Dietary intake of advanced glycation endproducts and risk of hepatobiliary cancers: A multinational cohort study

Abstract

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, N^ε -[carboxymethyl]lysine (CML), N^ε -[1-carboxyethyl]lysine (CEL) and N^δ -[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1), was estimated using country-specific dietary questionnaires linked to an AGEs database. Cause-specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow-up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR-_CML = 0.87, 95% CI: 0.76-0.99, HR-_CEL = 0.84, 95% CI: 0.74-0.96 and HR-_MH-G1 = 0.84, 95% CI: 0.74-0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR-_CML = 1.28, 95% CI: 1.05-1.56, HR-_CEL = 1.17; 95% CI: 0.96-1.40, HR-_MH-G1 = 1.27, 95% CI: 1.06-1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer.

Keywords: EPIC study; advanced glycation endproducts; bile duct cancers; gallbladder cancer; hepatocellular carcinoma.

FIGURE 1

Three knot splines for the association between energy‐adjusted dietary intakes of (A) CML, (B) CEL and (C) MG‐H1 with risk of hepatocellular carcinoma (HCC). CML, N^ε‐[carboxymethyl]lysine; CEL, N^ε‐[1‐carboxyethyl]lysine; MG‐H1, N^δ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine. Hazard ratios (HR) and 95% confidence intervals (black dashed lines) from Cox proportional hazard regression stratified by sex, center and age at recruitment (1‐year categories), and additionally adjusted for educational level, body mass index, physical activity, smoking intensity, lifetime and baseline alcohol intake, coffee intake, self‐reported diabetes and dietary fiber intake [Color figure can be viewed at wileyonlinelibrary.com]