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Nouso et al. Hepatoma Res 2018;4:73 I http://dx.doi.org/10.20517/2394-5079.2018.93 Page 5 of 7

patients who have achieved a sustained virological response [14-16] . The positive rate in DM patients was only
4.7%, using the same cut-off level. The rate was still low (9.4%) even when the cut-off was lowered to 3.6 ng/mL,
which is the cut-off adopted in this study. Approximately 80% of patients with NBNC-HCC showed an AFP
elevation over 3.6 ng/mL. These results indicate that AFP is a good marker for NBNC-HCC with the low cut-
off, in agreement with the results obtained in HCV patients with a sustained virological response. It should
be noted that the origin of serum AFP, whether from highly carcinogenic liver parenchymal cells or from
HCC, remains unclear.

In contrast to AFP, DCP is considered a reliable marker for NBNC-HCC, and was hence included in this
[17]
combination screen . The sensitivity and specificity of DCP at a commonly used cut-off (40 mAU/mL)
were 70.9% and 99.1%, respectively. Even on lowering the cut-off to 25 mAU/mL to maximize the detection
rate, we still observed a high specificity (91.5%). Although DCP testing is not meaningful in patients using
drugs affecting vitamin K levels (warfarin, menatetrenone, etc.), our results show that it is a good marker for
NBNC-HCC in the majority of cases.

Several reports indicate that an elevation in serum transaminase levels increases the risk for HCC [12,13] . A
large cohort study examining over 0.4 million people conducted by a private health screening firm in Taiwan
revealed that abnormal AST levels were associated with a 3.3-10.9-fold increased risk for HCC, compared
[13]
with normal AST levels (< 25 IU/L) . In contrast, hazard ratio of the patients with abnormal alanine ami-
notransferase (ALT) levels was not high (1.29). In preliminary analysis with our cohort, the AUROC for ALT
(0.68) was significantly lower than that of AST (0.84) (P < 0.001). Based on these findings, we included AST
in the triple screen.

In this study, we show that the use of a triple screening method increased the sensitivity for HCC to 97.5%.
Although the specificity was decreased to 72.6%, this index is useful because it reduced the number of candi-
dates who required further screening to one-fourth of the original population size, which is a more manage-
able number for screening with imaging. Notably, this screening strategy produced high sensitivity even in
patients in the early stages of HCC (tumor size ≤ 3 cm, ≤ 3 nodules), indicating that a triple screen for AST,
ALT, and DCP may be useful for early detection of HCC.

We also examined the effect of occult hepatitis B virus infection that might correlate with the development
of NBNC-HCC. Among 203 NBNC-HCC, 68 (33.5%) patients were positive for hepatitis B core antibody
(HBc-Ab). However, no difference of the positivity of AFP, DCP and AST was observed between the patients
with and without HBc-Ab in this cohort (data not shown).

This study has several limitations. First, we could not effectively select the patients with NASH who need
further examination with imaging. The patients with NASH often showed deterioration in liver function,
which resulted in high AST and/or AFP levels in about 50% of cases. Second, the cut-offs adopted for AST,
ALT, and DCP are optimized for each individual marker, but when used in combination, may not optimally
delineate the high-risk populations. While the usage of the formula obtained by logistic regression analysis
produced a high AUROC (0.971), the calculation was too complex for use in the clinical setting. Further-
more, no data of healthy control was presented although it might strength the conclusion of this study. Given
that this is a retrospective case study, another limitation is that use of the triple screen in this population
cannot predict the actual risk for developing HCC, but merely has diagnostic ability. Prospective periodic
measurement of these markers is required for early detection of HCC.

In conclusion, the screening method developed in this study is easy to use because it is a blood test consisted
of AST, AFP and DCP. This study clearly showed that being aware of the new low-cut offs of the markers
when we conduct blood tests with any reasons was important in achieving early diagnosis of NBNC-HCC.
Although it is necessary to use imaging as a confirmatory test for NBNC-HCC, the use of this triple screen