Disentangling the Effect of BMI on Hepatocellular Carcinoma From Cirrhosis With Multivariable Mendelian Randomization

Background & Aims:

While cirrhosis is a primary risk factor for hepatocellular carcinoma (HCC), a significant proportion of HCC cases attributed to metabolic dysfunction-associated steatotic liver disease (MASLD) develop in the absence of cirrhosis. MASLD is strongly linked to obesity, a known risk factor for multiple cancers. Whether the effect of obesity on HCC is mediated via cirrhosis or other factors is unknown.

Methods:

We used univariable Mendelian randomization (MR) to test the total effect of a higher body mass index (BMI), a proxy for obesity, on HCC, and multivariable MR to test the direct effect.

Results:

We estimated that the effect of BMI was a 1.65-fold higher risk of HCC per standard deviation increase (95% confidence interval (CI): 1.28–2.12, p-value = 1.0 × 10−5). The BMI effect became indistinguishable from zero when taking liability to cirrhosis into account with multivariable MR (odds ratio = 1.12, 95% CI: 0.84–1.50, p-value = 0.44). We investigated additional potential pathways linking BMI to HCC—such as inflammation and type 2 diabetes—and explored the direct effect of childhood obesity on the risk of HCC. We found no direct effect of inflammation or type 2 diabetes (p-values > 0.05). Childhood body size increased the risk of HCC (odds ratio = 1.78, 95% CI: 1.27–2.49, p-value = 8 × 10−4), but the effect disappeared when we took adult body size into account using multivariable MR.

Conclusions:

Cirrhosis liability is the primary mediator of the causal effect of obesity on HCC.

Summary:

Obesity significantly raises the risk of liver cell cancer. Using genetic evidence, our results show that the likelihood of developing cirrhosis (scarring of the liver) mediates the entire risk of liver cell cancer seen with obesity. This suggests that preventing liver scarring is the key to stopping obesity-related liver cell cancer and urges further investigation into alternative causes for obese patients who develop liver cell cancer without cirrhosis.