Kazuo Tarao, Akito Nozaki, Hirokazu Komatsu, Naomi Ideno, Tatsuji Komatsu, Takaaki Ikeda, Masataka Taguri, Shin Maeda

Abstract

Key Words: Hazard ratio of alanine aminotransferase; Hepatitis B virus; Hepatitis С virus; Hepatocellular carcinoma; Еlevated alanine aminotransferase

lNTRODUCTlON

It is generally accepted that the incidence of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-associated of patients is higher than that in hepatitis B virus (HBV)-associated patients. We demonstrated that the incidence of HCC in HCV-associated cirrhotic patients was 4.81%/year as compared with 3.23% in HBV-associated patients based on analytic assessment of already published papers[1].

However, the reason why this difference in incidence of HCC occurs in patients with HBV and HCV infections remains unclear. We have been considering this for many years, and finally arrived at the possibility that the contributing power of inflammation, which is the main risk factor for developing HCC, may be different with HBV and HCV infections.

Figure 1 Flow diagram of articles with hepatitis B virus infected patients. HBV: Hepatitis B virus.

Figure 2 Flow diagram of articles with hepatitis C virus infected patients. HCV: Hepatitis C virus; DAA: Direct acting antivirals.

To investigate this, we surveyed the hazard ratio (HR) of inflammation which was identified by serum alanine aminotransferase (ALT) levels between patients with HBV and HCV infections.

Why ALT, not AST was adopted in this study was as follows: We previously demonstrated[2] the strong association between sustained high serum ALT levels (≥ 80 international units (INU) annual average) and the development of HCC in patients with HCV-LC (Child Stage A) by long-term observation lasting about 7 years, (Cancer 1999; 86: 589-595). In this series of the study, we also investigated the association between sustained high serum AST levels (≥ 80 INU) and development, but the association was not so strong as ALT. Moreover, many studies have demonstrated a close association between severe inflammation as estimated by higher serum ALT level and initiation of HCC development (Veldtet al[3]; Miyakawaet al[4]).

MATERlALS AND METHODS

Search strategy

The PubMed database was searched (2001-2021) for studies published in English regarding the incidence of HCC in HBV or HCV infected patients. There were 8924 studies involving HBV patients, and 7376 studies of HCV patients. From these studies, interferon-treated patients with both HBV and HCV infections were excluded. Furthermore, in HBV patients, those who were administered nucleos(t)ide analogues were excluded, and HCV patients administered direct acting antivirals were also excluded. We also excluded articles which include co-existing liver disease such as alcoholic liver diseases and/or fatty liver diseases. Then, studies which dealt with the HR of HCC regarding inflammation (serum elevated ALT levels) were selected. Finally, there were 13 studies of HBV-infected patients[5-17], and 8 studies of HCV-infected patients[13,18-24] (Figures 1 and 2). In these selected papers, the HR of patients in a non-inflammatory state (serum ALT levels within normal range) was set as 1. We then calculated the HR in patients in an inflammatory state (serum ALT levels were above normal range).

Furthermore, for the purpose of comparing elevated ALT levels between hepatitis B and C patients, we examined the actual ALT levels cited in patients with chronic hepatitis B and hepatitis C included in this series (Tables 1 and 2) .

Table 1 Actual elevated alanine aminotransferase levels cited in patients with chronic hepatitis B

Table 2 Actual elevated alanine aminotransferase levels cited in patients with chronic hepatitis C

Statistical analysis

To compare HR of ALT for HCC between HBV and HCV patients, we calculated the weighted mean of HR for each type using the random effect model (Ref.: Dersimonian R, Laird N. Meta-analysis in Clinical trials. Controlled Clinic Trials 1986; 7: 177-188). To assess whether the mean HR among HBV patients was lower than that among HCV patients, we calculated thePvalue using aZtest. All reported p- values correspond to two-sided tests, and thoseP＜ 0.05 were considered significant. All analyses were performed using R (version 4.1.2) and R Studio (version 1.4) software.

RESULTS

In the 14 studies of HBV patients[5-17], the average HR of elevated ALT for developing HCC was 2.74 [1.98-3.77] (Figure 3), and that in 8 studies of HCV-infected patients[12,15-21] was 5.51 [3.08-9.83] (Figure 4). It was demonstrated that the HR of inflammation for HCC development in HCV-associated liver diseases is about twice that in HBV-associated liver diseases. The HR in HCV-infected patients was significantly (P= 0.0391) higher than that in HBV-infected patients.

In hepatitis B patients, the abnormal range adopted was 28-45 IU/L (Table 1), and in hepatitis C patients, it was 20-50 IU/L (Table 2). It was demonstrated that the abnormal ALT levels adopted in hepatitis B and C patients were very similar in this series.

Figure 3 ln hepatitis B virus patients, a non-inflammatory state (serum alanine aminotransferase levels were within normal range) were set as 1. Hazard ratios of patients in an inflammatory state (serum alanine aminotransferase levels above normal range) were calculated.

Figure 4 ln hepatitis C virus patients, Hazard ratios of patients in a non-inflammatory state (serum alanine aminotransferase levels were within normal range) were set as 1. Hazard ratios of patients in an inflammatory state (serum alanine aminotransferase levels above normal range) were calculated.

DlSCUSSlON

There are many risk factors for developing HCC: Sex, age, ALT, α-fetoprotein, presence of cirrhosis, habitual alcohol consumption, tabaco, and diabetes mellitus are typically cited, and HBV-DNA[1,3,6-8,10] and the HBV genotype[9] are added for chronic HBV infection. The HCV genotype is also cited for HCV infection[21]. To study the impact of ALT on HCC development in chronic hepatitis B and chronic hepatitis C virus infections, we initially surveyed risk factors for HCC that are strongly associated with its development.

