Dubin-Johnson Syndrome

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Diagnosis and reasoning

This pregnant lady has presented with nonpruritic jaundice for one week, with no other symptoms. She also claims to have experienced several episodes of jaundice during her teenage years. Broadly speaking, the causes of jaundice in pregnancy can be divided into those directly related to the pregnancy (e.g. HELLP syndrome, intrahepatic cholestasis of pregnancy, or acute fatty liver of pregnancy), and those which are unrelated (for example, cholecystitis, or acute viral hepatitis). Her examination does not provide any further significant findings; thus, a basic evaluation starting with a complete blood count, liver profile, abdominal ultrasound, and hepatitis panel is a good first step. Our patient's liver function parameters are normal, except for an increase in bilirubin - particularly the conjugated fraction; this suggests either a hepatic or extrahepatic cause. The abdominal ultrasound shows a pristine biliary tree with no evidence of gallbladder pathology or biliary stasis. She also tests negative for both chronic and acute viral hepatitis, and the normal platelet count, liver enzymes and blood pressure rule out HELLP syndrome. The absence of pruritus and normal liver enzymes makes intrahepatic cholestasis of pregnancy less likely as well. Given the episodes of jaundice in the past, a hereditary etiology is a possibility; in particular, Rotor syndrome and Dubin-Johnson syndrome (DJS) are the two hereditary disorders of bilirubin metabolism that present with conjugated hyperbilirubinemia. A urine coproporphyrin test is key to differentiate between the above two conditions; in this patient's case, total coproporphyrin is within the normal range, but coproporphyrin I is elevated, accounting for over 80% of the total; this reversed ratio is characteristic of Dubin-Johnson syndrome (DJS), clinching the diagnosis. There is no specific treatment for DJS; the condition has a benign course triggered by factors such as pregnancy, although it does not affect the eventual outcome. In particular, there is absolutely no need for an urgent cesarean section. Phenobarbital is no longer recommended in the management of these patients due to the high incidence of adverse effects; it is also teratogenic. Furthermore, the role of ursodeoxycholic acid in the management of these patients, if any, is yet to be defined.


Discussion

Dubin-Johnson syndrome (DJS) is a benign autosomal recessive disorder characterized by non-hemolytic conjugated bilirubinemia. It was first described in 1954 by Dubin and Johnson, who observed the condition in American soldiers. Specific data on the incidence and prevalence of the condition is lacking. However, while known to occur commonly among Iranian and Moroccan Jews, it is rare in the general population. The underlying etiology is a mutation in the ABCC2 gene, which codes for the organic anion transporter protein MRP2; the latter plays a key role in the secretion of conjugated bilirubin into the bile. Thus, there is progressive accumulation of bilirubin glucuronides and other bile pigments within the liver; the bilirubin also spills into the bloodstream, causing conjugated hyperbilirubinemia and jaundice. There is also increased urinary excretion of coproporphyrins; this is postulated to be because they are excreted by the same transporter protein. In normal persons, coproporphyrin III is the most common urinary metabolite, accounting for >75% of the total coproporphyrin levels; coproporphyrin I usually accounts for ≤20%. In DJS, the above ratio is reversed, with coproporphyrin I levels typically accounting for >80% of the total. A positive family history is the sole risk factor for acquiring the disease. That said, as the disorder is inherited in an autosomal recessive fashion, there are many cases with no obvious family history. The clinical onset usually occurs in early adulthood and is characterized by the development of intermittent jaundice. Occasional abdominal pain and fatigue have also been reported. The above symptoms may be exacerbated by infections, the use of oral contraceptives (OCP), and pregnancy; examination is usually unremarkable although hepatomegaly is seen in some instances. In patients suspected to have DJS, liver functions typically reveal conjugated hyperbilirubinemia, while assessment of urinary coproporphyrins shows the coproporphyrin-I isomer to account for over 80% of the total; this pair of findings is usually sufficient to establish the diagnosis. Where the above tests are equivocal, hepatobiliary scintigraphy showing intense and prolonged visualization of the liver with delayed or absent visualization of the gallbladder further aids the diagnosis. If performed, liver biopsies will show granular brown pigment within the centrilobular hepatocyte lysosomes, while genetic studies will reveal the presence of the ABCC2 gene mutation; however, neither is required for diagnosis. DJS is a benign condition which requires no specific treatment; affected individuals should be counseled about the condition, and reassured during exacerbations. In addition, female individuals may need to be counseled about the use of OCPs and the need for closer monitoring during pregnancy. Overall, the prognosis is good, with patients usually having a normal life expectancy.


Take home messages

  1. Dubin-Johnson syndrome (DJS) is a benign lifelong disorder of bilirubin metabolism which is inherited in an autosomal recessive manner.
  2. A history of intermittent jaundice, along with the laboratory findings of conjugated bilirubinemia, and a urinary coproporphyrin I fraction >80% of the total is sufficient to establish the diagnosis.
  3. DJS has no specific treatment. However, the disease course is mild, and affected individuals only require counseling and monitoring.

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