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Page 4 of 7 Onzi et al. Hepatoma Res 2019;5:7 I http://dx.doi.org/10.20517/2394-5079.2018.114

[9]
adiponectin . The presence of these chemical mediators leads to apoptosis of hepatocytes, compensatory
proliferation and, finally, carcinogenesis [2,7,13,25] . Accumulating evidence supports the importance of lipid
[26]
metabolic reprogramming in various situations of hepatocarcinogenesis . Given the increasing incidence of
NAFLD and advances in curative options for hepatitis C viral infection, NAFLD is expected to become the
leading cause of HCC in developed countries [2,3,27] . Absent washout and capsule appearance are associated
[28]
with increasing hepatic steatosis in patients with non-cirrhotic, NAFLD-associated HCC . Increased
incidence of NASH-related cirrhosis is also influencing trends in liver transplantation: there has been a
4-fold increase in the number of liver transplants due to NASH compared to a 2-fold increase in those due
[2,5]
to hepatitis C . However, comparing to other etiologies of cirrhosis, it is not clear wether HCC-related
NAFLD has similar outcomes [29,30] . In addition, NASH has already become the second leading cause of HCC-
[2]
related liver transplantation in USA .

HCC represents the fifth most common neoplasm and the second largest cause of cancer mortality
worldwide [2,31,32] . Despite its increasing incidence and the development of new therapies, overall 5-year
survival is still low, no more than 30% [33,34] . NAFLD is considered to be the third cause for HCC in the
[35]
USA . Early detection of HCC provides greater treatment options, significantly improving the prognosis
[31]
of patients . NAFLD increased substantially over the past 20 years among resectable HCCs and it is now
[36]
the leading cause of HCC occurance without or with minimal fibrosis . In terms of clinicopathological
findings, most studies agree that noncirrhotic NAFLD-related HCC patients were more likely to present with
larger tumors [37-39] . Although there are guidelines for routine HCC surveillance that allow early diagnosis
and improvement in curative outcomes, overall screening rates are below those considered ideal [31,32] . In
addition, it has been found that patients with cirrhosis due to NASH are less likely to undergo adequate
checks and monitoring of HCC compared to patients with other etiologies for chronic liver disease [1,5,31] .
[31]
This may be due to the lack of HCC screening in noncirrhotic NAFLD patients . It is widely reported that
the deficiency in HCC surveillance among NAFLD patients, with only 13% of HCC discovered through
[40]
surveillance, resulted in delayed detection in the majority of patients . Several factors may contribute to
this phenomenon: visceral adiposity, for example, is associated with a lower degree of ultrasonographic
[1]
tumor identification, limiting its sensitivity for screening . Other related variables are attributed to
[31]
difficulties in access to adequate health care . Patients with NAFLD-related HCC are older, have a shorter
survival time, have more cardiovascular diseases and diabetes and are more likely to die from their HCC
than other patients [41-43] . It has been demonstrated that curative treatment for HCC and serum albumin level
[44]
> 3.7 g/dL suggest best prognostic profile for NAFLD-related HCC .
Evidence of hepatocarcinogenesis arising in the absence of advanced fibrosis is of concern, as recent
guidelines recommending ultrasonographic abdominal screening and surveillance for HCC, every 6-12
months, only for patients with cirrhosis or chronic hepatitis B infection, failed to address this growing
patient population [1,2,7] . In addition, those with NAFLD-related HCC have a worse prognosis, since
they have a shorter survival time, a more advanced tumor at diagnosis and a lower probability of liver
transplantation [31,45] . This reinforces the idea that a rewording of current HCC screening recommendations
is needed so that these high-risk patients can be diagnosed via routine assessment [3,5,46] . It is also understood
that, because of the high prevalence of this type of liver disease, the extension of screening to this whole
[47]
group would greatly increase health spending, making it less viable . Stratification by fibrosis score may
offer some additional benefit to the subgroup of patients with non-cirrhotic NASH; however, reports of HCC
in patients with NAFLD and no fibrosis have been described, such as the reported case. Further research
to elucidate the association between the degree of fibrosis and the risk of HCC would provide a useful tool
[1]
in the screening for HCC in these patients . PNPLA3 gene polymorphism has been associated with an
increased risk of HCC and may assist in assessing the patient’s risk and personalizing surveillance. However,
[4]
it has not yet been validated for routine use because there is no well-documented cost-benefit ratio .
American Association for the Study of the Liver, European Association for the Study of the Liver and
the Brazilian Society of Hepatology do not recommend routine HCC screening in non-cirrhotic NASH