Dubin-Johnson Syndrome

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

Practice Essentials

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).

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.

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 illness 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. [1]

See Treatment and Medication for more detail.

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Background

First described in 1954, [2] 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 Clinical Presentation and Workup.)

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.

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. (See Pathophysiology and Etiology.) [3, 4, 5]

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. (See Epidemiology.) [6]

Hereditary hyperbilirubinemias can be divided into conjugated and unconjugated forms. Examples are as follows [7] :

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 Clinical Presentation, Workup, Treatment, and Medication.)

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.

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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. [3, 4, 8, 9] This protein mediates adenosine triphosphate (ATP)-dependent transport of certain organic anions across the canalicular membrane of the hepatocyte.

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

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. [11]

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. [12]

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. [13, 14]

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. [15, 16]

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. [17]

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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-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. [18] This group may have an associated deficiency in clotting factor VII that is not observed in other populations. [19] The prevalence in Moroccan Jews is nearly as high, a reflection of the fact that these populations diverged about 2000-2500 years ago. [19]

Sex- and age-related demographics

Dubin-Johnson syndrome occurs in both sexes, but some authors have reported increased incidence and earlier onset in males. [18]

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

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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. [20]

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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. [21]

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