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Page 8 of 14 Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20

In contrast, since the carcinogenic risk is not high in non-cirrhotic NAFLD, and because only 23% of all
[25]
NAFLD-related HCC cases are detected by screening and 62.3% of cases are found already symptomatic ,
the cost-effectiveness of HCC surveillance for non-cirrhotic NAFLD is poor. Furthermore, it is not at
a level to be recommended. For this reason, tools and biomarkers that help to narrow down high-risk
populations of cancer development is important for HCC surveillance among patients with non-cirrhotic
NAFLD.

The problem of HCC surveillance in NAFLD patients is to narrow down those patients who should be
screened. The most important approach would be to distinguish whether the patient exhibits severe fibrosis
and cirrhosis, which indicate a risk of HCC development. The gold standard for the diagnosis of fibrosis is
liver biopsy, but it involves the issue of invasiveness, and, in recent years, the problem of sampling error has
also been reported. To narrow down severe fibrosis populations, the use of the aspartate aminotransferase-
[105]
to-platelet ratio index (APRI) , NAFLD fibrosis score [106] , and FIB-4 index [107] have been reported as
a simple approach. There are also reports related to the usefulness of special ultrasound tests such as
[108]
Fibroscan .

In recent years, it has been reported that a scoring system based on age, sex, T2DM or viral hepatitis
[109]
history, aminotransferase, and AFP is useful regardless of the etiology of the condition , and we may
need to consider whether it can be introduced in the surveillance of NAFLD patients.

Furthermore, in view of the differences observed between races, it may be useful to actively screen more
Hispanic populations, who are at a high risk of developing NAFLD-related HCC. Additionally, although it
may be useful to use PNPLA3 rs738409 polymorphism for screening from a genetic point of view, it would
be difficult to introduce this approach to the surveillance procedures at this stage, when we take into
[110]
consideration the cost .
On the other hand, while HCC is often detected using ultrasound and AFP tests, the frequency of high
AFP levels in NAFLD-related HCC cases is not as high as that in HCV-related HCC cases, and there
are also reports suggesting that there are many cases with high PIVKA-II levels. As such, it may be one
approach to introduce the evaluation of PIVKA-II levels to the surveillance process.

PREVENTION AND TREATMENT
At present, it is important to prevent progression of NAFLD as early as possible by improving lifestyle; this
prevents the development of NAFLD-related HCC. It has also been reported that exercise has a preventive
effect on the development of HCC [111,112] and that exercising for ≥ 5 days per week reduces the RR of HCC
to 0.56 . Conversely, certain recent reports have suggested the possibility of therapy with drugs such as
[113]
GLP-1 receptor antagonists and metformin.

GLP-1 receptor antagonist
Fibrosis is a risk factor of cancer, and one target should be to prevent the development of fibrosis. The use
of drugs targeting dyslipidemia, insulin resistance, oxidative stress, inflammatory cytokines, apoptosis, and
the angiotensin pathway, among others, has been explored , but, until now, no definite drug therapy has
[114]
been established. However, reports from a phase 2 trial suggest that glucagon-like peptide-1 (GLP-1) receptor
antagonists may prevent the occurrence of HCC by ameliorating liver fibrosis in NAFLD patients . Phase
[115]
3 trials are expected to be conducted in the future.

Metformin
The use of metformin is related to the decrease in HCC incidence in T2DM patients [116-121] , and a meta-
analysis showed that the use of metformin in T2DM patients reduced the risk of HCC by 70% [122] or