現(xiàn)階段甲狀腺癌SLNB尚存在待解決的問(wèn)題，頸部淋巴結(jié)交通支豐富，當(dāng)合并淋巴管阻塞、術(shù)中擠壓腫瘤周?chē)馨徒M織、甲狀腺癌淋巴結(jié)跳躍式轉(zhuǎn)移及二次手術(shù)淋巴管破壞的患者，可能出現(xiàn)淋巴引流改變方向，使有轉(zhuǎn)移的前哨淋巴結(jié)不能顯示，造成前哨淋巴結(jié)假陰性，現(xiàn)階段SLNB技術(shù)尚無(wú)標(biāo)準(zhǔn)的操作規(guī)范，因此，SLNB在甲狀腺癌的應(yīng)用，尚需更多循證醫(yī)學(xué)臨床研究的支持。

As shown in Table 3, the HR for developing HCC for each item in patients with chronic hepatitis B virus infection was 2.52 for sex, 3.15 for age, 2.212 for HBV-DNA, 3.37 for ALT, and 6.42 for presence of cirrhosis. Except for the presence of cirrhosis, ALT shows the highest risk ratio for HCC development.

As shown in Table 4, in patients with chronic hepatitis C virus infection, it was 5.486 for age and 5.877 for ALT. The value for ALT was higher than that for age. In HBV infection, ALT is the second-highest risk factor, and in HCV infection, ALT is the higher risk factor.

Table 3 Hazard ratio for developing hepatocellular carcinoma for each item in various reports of patients with chronic hepatitis B virus infection

Table 4 Hazard ratio for developing hepatocellular carcinoma in each item in various reports of patients with chronic hepatitis C virus infection

In support of our findings, Benvegnùet al[25] demonstrated that patients with HCV infection with persistently elevated or fluctuating ALT levels during the observation period demonstrated a significantly higher rate of HCC development compared with patients in whom ALT remained or became normal during follow-up. This observation confirms that the activity of liver disease, which is characterized by inflammation, necrosis, and regeneration, plays an important role in promoting HCC development and suggests that medical interventions that limit disease activity may prevent or delay neoplastic transformation and tumor growth.

Furthermore, we demonstrated that the average HR of ALT for HCC development in HCV patients is about twice that in HBV patients (P＜ 0.05).

CONCLUSlON

In conclusion, the difference in the incidence of HCC development between HBV and HCV patients may depend on the difference in the HR of ALT between HBV and HCV infections.

ARTlCLE HlGHLlGHTS

Research background

It is generally accepted that the incidence of hepatocellular carcinoma (HCC) in hepatitis C virus (HCV)-associated patients is higher than that in hepatitis B virus (HBV)-associated patients. We demonstrated that the incidence of HCC in HCV-associated cirrhotic patients was 4.81%/year compared with 3.23% in HBV-associated patients based on analytic assessment of already published papers.

Research motivation

Research objectives

To investigate this, we surveyed the hazard ratio of inflammation for HCC development, which was identified by serum alanine aminotransferase levels between patients with HBV and HCV infections.

Research methods

The PubMed database was searched (2001-2021) for studies published in English regarding the incidence of HCC, identifying 8924 HBV-and7376 HCV-infected patients. From these studies, interferontreated patients with both HBV and HCV infections were excluded. Furthermore, in HBV patients, those administered nucleos(t)ide analogues were excluded, and in HCV patients, those administered direct acting antivirals were also excluded. Studies citing hazard ratios of HCC regarding inflammation (serum elevated alanine aminotransferase levels) were selected. Finally, there were 14 studies of HBV- infected patients and 8 studies of HCV-infected patients. We calculated the hazard ratio in patients in an inflammatory state (serum ALT levels were above the normal range).

Research results

In the 14 studies of HBV patients, the average hazard ratio (HR) of elevated ALT for developing HCC was 2.74 [1.98-3.77], and that in the 8 studies on HCV-infected patients was 5.51 [3.08-9.83]. HR in HCVinfected patients was about twice that in HBV-infected patient, and was significantly (P= 0.0391) higher than that in HBV-infected patients. In hepatitis B patients, the abnormal range adopted was 28-45 IU/L, and in hepatitis C patients, it was 20-50 IU/L. It was demonstrated that the abnormal ALT levels adopted in hepatitis B and C patients were very similar in this series.

Research conclusions

The difference in the incidence of HCC development between HBV and HCV patients may depend on the difference in the HR of ALT between HBV and HCV infections.

Research perspectives

In this study, it was demonstrated that the HR of inflammation for HCC development in HCVassociated liver diseases is about twice that in HBV-associated liver diseases. So, we must optimally suppress inflammation in patients with HCV-associated liver diseases to prevent HCC development.

FOOTNOTES

Author contributions:Tarao K summarized the data and wrote the paper; Nozaki A, Komatsu H, Ideno N, Komatsu T, Ikeda T, Maeda S were involved in the interpretation of data, and the development and critical revision of the manuscript for important intellectual content; Taguri M conducted statistical analysis.

Conflict-of-interest statement:All the authors declare no conflicts of interest associated with this manuscript.

PRlSMA 2009 Checklist statement:The authors have read the PRISMA 2009 Checklist, and the manuscript was prepared and revised according to the PRISMA 2009 Checklist.

Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

Country/Territory of origin:Japan

ORClD number:Kazuo Тarao 0000-0002-7161-6748; Akito Nozaki 0000-0002-3310-6632; Hirokazu Komatsu 0000-0001-9613-6698; Тatsuji Komatsu 0000-0002-8293-3773; Мa(chǎn)sataka Тaguri 0000-0001-8902-0056; Shin Мa(chǎn)eda 0000-0002-0246-1594.

S-Editor:Liu JH

L-Editor:A

P-Editor:Liu JH