Dubin Johnson Syndrome

Disease Overview

Summary

Dubin Johnson syndrome (DJS) is a rare, benign genetic liver disorder. It is inherited in an autosomal recessive pattern and is characterized by buildup of bilirubin, which is normally excreted by the liver into the bile. DJS is caused by a variant in the gene for the transporter protein that is responsible for moving the bilirubin, a normal breakdown product of red blood cells, into the bile which then leaves the body through the stool. It is a rare condition that is most often seen in Middle Eastern Jewish and Japanese people. In the Jewish population, about 60% of affected individuals also have an associated blood clotting abnormality, a prolonged prothrombin time (PT), caused by a decrease in factor VII. Most patients are asymptomatic and the other tests that are routinely used to measure liver function are normal. At times there can be jaundice, a yellowish color of the white portion of the eyes and rarely a slightly enlarged and tender liver. A characteristic aspect of DJS (which is unknown to the patient) is that the retained bilirubin pigment gives the liver a unique black color. Onset usually occurs during puberty or adulthood, but it has rarely been described in the newborn period. Use of alcohol, birth control pills, infection and pregnancy can lead to an increase in jaundice. In almost all patients, the most important aspect of DJS is recognizing that there is not a more serious cause of the jaundice.

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Synonyms

• chronic idiopathic jaundice
• conjugated hyperbilirubinemia
• DJS
• hyperbilirubinemia II
• black liver-jaundice syndrome
• Dubin-Sprinz syndrome

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Signs & Symptoms

Approximately 80% to 99% of people with DJS have intermittent jaundice caused by excess bilirubin (bile pigment) that cannot be excreted normally. It builds up in the liver cells and then goes into the blood and is deposited in the eyes and skin. The same pigment can cause an abnormal urine color. The liver functions normally aside from the loss of an important transporter protein needed to move bilirubin out of the liver. Other less common symptoms include fatigue and fever. Rarely, bilirubin levels can become so high that organ damage is possible.

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Causes

DJS is caused by changes (disease-causing variants) in the ABCC2 gene. This gene codes for a protein called multidrug resistance protein 2 (MRP2). This protein moves substances out of the liver cells into the bile ducts. It is found mainly in the liver but is also present in the kidneys, intestine and placenta. The normal functioning protein works to secrete bilirubin into the bile, which is then transported to the gallbladder where it is stored. When the gall bladder is contracted during digestion, the bile is secreted into the intestine and then passes into the feces. Several different gene variants have been identified that alter the function of the carrier protein.

Pregnancy or use of oral contraceptives may cause the condition to become apparent in females when no symptoms appeared previously.

DJS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

DJS is a rare disease that affects males and females in equal numbers. Onset occurs slightly earlier in males than females. The disorder can occur in all races. Among Iranian, Iraqi and Moroccan Jews the incidence is as high as one in 1,300. In Japan, an unusually high incidence of DJS was found in an isolated area where there was a high rate of marriage between blood relatives (consanguinity).

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Disorders with Similar Symptoms

Some features of the following disorders can be similar to those of Dubin Johnson syndrome and need to be considered in a patient prior to determining the diagnosis of DNS.

Rotor syndrome is very similar to DJS in that the main symptom is also jaundice and both have increases in conjugated or direct bilirubin and otherwise normal liver characteristics (these are all easily measured in the chemistry lab). However, the liver maintains a normal color unlike the liver in patients with DJS, which appears black. Rotor syndrome is much less common than DJS. Two other genetic diseases of bilirubin metabolism, Gilbert and Crigler-Najjar syndrome, also present with jaundice, but patients with these conditions have elevated unconjugated or indirect bilirubin.

Most diseases of the liver will have jaundice and can be confused with DJS. However, in almost all patients, the other liver tests, specifically the transaminases, will also be abnormal along with the bilirubin. In DJS the bilirubin elevation is usually mild, 2-3 mg/dl (normal is less than 1). Other causes of liver disease include drugs, infections, gallstones, tumors, ischemia or congestion (abnormal blood flow to the liver) other congenital diseases and inflammatory conditions, including autoimmune hepatitis. Liver abnormalities including jaundice can also be seen as part of several systemic illnesses that also affect the liver.

