Fatty liver and HCC: Cause for concern?

Nonalcoholic fatty liver disease (NAFLD) is a common condition, affecting as many as 30 percent of the U.S. population. Thus, every third person walking down the street may have NAFLD. Most of these individuals will live with NAFLD but die of other conditions, with heart disease being at the top of the list. However, some patients with NAFLD — studies suggest 10 to 20 percent — are at risk of progressive liver disease, including cirrhosis which is concerning given the known association between cirrhosis and hepatocellular cancer (HCC). Indeed, recent studies suggest that NAFLD (and related nonalcoholic steatohepatitis) may become the leading cause of HCC in the U.S.1,2

So, what are the implications of these recent trends for individual patients and for the population of patients in our health care systems?

Let us consider this question from the clinicians’ (and their patients’) viewpoint. Recent studies, including from our group, show that the patients with NAFLD are indeed at a relatively higher risk of developing HCC than age and gender matched controls without NAFLD.3 This relative risk was as high as 7.6 in our analysis. However, this excess risk seems to be mostly limited to patients with established cirrhosis. For example, the annual incidence of HCC was 10 to 15 per 1000 person-years (i.e., 1 to 1.5 percent per year), based on other characteristics such as age, gender and race/ethnicity.3  These risk estimates reach the cut-offs beyond which HCC surveillance may become cost effective. Thus, all patients with NAFLD cirrhosis are at a risk for HCC and should be enrolled in HCC surveillance programs, as long as they are eligible for potentially curative treatment options for HCC.

“Substantial efforts are needed that target risk stratification and risk modification to reduce the burden of NAFLD-related HCC.”

What about the vast majority of individuals with NAFLD who do not have cirrhosis? The absolute risk of HCC in NAFLD patients who do not have cirrhosis is too low to recommend HCC surveillance. In our study, the annual incidence of HCC was 0.08/1000 person-years in NAFLD patients without cirrhosis versus 10 to 15/1000 person-years in patients with NAFLD cirrhosis.3 The problem is that HCC can occur in NAFLD in the absence of advanced fibrosis/cirrhosis. For example, out of 100,000 people with NAFLD, approximately eight to 10 would be diagnosed with HCC each year but we do not have accurate screening biomarkers that allow identification of these eight to 10 patients without having to test/ screen the 99,990.  It is plausible that we might eventually have such screening biomarkers.  However, what can we do until then?

Studies suggest that presence of metabolic traits, especially diabetes, may help target risk modification and perhaps even HCC screening efforts. HCC risk is the highest in patients with diabetes who also have other traits, such as hypertension and obesity.  Thus, prioritizing NAFLD patients with diabetes and co-existing hypertension and obesity for risk modification and targeted HCC screening may be a fair option, although we will need studies that examine the cost effectiveness of these strategies in these patient groups before firm recommendations can be made.

Shifting gears from individual patients to populations. Over the next few decades, we will see more and more patients with HCC who will have NAFLD as their underlying etiology. This is the result of two contemporaneous trends; NAFLD is increasing in prevalence whereas active hepatitis c virus (HCV) is decreasing; the latter is due to the availability of direct acting antiviral agents. Although the risk of HCC is considerably higher in patients with (untreated) HCV related cirrhosis than in patients with NAFLD-related cirrhosis (HCC incidence ~3 to 4 percent per year vs. 1 to 1.5 percent per year, respectively), NAFLD is a common condition. The increasing proportions of NAFLD-related HCC are directly reflective of the size of the underlying at-risk population (a concept referred to as population attributable fraction). Given this, in about 20 years, we may see fewer HCC than now but many, if not most, of those cases will likely have NAFLD as the underlying risk factor.  Hence, NAFLD-related HCC is a cause for concern. Substantial efforts are needed that target risk stratification and risk modification to reduce the burden of NAFLD-related HCC.

Key takeaways

  1. All patients with NAFLD cirrhosis are at a risk for HCC and should be enrolled in HCC surveillance programs.
  2. The absolute risk of HCC in NAFLD patients who do not have cirrhosis too low to recommend HCC surveillance at this time.
  3. NAFLD patients with diabetes and co-existing metabolic traits (especially hypertension and obesity) are at the highest risk of progression to HCC.  Prioritizing these patients for risk modification may reduce the future risk of HCC, although we need more studies to confirm this hypothesis.

Disclosures: Dr. Kanwal has received research support from Gilead and Merck.


1 Younossi Z., Stepanova M., Ong J.P., Jacobson I.M., Bugianesi E., Duseja A., Eguchi Y., Wong V.W., Negro F., Yilmaz Y., Romero-Gomez M., George J., Ahmed A., Wong R., Younossi I., Ziayee M., Afendy A. Global Nonalcoholic Steatohepatitis Council. Nonalcoholic Steatohepatitis Is the Fastest Growing Cause of Hepatocellular Carcinoma in Liver Transplant Candidates. Clin Gastroenterol Hepatol. 2019;17(4):748-775.

2. Yang J.D., Larson J.J., Watt K.D., Allen A.M., Wiesner R.H., Gores G.J., Roberts L.R., Heimbach J.A., Leise M.D. Hepatocellular Carcinoma Is the Most Common Indication for Liver Transplantation and Placement on the Waitlist in the United States. Clin Gastroenterol Hepatol. 2017;15(5):767-777.e3.

3. Kanwal F., Kramer J.R., Mapakshi S., Natarajan Y., Chayanupatkul M., Richardson P.A., Li L., Desiderio R., Thrift A.P, Asch S.M., Chu J., El-Serag H.B. Risk of Hepatocellular Cancer in Patients With Non-Alcoholic Fatty Liver Disease. Gastroenterology. 2018;155(6):1828-1837.e2.


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