Persisting hyperbilirubinemia in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with eculizumab: The role of hepatocanalicular transporter variants.
Eur J Haematol
; 99(4): 350-356, 2017 Oct.
Article
in En
| MEDLINE
| ID: mdl-28692147
ABSTRACT
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antibodies, Monoclonal, Humanized
/
Hemoglobinuria, Paroxysmal
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Hyperbilirubinemia
Type of study:
Diagnostic_studies
/
Guideline
/
Prognostic_studies
Limits:
Adult
/
Aged
/
Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Eur J Haematol
Journal subject:
HEMATOLOGIA
Year:
2017
Type:
Article
Affiliation country:
Germany