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1 The first authors Juan Wang and Ruo-Chan Chen contributed equally to the work; they are the co-first authors
Juan Wang
Footnotes
1 The first authors Juan Wang and Ruo-Chan Chen contributed equally to the work; they are the co-first authors
Affiliations
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
1 The first authors Juan Wang and Ruo-Chan Chen contributed equally to the work; they are the co-first authors
Ruo-Chan Chen
Footnotes
1 The first authors Juan Wang and Ruo-Chan Chen contributed equally to the work; they are the co-first authors
Affiliations
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
Department of Infectious Diseases, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, Hunan Province, 410008, ChinaKey Laboratory of Viral Hepatitis, Hunan Province, China
A strong relationship was found between Helicobacter pylori infection and chronic hepatitis B.
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With the progression of chronic hepatitis B, the prevalence of H. pylori infection is higher.
•
Active screening for H. pylori in patients with chronic hepatitis B is proposed.
Summary
Objectives
Helicobacter pylori is a bacterium that infects over 50% of the human population worldwide. An increasing number of studies have demonstrated that H. pylori may cause liver diseases, and the underlying relationship between H. pylori infection and chronic hepatitis B has attracted much attention. This study aimed to examine the association between H. pylori infection and the progression of chronic hepatitis B in the Chinese population.
Methods
A search was performed of the PubMed/MEDLINE, Web of Science, and Cochrane Central Register of Controlled Trials (CENTRAL) databases, as well as the Chinese databases, China National Knowledge Infrastructure and Wanfang Data, for studies published between January 1, 1994 and November 1, 2015.
Results
In total, 2977 patients were included in the chronic hepatitis B group, while 1668 participants were included in the healthy control group. The prevalence of H. pylori among patients with chronic hepatitis B was significantly higher than that among those without chronic hepatitis B. The pooled odds ratio was 3.17. In the subgroup analysis, the odds ratio was 4.28 for hepatitis B virus (HBV)-related cirrhosis and 6.02 for hepatocellular carcinoma.
Conclusion
These results indicate a strong relationship between H. pylori and chronic hepatitis B, particularly during HBV progression.
HBV infection is the main cause of liver disease, with 25–30% of infected individuals ultimately developing hepatic cirrhosis, end-stage liver disease, or hepatocellular carcinoma (HCC), and even dying.
Association between hypoxia-inducible factor-1alpha gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case–control study.
Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1–241.
Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial.
Researchers have also found that H. pylori is associated with many extra-gastric diseases, such as hematological diseases, cardiovascular diseases, and especially liver diseases.
In the late 1990s, Fan et al. and Ponzetto et al. demonstrated that the rate of H. pylori infection in patients with chronic hepatitis B (CHB) was much higher than that in healthy individuals.
Recently, a growing number of studies have been conducted to determine the relationship between H. pylori infection and both HBV-related cirrhosis and HBV-related HCC in the Chinese population.
However, the association between H. pylori infection and the progression of HBV-related liver diseases remains unclear. The aim of this study was to explore the relationship between H. pylori infection and the progression of CHB by performing a systematic review.
2. Materials and methods
2.1 Search strategy
The following databases were used in this study: PubMed/MEDLINE, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL), as well as two Chinese databases, China National Knowledge Infrastructure (CNKI) and Wanfang Data. The keywords or subject headings used were “hepatitis B” and “H. pylori, Helicobacter pylori, or Helicobacter species”, from the earliest date available to November 1, 2015. The bibliographies of selected original studies, reviews, and relevant advance abstracts were screened.
2.2 Study selection
For each eligible study, the title and/or abstract was screened independently by two reviewers against specific criteria: (1) an original cross-sectional or case–control study, or a randomized controlled trial (RCT), comparing H. pylori-related morbidity between patients with CHB and healthy controls; (2) study reporting the absolute numbers of cases and controls as well as the positive rate of H. pylori infection; (3) study groups confirmed to be HBV-positive and control groups HBV-negative, with H. pylori being detected using serological tests. All studies had to have been performed in China. Finally, studies were excluded if they included patients with other viral hepatitis etiologies (e.g., hepatitis A, C, or E virus) or other types of hepatitis, such as autoimmune liver disease and non-alcoholic fatty liver disease.
