Abstract and Introduction
Abstract
Background: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD).
Aim: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD.
Methods: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs.
Results: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2–4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score.
Conclusions: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.
Introduction
It has been estimated that nonalcoholic fatty liver disease (NAFLD) affects up to a third of the world's adult population and the global prevalence of NAFLD will increase markedly in the next decade.[1,2] NAFLD includes a spectrum of potentially progressive liver conditions, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis.[3] About 20% of patients with NASH may progress to cirrhosis,[4,5] and it has been reported that the severity of liver fibrosis is the strongest histological predictor of liver-related outcomes and mortality in NAFLD.[6,7] To date, liver biopsy remains the "gold standard" method for staging fibrosis in NAFLD,[8] but this method is invasive, expensive, can cause morbidity and cannot be routinely used for monitoring disease progression or treatment responses in clinical practice.[9,10]
Dysregulated bile acid (BA) metabolism has been implicated in the pathophysiology of chronic liver diseases, including NAFLD.[11,12] Primary BAs are synthesised from cholesterol in the liver. Following their synthesis, BAs are conjugated to an amino acid such as taurine and glycine and secreted into bile, concentrated in the gall bladder, and then released into the intestine after food ingestion.[13] BAs carry out their important digestive functions aiding in the absorption of fats and fat-soluble vitamins.[14] Besides, primary BAs are transported into the distal small bowel from where they are actively reabsorbed by the gut epithelium and return to the liver via enterohepatic circulation.[12] Additionally, BAs pass into the colon and are transformed into secondary BAs by intestinal microbiota through multiple different reactions, including deconjugation, 7α-dehydroxylation, 6α-hydroxylation or epimerization.[15] These secondary BAs are also absorbed and diversify the BA pool in the body. During this process, BAs can enter into the systemic circulation, and act as biologically active signalling molecules to regulate glucose and lipid homeostasis,[16] mainly through the activation of specific receptors, such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5).[17] Dysregulated BA homeostasis and impaired BA signalling can lead to liver damage, thereby contributing to the development and progression of NAFLD.[18] Hepatic BA accumulation leads to hepatocyte apoptosis, mitochondrial damage and endoplasmic reticulum stress.[19] Both conjugated and unconjugated BAs at cholestatic levels lead to a release of multiple proinflammatory cytokines, which activate hepatic stellate cells and induce hepatic fibrogenesis.[20] Thus, it is conceivable that modulation of BA synthesis and metabolism could become a valid therapeutic option for NAFLD and its related metabolic diseases.[13,21]
It is known that the high heterogeneity of NAFLD may result from a complex and multilayered dynamic interaction between different factors, such as sex, obesity, diabetes and other coexisting metabolic disorders,[22,23] which are also closely associated with BA synthesis and metabolism. BA synthesis is higher in men than in women with a wider inter-individual variation.[24,25] Sex-related differences in BA synthesis and metabolism have been also shown in steatosis, NASH and hepatocellular carcinoma.[26] The differential BAs, related gut microbiota and signalling pathways need to be further investigated to better understand their effects on disease heterogeneity.[27] Moreover, individuals with lean NAFLD have an obesity-resistant phenotype that could be, at least in part, mediated by higher levels of certain BAs and different gut microbiota composition (with higher amounts of microbes involved in BA metabolism), thus contributing to explain their milder liver disease and more favourable metabolic profiles compared to NAFLD individuals with obesity.[28] Distinct signatures of gut microbiome and BAs have been also identified in the stool samples of individuals with lean NAFLD and fibrosis.[29] Thus, it is reasonable to assume that a better understanding of BA profiles in different subgroups of NAFLD individuals can also help to better decipher the clinical heterogeneity of NAFLD and to develop more targeted pharmacotherapies for NAFLD and NASH.
Therefore, in a large cohort of Chinese adults with biopsy-confirmed NAFLD and fibrosis, we aimed to examine the differences in a large panel of circulating BA levels in patients with varying levels of liver fibrosis. In addition, we developed and validated prediction models using serum BAs and clinical/biochemical biomarkers, alone or in combination, for the non-invasive identification of mild and significant fibrosis, both in the whole cohort and in different subgroups of patients stratified by sex, and the presence or absence of obesity and metabolic syndrome.
Aliment Pharmacol Ther. 2023;57(8):872-885. © 2023 Blackwell Publishing
