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Liver Int. 2018 Sep;38(9):1676-1685. doi: 10.1111/liv.13714. Epub 2018 Mar 12.

Comprehensive bile acid profiling in hereditary intrahepatic cholestasis: Genetic and clinical correlations.

Author information

1
Department of Pediatrics, Jinshan Hospital of Fudan University, Shanghai, China.
2
BC Cancer Agency, Vancouver, BC, Canada.
3
University of Victoria-Genome BC Proteomics Centre, University of Victoria, Victoria, BC, Canada.
4
Department of Pediatrics, Shanghai Medical College, Fudan University, Shanghai, China.
5
The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
6
Institut für Pathologie, Medizinische Universität Graz, Graz, Österreich/Austria.
7
Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada.
8
Gerald Bronfman Department of Oncology, Jewish General Hospital, McGill University, Montreal, QC, Canada.
9
Proteomics Centre, Segal Cancer Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.

Abstract

BACKGROUND & AIMS:

Genetic defects causing dysfunction in bile salt export pump (BSEP/ABCB11) lead to liver diseases. ABCB11 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 ABCB11-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 ABCB11, and 8 healthy controls, for further verification.

RESULTS:

The overall hydrophobicity indices of total bile acids in both the ABCB11-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 ABCB11-mutated cohort from healthy controls and undiagnosed cholestasis patients (AUC=0.946, p < 0.0001) and, in non-ABCB11-mutated cholestasis patients, could distinguish BSEP dysfunction from normal BSEP function (9/12 vs 0/38, p < 0.0000001).

CONCLUSIONS:

Profiling of plasma bile acids has provided insights into cholestasis alleviation and may be useful for the clinical management of cholestatic diseases.

KEYWORDS:

ABCB11 ; PFIC2; bile salt export pump; liquid chromatography-mass spectrometry

PMID:
29412511
DOI:
10.1111/liv.13714

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