Combination of lysosphingomyelin, 7-ketocholesterol and bile acid W for diagnosis of Japanese patients with Niemann Pick disease type C by MS/MS

Abstract

Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is characterized by conjugated hyperbilirubinemia and increased plasma bile acid concentrations. However, the underlying mechanisms remain unclear. We established a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneously quantifying plasma bile acids and examined bile acid profiles in NICCD infants.We measured 15 bile acids within 15 min and found a wide linear range for individual bile acids.The within-run and run-to-run CV of all bile acids was 1.2–10.9% and 3.1–10.8%, respectively, with a mean recovery of 90.5–112.6%. Compared to infants with citrullinemia without mutations in SLC25A13 (non-NICCD), NICCD infants showed increased plasma total bile acid concentrations (mean: 201 vs. 42 μM, p < 0.001), with a distinct bile acid profile characterized by increased conjugated primary bile acid concentrations. The calculated ratios, including primary/secondary bile acid (714 vs. 235, p < 0.05) and conjugated/free bile acid (371 vs. 125, p < 0.05) ratios, were higher in NICCD infants. The area under receiver operating characteristic curve for conjugated/free bile acid ratio to identify infants with NICCD was 0.871 (95% confidence interval, 0.713–1.0).Together, our findings indicated plasma bile acid profile as a potential noninvasive diagnostic biomarker for NICCD.