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Persisting hyperbilirubinemia in patients with paroxysmal nocturnal hemoglobinuria ( PNH ) chronically treated with eculizumab: The role of hepatocanalicular transporter variants
Author(s) -
Alashkar Ferras,
Weber Susanne N.,
Vance Colin,
HerichTerhürne Dörte,
Dührsen Ulrich,
Lammert Frank,
Röth Alexander
Publication year - 2017
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/ejh.12927
Subject(s) - paroxysmal nocturnal hemoglobinuria , eculizumab , medicine , hemoglobinuria , bilirubin , gastroenterology , hemolysis , endocrinology , immunology , complement system , antibody
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 ( ABCB 4, ABCB 11, ATP 8B1, NR 1H4 ) 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 ABCB 4 , ABCB 11, and ATP 8B1 genes were identified in all eight pts. All carried the common ABCB 4 c.787A>T polymorphism. The A( TA ) 7 TAA variant in the UGT 1A1 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.