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Page 2 of 7 Nouso et al. Hepatoma Res 2018;4:73 I http://dx.doi.org/10.20517/2394-5079.2018.93

INTRODUCTION
Hepatocellular carcinoma (HCC), a frequent complication of chronic hepatitis virus infection, is the second-
[1]
leading cause of cancer death worldwide . Due to the development of a HCC screening system with ultraso-
[2,3]
nography in patients with viral hepatitis, early diagnosis of HCC has been improved in Japan . Moreover,
the spread of direct acting antivirals for hepatitis C virus and nucleoside analogues for hepatitis B virus, has
[4-6]
curtailed the incidence of hepatitis virus-related HCC .
[7]
In contrast, the incidence of non-virus-related nonB-nonC HCC (NBNC-HCC) is on the rise . Aging, exces-
sive alcohol consumption, diabetes mellitus (DM), and non-alcoholic steatohepatitis (NASH) are considered
[8,9]
major risk factors for NBNC-HCC . However, periodic screening of patients at risk using imaging modali-
[9]
ties, which is the recommended practice by the Japan society of hepatology , is not realistic due to the large
[10]
number of patients with these risk factors . Even if screening were limited to only the patients with DM,
[11]
the estimated patient number in Japan would be over 7 million . In order to implement a comprehensive
screening for NBNC-HCC, the development of effective non-imaging screening methods is necessary.
There are several reports indicating that an elevation in the serum transaminase levels is a risk factor for
HCC [12,13] . In addition, serum levels of alpha-fetoprotein (AFP) were found to reliably predict the develop-
ment of HCC in patients with chronic hepatitis C virus infection who had achieved a sustained virological
response [14-16] . A third potential biomarker, des-gamma-carboxy prothrombin (DCP) should also be consid-
[17]
ered as it was reported to be a better marker for HCC than AFP in NBNC-HCC .

In this study, we examined the diagnostic utility of aspartate aminotransferase (AST), AFP, and DCP as
non-imaging screening markers for NBNC-HCC.

METHODS
Patients
Between January 2001 and December 2016, 1,285 consecutive patients were initially diagnosed with HCC
and treated at the Okayama University Hospital. Among these, 203 patients who were negative for both the
hepatitis B virus surface antigen and hepatitis C virus antibody were diagnosed with NBNC-HCC and en-
rolled to the test group. Additionally, 106 patients with DM treated at the outpatient clinic of Okayama City
Hospital were enrolled to the control group. For validation, 86 NBNC-HCC patients treated at Okayama City
Hospital were also enrolled.

Diagnosis
HCC was diagnosed using imaging modalities such as computed tomography (CT), magnetic resonance
imaging (MRI), or angiography. Diagnostic criteria for HCC were based on previous reports of hyperattenu-
ation at the arterial phase or hypoattenuation at the portal phase, determined with dynamic CT or MRI, and
[18]
tumor staining in angiography .

There was no history of cancers, including HCC, in the control group, and abdominal ultrasonography was
used to rule out HCC in the 6 months prior to enrollment. None of the patients were on warfarin or vitamin K.

Determination of diagnostic accuracy
Serum levels of AST, AFP, and DCP were compared between the NBNC-HCC and control groups. Sensitiv-
ity and specificity for the three markers used in the diagnosis of HCC were analyzed at different cut-offs.
In addition, optimal cut-offs were determined using the receiver operating characteristic (ROC) curve and
by calculation of Youden index. The rate of patients whose serum levels for any of the three markers were
higher than the optimal cut-offs, was also analyzed.