Introduction
Viral hepatitis, which causes liver cirrhosis (LC) and hepatocellular carcinoma (HCC), is a worldwide health concern [
1,
2]. Because of recent advances in the treatment of viral hepatitis, the World Health Organization aimed to achieve a 90% reduction of new infections and 65% reduction of viral hepatitis-related mortality by 2030 [
3]; however, only a limited number of countries are expected to reach the goal [
4]. In Japan, the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) are high, and several measurements for viral hepatitis have been officially conducted by the Ministry of Health, Labour and Welfare (MHLW) [
5,
6]. Japan is considered to be one of the most successful countries in the world with regard to the suppression of viral hepatitis [
4].
The aim of the antiviral treatments is to improve the prognosis of viral hepatitis-infected patients through precautions to prevent the development of fatal complications, such as liver failure and HCC [
7,
8]. In our recent nationwide survey to assess the transition in the etiologies of LC in Japan [
9], we found a decrease in hepatitis virus-related LC, particularly in HCV-related LC and an increase in non-viral LC. However, the incidence of HCC development differed among the etiologies, and viral hepatitis-related LC is known to show a higher risk of HCC development in comparison to non-viral LC [
10]. Thus, the etiology of HCC is also clinically relevant. In the present study, we used nationwide data to analyze the transition in the etiologies of HCC-complicated LC.
Discussion
HCC is a major complication of LC patients. In the present study, we showed the changing etiology of HCC-complicated LC in Japan. Our previous report on the survey on the etiologies of LC revealed that the contribution of viral hepatitis remarkably decreased, and the ratio of HCV-related LC dropped to < 50% after 2014. We considered that this was due to recent advances in treatment for viral hepatitis [
13‐
18] and official measures that are provided in Japan such as the financial support system for patients to receive antiviral treatment [
5,
6]. However, in the current study, viral hepatitis was shown to remain a major cause of HCC in Japan, although the contribution had gradually decreased during the recent decade. Viral hepatitis-related LC is known to be associated with a high rate of HCC development in comparison to non-viral LC; and our results are consistent with this fact, and showed that viral hepatitis remains an important etiology of HCC in Japan.
The etiologies of HCC in Japan have been the subject of previous studies [
19‐
22]. In the surveillance of LC etiology in 2008 [
19], the etiological distribution of HCC-complicated LC patients was reported as follows: HBV (14.1%), HCV (73.1%), ALD (6.3%), and NASH (1.6%). Although the rate of HBV and HCV co-infection was not mentioned, approximately 90% of the patients with HCC were diagnosed with hepatitis virus infection. In the results of a nationwide survey on HCC in 2009 [
20], the distribution of the major etiologies was reported to be as follows: HBV (14.1%), HCV (66.3%), HBV + HCV (3.7%), ALD (7.2%), and NAFLD (2.0%). In our study, the etiologies of HCC in patients diagnosed before 2008 were as follows: HBV (14.7%), HCV (69.2%), HBV + HCV (1.4%), ALD (8.5%), and NASH (1.5%) (Fig.
5). A recent report also provided similar results regarding the data of HCC patients diagnosed in 2008 or 2009 [
21]. The comparable findings of the different surveys, including the current study, are suggested to appropriately reflect the real-world data of Japanese HCC patients around 10 years previously. In the current study, we found an increase in non-viral HCC (Fig.
5), and ALD-related HCC and cryptogenic HCC were calculated to be responsible for approximately 55 and 20% of non-viral HCC, respectively (Supplementary Fig. 1). These results were—to some extent—different from the results of the recent nationwide survey on non-viral HCC [
22], which showed a lower rate of ALD-related HCC (32.3%) and a higher rate of HCC with unclassified and other etiologies (46.7%). The discrepancies may have been caused by the different definitions for the etiological classifications in each study, as the rate of non-viral HCC among all HCC cases was comparable in the two studies, at 32.5% in the previous study [
22] and 35.6% in the current study (see the HCC patients diagnosed in 2014 and thereafter in Fig.
