Incidence of hepatocellular carcinoma in nonalcoholic fatty liver disease without cirrhosis or advanced liver fibrosis

Background: HCC can develop in the absence of cirrhosis in patients with NAFLD. We aimed to estimate the incidence of HCC in patients with NAFLD with and without cirrhosis or advanced liver fibrosis. Methods: We performed a cohort study to determine the incidence of HCC in patients with NAFLD identified by the International Classification of Diseases 9/10 codes in the electronic health records of a US health care system between 2004 and 2018. The incidence of HCC was stratified by the presence or absence of cirrhosis and by the Fibrosis-4 index (FIB-4) at the time of HCC diagnosis. Results: Of 47, 165 patients with NAFLD aged 40-89 years, 981 (2.1%) developed HCC (mean follow-up 3.4 y). Among patients with HCC, 842 (85.8%) had cirrhosis, while 139 (14.2%) did not. Of the 139 patients with HCC without cirrhosis-related diagnostic codes, 26 (2.7%) had FIB-4 > 2.67 (advanced fibrosis likely), whereas 43 (4.4%) had FIB-4 < 1.30 (excluding advanced fibrosis). The annual incidence of HCC in patients with NAFLD with and without cirrhosis was 23.6 and 1.1 per 1000 person-years, respectively. Among patients without cirrhosis, the annual incidence of HCC was 2.8 per 1000 person-years with FIB-4 > 2.67 and 0.7 per 1000 person-years with FIB-4 <1.30. Patients with NAFLD and cirrhosis were 31.8 times (95% CI, 23.3-43.4) more likely to develop HCC than those without cirrhosis and FIB-4 <1.30, after adjustment for age and sex. Conclusions: Patients with NAFLD without cirrhosis nor advanced fibrosis have a low incidence of HCC.