A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary tract cancer

Abstract

Bile acids (BAs), major regulators of the gut microbiota, may play an important role in hepatobiliary cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and liver or biliary tract cancer. In the Alpha‐Tocopherol, Beta‐Carotene Cancer Prevention (ATBC) study, we designed 1:1 matched, nested, case–control studies of primary liver cancer (n = 201 cases), fatal liver disease (n = 261 cases), and primary biliary tract cancer (n = 138 cases). Using baseline serum collected ≤30 years before diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography–tandem mass spectrometry. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable conditional logistic regression models, adjusted for age, education, diabetes status, smoking, alcohol intake, and body mass index. We accounted for multiple comparisons using a false discovery rate (FDR) correction. Comparing the highest to the lowest quartile, seven BAs were positively associated with liver cancer risk, including taurocholic acid (TCA) (OR, 5.62; 95% CI, 2.74–11.52; Q trend < 0.0001), taurochenodeoxycholic acid (TCDCA) (OR, 4.77; 95% CI, 2.26–10.08; Q trend < 0.0001), and glycocholic acid (GCA) OR, 5.30; 95% CI, 2.41–11.66; Q trend < 0.0001), and 11 were positively associated with fatal liver disease risk, including TCDCA (OR, 9.65; 95% CI, 4.41–21.14; Q trend < 0.0001), TCA (OR, 7.45; 95% CI, 3.70–14.97; Q trend < 0.0001), and GCA (OR, 6.98; 95% CI, 3.32–14.68; Q trend < 0.0001). For biliary tract cancer, associations were generally >1 but not significant after FDR correction. Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between BA metabolism and liver cancer or death from liver disease.

Integrated microbiome and metabolome analysis reveals the interaction between intestinal flora and serum metabolites as potential biomarkers in hepatocellular carcinoma patients

“…TCDCA and GCDCA were discovered to be involved in the bile secretion and cholesterol metabolism pathways, and their serum concentrations were both significantly different in pairwise comparisons, suggesting that they could be used as clinical biomarkers. Previous research has discovered that TCDCA not only causes oxidative stress in gastrointestinal tumors, resulting in compensatory upregulation of TR mRNA ( Lechner et al., 2002 ), but it also reduces expression of the tumor suppressor gene CEBP in HepG2 cell lines ( Xie et al., 2016 ), which is correlated with the risk of colon cancer and HCC ( Kühn et al., 2020 ; Farhat et al., 2022 ).…”

Identification of pre‐diagnostic lipid sets associated with liver cancer risk using untargeted lipidomics and chemical set analysis: A nested case‐control study within the ATBC cohort

“…In comparison to prior epidemiology studies, 14,[29][30][31][32][33][34][35][36][37][38][39][40] the majority of which have utilized generic and broad metabolic extraction and data collection protocols, this study, to the best of our knowledge, is the first liver cancer study to characterize the pre-diagnostic circulating lipidome using an untargeted lipidomics method. We tested over 400 annotated lipids from 28 lipid classes using chemical set enrichment analysis methods to identify structural and functional lipid sets that were associated with liver cancer.…”

“…We tested over 400 annotated lipids from 28 lipid classes using chemical set enrichment analysis methods to identify structural and functional lipid sets that were associated with liver cancer. In prior prospective cohort studies from Europe and Asia, higher pre-diagnostic levels of bile acids 13,14,33,37,38 and triglycerides 34,35 have been shown to increase risk, suggesting changes in liver metabolic pathways are perturbed to create a pro-carcinogenic environment.…”

An AgPd NP-based lateral flow immunoassay for simultaneous detection of glycocholic acid and alpha-fetoprotein

“…6 Previous work has shown that serum GCA is signicantly associated with hepatocellular carcinoma and fatal liver diseases and becomes a potential target for the prevention of liver disease progression and hepatocellular carcinoma. 7,8 Under normal circumstances, the content of serum GCA is low with its normal range between 0.4 and 2.98 mg mL −1 , but when liver cells decrease, the serum GCA concentration is signicantly increased. Meanwhile, alphafetoprotein (AFP) was rst identied in 1956 and is typically present at levels less than 10 ng mL −1 in the blood of healthy non-pregnant adults.…”