Association between Pre-Diagnostic Serum Bile Acids and Hepatocellular Carcinoma: The Singapore Chinese Health Study

Abstract

Hepatocellular carcinoma (HCC) is a commonly diagnosed malignancy with poor prognosis. Rising incidence of HCC may be due to rising prevalence of metabolic dysfunction-associated fatty liver disease, where altered bile acid metabolism may be implicated in HCC development. Thirty-five bile acids were quantified using ultra-performance liquid chromatography triple-quadrupole mass spectrometry assays in pre-diagnostic serum of 100 HCC cases and 100 matched controls from the Singapore Chinese Health Study. Conditional logistic regression was used to assess associations for bile acid levels with risk of HCC. Conjugated primary bile acids were significantly elevated whereas the ratios of secondary bile acids over primary bile acids were significantly lower in HCC cases than controls. The respective odds ratios and 95% confidence intervals of HCC were 6.09 (1.75–21.21) for highest vs. lowest tertile of cholic acid species and 30.11 (5.88–154.31) for chenodeoxycholic acid species. Doubling ratio of taurine-over glycine-conjugated chenodeoxycholic acid was associated significantly with 40% increased risk of HCC whereas doubling ratio of secondary over primary bile acid species was associated with 30–40% reduced risk of HCC. In conclusion, elevated primary bile acids and taurine over glycine-conjugated ratios were strongly associated with HCC risk whereas the ratios of secondary bile acids over primary bile acids were inversely associated with HCC risk.

Lipid alterations in chronic liver disease and liver cancer

“…Conjugated primary BAs are significantly elevated at the stage of cirrhosis and continue to increase with the progression of HCC. 148 , 149 The role of BAs in the development of HCC is well-established and was extensively reviewed elsewhere. 150 Fundamentally, BAs activate farnesoid X receptor (FXR) and G-protein coupled BA receptor 1 (GPBAR1) that both control numerous oncogenic processes, including inflammation, oxidative stress, and the regulation of many cancer-related genes.…”

Concurrent Cholecystectomy Is Associated with a Lower Risk of Recurrence after Curative Resection in Early-Stage Hepatocellular Carcinoma: A 10 Year Observational Single-Center Study

“…In another study from Taiwan, the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer (REVEAL) cohort did not support the hypothesis that higher levels of secondary bile acids increase liver cancer risk; in fact, higher levels of the secondary bile acid deoxycholic acid were inversely associated with HCC [35]. This concept is compatible with a recent study from Singapore, in which the ratios of secondary bile acids over primary bile acids were associated with a decreased HCC risk [36]. The results of the present study demonstrate that HCC patients received cholecystectomy with a lower recurrence rate, rather than non-HCC patients receiving cholecystectomy with increasing rates of liver tumors.…”

Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review)

“…However, the result of another study was that conjugated primary BAs were significantly elevated, whereas the ratios of secondary BAs over primary BAs were significantly lower in HCC cases than in controls (36). The doubling ratio of taurine-over glycine-conjugated CDCA was significantly associated with a 40% increased risk of HCC, whereas the doubling ratio of secondary over primary BAs was associated with a 30-40% reduced risk of HCC (36). In addition, a weighted relative difference accumulation algorithm study suggested that patients with hepatitis and cirrhosis had increased serum levels of G-CDCA, G-CA and T-CA and decreased serum levels of CDCA (37).…”

“…A retrospective cohort study from 2004 to 2014 including 2,262 patients with chronic hepatitis B on conventional antiviral therapy indicated that persistent elevation of serum total BAs was an independent risk factor for HCC (35). However, the result of another study was that conjugated primary BAs were significantly elevated, whereas the ratios of secondary BAs over primary BAs were significantly lower in HCC cases than in controls (36). The doubling ratio of taurine-over glycine-conjugated CDCA was significantly associated with a 40% increased risk of HCC, whereas the doubling ratio of secondary over primary BAs was associated with a 30-40% reduced risk of HCC (36).…”