NAFLD and HCC: Time to Bridge the Gap

Abstract

NAFLD is the leading etiology for chronic liver disease, affecting > 25% of the global population.(1) The spectrum of NAFLD is diverse, ranging from steatosis to a more progressive form, NASH, that can lead to fibrosis and cirrhosis. NAFLD is emerging as one of the leading risk factors for HCC. Despite the growing concern for HCC attributed to NAFLD, the precise HCC risk according to the presence and severity of NAFLD is not well established. In this issue of Hepatology, Simon and colleagues report data from a large populationbased cohort to fill this key gap.(2) The authors collected information on a cohort of 8,892 Swedish adults with histologically confirmed NAFLD from 1966 through 2016 (steatosis, n = 5,939, 66.8%; NASH without fibrosis, n = 1,050, 11.8%; NASH with noncirrhotic fibrosis, n = 1,400, 15.7%; NASH with cirrhosis, n = 503, 5.7%). The study also included an agematched and gendermatched control group of individuals from the general population and estimated the excess risk for cancer across the full histological spectrum of NAFLD. Over a median of 14 years of followup, the incidence for HCC was 1.2 per 1,000 personyears (PY); NAFLD carried a 17fold excess risk (adjusted HR [aHR], 17.1) compared to the general population. There was also a strong stepwise association between worsening histological severity and incidence of HCC. HCC developed at the rate of 0.8 per 1,000 PY in individuals with simple steatosis (aHR versus matched controls, 9.3), 1.2 per 1,000 PY in those with NASH but without fibrosis (aHR, 55.7), 2.3 per 1,000 PY in NASH with advanced fibrosis (aHR, 72.7), and 6.2 per 1,000 PY in those with cirrhosis (aHR, 49.8). These results are generally consistent with overall estimates from large retrospective cohort studies, providing convergent validity to these previous data.(3) However, they also significantly extend the evidence base, as we discuss. The risk of HCC associated with cirrhosis, the predominant risk factor for HCC, is variable across etiologies and noted to be lower in NAFLD than in virusassociated cirrhosis. In this study, the annual incidence rate for cirrhosis in NAFLD was 0.62%, far below the 1.5% annual incidence rate beyond which HCC surveillance may be costeffective.(4) However, the authors found a significantly higher risk of HCC in patients with cirrhosis and diabetes— with the annual incidence rate 1.52%, reaching the surveillance benchmark. This brings up an important point. The risk of HCC is not uniform across all patients with NAFLD cirrhosis. Some patients progress rapidly, while others progress more slowly, and a large fraction does not develop HCC and dies from other causes. The existing risk stratification methods have modest discriminative ability for HCC in NAFLD cirrhosis, leaving room for improvement. In this regard, presence of diabetes serves as a marker for higher HCC risk, as noted.(3) However, there are other clinical and genetic factors that could improve risk stratification. HCC risk is higher in older patients, men (2fold to 4fold more than women), and those who smoke Abbreviations: aHR, adjusted HR; PY, personyears.