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Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20 Page 7 of 14

and NAFLD was suggested, and many of the CC cases were severely advanced NASH, that is, burned-out
NASH [83-86] .

Based on the abovementioned data, it is speculated that the role of NAFLD in HCC etiology is greater
than the data that have been reported, and the existence of burned-out NASH is a point to be noted in
epidemiological research related to NAFLD-related HCC.

HCC in NAFLD without cirrhosis
Several cross-sectional studies showed that 15%-50% of patients diagnosed with HCC without cirrhosis
were patients with non-cirrhotic NAFLD [35,87-89] . This suggests the possibility that NAFLD is an independent
risk factor of HCC, even in those cases without cirrhosis [82,90,91] .

There has been an increase in the number of cases of HCC that developed in NAFLD patients without
cirrhosis [92,93] . The characteristics of NAFLD-related HCC without cirrhosis include a larger tumor size [94-96] ,
older age, and slightly lower prevalence of T2DM than those of NAFLD-related HCC patients with
[94]
cirrhosis . In a recent meta-analysis of a cohort of NAFLD patients without cirrhosis, the cumulative
[77]
HCC mortality for the study periods of up to 20 years was between 0% and 3% .
In the cohort study mentioned above, approximately 20% of NAFLD-related HCC patients did not have
[21]
cirrhosis , and NAFLD patients without cirrhosis had an annual HCC incidence of 0.08 per 1000 PYs
(vs. 0.02 per 1000 PYs in the control group without NAFLD), whereas reports from Japan also suggested
that approximately 32% to 49% (28% being in stages 1-2 of fibrosis) of NAFLD-related HCC cases had
[30]
[22]
no cirrhosis. A separate study reported that 10%-75% of NAFLD-related HCC patients had no cirrhosis in
their background [87,89,97] , suggesting that NASH itself can promote the development of HCC and that HCC
[33]
can develop from NASH and simple steatosis without fibrosis .
As a mechanism of how HCC develops in NAFLD patients without cirrhosis, the possibility of
transformation of hepatocellular adenoma (HCA) comes to mind. NAFLD is strongly correlated to obesity,
[30]
MetS, and T2DM, among others . Furthermore, it has also been reported that there is a relationship
between the prevalence of obesity/MetS and HCA (particularly related to the subtype that has a risk of
malignant transformation: inflammatory HCA) [98,99] , which seems to support this possibility. Furthermore,
as a result of a recent study, some of the cases of HCC developing in NAFLD patients show steatosis,
ballooning, Mallory bodies, and pericellular fibrosis in its histological presentation, and there is also a
[100]
characteristic subtype called steatohepatitic HCC that resembles steatohepatitis , which suggests that
there is a close relationship between non-cirrhotic NAFLD and development of HCC.

CLINICAL ISSUES AND CHALLENGES IN HCC SURVEILLANCE OF NAFLD PATIENTS
With the increase in NAFLD prevalence, there has been an increase in the prevalence of NAFLD-related
HCC, albeit not as high as that of viral-related HCC, which has led to the increasing importance of
surveillance.

Even though the AASLD (American Association for the Study of Liver Diseases) and EASL-EORTC (The
European Association for the Study of the Liver-The European Organisation for Research and Treatment of
[101]
Cancer) Guidelines recommend patients with cirrhosis to be screened for HCC every six months , HCC
[102]
surveillance of NAFLD-cirrhosis cases is included under “Other conditions” in the AASLD Guidelines ,
and there are no specific recommendations. In general, screening is performed using ultrasound
examinations, but there are limitations of using this approach for patients with obesity [103,104] . Although
magnetic resonance imaging scans provide excellent lesion detectability, it is difficult to recommend this
approach for screening due to its high cost and availability issues.