Effect of Metabolic Traits on the Risk of Cirrhosis and Hepatocellular Cancer in Nonalcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is now the most common liver condition. Predicting its progression could help clinicians manage and potentially prevent complications. We evaluated the independent and joint effects of metabolic traits on the risk of cirrhosisand hepatocellular carcinoma (HCC) among patients with NAFLD. We assembled a retrospective cohort of patients with NAFLD diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008 with follow-up through 12/31/2015. We performed competing risk, adjusted cause-specific Cox models to evaluate the effects of metabolic traits (diabetes, hypertension, dyslipidemia, obesity) as additive or combined indicators on time to develop cirrhosis or HCC or a composite endpoint of both. Of the 271,906 patients, 22,794 developed cirrhosis, and 253 developed HCC during a mean of 9 years follow up. At baseline, the mean BMI was 31.6 (SD, 5.6), 28.7% had diabetes, 70.3% hypertension, and 62.3% had dyslipidemia with substantial overlap among the these traits. The risk of progression was the lowest in patients with only one or no metabolic trait. There was a stepwise increase in risk with each additional metabolic trait. Compared to patients with no metabolic trait, patients with both hypertension and dyslipidemia had 1.8-fold higher risk of progression to cirrhosis/HCC (hazard ratio (HR) =1.8, 95% CI=1.59-2.06); the risk was 2.6-fold higher in patients with diabetes, obesity, dyslipidemia and hypertension (HR=2.6, 95% CI=2.3,2.9). These associations were stronger for HCC. Diabetes had the strongest association with HCC in this cohort. CONCLUSIONS: Each additional metabolic trait increased the risk of cirrhosis and HCC in patients with NAFLD. Diabetes conferred the highest risk of progression to HCC. Diabetic patients with co-existing hypertension and obesity may be important targets for secondary prevention.