Review article 1309
Association between cirrhosis and Helicobacter pylori infection: a meta-analysis Hao Fenga,b,*, Xiaoying Zhoua,* and Guoxin Zhanga Cirrhosis is a severe threat to public health. Some studies have suggested that cirrhosis is associated with Helicobacter pylori infection, but the results remain controversial. This meta-analysis was conducted to quantify the association between cirrhosis and H. pylori infection. Published articles on H. pylori prevalence in patients with cirrhosis were collected to assess the potential associations between H. pylori infection and cirrhosis risk. Twenty-one eligible studies were included for the analysis. Data on publication year, geographic region, and etiology were summarized. Metaregression models and subgroup analyses were established to screen the factors for heterogeneity. Of the 322 articles retrieved, 21 met the inclusion criteria. These studies involved 6135 cases, with a total H. pylori infection rate of 52.26%. This meta-analysis showed significant difference in H. pylori infection between patients with cirrhosis and controls [odd ratio (OR) = 2.05, 95% confidence interval (CI): 1.33–3.18, P < 0.0001]. The subgroup analysis revealed, in contrast to Asia (OR = 0.90, 95% CI: 0.48–1.66, P < 0.0001), Europe (OR = 2.98, 95% CI: 2.02–4.39, P < 0.0001), and America (OR = 4.75, 95% CI: 1.42–15.95, P = 0.249), a significantly higher prevalence of H. pylori infection in patients with cirrhosis. On the basis of
etiology, there was a higher prevalence of H. pylori infection due to primary biliary cirrhosis (OR = 1.75, 95% CI: 1.15–2.64, P = 0.147) and viral cirrhosis (OR = 2.66, 95% CI: 1.24–5.71, P < 0.0001) compared with alcohol cirrhosis (OR = 0.77, 95% CI: 0.04–16.59, P < 0.0001). The pooled data suggest that there is a significantly high prevalence of H. pylori infection in patients with cirrhosis. Large-scale and multicenter studies are needed to further investigate the relation between cirrhosis and H. pylori infection. Eur J Gastroenterol Hepatol 26:1309–1319 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
cirrhosis has attracted a lot of attention [16]. Many studies have suggested that H. pylori infection has an important role in the pathogenesis of PU in cirrhotic patients and contributes to the development of HE and hyperammonemia [17]. HE is a complex neuropsychiatric syndrome caused by brain function disorder mainly due to chronic liver failure. It was established that H. pylori separates urea into ammonia and carbon dioxide, and plasma ammonia levels were firmly related to HE [18]. A systematic review has shown that eradication therapy in H. pylori-positive cirrhotic patients may have a beneficial effect on hyperammonemia and (minimal) hepatic encephalopathy [(M)HE] [19]. Concerned with the relationship between H. pylori infection and cirrhosis, many observational studies have been conducted, revealing the relationship, but large differences exist among them. Some studies that included case reports proved the high prevalence of H. pylori infection in patients with cirrhosis, but others found no relationship.
Cirrhosis is a severe threat to public health all over the world. It can develop into hepatocellular carcinoma [1,2]. Patients with cirrhosis are more likely to develop gastrointestinal mucosal lesions. The previous study based on endoscopy screening showed that the frequency of peptic ulcer (PU) disease in liver cirrhosis patients was increased to ∼ 5–20% compared with 2–4% in the general population [3–7]. Because of the high rate of life-threatening complications like PU, hepatic encephalopathy (HE), and upper gastrointestinal hemorrhage, the medical history of cirrhotic patients was frequently punctuated and caused a heavy burden on the National Health Service [8,9]. As a microphilic, Gram-negative bacterium [10], Helicobacter pylori is mainly associated with PU disease, gastric mucosa-associated lymphoid tissue lymphoma, chronic gastritis, and gastric cancer [11,12]. Furthermore, some reports have focused on the effects between H. pylori and the host [13] and found that H. pylori infection could cause extragastrointestinal diseases such as cardiovascular, liver, and biliary diseases [14,15]. However, the role of H. pylori infection in these diseases is still unclear. The relationship of H. pylori with liver 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
European Journal of Gastroenterology & Hepatology 2014, 26:1309–1319 Keywords: cirrhosis, Helicobacter pylori, meta-analysis a Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, First Clinical Medical College of Nanjing Medical University and b Nanjing Jiangbei People’s Hospital, Nanjing, China
Correspondence to Guoxin Zhang, PhD, MD, Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Tel: + 86 25 83718836 x6973; fax: + 86 25 83674636; e-mail: [email protected] *Hao Feng and Xiaoying Zhou contributed equally to the writing of this article. Received 14 May 2014 Accepted 4 September 2014
The aim of this meta-analysis was to summarize the epidemiologic evidence on the association between H. pylori and cirrhosis. Strong existence of a correlation between H. pylori infection and cirrhosis may benefit the DOI: 10.1097/MEG.0000000000000220
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1310 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
clinic with a more in-depth understanding of the mechanisms of H. pylori infection in cirrhosis patients and aid in prevention.
