NAFLD and HCC: Time to Bridge the Gap
Authors: George Cholankeril, Fasiha Kanwal
Journal: Hepatology (2021)

Supported by the Cancer Prevention & Research Institute of Texas (RP150587) and the National Cancer Institute (U01 CA230997). Potential conflict of interest: Dr. Kanwal received grants from Gilead and Merck. SEE ARTICLE ON PAGE 2410 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 population‐based 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 age‐matched and gender‐matched 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 follow‐up, the incidence for HCC was 1.2 per 1,000 person‐years (PY); NAFLD carried a 17‐fold 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 virus‐associated 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 cost‐effective.(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 (2‐fold to 4‐fold more than women), and those who smoke tobacco.(1) In addition, a recent non‐US study has demonstrated potential utility of a polygenic risk score derived from these NAFLD‐related single‐nucleotide polymorphisms for predicting HCC in patients with NAFLD.(5) The authors found an increased HCC risk in patients with NAFLD without evidence of cirrhosis. Strikingly, simple steatosis, the most common subtype of NAFLD, carried a 9‐fold higher risk for HCC (aHR, 9.3) than the matched population. It is possible that some patients classified as developing HCC in the absence of cirrhosis (noncirrhotic HCC) actually developed cirrhosis during follow‐up and were misclassified (as noncirrhotic) due to ascertainment bias. However, cases of HCC have been reported in patients with mild or absent fibrosis, suggesting that HCC can develop in patients with NAFLD without advanced fibrosis. Having said that, as shown in this study, the overall risk of HCC in patients with NAFLD without cirrhosis is too low for the currently available HCC prevention strategies, including HCC surveillance, to be cost‐effective. It will take highly precise biomarkers and well‐designed studies to winnow down the large group of individuals with NAFLD to those who are at risk for HCC (in the absence of cirrhosis). Extrahepatic solid organ cancer is one of the leading contributors of death in NAFLD. Simon et al. found a modest 12% increase in risk for extrahepatic solid organ cancer (aHR, 1.1) compared to the general population. The authors found a 2‐fold higher risk for pancreatic cancer (aHR, 2.2) and a 40% increased risk for kidney and bladder cancer (aHR, 1.4) in patients with NAFLD. Without data on important confounding factors, such as smoking, the validity of these associations should be explored further.(6) The authors should be congratulated for their work. However, despite the clear strengths of this study, there are limitations inherent in any retrospective study. Few patients undergo liver biopsy, and hence there is a clear selection bias that limits the generalizability of these data to the general population with NAFLD. In addition, NAFLD is a relatively new disease entity, and including a study period spanning 50 years from 1966 onward leaves the study group open to misclassification of exposure. For example, Miller et al. first described the histological features of NAFLD in 1979, followed by Ludwig et al., who described the progressive form of fatty liver disease, coining the term "NASH" in 1980—15 years after the start of the patient accrual period in this study.(7) The prevalence rates of metabolic syndrome, obesity, and diabetes were low (2.3%, 1.5%, and 7.7%, respectively); it is unclear if this reflects a low prevalence within this Nordic population or misclassification due to reliance on International Classification of Diseases coding, although we suspect the latter. The authors approached these limitations with detailed and robust sensitivity analyses, considering several potential confounders, such as competing risks of noncancer mortality and time‐varying use of medications, to explain the excess cancer risk associated with NAFLD. More importantly, these data are consistent with those from other studies. The authors' findings are important for designing future cost‐effective analyses and randomized controlled trials and, most importantly, for guiding HCC surveillance recommendations. Nonetheless, they do not speak to the much larger issue: most people with NAFLD are undiagnosed and unaware of their liver condition. The first step in stemming the rising tide of NAFLD‐related complications is to increase awareness and diagnosis of individuals with NAFLD who are at risk for progressive disease.(8) There is no general consensus on how best to identify patients with NAFLD, a stark contrast to the safety nets implemented for patients with chronic viral hepatitis and diabetes. Most patients with NAFLD are seen in primary care or endocrine clinics. While not all patients with NAFLD require secondary (i.e., hepatology) care, not knowing which patients may benefit from such care and when to refer them results in inconsistent care processes and possibly poor outcomes. There is a clear need for developing a care pathway and risk stratification tools to identify the subset of patients with NAFLD at the highest risk. Collaborative efforts are underway to provide practical guidance across the spectrum of care from screening and diagnosis to management of individuals with NAFLD.(8) Similarly, several multi‐institutional consortia are attempting to answer unaddressed questions around risk stratification for and early detection of HCC in high‐risk populations, including those with NAFLD cirrhosis.(4,9) However, these latter efforts are focusing on patients with cirrhosis. Patients with NAFLD (but without cirrhosis) who remain at risk for HCC are missed by these large studies and need to be taken into consideration for future studies. In the interim, we should continue to educate our colleagues in primary care about the importance of recognizing NAFLD, risk‐stratifying patients based on liver fibrosis/cirrhosis (and diabetes) for surveillance, and closely monitoring for development of cirrhosis and diabetes.