Obesity and Alcohol in Hepatocellular Carcinoma Risk
Obesity and Alcohol in Hepatocellular Carcinoma Risk
Obesity and alcohol interact to increase the risk of death from liver failure in men. In the present study, we aimed to examine whether obesity and alcohol were multiplicative or additive in increasing the risk of hepatocellular carcinoma (HCC) in both men and women. We conducted a prospective, population-based study of 23,712 Taiwanese residents (50.3% men) from 7 townships who underwent an evaluation for liver disease and were followed for 11.6 years for incident HCC. The mean age was 47 (standard deviation, 10) years and the mean body mass index (weight (kg)/height (m)) was 24 (standard deviation, 3). Overall, 305 cases of HCC were identified over 275,126 person-years of follow-up. Age, male sex, alcohol drinking, cigarette smoking, elevated alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus positivity, and diabetes mellitus were each statistically significant predictors of incident HCC in univariate analyses (P < 0.05). Alcohol use and obesity (body mass index ≥30) showed a synergistic association with the risk of incident HCC in both unadjusted analyses (hazard ratio = 7.19, 95% confidence interval: 3.69, 14.00; P < 0.01) and multivariable-adjusted analyses (age, sex, smoking, serum alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus antibody, and diabetes mellitus) (hazard ratio = 3.82, 95% confidence interval: 1.94, 7.52; P < 0.01). Relative excess risks due to interaction, attributable proportion, and synergy index were 4.83, 0.67, and 4.53, respectively, suggesting a multiplicative interaction between alcohol use and obesity. Obesity and alcohol synergistically increase the risk of incident HCC.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide. It is estimated that by the year 2030, HCC will become the third most fatal cancer. This rising incidence of HCC is preceded by the obesity epidemic worldwide. Several studies have shown that obesity increases the risk of HCC. Another modifiable risk factor that is strongly associated with liver disease and HCC is excessive alcohol use. Both alcohol use and obesity are associated with fatty liver disease. Epidemiologic studies have suggested that fatty liver disease, both alcoholic and nonalcoholic in etiology, is associated with increased risk of HCC.
Previous studies have shown that alcohol and obesity synergistically increase the risk of elevated serum alanine aminotransferase and aspartate aminotransferase levels. It is plausible that obesity and alcohol both lead to increased cytokine release by hepatocytes and Kupffer cells that may lead to hepatic stellate cell activation. These mechanistic pathways, along with other hitherto unknown pathways, increase the risk of progressive steatohepatitis. Understanding the impact of this synergism between obesity and alcohol use at the population level is important because these are modifiable risk factors. Previous epidemiologic investigations have shown that seeing a synergistic interaction strengthens the expectation that there is biologic plausibility for a relationship between a primary risk factor and disease, for example, cigarette smoking and alcohol use with oral cancer. Given that incidence and mortality rates due to HCC mirror each other, prevention is the preferred strategy in reducing the worldwide burden of HCC.
In a recent study, Hart et al. followed 9,559 Scottish men for up to 42 years and found that obesity and alcohol use had a supra-additive interaction in their association with the risk of liver disease morbidity and mortality. Because of the small number of events, the effect of obesity and alcohol on HCC was not examined. That study included only men. We recently conducted a pilot study in a high-risk population and found that obesity and alcohol use raised the risk of HCC in Taiwanese men with hepatitis B. However, the study was limited, as the confidence intervals for synergy index overlapped 1 because of the smaller sample size.
In the present study, we aimed to examine whether obesity and alcohol were either multiplicative or additive in increasing the risk of incident HCC in both men and women in a larger, well-characterized, population-based cohort that was representative of the general population of Taiwan.
Abstract and Introduction
Abstract
Obesity and alcohol interact to increase the risk of death from liver failure in men. In the present study, we aimed to examine whether obesity and alcohol were multiplicative or additive in increasing the risk of hepatocellular carcinoma (HCC) in both men and women. We conducted a prospective, population-based study of 23,712 Taiwanese residents (50.3% men) from 7 townships who underwent an evaluation for liver disease and were followed for 11.6 years for incident HCC. The mean age was 47 (standard deviation, 10) years and the mean body mass index (weight (kg)/height (m)) was 24 (standard deviation, 3). Overall, 305 cases of HCC were identified over 275,126 person-years of follow-up. Age, male sex, alcohol drinking, cigarette smoking, elevated alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus positivity, and diabetes mellitus were each statistically significant predictors of incident HCC in univariate analyses (P < 0.05). Alcohol use and obesity (body mass index ≥30) showed a synergistic association with the risk of incident HCC in both unadjusted analyses (hazard ratio = 7.19, 95% confidence interval: 3.69, 14.00; P < 0.01) and multivariable-adjusted analyses (age, sex, smoking, serum alanine aminotransferase, serum hepatitis B surface antigen, anti-hepatitis C virus antibody, and diabetes mellitus) (hazard ratio = 3.82, 95% confidence interval: 1.94, 7.52; P < 0.01). Relative excess risks due to interaction, attributable proportion, and synergy index were 4.83, 0.67, and 4.53, respectively, suggesting a multiplicative interaction between alcohol use and obesity. Obesity and alcohol synergistically increase the risk of incident HCC.
Introduction
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide. It is estimated that by the year 2030, HCC will become the third most fatal cancer. This rising incidence of HCC is preceded by the obesity epidemic worldwide. Several studies have shown that obesity increases the risk of HCC. Another modifiable risk factor that is strongly associated with liver disease and HCC is excessive alcohol use. Both alcohol use and obesity are associated with fatty liver disease. Epidemiologic studies have suggested that fatty liver disease, both alcoholic and nonalcoholic in etiology, is associated with increased risk of HCC.
Previous studies have shown that alcohol and obesity synergistically increase the risk of elevated serum alanine aminotransferase and aspartate aminotransferase levels. It is plausible that obesity and alcohol both lead to increased cytokine release by hepatocytes and Kupffer cells that may lead to hepatic stellate cell activation. These mechanistic pathways, along with other hitherto unknown pathways, increase the risk of progressive steatohepatitis. Understanding the impact of this synergism between obesity and alcohol use at the population level is important because these are modifiable risk factors. Previous epidemiologic investigations have shown that seeing a synergistic interaction strengthens the expectation that there is biologic plausibility for a relationship between a primary risk factor and disease, for example, cigarette smoking and alcohol use with oral cancer. Given that incidence and mortality rates due to HCC mirror each other, prevention is the preferred strategy in reducing the worldwide burden of HCC.
In a recent study, Hart et al. followed 9,559 Scottish men for up to 42 years and found that obesity and alcohol use had a supra-additive interaction in their association with the risk of liver disease morbidity and mortality. Because of the small number of events, the effect of obesity and alcohol on HCC was not examined. That study included only men. We recently conducted a pilot study in a high-risk population and found that obesity and alcohol use raised the risk of HCC in Taiwanese men with hepatitis B. However, the study was limited, as the confidence intervals for synergy index overlapped 1 because of the smaller sample size.
In the present study, we aimed to examine whether obesity and alcohol were either multiplicative or additive in increasing the risk of incident HCC in both men and women in a larger, well-characterized, population-based cohort that was representative of the general population of Taiwan.
