Dubin Johnson syndrome

Dubin Johnson syndrome

Dubin-Johnson syndrome is a rare inherited disorder of bilirubin that is characterized by buildup of bilirubin in the bloodstream (hyperbilirubinemia), jaundice, which is a yellowing of the skin and whites of the eyes. In most affected people jaundice appears during adolescence or early adulthood. Jaundice is typically the only feature of Dubin-Johnson syndrome, but some people can experience weakness, mild abdominal pain, enlarged and tender liver, nausea, or vomiting. In most people with Dubin-Johnson syndrome, certain deposits build up in the liver but do not seem to impair liver function. The deposits make the liver appear black when viewed with medical imaging.

Rarely, jaundice develops soon after birth in individuals with Dubin-Johnson syndrome. Affected infants typically also have enlarged livers (hepatomegaly) and a severely reduced ability to produce and release a digestive fluid called bile (cholestasis). As these children get older, their liver problems go away and they usually do not have any related health problems later in life. Factors that may worsen symptoms include: alcohol use, birth control pills, infection, and pregnancy. In most cases, treatment is not required.

The prevalence of Dubin-Johnson syndrome is unknown. It appears to be most common in Iranian and Moroccan Jews living in Israel, with 1 in 1,300 individuals affected. Additionally, several people in the Japanese population have been diagnosed with Dubin-Johnson syndrome. This condition appears to be less common in other populations.

Can Dubin-Johnsons syndrome be passed along to another individual through sexual intercourse?

No, Dubin Johnson syndrome is caused by a gene mutation that is passed down (inherited) through families. Dubin Johnson syndrome is not a contagious condition and cannot be passed along to another individual through sexual intercourse.

Dubin Johnson syndrome causes

Dubin-Johnson syndrome is caused by changes in a gene known as ABCC2. The ABCC2 gene provides instructions for making a protein that transports certain substances out of cells so they can be released (excreted) from the body. For example, this protein transports a substance called bilirubin out of liver cells and into bile (a digestive fluid produced by the liver). Bilirubin is produced during the breakdown of old red blood cells and has an orange-yellow tint.

ABCC2 gene mutations result in the production of a protein with reduced or absent activity that cannot effectively transport substances out of cells. These mutations particularly affect moving bilirubin into bile. As a result, bilirubin accumulates in the body, causing a condition called hyperbilirubinemia. The buildup of bilirubin in the body causes the yellowing of the skin and whites of the eyes in people with Dubin-Johnson syndrome. The black liver in affected individuals is due to a buildup of different substance normally transported out of the liver by the protein produced from the ABCC2 gene.

Dubin-Johnson syndrome inheritance pattern

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

It is rare to see any history of autosomal recessive conditions within a family because if someone is a carrier for one of these conditions, they would have to have a child with someone who is also a carrier for the same condition. Autosomal recessive conditions are individually pretty rare, so the chance that you and your partner are carriers for the same recessive genetic condition are likely low. Even if both partners are a carrier for the same condition, there is only a 25% chance that they will both pass down the non-working copy of the gene to the baby, thus causing a genetic condition. This chance is the same with each pregnancy, no matter how many children they have with or without the condition.

  • If both partners are carriers of the same abnormal gene, they may pass on either their normal gene or their abnormal gene to their child. This occurs randomly.
  • Each child of parents who both carry the same abnormal gene therefore has a 25% (1 in 4) chance of inheriting a abnormal gene from both parents and being affected by the condition.
  • This also means that there is a 75% ( 3 in 4) chance that a child will not be affected by the condition. This chance remains the same in every pregnancy and is the same for boys or girls.
  • There is also a 50% (2 in 4) chance that the child will inherit just one copy of the abnormal gene from a parent. If this happens, then they will be healthy carriers like their parents.
  • Lastly, there is a 25% (1 in 4) chance that the child will inherit both normal copies of the gene. In this case the child will not have the condition, and will not be a carrier.

These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

Figure 1 illustrates autosomal recessive inheritance. The example below shows what happens when both dad and mum is a carrier of the abnormal gene, there is only a 25% chance that they will both pass down the abnormal gene to the baby, thus causing a genetic condition.

Figure 1. Dubin-Johnson syndrome autosomal recessive inheritance pattern

Dubin-Johnson syndrome autosomal recessive inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

Dubin Johnson syndrome symptoms

Jaundice, which is caused by excess bilirubin (bile pigment), is usually the only symptom of Dubin Johnson syndrome. Otherwise a physical examination is normal. Dubin Johnson syndrome rarely appears before puberty. Occasionally the patient may have an enlarged and tender liver and complain of weakness and a painful abdomen, but the liver will function normally. There may sometimes be a mild recurrence of the jaundice. Pregnancy or use of oral contraceptives may cause the disease to become apparent in women when no symptoms appeared previously.

People with Dubin Johnson syndrome have lifelong mild jaundice that may be made worse by:

  • Alcohol
  • Birth control pills
  • Environmental factors that affect the liver
  • Infection
  • Pregnancy

Dubin Johnson syndrome 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 1).

Dubin Johnson syndrome diagnosis

The diagnosis of Dubin-Johnson syndrome 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.

The following tests can help diagnose Dubin Johnson syndrome:

  • Liver enzyme levels (blood test)
  • Serum bilirubin
  • Urinary coproporphyrin levels

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.

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 2).

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 3).

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 4). 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 5). 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 6).

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

Dubin Johnson syndrome treatment

Treatment of Dubin Johnson syndrome is symptomatic and supportive. In many cases patients may require no treatment even though they have recurrent mild jaundice. However, metabolism of certain drugs may be affected in patients with Dubin-Johnson syndrome since many pharmaceutical products are metabolized in the liver. Therefore, medications should be carefully supervised by a physician. Genetic counseling may be of benefit for patients and their families affected by Dubin Johnson syndrome.

Dubin Johnson syndrome 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 8).

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