Primary biliary cholangitis (PBC), sclerosing cholangitis and autoimmune hepatitis are chronic progressive diseases of the liver and biliary system (the ducts that are within the liver and secrete the bile into the intestines). These three autoimmune disorders are caused by abnormalities in the immune system where the body literally attacks itself. Inflammation, obstruction or injury involving the bile ducts leads to jaundice. Excessive amounts of copper, usually excreted in the bile, also accumulate in the liver. The associated inflammation leads to scarring of the liver and decrease in function. PBC occurs mainly in females during the fourth to the seventh decade of life and has four progressive stages. (For more information on these disorders, search for them in the Rare Disease Database.)

Among the liver infections, viral hepatitis particularly from hepatitis A (HAV), hepatitis B virus (HBV), and hepatitis C (HV) are worldwide the most common causes of liver disease. Hepatitis A is transmitted from water or food that has been exposed to an individual with an active hepatitis A infection. The virus is passed in the classic fecal oral pathway. Hepatitis B and C are transmitted by parenteral means (IV, needle exposure, sexual contacts, tattoos, etc.). HBV begins with a prodrome including anorexia (loss of appetite), fever, nausea, lethargy and vomiting and usually results in jaundice. Hepatitis B is a common cause of chronic hepatitis leading to liver failure, cirrhosis and / or liver cancer. A mother with HBV has a high likelihood of passing the virus to her baby unless the newborn is immunized and treated immediately after delivery. It can also be easily passed through bodily fluids such as blood, semen and possibly saliva. HCV is more insidious, meaning less clinically apparent and many people who have it do not know it. Like HBV it is often spread from person to person through intravenous drug use, sexual contact and other injection treatments. Patients with DJS are often tested for these infections. Vaccination for HBV is recommended universally and for HAV if you are going into an endemic area and do not have natural immunity.

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Diagnosis

The presenting symptom in DJS is jaundice. The first test performed documents the presence of elevated blood levels of bilirubin and determines if it is direct (conjugated) or indirect, (unconjugated). In conjunction with this examination, the laboratory will look for other evidence of liver disease by measuring transaminases, proteins found within liver cells. Elevation implies that there is damage to the liver and rules out DJS. If transaminases are normal and bilirubin is elevated, a diagnosis for DJS is confirmed by examining an unusual feature of bilirubin degradation seen exclusively in DJS. In normal individuals coproprohyrin III is 3-4 times higher than coproporphyrin I in the urine. However, this ratio is reversed in DJS and an elevated ratio of coproporphyrin I to III is seen. The gene variants responsible for DJS in a patient or family can be determined through genetic testing. A test often employed to investigate other liver diseases, a liver biopsy, is very rarely indicated in a patient with DJS.

Another investigation that is not commonly required is a HIDA or DISIDA scan, which is typically performed to look at biliary system transit. A unique pattern is noted in DJS where the liver immediately shows tracer and then remains prominent for two hours while the gall bladder shows either delayed transit or is not visualized at all.

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Standard Therapies

Treatment
Treatment of DJS is symptomatic and supportive. Many patients never require any treatment even though they have recurrent mild jaundice. However, metabolism of certain drugs may be affected in patients with DJS as many drugs are metabolized in the liver. Therefore, a physician should carefully supervise medications.

Genetic counseling is recommended for patients and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
http://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Togawa T, Mizuochi T, Sugiura T, et al. Clinical, pathologic, and genetic features of neonatal Dubin-Johnson syndrome: a multicenter study in Japan. The Journal of Pediatrics. 2018;196:161-167.

Wu L, Zhang W, Jia S, et al. Mutation analysis of the ABCC2 gene in Chinese patients with Dubin‑Johnson syndrome. Experimental and Therapeutic Medicine. 2018;(16): 4201-4206.

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. European Journal of Human Genetics. 2015;24(5):704-709.

INTERNET
Talaga ZJ, Vaidya PN. Dubin-Johnson Syndrome. [Updated 2023 Jul 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK536994/ Accessed March 11, 2024.

Rabinowitz SS. Dubin-Johnson Syndrome. Medscape. Updated Dec 15, 2022. www.emedicine.com/med/topic588.htm Accessed March 11, 2024.

Martin LJ. Dubin-Johnson Syndrome. Medline Plus. Review Date 7/21/2022. https://medlineplus.gov/ency/article/000242.htm Accessed March 11, 2024.

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Programs & Resources

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Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

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Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

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Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

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