Systematic Review and Meta-Analysis: NAFLD and risk of developing extra-hepatic cancer

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in adults and is increasingly recognized as a systemic metabolic condition rather than an isolated liver disorder. While the association between NAFLD and hepatocellular carcinoma is well established, growing cohort-level evidence suggests that NAFLD may also be associated with an increased risk of multiple extrahepatic malignancies. These include gastrointestinal, gynecologic, endocrine, and genitourinary cancers. To date, these associations have not been comprehensively synthesized across cancer sites. The purpose of this study is to systematically review and meta-analyze cohort studies evaluating the association between NAFLD and the incidence of extrahepatic cancers in adults. This review will include prospective and retrospective cohort studies that compare adults with NAFLD to those without NAFLD and report adjusted hazard ratios or risk ratios for incident extrahepatic cancers. Studies of pediatric populations, non-NAFLD liver diseases, and primary liver cancers will be excluded. The primary outcome will be the pooled risk of any extrahepatic cancer among adults with NAFLD compared with adults without NAFLD. Secondary outcomes will include pooled, site-specific risk estimates for individual cancer types such as colorectal, pancreatic, breast, thyroid, endometrial, ovarian, gastric, esophageal, kidney, bladder, biliary tract, and lung cancers where sufficient data are available. A random-effects meta-analysis will be performed using adjusted effect estimates. Heterogeneity, risk of bias, and potential publication bias will be assessed, and prespecified subgroup and sensitivity analyses will explore the impact of sex, geographic region, NAFLD definition, metabolic comorbidities, and NAFLD severity. The expected outcome of this project is a quantitative synthesis of existing cohort evidence clarifying whether NAFLD is associated with an increased risk of extrahepatic cancers overall and by cancer site. The findings are intended to inform clinicians and researchers about the broader oncologic implications of NAFLD and to identify areas where further mechanistic or prospective research is needed.