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Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations
Author(s) -
Liu Teng,
Wang RenXue,
Han Jun,
Hao ChenZhi,
Qiu YiLing,
Yan YanYan,
Li LiTing,
Wang NengLi,
Gong JingYu,
Lu Yi,
Zhang MeiHong,
Xie XinBao,
Yang JunCong,
You YiJie,
Li Jiaqi,
Knisely A. S.,
Borchers Christoph H.,
Ling Victor,
Wang JianShe
Publication year - 2018
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13714
Subject(s) - bile salt export pump , cholestasis , bile acid , progressive familial intrahepatic cholestasis , lithocholic acid , medicine , ursodeoxycholic acid , gastroenterology , biology , endocrinology , biochemistry , gene , transplantation , transporter , liver transplantation
Abstract Background & Aims Genetic defects causing dysfunction in bile salt export pump ( BSEP / ABCB 11 ) lead to liver diseases. ABCB 11 mutations alter the bile acid metabolome. We asked whether profiling plasma bile acids could reveal compensatory mechanisms and track genetic and clinical status. Methods We compared plasma bile acids in 17 ABCB 11 ‐mutated patients, 35 healthy controls and 12 genetically undiagnosed cholestasis patients by ultra‐high‐performance liquid chromatography/multiple‐reaction monitoring‐mass spectrometry ( UPLC / MRM ‐ MS ). We developed an index to rank bile acid hydrophobicity, and thus toxicity, based on LC retention times. We recruited 42 genetically diagnosed hereditary cholestasis patients, of whom 12 were presumed to have impaired BSEP function but carried mutations in genes other than ABCB 11 , and 8 healthy controls, for further verification. Results The overall hydrophobicity indices of total bile acids in both the ABCB 11 ‐mutated group (11.89 ± 1.07 min) and the undiagnosed cholestasis group (11.46 ± 1.07 min) were lower than those of healthy controls (13.69 ± 0.77 min) (both p < 0.005). This was owing to increased bile acid modifications. Secondary bile acids were detected in patients without BSEP expression, suggesting biliary bile acid secretion through alternative routes. A diagnostic panel comprising lithocholic acid ( LCA ), tauro‐ LCA , glyco‐ LCA and hyocholic acid was identified that could differentiate the ABCB 11 ‐mutated cohort from healthy controls and undiagnosed cholestasis patients ( AUC =0.946, p < 0.0001) and, in non‐ ABCB 11 ‐mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.1). Conclusions Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.