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

Claire E Thomas,Guoxiang Xie,Jennifer Adams-Haduch,Wei Jia,Renwei Wang,Jaideep Behari,Jian-Min Yuan,Hung N Luu,Aizhen Jin,Woon-Puay Koh

doi:10.3390/cancers13112648

Abstract

Simple SummaryHepatocellular carcinoma (HCC) is a common cancer with poor prognosis. The increasing incidence rate of HCC in developed countries has been linked to increasing prevalence of metabolic dysfunction-associated fatty liver disease, which has characteristics of altered bile acid metabolism that may predate hepatocarcinogenesis. The aim of the present study was to assess the association of circulating bile acid levels in pre-diagnostic serum with the risk of developing HCC in a general population in Singapore. Primary conjugated bile acids were most strongly associated with increased risk of HCC whereas the ratios of secondary over primary bile acids were significantly associated with reduced risk. These results support a contributing role of dysmetabolism of bile acids in the development of HCC. The modulation of bile acid metabolism through alteration of gut microbiota may be an effective strategy for primary prevention against HCC in individuals with metabolic dysfunction-associated fatty liver disease.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.

Highlights

Liver cancer is the sixth most commonly diagnosed cancer and fourth most common cause of cancer-related death globally [1]
The present study demonstrated that hepatocellular carcinoma (HCC) cases had significantly lower ratios of major secondary bile acid species over their parent primary bile acid species (i.e., deoxycholic acid (DCA)/cholic acid (CA) ratio, lithocholic acid (LCA)/chenodeoxycholic acid (CDCA) ratio, and ursodeoxycholic acid (UDCA)/CDCA ratio) than controls, suggesting that the reduction in gut microbiota capable of producing secondary bile acids may play a significant role in the development of HCC
Our study clearly demonstrates a strong association between elevated serum concentrations of major primary bile acids measured approximately four years prior to diagnosis and greater risk of developing HCC

Summary

Introduction

Liver cancer is the sixth most commonly diagnosed cancer and fourth most common cause of cancer-related death globally [1]. The major risk factors for HCC are chronic infection with hepatitis B virus (HBV) and/or hepatitis C virus (HCV), alcohol abuse, and dietary exposure to aflatoxin B1 [4,5,6]. Given the diminishing contributing role of HBV and HCV to HCC development, non-alcoholic fatty liver disease (NAFLD), recently redefined under the term metabolic dysfunction-associated fatty liver disease (MAFLD) [7], has emerged as an important risk factor for HCC. Emerging data suggest that altered gut microbiome (i.e., dysbiosis) due to dietary and other lifestyle exposures may play a significant role in the development of various liver diseases including MAFLD and HCC [12,13]. One of the direct links from the gut microbiome to the host liver is through microbial-produced secondary bile acids via enterohepatic circulation [14]

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