Abstract
To assess the potential of individual bile acids (IBA) and their profiles as mechanistic biomarkers of liver injury for humans in real world situations, we interrogated samples collected under minimum controlled conditions (ie subjects were not fasted). Total bile acids (TBA) have been considered to be biomarkers of liver injury for decades, and more recently, monitoring of IBA has been proposed for differentiation of variety of etiologies of liver injury. We established a LC-MS/MS methodology to analyze nine IBA, generated reference ranges, and examined effects of age, gender, and ethnicity for each IBA. Furthermore, we evaluated the ability of IBA and their profiles to detect hepatic injury in subjects with a broad range of liver impairments. To date, our study utilized the largest total cohort of samples (N = 645) that were divided into 2 groups, healthy or liver impaired, to evaluate IBA as biomarkers. The TBA serum levels in the Asian ethnic group trended higher when compared to other ethnic groups, and the serum concentrations of IBA, such as glycocholic acid (GCA), glycochenodeoxycholic acid (GCDCA), chenodeoxycholic acid (CDCA), and taurochenoxycholic acid (TCDCA) were significantly increased. To our knowledge, this report is the first to describe ethnic differences in serum concentrations of IBAs. In patients with hepatic impairments, with the exception of deoxycholic acid (DCA), the concentrations of IBAs were significantly elevated when compared with healthy subjects. The conjugated bile acids displayed greater differences between healthy subjects and subjects with hepatic impairments than non-conjugated bile acids. Furthermore, the subjects with hepatic impairments exhibited distinct profiles (signatures) of IBAs that clustered subjects according the nature of their liver impairments. Although additional studies are needed, our data suggested that the analysis of IBA has the potential to become useful for differentiation of various forms of liver injury.
Highlights
Better biomarkers of liver injury are needed to aid in the early detection of liver diseases, as well as facilitate the development of safer drugs
The LC-MS/MS assay developed was able to quantitate a set of 9 individual bile acids (IBA): cholic acid (CA), glycocholic acid (GCA), taurocholic acid (TCA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid (GCDCA), TCDCA, deoxycholic acid (DCA), glycodeoxycholic acid (GDCA), and taurodeoxycholic acid (TDCA)
This study provided normal serum reference ranges for 9 individual bile acids in a large population of human subjects with no consideration to diet, alcohol, smoking, or other factors
Summary
Better biomarkers of liver injury are needed to aid in the early detection of liver diseases, as well as facilitate the development of safer drugs. Over thirty million Americans (one in ten) have liver disease, which includes over 100 different forms of the disease (www.liverfoundation.org). This includes thirty thousand individuals diagnosed with primary liver cancer, one of the few cancers with increasing incidence, as well as the millions diagnosed with hepatitis B and C. The development of new biomarkers is a challenging and lengthy process requiring extensive data sets that demonstrate their diagnostic utility. It requires validated analytical assays and thorough evaluation of biomarker performance according to its context of use in large populations
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