NORD gratefully acknowledges Ryan Gensler and Dean Delp, NORD editorial interns from the University of Notre Dame, and Simon S. Rabinowitz, PhD, MD, FAAP, Professor of Clinical Pediatrics, Vice Chairman, Clinical Practice Development, Pediatric Gastroenterology, Hepatology, and Nutrition, SUNY Downstate College of Medicine, The Children's Hospital at Downstate, for assistance in the preparation of this report.
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 defect (gene mutation) in 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 entity 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 actually 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 cases, the most important aspect of DJS is recognizing that there is not a more serious cause of the jaundice.
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.
DJS is caused by changes (mutations) in the ABCC2 gene. This gene codes for a protein called multidrug resistance protein 2 (MRP2). This protein moves substances out of the cell and is found mainly in the liver but is also present in the kidneys, the intestine, and the 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 mutations have been identified that alter the function of the carrier protein. This process requires energy in the form of ATP and a common site of mutation is the part of the carrier that coordinates this aspect of the process.
Pregnancy or use of oral contraceptives may cause the disease to become apparent in women when no symptoms appeared previously.
DJS is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, 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 non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
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).
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 hepatocytes, 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 exact mutation responsible for DJS in a given 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 investigate 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.
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 pharmaceutical products 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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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.
Talaga ZJ and Vaidya PN. Dubin Johnson Syndrome. StatPearls, Last Update: April 30, 2020. https://www.ncbi.nlm.nih.gov/books/NBK536994/ Accessed August 4, 2020.
Rabinowitz SS. Dubin-Johnson Syndrome. Medscape. Updated: Mar 08, 2018 www.emedicine.com/med/topic588.htm Accessed August 4, 2020.
Martin LJ. Dubin-Johnson Syndrome. Medline Plus. Review Date 7/12/2018. https://medlineplus.gov/ency/article/000242.htm Accessed August 4, 2020.
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