Dubin-Johnson Syndrome

What are the other Names for this Condition? (Also known as/Synonyms)

• Chronic Idiopathic Jaundice
• Conjugated Hypervilirubinemia
• Sprinz-Nelson syndrome

What is Dubin-Johnson Syndrome? (Definition/Background Information)

• Dubin-Johnson Syndrome (DJS) is a rare genetic disorder, which is characterized by mild jaundice that is present throughout the life of the individual
• The basic defect in this condition is that the liver is not able to transport bilirubin out of it. Some individuals may have liver enlargement, liver tenderness, weakness, nausea or vomiting
• Normally, bilirubin (a yellow chemical) is the main breakdown product of older red blood cells. It is then packaged in the liver (conjugation) and sent in the bile (digestive fluid that helps in fat digestion) to the gastrointestinal tract to be excreted in the feces. If there is either excess bilirubin or a disruption of the bilirubin pathway, it starts accumulating in the liver
• Eventually, excess bilirubin in the liver, passes into the bloodstream thereby increasing bilirubin levels in blood, resulting in hyperbilirubinemia. Hyperbilirubinemia causes jaundice, which is yellowing of the white region (sclera) of eyes, skin, and nails
• Jaundice can occur when one of the following pathways is affected:
  • There is too much breakdown of red blood cell
  • The liver cannot package bilirubin adequately
  • Obstruction of the flow of bile

  • Impaired entry of packaged bilirubin into bile; Dubin-Johnson Syndrome affects this pathway

• Usually, there is no elevation of other liver enzymes, unlike with other liver diseases, and a majority of the individuals need no treatment. The prognosis of Dubin-Johnson Syndrome is generally good in most individuals

Who gets Dubin-Johnson Syndrome? (Age and Sex Distribution)

• Dubin-Johnson Syndrome usually presents at late adolescence and early adulthood. However, DJS has also been found to occur at infancy through to the mid-50s
• Although it is seen in equal numbers in both gender, some research studies suggest that it is slightly more common in men
• The syndrome has been described in all races, ethnicities, and nationalities
• Nevertheless, DJS has been noted to occur in increasing numbers in Jews of Iranian and Moroccan origin (affects 1 in 1,300 population) and in certain populations of Japan. Consanguineous (closely-related) marriages have been attributed to this phenomenon

Note: It was observed that this Jews population also had a higher incidence of clotting factor VII deficiency (an important factor for blood to clot).

What are the Risk Factors for Dubin-Johnson Syndrome? (Predisposing Factors)

Dubin-Johnson Syndrome is inherited as an autosomal recessive disorder. Thus, one’s risk of DJS is increased by:

• Having a positive family history
• Or, a history of closely-related marriages (partners)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Dubin-Johnson Syndrome? (Etiology)

• In Dubin-Johnson Syndrome (DJS), there is mutation in the CMOAT gene located in chromosome 10q23-q24. The product of this defective gene is a nonfunctional ‘canalicular multispecific organic anion transporter’ (CMOAT) protein. This defect leads to inefficient transport of conjugated bilirubin into bile, leading to the build-up of bilirubin in the liver
• Scientists believe that there is another mutation involving the ABCC2 gene which codes for MRP2 (multidrug resistance protein 2). A defective MRP2 too, cannot transport bilirubin into the bile
• When there is too much bilirubin in the liver, it pours into the bloodstream increasing the bilirubin levels in blood (termed hyperbilirubinemia). The hyperbilirubinemia is of the conjugated type
• The CMOAT gene defect is inherited (passed on to children) as an autosomal recessive disorder

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected).

What are the Signs and Symptoms of Dubin-Johnson Syndrome?

The signs and symptoms of Dubin-Johnson Syndrome, which may not emerge until puberty or early adulthood include:

• Mild jaundice: It is the main and only symptom in many individuals, though liver function is usually normal
  • Mild indicates that there is only a minimal elevation of bilirubin in blood, in comparison to jaundice of other types
  • Normal conjugated bilirubin level is less than 0.3 mg/dl, whereas in DJS, it is usually in the 2-5 mg/dl range
• Jaundice is characterized by yellowish tint to the white area of eyes, skin, and nails. The condition may appear or become more prominent with any stressful situations, such as infection, medications, pregnancy, etc.
• Enlargement of the liver and or spleen
• Tender liver (pain in the right upper abdomen)
• Weakness, fatigue
• Nausea, vomiting

How is Dubin-Johnson Syndrome Diagnosed?

The following procedures may be used to diagnose Dubin-Johnson Syndrome:

• Thorough evaluation of the individual’s medical history and a complete physical examination of the body, including of the skin, abdomen, and eyes
• During history taking the physician may want to know the following:
  • When the symptoms began and whether they are becoming worse
  • List of prescription and over-the-counter medications currently being taken
  • Details of personal and family history of liver diseases, travel history, sexual history, etc.
• Consultation with a gastroenterologist and a hepatologist is often necessary to rule-out other serious liver diseases and also to avoid unwanted testing for this ‘relatively’ benign condition
• Serum bilirubin levels are elevated, especially for the conjugated part; all the other liver enzyme levels are usually normal
• Urinary coproporphyrin I to coproporphyrin III ratio is increased, which is characteristic of DJS
• Sulfobromophthalein test to evaluate liver function, which may show prolonged retention in DJS
• 99mTc-HIDA scan may show prominence of liver activity and absence of gallbladder abnormality. This may be helpful to rule out gallstone-related jaundice
• Gene analysis of the ABCC2 gene in an affected individual can confirm the diagnosis
• Liver biopsy is usually not required due to the benign behavior of this condition, and also due to  the invasive nature of the test
• Laproscopy, to visualize the liver is usually not required: It may show alteration in normal liver color (darker) due to deposition of bilirubin

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Dubin-Johnson Syndrome?

In most individuals, complications are uncommon with Dubin-Johnson Syndrome. In others, the complications could include:

• Decreased liver function
• Jaundice may progress
• Gallstone and common bile duct stone formation
• These complications may be precipitated by stresses to the liver, such as the use of medications, oral contraceptive pills, etc.

How is Dubin-Johnson Syndrome Treated?

There is no specific treatment for Dubin-Johnson Syndrome.

• Symptom management
• Careful monitoring of medication intake (especially those metabolized by the liver) is all that is required in most individuals
• Reassurances may be provided to the affected individuals that no further investigations are necessary and that they will have a normal life span

How can Dubin-Johnson Syndrome be Prevented?

• Currently, there are no specific methods or guidelines to prevent Dubin-Johnson Syndrome, since it is a genetic condition
• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders

What is the Prognosis of Dubin-Johnson Syndrome? (Outcomes/Resolutions)

• The prognosis of Dubin-Johnson Syndrome is generally good. Individuals with DJS have a normal life span
• If symptoms worsen over time and becomes increasingly more severe, the healthcare provider should be informed

Additional and Relevant Useful Information for Dubin-Johnson Syndrome:

The following DoveMed website link is a useful resource for additional information:

http://www.dovemed.com/diseases-conditions/rare-disorders/