2.3 Data extraction and quality assessment
The following data were collected from each original study: first author, year of publication, numbers included in the two groups (CHB and control), incidence of H. pylori infection in the two groups, and the numbers of patients with CHB who had no cirrhosis, cirrhosis present, and HCC. Discrepancies were resolved by consensus between the two reviewers. Finally, 15 case–control studies were included. The Newcastle–Ottawa Scale was used to assess the methodological quality of the studies.
The meta-analysis was performed using Stata 12.0 (StataCorp, College Station, TX, USA). Risk ratios (RRs) were used to assess the risk estimate for RCTs. Odds ratios (ORs), which were considered approximate RRs in this meta-analysis, were used for case–control studies. The heterogeneity of the studies was evaluated using the Chi-square test and I2 statistic. The fixed-effects model was used if the heterogeneity was insignificant (Chi-square test p ≥ 0.10 and I2 ≤ 50%), while the random-effects model was preferred if significant heterogeneity was found (Chi-square test p < 0.10 or I2 > 50%). Egger's regression test and the trim and fill method were used to analyze publication bias.
3. Results
A total of 15 case–control studies were included from 333 studies identified in the online search. The process of selection and analysis is shown in the flow diagram in Figure 1. A description of the included studies is given in Table 1.
3.1 H. pylori-positive rate in the HBV and control groups
In the meta-analysis (Figure 2), the heterogeneity of all 15 studies was found to be significant (I2 = 77.9%). Using a random-effects model, the pooled OR was 3.17 (95% confidence interval (CI) 2.38–4.22; p < 0.01), indicating that the H. pylori-positive rate in patients with CHB is approximately 3.17 times that in the healthy population.
Figure 2Forest plot of the meta-analysis for the Helicobacter pylori-positive rate between the HBV group and the control group.
In order to attenuate the influence of HBV disease stage on the results of the meta-analysis, the extracted data of the included studies were classified into non-cirrhosis, cirrhosis, and HCC groups, and these groups were compared with the control group. Forest plots of the meta-analysis are shown in Figure 3. For patients with CHB only, the H. pylori-positive rate in patients without cirrhosis or HCC was 2.44-fold higher than that in healthy controls (pooled OR 2.44, 95% CI 1.85–3.24; p < 0.01). With HBV progression, patients with cirrhosis and HCC might have a higher risk of acquiring an H. pylori infection. The H. pylori-positive rate in patients with CHB and cirrhosis was 4.28-fold higher (pooled OR 4.28, 95% CI 2.99–6.13; p < 0.01) than that in the healthy population, while it was 6.02-fold higher (pooled OR 6.02, 95% CI 4.33–8.37; p = 0.821) in patients with HBV-related HCC. Because the heterogeneities were both significant (I2 > 50%) in Figure 3A and 3B, a random-effects model was used for the calculations, while a fixed-effects model was used for the data in Figure 3C.
Figure 3Forest plots of the meta-analysis according to the HBV progression stage: (A) Helicobacter pylori positivity rate between the non-cirrhosis group and the control group; (B) Helicobacter pylori positivity rate between the cirrhosis group and the control group; (C) Helicobacter pylori positivity rate between the HBV-related hepatocellular carcinoma group and the control group.
Figure 3Forest plots of the meta-analysis according to the HBV progression stage: (A) Helicobacter pylori positivity rate between the non-cirrhosis group and the control group; (B) Helicobacter pylori positivity rate between the cirrhosis group and the control group; (C) Helicobacter pylori positivity rate between the HBV-related hepatocellular carcinoma group and the control group.
In order to determine the influence of each individual study on the pooled OR, a sensitivity analysis was performed by the omission of individual studies. Pooled OR values were not significantly affected by any individual study (Figure 4).
Figure 4Sensitivity analysis of the studies included.
Egger's regression test was used to assess publication bias in the 15 studies included in the meta-analysis (Figure 5A). The graph appeared asymmetric, which indicates that a risk of publication bias may exist. The trim and fill method was used to determine whether the results were reliable. Before and after trimming and filling, the 95% CI of the result was 1.153 (0.868–1.438) and 1.122 (0.836–1.409), respectively, using a random-effects model. As shown in Figure 5B, this means that the results of the study are stable and reliable.
Figure 5A Egger's funnel plot—the Egger's funnel plot showed the existence of a small publication bias. (B) Trim and fill method—just filling one study corrected the publication bias, indicating the results to be reliable.
