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, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[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.
Highlights
Liver cancer was the sixth most common cancer and the fourth leading cause of cancer-related death worldwide in 2018.1 The most common type of liver cancer is hepatocellular carcinoma (HCC).[2]
In our study, using the large multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the association between dietary intake of Advanced glycation endproducts (AGEs) and the risk of HCC and other hepatobiliary cancers
To test whether associations with dietary AGEs were modified by a priori defined covariates, we repeatedly ran our fully adjusted model with a cross-product term between AGEs and potential effect modifiers: sex, body mass index (BMI), smoking status, diabetes, lifetime alcohol consumption pattern, study region (North: Sweden, Denmark and Norway; Central: France, the United Kingdom, the Netherlands and Germany; South: Italy and Spain), median age at recruitment and dietary energy intake misreporting according to Goldberg cut-offs.[28]
Summary
Liver cancer was the sixth most common cancer and the fourth leading cause of cancer-related death worldwide in 2018.1 The most common type of liver cancer is hepatocellular carcinoma (HCC).[2]. Higher dietary AGEs administration led to liver tissue deposition and increased hepatic expression of receptor of AGEs (RAGE).[15] The binding of AGEs to RAGE triggers oxidative stress and chronic/acute inflammation.[16] It has been reported that ingested dietary AGEs can accumulate in the gallbladder.[10] several human and experimental studies have shown an association of higher AGEs exposure with hepatic disorders—from minor steatosis to hepatic cirrhosis.[15] The literature suggests a link between AGE-RAGE binding and malignant transformations of hepatic cells.[17] Dietary AGEs may play an important role in the development of cancers of the liver. In our study, using the large multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the association between dietary intake of AGEs and the risk of HCC and other hepatobiliary cancers
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