5). Our results were also consistent with various studies that assessed the transition in the etiologies of HCC in Japan [
23,
24]. In addition, we showed that HCV infection still maintained an important role in the clinical practice of HCC, despite an increase in non-viral HCC, and the results seemed to be consistent with the data reported from outside Japan [
25‐
28]. These findings suggested that our results appropriately reflect recent trends in the etiologies of HCC.
The current study included some unique results. This study is the most recent nationwide survey that analyzed a large number of patients with both viral HCC and non-viral HCC. In addition, we analyzed the differences in the etiologies of HCC among various areas, which have not been routinely assessed. Although HCV-related HCC was the leading cause in all areas (Fig.
4), each area had its own characteristics, which was similarly observed in previous studies on the etiologies of LC [
9]. Furthermore, similarly to our previous study [
9], we analyzed the data from designated hospitals that were able to provide the annual numbers of newly identified HCC patients from 2008 to 2016. The transition in the new HCC patients in the same hospitals suggested that the decrease in viral hepatitis-related HCC and the increase in non-viral HCC reflected both changes in the rates of each etiology (Fig.
5) and in the real numbers of newly identified HCC patients (Fig.
6). However, we should note that the absolute number of non-viral HCC patients in Japan was smaller than the number of viral hepatitis-related HCC patients. The number of newly diagnosed cases of non-viral HCC, particularly NASH-related HCC, increased in real numbers (Fig.
7); however, the changes were relatively mild in comparison to the remarkable decrease in HCV-related HCC (Fig.
6). In light of the data with real numbers, the decrease in viral hepatitis-related HCC, particularly HCV-related HCC, was suggested to contribute more strongly to the changing distribution of the HCC etiologies in Japan in comparison to the increase in non-viral HCC cases.
As described in the previous paper [
9], because of the high prevalence of viral hepatitis, various measures against viral hepatitis have been implemented at the national level, and Japan is considered to be one of the most successful countries in the world with regard to the suppression of viral hepatitis. HCV-infected patients in Japan tend to be elderly individuals with long-term infection, since HCV infection is thought to have been widespread approximately 60 years ago [
29]. Although our current data were only obtained from Japan, the transition in the etiologies, with a reduction in the numbers of viral hepatitis-related HCC cases, particularly HCV-related HCC, could help predict the future changes in the etiologies of HCC in other countries [
30].
The present study was associated with some limitations. First, we only surveyed the numbers of patients with HCC-complicated LC. Our nationwide data demonstrated a difference in the etiology between the whole LC patients and the HCC-complicated LC patients, and viral hepatitis remains an important etiology of HCC in Japan. Previous reports that focused on specific patients, such as non-viral HCC cases, have provided significant findings for physicians [
20,
22]. We, therefore, feel that the current results focusing on LC patients could be clinically useful. However, analyzing the whole HCC patient cohort, including non-cirrhotic patients, would be quite informative. Second, although the current study was the latest nationwide survey, we did not include the detailed clinical data. Thus, we were unable to include data that might be affected by the etiologies, including the composition of HCC by cause and sex ratio of HCC by cause. In addition, the number of patients was not directly associated with the prevalence of liver diseases, as our survey did not include the data of the general population. Third, LC and HCC were determined based on the clinical diagnosis, without histological assessments. Finally, we analyzed the hospitals with annual data on the number of newly diagnosed HCC patients for every year from 2008 to 2016 (Figs.
6,
7). In these hospitals, the real numbers of new HCC patients were considered to have been regularly recorded, independently of the current survey, and may simulate prospectively accumulated data. However, the analysis of a prospectively enrolled cohort would be warranted to precisely assess the transition in the real numbers of HCC patients in Japan.
In summary, viral hepatitis infection was considered to remain a major cause of HCC in Japan; however, its contribution as a cause of HCC has been decreasing during the recent decade. The decrease in viral hepatitis-related HCC, particularly HCV-related HCC, was suggested to highly contribute to the change in the distribution of the etiologies of HCC in Japan.
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