Both H. pylori and HBV infection are prevalent in China, and many researchers have found a relationship between H. pylori and HBV-related liver disease. H. pylori may be a putative risk factor in the development of HBV. A meta-analysis was conducted to explore H. pylori infection and the progression of CHB.
This study showed that the H. pylori-positive rate of patients with CHB was higher than that in the healthy population. Huang et al. demonstrated that oral inoculation with H. pylori leads to hepatitis of varying severity in mice. They also found that specific H. pylori genes could be detected in murine liver samples.
Huang et al. concluded that H. pylori reach the liver via the blood stream or the biliary system and then become an independent etiological factor causing inflammation. Moreover, many studies have reported that H. pylori exert cytopathic effects on hepatocytes in vitro.
The present study results are consistent with these findings.
Heterogeneity was significant in the studies above. Although a sensitivity analysis was performed, no single article that could influence the result by itself was found. Consequently, the random-effects model was used. The source of the heterogeneity could be the difference in constituent ratios of CHB disease progression between the studies. To address this, a subgroup analysis of patients at different disease stages was performed. Differences in viral load of patients with CHB could also have contributed to the heterogeneity. Xi et al. reported that the rate of H. pylori infection in patients with HBV-DNA >103 copies/ml was higher than that in patients with HBV-DNA <103 copies/ml.
In contrast, Wang et al. and Ji et al. showed that there was no significant difference in the prevalence rate of H. pylori in CHB patients with different levels of HBV-DNA.
Unfortunately, since none of the studies included here mentioned the genotypes, it was not possible to further analyze the influence of HBV genotype on H. pylori prevalence in patients with CHB.
All of the studies included reported a higher prevalence of H. pylori infection in patients with cirrhosis. However, Hu and Deng
reported that the prevalence of H. pylori infection is significantly higher in patients with more severe cirrhosis as assessed by Child–Pugh class, while Wang et al.
reported no significant difference. Thus, the difference in Child–Pugh class in each study may account for the heterogeneity in the group with HBV-related cirrhosis.
This study also suggested that H. pylori incidence correlates positively with HBV-related HCC. Huang et al. detected H. pylori in HBV-related primary HCC using morphological and immunohistochemical methods.
They inferred that H. pylori could be a risk factor for HCC progression. Abu Al-Soud et al. reported that the presence in liver specimens of Helicobacter DNA (H. pylori was the most prevalent species), but not that of other common gut bacteria, was associated with human hepatic carcinogenesis.
These findings are consistent with the present study results.
This study has some limitations. First, the results showed moderate publication bias using Egger's test. However, when fewer than 20 trials are included, the sensitivity of Egger's test for meta-analyses is usually low.
Consequently, the trim and fill method showed the results to be stable and reliable. Additionally, the results of the meta-analysis may have been affected by the limitations of the publications included. Although great care was taken to identify all related studies, some may have been overlooked. In addition, some studies might not have been published because of negative results, which would lead to an unavoidable publication bias. Moreover, all articles that were included were published in English or Chinese and originated in China. Thus, the results may not be representative of other non-Chinese populations. This study was further limited by the inclusion of only case–control studies. The quality of such studies is lower than that of RCTs.
In summary, the results of this study revealed that H. pylori infection is positively associated with CHB and particularly with HBV-related cirrhosis and HBV-related HCC. Therefore, it is vital to screen patients with CHB for H. pylori infection. Moreover, these results highlight the urgent need for H. pylori eradication. Unfortunately, due to the limited number of studies included, additional RCTs should be conducted to further support the findings of this study.
Acknowledgements
This study was funded in full by The National Natural Science Foundation of China (grant number 30271171).
Conflict of interest: The authors declare that there is no conflict of interest regarding the publication of this paper.
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Current treatment guidelines for chronic hepatitis B and their applications.
Association between hypoxia-inducible factor-1alpha gene polymorphisms and risk of chronic hepatitis B and hepatitis B virus-related liver cirrhosis in a Chinese population: a retrospective case–control study.
Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum 1994;61:1–241.
Efficacy, safety, and immunogenicity of an oral recombinant Helicobacter pylori vaccine in children in China: a randomised, double-blind, placebo-controlled, phase 3 trial.
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