Materials and methods Literature search
Our meta-analysis was conducted following the guidelines of PRISMA and MOOSE [20]. Two independent investigators (Hao Feng and Xiaoying Zhou) launched a systematic literature search and summarized their results from the PubMed and Embase database from inception to February 2014 at medical science information centers affiliated to Nanjing Medical University. The search strategy was as follows: First, the following combinations were used as search keywords – Helicobacter pylori OR H. pylori AND cirrhosis, Helicobacter pylori OR H. pylori AND cirrhotic. The search was repeated three times at different time points, with the last search taking place on 21 February 2014. Second, searches were expanded by reviewing the corresponding reference lists of every article that met our inclusion criteria. When further information was required for a potentially relevant paper, we contacted the article’s corresponding author. All findings were categorized as review articles or original papers (see the flowchart in Fig. 1). Inclusion criteria
(1) The studies had to be case–control or cross-sectional in design. (2) Raw data on H. pylori infection in both the cirrhosis group and the control group had to be available. (3) H. pylori infection had been detected by means of the 13 C-urea breath test (UBT), rapid urea test (RUT), PCR, histological assessment, or enzyme-linked immunosorbent assay (ELISA). At least one positive test result was regarded as confirmation of infection.
Statistical analysis
The meta-analysis consisted of two parts. One part was an epidemiological description of H. pylori prevalence in patients with cirrhosis. The other comprised a description of the publication year, origin, etiology, and the methods used to test the bacterium. The prevalence rate and odds ratio (OR) were the two main parameters. Choice between the random-effects model and the fixedeffects model was decided on the basis of heterogeneity between studies. Heterogeneity was determined by the I2 statistic test, which considered heterogeneity to indicate low, medium, and high by the values of 25, 50, and 75%. The Q statistics test was also used to determine heterogeneity and P values less than 0.10 were considered indicative of significant heterogeneity. The fixed-effects model was used if I2 values were less than 50%, indicating no significant heterogeneity; otherwise, the random-effects model was used [21]. All reported P values are two sided, and P values less than 0.05 were regarded as indicating statistical significance. We used the OR with the 95% confidence interval (CI) as the summary statistic to carry out the calculation of dichotomous variables. In addition, the Mantel–Haenszel method was used to combine ORs for the outcome parameters. Yates’s correction was used in studies containing a ‘zero’ value in each group [22]. Egger’s unweighted regression asymmetry test was used to test the degree of asymmetry. Publication bias was tested by the rank correlation coefficient from Begg’s test to a value of 1, or to the slope parameter from Egger’s regression [23]. Data manipulation and statistical analyses were carried out using the STATA statistical software package, version 12.0 (STATA Corp., College Station, Texas, USA).
Results Exclusion criteria
Description of studies
(1) The studies had only case reports with no control groups. (2) The control group comprised patients with hepatitis, ulcers, or gastritis, instead of healthy individuals. (3) The articles were review articles, laboratory studies, or studies on animals.
