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Farrell et al. Hepatoma Res 2020;6:18 I http://dx.doi.org/10.20517/2394-5079.2019.019 Page 7 of 13

Incidence of HCC in NAFLD
Although NAFLD represents an increasing proportion of HCC cases, the true risk of HCC in NAFLD
patients with and without cirrhosis is not clear. As HCC is an infrequent outcome of chronic liver disease,
there are limited studies with the adequate cohort size and duration of follow up required to accurately
assess incidence rates. As a result, several meta-analyses have been performed to pool data and increase
[43]
the sample size. A systematic review by White et al. found the risk of HCC in NAFLD patients to be in
[1]
the range of 0%-38% over a median of 5-10 years of follow up. More recently, Younossi et al. performed
a meta-analysis to evaluate the global prevalence and outcomes of NAFLD, and calculated an annual HCC
incidence of 0.44 per 1000 person years (95%CI: 0.29-0.66) in patients with NAFLD, with much higher rates
in those with NASH, 5.29 per 1000 person years (95%CI: 0.75-37.56). These meta-analyses are somewhat
limited by the heterogeneity of the included studies, with small retrospective cohorts and inconsistent
[32]
methods of defining NAFLD. As a result, a large United States longitudinal study led by Kanwal et al.
compared 296,707 patients with NAFLD to 296,707 matched healthy controls to determine the incidence
of HCC in these cohorts. NAFLD was defined by persistently elevated transaminases (> 40 IU/mL for men
and > 31 IU/mL for women, with a minimum of two results at least six months apart), in the absence of any
significant alcohol intake or another cause of liver disease. The healthy controls had normal liver function
tests, no other history of liver disease and minimal alcohol intake. The overall incidence of HCC in the
NAFLD patients was low, 0.21 per 1000 patient years; however, HCC incidence was much higher in patients
with NAFLD cirrhosis, 10.6 per 1000 patient years. Overall, cirrhosis in NAFLD appears to be the most
significant risk factor for HCC [Figure 1], with approximately 6%-13% of patients with NAFLD cirrhosis
developing a HCC during 3-10 years of follow up in a number of prospective observational cohorts [44-47] .

NAFLD-related HCC in the absence of cirrhosis
NAFLD patients without liver cirrhosis are also at increased risk of HCC compared to those without liver
disease [32,43] . This is particularly concerning given the high population prevalence of NAFLD, and the
[36]
[1]
implications for HCC screening and increasing disease burden . In the US, Sanyal et al. found that,
among patients with NAFLD-related HCC, as many as 54% were not known to be cirrhotic based on
health care coding information. The proportion of non-cirrhotic patients was similarly high in the smaller
[48]
Cleveland clinic cohort, which found that 43.4% of cases occurred in the absence of cirrhosis . Those
patients tended to be older (67.5 ± 12.3 years vs. 62.7 ± 8.1 years), and less likely to be obese (52% vs. 83%)
or have type 2 diabetes (38% vs. 83%), than their cirrhotic counterparts. Similar findings have also been
reported from European cohort studies, with a high proportion of NAFLD-related HCC occurring in non-
cirrhotic patients: 46.2% in a multicentre Italian study, 41.7% in a single centre German study and 22.7% in
a UK-based cohort [34,49,50] . In the cohort study by Kanwal et al. , the risk of HCC in non-cirrhotic NAFLD
[32]
was higher than in the healthy controls, but the overall incidence rates were low (0.08 vs. 0.02 per 1000
person years). Despite this, due to the high global prevalence of NAFLD, the absolute burden of NAFLD-
related HCC, including those with and without cirrhosis, remains significant.

Clinical outcomes in NAFLD-related HCC
Patients with NAFLD-related HCC tend to present at an older age compared to patients with HCC due
to other aetiologies [8,28,31] . In the SEER cohort, NAFLD-related HCC patients were older (73 ± 8 years vs.
66 ± 11 years), had more heart disease (35.1% vs. 7%-27%) and had a shorter mean survival time (14.17 ±
17.14 months vs. 17.85 ± 21.47 months), compared to other aetiologies; and 84.3% died of their primary liver
cancer . This group found higher odds of one-year mortality (OR: 1.21, 95%CI: 1.01-1.45) in those with
[8]
NAFLD-related HCC, although other large HCC cohorts have found no difference in overall survival [34,37,49] .
Furthermore, a Canadian study of 929 patients who underwent a transplant for HCC, including 60 with
NAFLD-related HCC, also found that these patients had similar one-, three- and five-year survival
outcomes (98%, 96% and 80%, respectively) compared to non-NAFLD HCC (95%, 84% and 78%,
[51]
respectively), with no difference in tumour recurrence (13.3% vs. 14%) . As patients with NAFLD-related