Clinical onset of Dubin-Johnson syndrome 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.[11] (See Epidemiology.)

Hereditary hyperbilirubinemias can be divided into conjugated and unconjugated forms, and they may be caused by increased bilirubin production or decreased bilirubin clearance.[12] Examples are as follows[13] :

The conjugated and unconjugated hyperbilirubinemias are also classified as being, respectively, directly reacting and indirectly reacting. Directly reacting bilirubin reacts quickly with diazotized sulfanilic acid, forming a colored azodipyrrole, while indirectly reacting bilirubin reacts very slowly with the acid unless an accelerator, such as ethanol, is present.

Both inherited conjugated hyperbilirubinemias have a relatively benign course. However, diagnosing these conditions allows the physician to exclude more serious causes of hyperbilirubinemia and, thus, avoid unnecessary investigations and procedures. (See Presentation, Workup, Treatment, and Medication.)

Rarely, combined Dubin-Johnson and Gilbert syndromes can exist (“dual hereditary jaundice”), owing to compound anomalies in bilirubin conjugation and transport.[14] One study comprising 56 affected members across seven apparently unrelated Roma families revealed a novel deletion in the ABCC2 gene (homozygous novel variant c.1013_1014delTG in the eighth exon of ABCC2) in 17 individuals, as well as a homozygous dual defect (NG_011798.1:c.[1013_1014delTG]; NG_002601.2:g.[175492_175493insTA]) in 4 people, and a common 86 kbp haplotype encompassing promoter and part of the ABCC2 coding region among all families.[14]

Pathophysiology and Etiology

Dubin-Johnson syndrome 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, also called the multidrug resistance protein 2 (MRP2) or ABCC2.[4, 5, 6, 7, 8, 9, 10] This protein mediates adenosine triphosphate (ATP)-dependent transport of certain organic anions across the canalicular membrane of the hepatocyte, as well as exports conjugated bilirubin into bile.[9]

The cMOAT/MRP2/ABCC2 protein is encoded by a single-copy gene, MRP2/cMOAT/ABCC2, on chromosome 10q24.[15]

The conjugated hyperbilirubinemia observed in Dubin-Johnson syndrome 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.

A hallmark of Dubin-Johnson syndrome, the mechanism of which is not fully understood, is a reversal of the usual ratio between the byproducts of heme biosynthesis: urinary coproporphyrin I levels are higher than coproporphyrin III levels. In unaffected individuals, the ratio of coproporphyrin III to coproporphyrin I is approximately 3-4:1.[16]

MRP2

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 expressed only on the apical membrane domain of polarized cells. Besides hepatocytes, MRP2 is located in renal proximal tubular cells, enterocytes, and syncytiotrophoblasts of the placenta.[17]

Energy derived from ATP is critical for the secretory function of MRP2. Mutations in the ATP-binding region of MRP2 represent a significant proportion of the recognized genetic defects in Dubin-Johnson syndrome.[18, 19]

Mutations

A common missense mutation, Delta (R,M), leads to the loss of 2 amino acids from the second ATP-binding domain of MRP2. Delta (R,M) is associated with the absence of the MRP2 glycoprotein from the apical membrane of the hepatocytes. In this mutation, only core glycosylation of the protein occurs, which interferes with transport from the endoplasmic reticulum to the canalicular membrane of the hepatocyte. The mutated protein is sensitive to endoglycosidase H digestion in the endoplasmic reticulum. Proteasomes are also involved in the degradation of the mutated protein.[20, 21]

A report from China described mutations in 2 patients with neonatal-onset Dubin-Johnson syndrome who also had no immunohistochemical staining for MRP2. These children, along with 2 patients with adolescent-onset Dubin-Johnson syndrome, had a total of 6 novel mutations, including deletions and missense and nonsense mutations, all of which involved 1 of the 2 ATP-binding cassettes (ABC) of the MRP2 protein.[22]

Epidemiology

Occurrence in the United States

The overall prevalence of Dubin-Johnson syndrome is extremely low. However, although no accurate prevalence figures are available, it is known to be far more common than Rotor syndrome.

