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Page 12 of 16 Chen et al. Hepatoma Res 2018;4:72 I http://dx.doi.org/10.20517/2394-5079.2018.103

different cohorts, suggesting that the benefit is not homogeneous in all HCC patients. Different ethnic origin
and HCC etiologies likely contributed to this heterogeneity. Patients with NASH and alcoholic liver disease
are more common in the United States than Asian and European population, and has lower risk of develop-
[48]
ing HCC .
Non-alcoholic fatty liver disease (NAFLD) and NASH are emerging causes of liver cirrhosis and HCC. It has
[49]
been reported that the yearly HCC incidence among NASH-cirrhotic patients was 2.6% , and a significant
number of patients with NAFLD-related HCC did not have cirrhosis [50,51] . NASH-related HCC patients re-
ceived significantly less HCC surveillance compared to HCV or alcohol-related HCC patients, and received
[51]
less HCC-related treatment. However, the one-year survival rate was similar . At present, AASLD and
EASL guidelines do not recommend routine HCC surveillance for non-cirrhotic NASH patients. More stud-
ies are needed to develop a cost-effective surveillance program in this population.

Chronic hepatitis C infection had been a major risk factor for liver cirrhosis and HCC in the world. The in-
cidence of HCC in patients with chronic hepatitis C infection was reported to be 1%-4%, higher in patients
with cirrhosis [52-54] . Treatment with direct-acting antivirals (DAAs) has impressive efficacy in Hepatitis C
[56]
[55]
eradication. However, its effect on the long-term clinical outcome was lacking . Conti et al. found that
unfortunately HCC occurrence was not reduced in successfully treated cirrhotic patients. Recently, a sys-
[57]
temic review and meta-analysis was performed by Singh et al. on oral DAAs use and risk of HCC develop-
ment. A total of 8 controlled studies and 36 uncontrolled studies were reviewed, and the estimated incidence
of HCC was 3.3% and 1.5% (1 in 67 DAA users) in controlled and uncontrolled studies respectively, not
significantly different from the previously reported incidence in chronic hepatitis C patients. Moreover, the
HCC recurrence rate was as high as 16.7%-20.1% with DAAs treatment. Hence, continuing HCC surveillance
is still important in patients treated with DAA for hepatitis C, even after achievement of sustained virologi-
cal response.

[58]
Two earlier reviews on HCC surveillance were published in 2014. A meta-analysis done by Singal et al.
aimed to determine the effect of surveillance on cirrhotic patients. Studies published from 1990 to 2014 were
reviewed and pooled odds ratio was calculated on 47 selected studies with a total of 15,158 HCC patients.
Surveillance was associated with early-stage cancer detection (OR 2.08 CI 1.8-2.37), curative treatment rates
(OR 2.24 CI 1.99-2.52), and prolonged survival (OR 1.9 CI 1.67-2.17), supporting HCC surveillance in cir-
[59]
rhotic patients. On the other hand, Kansagara et al. did a systemic review to study the strength of evidence
supporting HCC surveillance. A total of 22 studies were selected and the overall strength of evidence on the
effect of screening was very low owing to limited randomized trials and significant confounders in cohort
studies. Screening identified early-stage HCC. However, its effect on mortality and survival in chronic liver
disease patients is not clear. The conflicted evidence may have contributed to the underutilization of HCC
surveillance in some regions.

The harm of HCC surveillance is an important issue but there were few studies published. One retrospec-
tive cohort study demonstrated that one fourth of the patients who underwent HCC surveillance required
additional tests due to false positive or indeterminate results. This calls for development of new surveillance
modalities that minimize false positive results without compromising the diagnostic accuracy for HCC.
Although imaging modalities such as contrast-enhanced CT and MRI have high sensitivity and specificity,
they are not recommended for surveillance due to the high cost and limited availability. Other than AFP, se-
rum biomarkers are not widely accepted as surveillance tools except in a few countries, such as Japan. More
studies are needed to evaluate the clinical utility of novel serum biomarkers and their role in HCC surveil-
lance. Liquid biopsy is the latest tool in cancer diagnosis and prognosis. Emerging evidence indicates that
liquid biopsy can be used in HCC surveillance as it is noninvasive and provides a dynamic profile of disease
progression.