Persisting hyperbilirubinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with eculizumab: The role of hepatocanalicular transporter variants.

BACKGROUND: Eculizumab-treated paroxysmal nocturnal hemoglobinuria (PNH) patients (pts) show a dramatic decrease in serum lactate dehydrogenase (LDH) activities and bilirubin concentrations. However, some pts remain hyperbilirubinemic, possibly indicating an inadequate response due to extravascular hemolysis.

METHODS: Mutation analyses of hepatocanalicular transporter/nuclear receptor variants (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight (five of eight males; mean age 38 years [range 26-68 years]) out of the 174 pts with PNH/-clone at our department due to a persistent increase in total bilirubin concentrations (median 3.4 mg/dL; range 2.1-8.1 mg/dL) during chronic eculizumab treatment and normal/or slightly increased serum aminotransferase activities. Median observation time was 70.1 months (range 10.6-135.2 months). All pts were treated according to German PNH guidelines.

RESULTS: Homozygous and heterozygous procholestatic variants in the ABCB4, ABCB11, and ATP8B1 genes were identified in all eight pts. All carried the common ABCB4 c.787A>T polymorphism. The A(TA)7 TAA variant in the UGT1A1 promoter causing Gilbert syndrome was detected in three pts (5/8).

CONCLUSIONS: Hyperbilirubinemia in PNH pts treated with eculizumab might not only be due to an insufficient response but rather a combination of mutations in hepatocanalicular transporter variants, Gilbert syndrome, and extravascular hemolysis. Our findings warrant further studies concerning transporter and enzyme variants in PNH to determine their clinical significance.