Dubin-Johnson Syndrome

Benign disease characterized by familial idiopathic jaundice presenting with chronic intermittent conjugated hyperbilirubinemia.

Dubin-Johnson-Sprinz Nelson Syndrome.

Occurs in both sexes (although males are affected about 1.5 times more often than females) and in all nationalities and races. The highest prevalence in the general population (1:1300) is found in Iranian Jews.

Autosomal recessive, with a reduced penetrance in females. The gene encoding for the human canalicular multispecific organic anion transporter (cMOAT) protein has been mapped to 10q24.

The cMOAT protein is involved in the energy-dependent transport of certain bilirubin glucuronides and organic acids (except bile acids) against a concentration gradient across the canalicular membrane of the hepatocyte. The cMOAT protein defect in Dubin-Johnson syndrome (DJS) leads to decreased hepatobiliary transport and seems to be responsible for the predominantly conjugated hyperbilirubinemia and the intralysosomal accumulation of pigment in hepatocytes.

In healthy people, the total daily biliary coproporphyrinogen (CPG) excretion (a by-product of the heme synthesis) is about three times higher than urinary CPG excretion, and urinary CPG III concentration is about three times higher than CPG I concentration. In DJS, the total amount of urinary CPG is normal, but CPG isomer I accounts for 80% of total CPG. Hence, the diagnosis is based on increased levels of CPG I in the urine, whereas the CPG III level is below normal. Furthermore, the rise in the sulfobromophthalein sodium test is delayed, and the liver appears macroscopically dark blue or even black. Histologically, the cytoplasm of hepatocytes (especially in zone III) contains big lysosomes packed with a lipochromic pigment, which is responsible for the brown-black color. This pigment has many similarities to melanin but is not melanin. It has been theorized that the pigment may be composed of polymers of epinephrine metabolites. The amount of pigment is variable; for example, it can disappear almost completely during an acute viral hepatitis but then reappear slowly after recovery.

Main findings of the disease are hepatomegaly associated with abdominal pain and jaundice. Although cases in neonates have been described, onset usually is in early adulthood, presenting with a nonpruritic jaundice that is caused by increased conjugated hyperbilirubinemia. Liver function is otherwise normal. However, in up to two thirds of DJS patients (especially those of Iranian Jewish descent), a prolonged prothrombin time secondary to reduced activity of factor VII has been reported.

Ensure the liver anomalies truly result from DJS and that no other intercurrent disease is causing the liver dysfunction. Ask about prolonged bleeding; if in doubt or before major surgery, check for coagulation disorder.

If blood loss is significant, check coagulation and treat accordingly.

Jaundice may transiently increase postoperatively. Consequently, it seems prudent to avoid halothane to prevent its implication in the development of postoperative jaundice. Pregnancy, exogenous administration of hormones (e.g., oral contraceptives), and stress can trigger or exacerbate an existing jaundice. Factor VII concentrate is available, but its use likely is not indicated in DJS.

Gilbert Syndrome: Genetic disorder resulting in mild jaundice, which tends to fluctuate in severity and results from a mutation in the uridyl diphosphate-glucuronosyltransferase gene, thus being allelic to the mutation for the Crigler-Najjar syndrome.

Crigler-Najjar Syndrome: Genetic disorder leading to severe neonatal jaundice (typically with kernicterus).

Rotor Syndrome: Rare autosomal recessive disease characterized by a chronic, predominantly conjugated hyperbilirubinemia. It has many similarities to DJS, but total urinary CPG is elevated, as is the CPG I concentration; however, CPG I accounts for less than 80% of total urinary CPG. The liver is a normal color on biopsy, unlike DJS.