Women With Nonalcoholic Fatty Liver Disease Lose Protection Against Cardiovascular Disease: A Longitudinal Cohort Study

y OBJECTIVES: Cardiovascular (CV) disease is the top cause of mortality in patients with nonalcoholic fatty liver disease (NAFLD). Female sex is protective against CV disease. We aimed to determine whether female sex remains a protective factor against CV disease (myocardial infarction, angina, and stroke) in NAFLD. METHODS: We identified all adults diagnosed with NAFLD in Olmsted County, Minnesota, between 1997 and 2014 and selected an age- and sex-matched (1:4) referent cohort from the general population. NAFLD was ascertained using a code-based algorithm with high validity tested by medical record review. The impact of female sex on incident CV events was examined using Cox proportional hazards regression analysis stratified by standard clinical risk factors. RESULTS: A total of 3,869 NAFLD and 15,209 age- and sex-matched referent subjects were identified. After a median follow-up time of 7 (range 1-20) years, 3,851 CV events were recorded. Female sex was protective for ischemic CV events in the general population (hazard ratio = 0.71, 95% confidence interval 0.62-0.80, P < 0.001), but the impact was significantly diminished among those with NAFLD (hazard ratio=0.90, 95% confidence interval 0.74-1.08, P=0.25), even after stratification by timed-ependent CV risk factors and control for diagnostic testing (liver enzymes and ultrasound) during routine medical evaluations, as a surrogate of access to care. Among those with NAFLD, excess events were higher in women than in men: CV disease (18% vs 9%) and mortality (9% vs 6%). DISCUSSION: Women with NAFLD lose the CV protection conferred by the female sex, and their risk is underestimated by current estimating methods in clinical practice.