A total of 322 articles were retrieved and 21 studies published between 1990 and 2014 met the inclusion criteria and were selected for the meta-analysis (Table 1 and Fig. 2) [6,17,24–35,37–43]. These studies included a total of 6135 cases, and the total H. pylori infection rate was 52.26% (3206/6135). The cumulative sample size of the cirrhosis group was 1941, and 1151 were H. pylori positive (59.30%). Of the total number of 4194 controls, 2055 (49.00%) were H. pylori positive.
Data extraction
The two investigators who launched the literature search also performed the data extraction independently, but in agreement. The following data were collected for each included study: first author, year and origin of the study, etiology, and methods of H. pylori detection. The numbers of H. pylori-positive and H. pylori-negative patients in each study’s cirrhosis group and control group were recorded. When data from the same study were reported in different papers, only one was included in the metaanalysis.
With respect to the origin of studies, 10 studies were from Europe, eight were from Asia, two were from America, and one was from Africa. The prevalence of H. pylori infection in cirrhotic patients was the highest in European patients (88.98%) and the lowest in Asian patients (31.85%). Compared with Asia (43.73%), the prevalence of H. pylori infection in cirrhotic patients was demonstrated to be significantly higher in European (72.12%) and American (45.78%) patients.
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Cirrhosis and H. pylori Feng et al. 1311
Fig. 1
Records identified through “Helicobacter pylori” OR “H . pylori” AND “cirrhosis” searching (n=311)
Records identified through “Helicobacter pylori” OR “H . pylori” AND “cirrhotic” searching (n=322)
Records after duplicates removed (n=322)
Records after articles not in English or English abstract removed (n=301)
Records excluded on the basis of an assessment of title and abstract (n=254)
Records screened (n=301)
Full-text articles excluded, (reviews, comments, without control studies, animal models (n=12)
Full-text articles assessed for eligibility (n=47)
Prospective studies included in qualitative synthesis (n=35)
Flowchart.
Table 1
Characteristics of studies on H. pylori infection in cirrhosis patients and controls
References Ram et al. [24] Shapira et al. [25] Silva et al. [26] Chen et al. [27] El-Masry et al. [28] Ibrişim et al. [29] Kim et al. [30] Abdel-Hady et al. [17] Castéra et al. [31] Nam et al. [32] Konturek et al. [33] Chen et al. [34] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36] Ponzetto et al. [36] Shimamoto et al. [37] Zullo et al. [38] Wang et al. [39] Siringo et al. [40] Wu et al. [41]
Origin
Cirrhosis with H. pylori (+ / − )
Age (years)
Sex (M/F)
Control with H. pylori (+ / − )
Age (years)
Sex (M/F)
Detection
Europe Europe America Asia Africa Asia Asia America Europe Asia Europe Asia Europe Europe Europe Europe Asia Europe Asia Europe Asia
37/31 37/32 41/65 14/16 50/40 43/92 101/187 35/25 5/7 19/11 50/10 43/15 78/71 226/28 40/5 54/16 9/11 88/47 19/30 117/36 45/15
ND ND 49.6 ± 13.4 ND ND 46.04 ± 10.79 49.3 ± 11.1 ND 60 ± 11 ND 53.35 ± 11.84 65.5 ± 0.8 58.2 ± 11 ND 57.1 ± 6.5 ND ND ND 57.5 ± 10.5 57.6 ± 12.8 ND
ND ND 58/48 ND 58/32 64/71 229/59 33/27 5/7 ND 40/20 43/15 10/139 127/127 45/0 ND 17/3 ND 26/23 99/54 ND
150/235 31/69 1/19 0/20 26/40 61/62 201/121 6/14 4/22 19/14 33/32 29/7 291/328 275/188 183/127 183/127 2/8 53/68 52/23 422/588 33/27
ND ND 32.9 ± 13.4 ND ND 46.99 ± 11.06 49 ± 10 ND 49 ± 12 ND 40.62 ± 11.9 63.7 ± 11 47 ± 5.3 ND ND ND ND ND 53.8 ± 10.7 44.2 ± 9.2 ND
ND ND 10/4 ND 31/35 59/64 259/63 13/7 13/13 ND 22/43 29/7 523/96 254/209 ND ND 8/2 ND 47/28 559/451 ND
ELISA ELISA PCR PCR RUT RUT/H RUT RUT ELISA RUT ELISA ELISA ELISA ELISA ELISA ELISA UBT RUT/H H ELISA ELISA
ELISA, enzyme-linked immunosorbent assay; F, female; H, histological assessment; H. pylori, Helicobacter pylori; M, male; ND, no data; RUT, rapid urea tests; UBT, 13 C-urea breath test.
