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.