Race-, sex-, and age-related demographics

Dubin-Johnson syndrome has been described in all nationalities, ethnic backgrounds, and races. The highest recognized prevalence of the disease (1 case per 1300 population) is in Iranian Jews and is clustered in the same families.[23] This group may have an associated deficiency in clotting factor VII that is not observed in other populations.[24] The prevalence in Moroccan Jews is nearly as high, a reflection of the fact that these populations diverged about 2000-2500 years ago.[24]

Dubin-Johnson syndrome occurs in both sexes, but some authors have reported an increased incidence and earlier onset in males.[23]

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

Prognosis

Dubin-Johnson syndrome is a benign condition, and life expectancy among patients is normal. An interesting case report describes an infant who received a living related liver transplant donor graft from his mother, who had Dubin-Johnson syndrome. One year after transplantation there were no unexpected issues with the donor or the child who had "inherited" Dubin-Johnson syndrome from his mother.[25]

Complications

Complications of Dubin-Johnson syndrome include jaundice (the most consistent finding) and hepatomegaly. Oral contraceptives, pregnancy, and intercurrent illness may exacerbate jaundice. Reduced prothrombin activity, resulting from lower levels of clotting factor VII, is found in 60% of patients.

Some neonates present with cholestasis, which may be severe. Increased fetal wastage was reported in one study. In a case report, cholecystolithiasis and choledocholithiasis developed in the presence of Dubin-Johnson syndrome.[26]

History and Physical Examination

History

Patients with Dubin-Johnson syndrome 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 following the initiation of oral contraceptives (which are known to impair organic anion transport) or during pregnancy.

Associated findings include the presence of hepatitis B virus (HBV)-related chronic hepatitis, a history of tubercular lymphadenitis, chronic cholecystitis, and coronary heart disease. A thorough family history can reveal a history of jaundice in an autosomal recessive pattern.

Reports have documented that patients with both Dubin-Johnson syndrome and hemolytic disease (eg, hereditary spherocytosis,[27] thalassemia[28] ) may experience worse jaundice than anticipated.

Physical examination

Nonpruritic jaundice is the most striking clinical feature of Dubin-Johnson syndrome. Aside from that, physical examination findings are generally normal, with the exception of possible hepatosplenomegaly.

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).

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 (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase [ALP]), 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.[24]

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.[30]

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.[16] 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 other persons.[31] (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.[32]

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.[33] Ultrasonography reveals a normal biliary tree and, in the first image below, demonstrates acalculous cholecystitis. The second image, a radiograph, shows acute cholecystitis.



View Image

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 son....



View Image

Plain abdominal radiograph from a patient with a clinical diagnosis of acute cholecystitis. The diagnosis was confirmed by means of abdominal ultrason....

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.

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.

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.)



View Image

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.



View Image

Microscopic histology of the liver in Dubin-Johnson syndrome showing multiple areas of granulated pigment. Fontana Mason stain. Image courtesy of Ciri....

The changes in the hepatocytes coexist with marked stimulation and enhanced phagocytic activity of Kupffer cells.[34] 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.

Other Tests

Togawa et al found that targeted next-generation sequencing (NGS) can be used for molecular genetic diagnosis in patients with neonatal/infantile intrahepatic cholestasis (NIIC).[35] For 109 patients with NIIC who had no definitive molecular genetic diagnosis, the researchers developed a diagnostic custom panel of 18 genes and sequenced the amplicon library via NGS. A molecular genetic diagnosis was made for 28 subjects (26%), including 5 patients in the group with genetic cholestasis who were given the molecular genetic diagnosis of neonatal Dubin-Johnson syndrome.[35]

In a separate, retrospective study (2013-2016), Togawa et al indicated that immunohistochemical staining of the liver for multidrug resistance-associated protein 2 (MRP-2) as well as molecular genetic analysis of ABCC2 are essential elements for accurately identifying and diagnosing neonatal Dubin-Johnson syndrome.[36]

Approach Considerations

Dubin-Johnson syndrome is a benign disorder and does not require any specific therapy, although patients should be warned that pregnancy, oral contraceptive use, and intercurrent illness can exacerbate the associated jaundice.

In the past, patients were treated with phenobarbital, which was used primarily to reduce the serum bilirubin levels. This treatment is no longer recommended.

