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

Liver Int. 2018 Feb 7. doi: 10.1111/liv.13714. [Epub ahead of print]
Liu T, Wang RX, Han J, Hao CZ, Qiu YL, Yan YY, Li LT, Wang NL, Gong JY, Lu Y, Zhang MH, Xie XB, Yang JC, You YJ, Li JQ, Knisely AS, Borchers CH, Ling V, Wang JS.

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 if 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 cholestatic patients by ultrahigh-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 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 due 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 (HCA) was identified that could differentiate the ABCB11-mutated cohort from healthy controls and undiagnosed cholestatic 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.