Excessive vincristine exposure in a child being treated for acute lymphoblastic leukaemia with underlying Dubin-Johnson syndrome: a case report.

BACKGROUND: Dubin-Johnson syndrome is a rare benign autosomal recessive condition that causes an isolated increase of conjugated bilirubin in the serum. Impaired biliary excretion is due to mutation in the multiple drug-resistance protein 2 gene (MRP2). CASE PRESENTATION: We describe the case of a 4-year-old girl being treated for acute lymphoblastic leukaemia who had a history of conjugated hyperbilirubinaemia and persistently elevated bilirubin levels on initiation of chemotherapy. During treatment for leukaemia, she was diagnosed with Dubin-Johnson syndrome for the underlying condition. Following administration of vincristine at the recommended dose of 1.5 mg/m2, an abnormally high vincristine exposure was observed (AUC > 200 µg/L*h), approximately 3 times higher than previously reported exposures in a comparable clinical setting. Vincristine dose reductions were applied on subsequent cycles of treatment and resulted in markedly reduced drug exposures, within the normal target range. CONCLUSION: This case provided a rare opportunity to assess the impact of MRP2 mutations associated with Dubin-Johnson syndrome on the pharmacokinetics of vincristine and strongly indicates that a marked dose reduction should be recommended. Clinicians should be made aware of the potential for altered drug disposition for agents such as vincristine in patients with this rare genetic condition.

Treatment for tuberculosis in a patient with Dubin-Johnson syndrome.

Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder characterised by conjugated hyperbilirubinemia resulting from mutations of ABCC2/MRP2 gene. The beneficial effects of ursodeoxycholic acid (UDCA) and rifampicin were found to be complementary in the treatment of cholestatic liver disease secondary to DJS. We present a case of a young woman with tubercular meningitis. She was started on modified antitubercular therapy in view of conjugated hyperbilirubinemia. However, reinitiation of rifampicin resulted in redevelopment of jaundice. Liver biopsy was suggestive of DJS. The patient was started on rifampicin along with UDCA. There was improvement in hyperbilirubinemia and a full course of antituberculous therapy without further worsening of the disorder was possible. This is a rare case of DJS with tuberculosis, showing beneficial effects of rifampicin and UDCA combination therapy, which so far has been considered doubtful. It is uncertain what the level of efficacy of therapy is in various MRP2 gene mutations.

The effect of phenobarbital on patients with Dubin-Johnson syndrome.

11 patients with jaundice of Dubin-Johnson type were treated for 2 weeks with phenobarbital. Serum bilirubin diminished and hepatic clearance of sulfobromophthalein was variably enhanced; other measures of hepatic function were not significantly changed during therapy.

The nicotinic acid test in constitutional conjugated hyperbilirubinemias and effects of corticosteroid.

The nicotinic acid test was performed in 5 patients with Dubin-Johnson syndrome, 5 with Rotor syndrome and 13 with Gilbert's syndrome. The increment in serum bilirubin concentration and bilirubin retention 5 hr later differed; the proportion of conjugated bilirubin in the increment of total bilirubin in Dubin-Johnson and Rotor syndromes was greater than in Gilbert's syndrome. These observations suggest that the nicotinic acid test reflects, in part, impaired biliary excretion of conjugated bilirubin. The results did not differentiate the two conjugated hyperbilirubinemias. The nicotinic acid test was also performed before and after corticosteroid treatment in four patients with Dubin-Johnson or Rotor syndrome. Although serum total and unconjugated bilirubin concentrations were reduced by corticosteroids, no significant change occurred in the parameters of the nicotinic acid test, suggesting that corticosteroids may enhance uptake of bilirubin without significantly altering biliary excretion of conjugated bilirubin.

Neonatal Dubin-Johnson syndrome with severe cholestasis: effective phenobarbital therapy.

We described Dubin-Johnson syndrome (DJS) with severe cholestasis in a 20-day-old Japanese boy. Although neonatal DJS has been sporadically reported. DJS with severe cholestasis has not to our knowledge been described in the English literature. The ratio of urinary coproporphyrin isomer I to urinary total coproporphyrin in our patient was high (93%). Liver histology showed cytoplasmic pigment granules in the liver cells. Administration of phenobarbital (PB) significantly decreased the levels of bilirubin and bile acids in the serum. There was a significant elevation of 1 beta-hydroxylated bile acids in the urine. It is predicted that severe cholestasis in neonatal DJS may cause metabolic abnormalities in both bilirubin and bile acids transport.

[Treatment of various forms of icterus or cholestasis with phenobarbital (author's transl)]. / Die Behandlung von Patienten mit Ikterus oder Cholestase mit Phenobarbital.

Phenobarbital induces microsomal enzymes such as bilirubinglucoronyltransferase and increases bile flow. Therefore Phenobarbital has been used in the treatment of various forms of icterus or cholestasis. The present paper reviews the results of treatment obtained by various authors.

Sn-mesoporphyrin suppression of hyperbilirubinemia in EHBR/Eis rats, an animal model of Dubin-Johnson syndrome.

Sn-mesoporphyrin (SnMP), a potent inhibitor of heme oxygenase (HO), controlled hyperbilirubinemia in rats of the mutant strain EHBR/Eis. This mutant strain displays pronounced conjugated hyperbilirubinuria and dark pigmentation of hepatocytes, characteristics of the Dubin-Johnson syndrome. SnMP administered at a dose of 10 mumol/kg body weight produced an immediate decrease in plasma bilirubin concentrations which could be maintained by weekly injections of this synthetic heme analogue. Marked inhibition of HO activity was demonstrated in liver, kidney and spleen but not in brain. These results demonstrate that SnMP can lower plasma bilirubin concentrations for extended periods in a new mutant rat model of Dubin-Johnson syndrome.

Barbituates and biliary function.

This paper reviews the principal effects of phenobarbital on biliary function. Phenobarbital administration is followed by an increase in bile flow. This is mainly due to an increase in the bile salt-independent fraction of canalicular bile flow possibly through an increase in canilicular Na+-K+ ATPase activity. In addition, bile salt excretion may be increased. This effect of barbiturates on choleresis appears to be independent of microsomal enzyme induction. Barbiturates increase the uptake, storage and excretion of various dyes, for example sulfobromophthalein. Phenobarbital increases bilirubin clearance by the liver; it enhances bilirubin-UDP-glucuronyl transferase activity; whether the influence on bilirubin clearance is related to the effect on the enzyme is unknown. The influence of phenobarbital on biliary lipids is markedly different from one species to the other. In the rhesus monkey and in the rat, the relative concentration of cholesterol is decreased; in the hamster it is increased, and in man it appears largely unaffected. These effects of phenobarbital have been utilized in the treatment of chronic unconjugated hyperbilirubinemia and of certain cholestatic syndromes. Phenobarbital alone has been useful, so far, in the treatment of cholesterol gallstones.