On the basis of the year of publication, studies were divided into three groups surrounding the years 2000–2010: studies published before 2000 (4), those published between 2000 and 2010 (12), and those
published after 2010 (5). Although the proportion of H. pylori-positive patients in each cirrhotic group was decreasing (67.76 vs. 59.53 vs. 49.31%), the result showed no statistical significance.
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1312 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 2
References
Total
OR (95%CI)
Weight %
Ram et al. [24]
453
1.87 (1.11−3.14)
5.57
Shapira et al. [25]
169
2.57 (1.36−4.86)
5.36
Silva et al. [26]
126
11.98 (1.55−92.96)
2.60
Chen et al. [27]
50
36.03 (2.00−650.09) 1.66
El-Masry et al. [28]
156
1.92 (1.01−3.67)
5.34
Ibrişim et al. [29]
258
0.48 (0.29−0.79)
5.59
Kim et al. [30]
610
0.48 (0.34−0.68)
5.82
Abdel-Hady et al. [17]
80
3.27 (1.10−9.67)
4.41
Castéra et al. [31]
38
3.93 (0.82−18.81)
3.41
Nam et al. [32]
63
1.27 (0.46−3.51)
4.56
Konturek et al. [33]
125
4.85 (2.10−11.18)
4.95
Chen et al. [34]
94
0.69 (0.25−1.91)
4.56
Vergara et al. [6]
768
1.24 (0.87−1.77)
5.80
Pellicano et al. [35]
717
5.52 (3.57−8.52)
5.70
Ponzetto et al. [36]
355
5.55 (2.13−14.45)
4.69
Ponzetto et al. [36]
380
2.34 (1.28−4.28)
5.42
Shimamoto et al. [37]
30
3.27 (0.55−19.45)
3.02
Zullo et al. [38]
256
2.40 (1.45−3.98)
5.59
Wang et al. [39]
124
0.28 (0.13−0.60)
5.12
Siringo et al. [40]
1163
4.53 (3.05−6.71)
5.76
Wu et al. [41]
120
2.45 (1.13−5.33)
5.08
2.05 (1.33−3.18)
100.00
2=
Overall (I
89.2%, P= 0.000)
Note: Weights are from random effects analysis 0.00154
1
650
Association between H. pylori infection and cirrhosis risk (ORs). Eight studies that adopted control groups were selected for the analysis of H. pylori infection and cirrhosis risk. The random-effects model was chosen to estimate the ORs after pooling, because of the high heterogeneity among these studies (I2 = 89.2%, P < 0.0001). CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
Several methods were used in these studies to detect H. pylori infection: 11 studies used anti-H. pylori IgGELISA alone to detect the presence of H. pylori; two studies tested H. pylori infection by PCR; four studies used RUT; two studies used RUT and/or histological assessment; and one study used UBT or histological assessment. The method of ELISA was used the most (4382/6135) and yielded a positive rate for H. pylori infection in cirrhosis patients of 73.35%. The etiology of cirrhosis was viral in nine studies, primary biliary cirrhosis (PBC) in two, and alcoholic in two. The prevalence of H. pylori infection in cirrhotic patients was significantly higher in viral cirrhosis (70.70%) and PBC patients (54.68%) than in alcoholic cirrhotic patients (28.22%). The random-effects model was chosen on the basis of estimated OR (I2 = 89.2%, P < 0.0001) (Fig. 2). H. pylori infection was associated with a 1.05-fold (95% CI:
1.33–3.18) increased cirrhosis risk, which indicates that the prevalence of H. pylori infection was significantly different between cirrhotic patients and controls (Begg’s test, P = 0.545). Egger’s test (P = 0.144, 95% CI: − 0.39 to 2.49) was used to measure publication bias and show insignificance (Figs 3 and 4). Subgroup analysis of H. pylori infection prevalence
We performed a subgroup analysis to investigate the factors influencing the overall results (Table 2). Geographic distribution and the etiology of cirrhosis were determined to have the most influence on the results. Stratification analysis by geographic region showed that in Europe and America the level of H. pylori infection was significantly higher in patients with cirrhosis than in controls, in contrast to Asia (Table 2 and Fig. 5). The ORs were 2.98 (95% CI: 2.02–4.39, P < 0.0001) in the 10 studies conducted in Europe, 4.75 (95% CI: 1.42–15.92, P = 0.249) in the two studies from America, 0.90 (95% CI:
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Cirrhosis and H. pylori Feng et al. 1313
0.48–1.66, P < 0.0001) in the eight studies from Asia, and 1.92 (95% CI: 1.01–3.67) in the study from Africa.