Rifampicin 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 Dubin-Johnson syndrome has been defined.[2]

These drugs, in fact, should be used with caution in patients with Dubin-Johnson syndrome. Reporting on a patient with the disease who had a novel 974C→G nonsense mutation of the MRP2 gene, Corpechot et al found a rise in conjugated bilirubinemia following the chronic administration of rifampicin, as well as a sharp increase in serum bile acid concentration following the concomitant chronic administration of rifampicin and UDCA.[37] These adverse effects may result from an increased expression of MRP3 at the basolateral membrane of hepatocytes as a direct consequence of drug induction.

This observation suggests that these drugs should be used with caution in situations in which MRP2 expression may be decreased, as observed in the late stage of cholestasis.[37]

Patient education

Once diagnosed with Dubin-Johnson syndrome, patients should be informed of the disease process and its benign nature, and they should understand that no further investigative workup is required in the future.

For patient education information, see the Digestive Disorders Center and the Children's Health Center, as well as Jaundice and Newborn Jaundice.

Consultations

The following consultations are indicated in Dubin-Johnson syndrome:

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

Disclosure: Nothing to disclose.

Chief Editor

BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

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. Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar. 79 (3):378-86. [View Abstract]
  2. 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. [View Abstract]
  3. 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. [View Abstract]
  4. 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. [View Abstract]
  5. 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. [View Abstract]
  6. 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. [View Abstract]
  7. 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. [View Abstract]
  8. Nisa AU, Ahmad Z. Dubin-Johnson syndrome. J Coll Physicians Surg Pak. 2008 Mar. 18(3):188-9. [View Abstract]
  9. van Dijk R, Beuers U, Bosma PJ. Gene replacement therapy for genetic hepatocellular jaundice. Clin Rev Allergy Immunol. 2015 Jun. 48(2-3):243-53. [View Abstract]
  10. van der Schoor LW, Verkade HJ, Kuipers F, Jonker JW. New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition. Expert Opin Drug Metab Toxicol. 2015 Feb. 11(2):273-93. [View Abstract]
  11. 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. [View Abstract]
  12. Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar. 79(3):378-86. [View Abstract]
  13. Strassburg CP. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct. 24(5):555-71. [View Abstract]
  14. Slachtova L, Seda O, Behunova J, Mistrik M, Martasek P. Genetic and biochemical study of dual hereditary jaundice: Dubin-Johnson and Gilbert's syndromes. Haplotyping and founder effect of deletion in ABCC2. Eur J Hum Genet. 2016 May. 24(5):704-9. [View Abstract]
  15. 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. [View Abstract]
  16. 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. [View Abstract]
  17. 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. [View Abstract]
  18. 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. [View Abstract]
  19. 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. [View Abstract]
  20. 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. [View Abstract]
  21. 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. [View Abstract]
  22. 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. [View Abstract]
  23. Zlotogora J. Hereditary disorders among Iranian Jews. Am J Med Genet. 1995 Jul 31. 58(1):32-7. [View Abstract]
  24. 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. [View Abstract]
  25. 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. [View Abstract]
  26. 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. [View Abstract]
  27. 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. [View Abstract]
  28. 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. [View Abstract]
  29. Kularatnam GAM, Warawitage D, Vidanapathirana DM, et al. Dubin-Johnson syndrome and intrahepatic cholestasis of pregnancy in a Sri Lankan family: a case report. BMC Res Notes. 2017 Sep 18. 10(1):487. [View Abstract]
  30. 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. [View Abstract]
  31. 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. [View Abstract]
  32. Rocchi E, Balli F, Gibertini P, et al. Coproporphyrin excretion in healthy newborn babies. J Pediatr Gastroenterol Nutr. 1984 Jun. 3(3):402-7. [View Abstract]
  33. 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. [View Abstract]
  34. 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. [View Abstract]
  35. Togawa T, Sugiura T, Ito K, et al. Molecular genetic dissection and neonatal/infantile intrahepatic cholestasis using targeted next-generation sequencing. J Pediatr. 2016 Apr. 171:171-7.e1-4. [View Abstract]
  36. Togawa T, Mizuochi T, Sugiura T, et al. Clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome: a multicenter study in Japan. J Pediatr. 2018 Feb 28. [View Abstract]
  37. 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. [View Abstract]

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

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

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 from 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.

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.

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 from 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.