Altered Bile Acid Metabolome in Patients with Nonalcoholic Steatohepatitis

Abstract

Background & Aims The prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is increasing at an alarming rate. The role of bile acids in the development and progression of NAFLD to NASH and cirrhosis is poorly understood. This study aimed to quantify the bile acid metabolome in healthy subjects and patients with non-cirrhotic NASH under fasting conditions and after a standardized meal. Methods Liquid chromatography tandem mass spectroscopy was used to quantify 30 serum and 16 urinary bile acids from 15 healthy volunteers and 7 patients with biopsy-confirmed NASH. Bile acid concentrations were measured at two fasting and four post-prandial timepoints following a high-fat meal to induce gallbladder contraction and bile acid reabsorption from the intestine. Results Patients with NASH had significantly higher total serum bile acid concentrations than healthy subjects under fasting conditions (2.2- to 2.4-fold increase in NASH; NASH: 2595–3549 μM and healthy: 1171–1458 μM) and at all post-prandial time points (1.7- to 2.2-fold increase in NASH; NASH: 4444–5898 μM and healthy: 2634–2829 μM). These changes were driven by increased taurine- and glycine-conjugated primary and secondary bile acids. Patients with NASH exhibited greater variability in their fasting and post-prandial bile acid profile. Conclusions Results indicate that patients with NASH have higher fasting and post-prandial exposure to bile acids, including the more hydrophobic and cytotoxic secondary species. Increased bile acid exposure may be involved in liver injury and the pathogenesis of NAFLD and NASH.

Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD

“…Elevated serum total bile acids in NASH were first reported by Ferslew et al 37. Using approaches that are complementary to ours, Mouzaki et al 17 concluded that bile acid production is elevated in NAFLD livers, based on the findings that faecal total bile acid and faecal primary bile acid levels are elevated in patients with NAFLD, and that serum marker of bile acid synthesis 7-alpha-hydroxy-4-cholesten-3-one is elevated in NAFLD.…”

Characterization of the Cytochrome P450 epoxyeicosanoid pathway in non-alcoholic steatohepatitis

“…Human samples were obtained from a single-center, case:control study of male and female patients with biopsy-confirmed NASH (n=7) and corresponding healthy volunteer controls (n=15) (18, 19). The inclusion and exclusion criteria have been described in detail previously (18).…”

Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease

“…Concentrations of bile acids such as CDCA, DCA and ursodeoxycholic acid are increased in serum and urine samples of patients with NASH compared with healthy subjects 84. Levels of cholic acid are increased in liver tissues from patients with NASH 85.…”