Fig. 3
Begg′s funnel plot with pseudo 95% confidence limits 400
var6
200
0
−200 0
50
100
150
SE of: var6 Publication bias estimated by Begg’s test.
With regard to the study publication year, we divided all studies into three groups surrounding the years 2000–2010 (Table 2 and Fig. 6), and found that the level of H. pylori infection in cirrhosis had gradually increased. The ORs were 1.70 (95% CI: 0.59–4.92, P < 0.001) for four studies before 2000, 1.87 (95% CI: 1.01–3.48, P < 0.001) for 12 studies between 2000 and 2010, and 2.53 (95% CI: 1.49–4.29, P = 0.116) for five studies after 2010 (Table 2 and Fig. 7).
Fig. 4
Egger′s publication bias plot
Standardized effect
8 6 4
Using stratified analysis based on different methods, the pooled data showed that the prevalence of H. pylori was increased significantly by using ELISA (OR = 2.71, 95% CI: 1.80–4.08, P < 0.001) and PCR (OR = 17.31, 95% CI: 3.25–92.12, P = 0.542), but it was not statistically significant difference in other groups (Table 2 and Fig. 8).
2 0 0
0.1 Precision
0.2
Discussion Current studies on the association between cirrhosis and H. pylori infection give conflicting results. This article
Publication bias estimated by Egger’s test.
Table 2
Subgroup analysis of the prevalence of H. pylori infection in cirrhotic patients versus controls
Category Origin
Publication calendar period
Method
The subgroup analysis on the etiology of cirrhosis revealed that 12 articles had provided a clear etiology for cirrhosis as well as the number of patients enrolled, whereas two studies had included different cirrhotic diseases and had provided the respective number of patients. All reports had three groups on the basis of etiology (Table 3 and Fig. 6) and had found that the prevalence of H. pylori infection in PBC and viral cirrhosis was significantly elevated compared with control (OR = 1.75, 95% CI: 1.15–2.64, P = 0.147 and OR = 2.66, 95% CI: 1.24–5.71, P < 0.0001). In contrast, the prevalence of H. pylori infection in alcohol cirrhosis was not significantly different compared with control (OR = 0.77, 95% CI: 0.04–16.59, P < 0.001).
