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Page 4 of 14 Moriguchi et al. Hepatoma Res 2019;5:43 I http://dx.doi.org/10.20517/2394-5079.2019.20
[22]
advanced form of NAFLD, is reported to be 5.29 per 1000 person-years (95%CI: 0.75-37.56) , whereas the
[21]
incidence rate of HCC in NAFLD patients with cirrhosis is reported to be 10.6 people per 1000 PYs . In
contrast, investigations in Japan revealed that approximately 32% of NAFLD-related HCC cases did not
[23]
have cirrhosis, which may be a characteristic of NAFLD-related HCC .

CLINICAL FEATURES OF NAFLD-RELATED HCC
Unlike other etiologies, NAFLD-HCC is generally characterized by a large tumor size, moderately to highly
[24]
differentiated histology, and absence of encapsulation and is often discovered in the advanced stages of
the disease [5,25] . Furthermore, NAFLD-related HCC is more infiltrative than HCV-related HCC, and often
[26]
tends to be detected outside of surveillance .
There have been reports comparing HCV-related HCC and NASH-related HCC that have shown NASH-
[27]
related HCC occurs at older age than HCV-related HCC , and the prevalence of obesity, T2DM, and
[28]
dyslipidemia is greater in NASH-related HCC . Furthermore, although an elevated alpha-fetoprotein (AFP)
[29]
level is observed in 69.6% of HCV-related HCC patients , this occurs in < 1/3 of NASH-related HCC
[28]
patients , and an elevated prothrombin induced by vitamin K absence-II (PIVKA-II) level is relatively
[30]
common in NAFLD-related HCC patients .
[31]
Strategies have been provided to treat HCC, regardless of its etiology , and there have been various
reports related to the treatment results and prognosis. It has been reported that the percentage of patients
who were able to receive curative treatments such as liver resection, including liver transplant, was lower
for NAFLD-related HCC than HCV-related HCC (NAFLD-related HCC: 21/212 vs. HCV-related HCC:
[27]
[32]
80/275) and other etiologies of HCC . In contrast, NAFLD-related HCC patients had a low cirrhosis
prevalence, liver functions such as the synthetic capacity were relatively well preserved [32,33] , and liver
resection rates were higher than those of HCV-related HCC [26,33] . However, as NAFLD-related HCC
occurred at an advanced age and patients often had cardiovascular and metabolic complications, there was
no difference in the overall survival rate between NAFLD-related HCC (one year: 56%; three years: 23%)
and HCV-related HCC (one year: 58%; three years: 21%) . In some reports, the overall survival of NAFLD-
[27]
related HCC patients was lower than that of HCV-related HCC patients [29,32] . Conversely, there are reports
[34]
suggesting that the relapse-free survival rate was high after curative resection of NAFLD-related HCC
and that the overall survival was nearly the same or greater than that for HCV-related HCC or alcoholic
cirrhosis-related HCC [35,36] , thus a consensus has not been obtained.

Link to obesity and T2DM
NAFLD is strongly related to insulin resistance, MetS, and cardiovascular disease [9-11] . In the UK, it was
reported that the increase in cancer incidence and cases attributed to NAFLD occur in parallel with the
[25]
steady increase in MetS incidence observed among HCC patients . In particular, T2DM and obesity are
closely related to NAFLD/NASH, and there are concerns that HCC will increase in the future .
[37]

It has been reported that up to 70% of T2DM patients and up to 90% of patients with obesity have
NAFLD [37,38] . Furthermore, a high percentage of patients with T2DM and obesity have advanced
fibrosis [39-43] . The emergence of T2DM occurs in parallel with fibrosis, and the increase or decrease in
body mass index (BMI) over time is related to the progression or improvement of liver fibrosis in NAFLD
patients [39-41,43] .

Obesity
Obesity has been increasing globally for the past several decades along with the changes in the food and
lifestyle culture. HCC has been increasing among patients with obesity, and a perspective study involving a
US population showed that the relative risk (RR) of death in patients with obesity grade II and I is 4.52 and