Subcategory
Number of studies
H. pylori (+ ) in alcoholic cirrhosis group
H. pylori (+ ) in control group
Total Europe Asia America Africa Total
21 10 8 2 1 21
1511/1941 732/1015 293/670 76/166 50/90 1511/1941
2055/4194 1625/3409 397/679 7/40 26/66 2055/4194
2.05 2.98 0.90 4.75 1.92 2.05
(1.33–3.18) (2.02–4.39) (0.48–1.66) (1.42–15.92) (1.01–3.67) (1.33–3.18)
< 0.0001 < 0.0001 < 0.0001 0.249 – < 0.0001
Before 2000 2000–2009 After 2010 Total ELISA RUT RUT/H PCR UBT H
4 12 5 21 11 4 2 2 1 1
269/397 703/1181 179/363 1511/1941 732/998 205/468 131/270 55/136 9/20 19/49
560/1266 1287/2337 208/591 2055/4194 1634/3384 252/441 114/244 1/40 2/10 52/75
1.70 1.87 2.53 2.05 2.71 1.31 1.07 17.31 3.27 0.28
(0.59–4.92) (1.01–3.48) (1.49–4.29) (1.33–3.18) (1.80–4.08) (0.50–3.44) (0.22–5.23) (3.52–92.12) (0.55–19.45) (0.13–0.60)
< 0.0001 < 0.0001 0.116 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.542 – –
OR (95% CI)
P value
CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; H, histological assessment; H. pylori, Helicobacter pylori; OR, odds ratio; RUT, rapid urea tests; UBT, C-urea breath test.
13
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1314 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 5
References
Total
Europe 453 Ram et al. [24] Shapira et al. [25] 169 Castéra et al. [31] 38 Konturek et al. [33] 125 768 Vergara et al. [6] 717 Pellicano et al. [35] 355 Ponzetto et al. [36] 380 Ponzetto et al. [36] 256 Zullo et al. [38] 1163 Siringo et al. [40] Subtotal (I2= 78.6%, P = 0.000) . America Silva et al. [26] 126 Abdel-Hady et al. [17] 80 Subtotal (I2= 24.7%, P = 0.249) . Asia Chen et al. [27] 50 258 Ibrişim et al. [29] Kim et al. [30] 610 Nam et al. [32] 63 94 Chen et al. [34] 30 Shimamoto et al. [37] Wang et al. [39] 124 Wu et al. [41] 120 Subtotal (I2= 78.8%, P = 0.000) . Africa 156 El-Masry et al. [28] Subtotal . Overall (I2= 89.2%, P = 0.000)
OR (95% CI)
Weight %
1.87 (1.11−3.14) 2.57 (1.36−4.86) 3.93 (0.82−18.81) 4.85 (2.10−11.18) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 2.40 (1.45−3.98) 4.53 (3.05−6.71) 2.98 (2.02−4.39)
5.57 5.36 3.41 4.95 5.80 5.70 4.69 5.42 5.59 5.76 52.24
11.98 (1.55−92.96) 3.27 (1.10−9.67) 4.75 (1.42−15.95)
2.60 4.41 7.01
36.03 (2.00−650.09) 0.48 (0.29−0.79) 0.48 (0.34−0.68) 1.27 (0.46−3.51) 0.69 (0.25−1.91) 3.27 (0.55−19.45) 0.28 (0.13−0.60) 2.45 (1.13−5.33) 0.90 (0.48−1.66)
1.66 5.59 5.82 4.56 4.56 3.02 5.12 5.08 35.41
1.92 (1.01−3.67) 1.92 (1.01−3.67)
5.34 5.34
2.05 (1.33−3.18)
100.00
Note: Weights are from random effects analysis 0.00154
1
650
Subgroup analysis of H. pylori infection according to geographic region. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
investigated the potential relationship between cirrhosis and H. pylori infection through the published evidence in previous studies. The meta-analysis of 21 studies across the globe indicated that the prevalence of H. pylori infection is significantly higher in cirrhosis patients in comparison with controls, which could be explained as follows. First, there was a big difference in the prevalence of H. pylori infection in patients with cirrhosis [25,26]; some authors found that the prevalence of H. pylori infection in cirrhotic patients was significantly higher than that in controls [29,30], whereas others did not. Some studies that enrolled PU or hepatitis patients as controls were excluded to reduce selected bias, and it led to a reduction in the sample size. Second, H. pylori
infection may occur during childhood, and the infection is much less in adulthood [43,44]. Our study did not analyze the subject by age and this may have caused collection bias. Finally, several methods were used to detect H. pylori infection in this study and this may have led to a high level of heterogeneity in this study. Sixteen studies in this meta-analysis showed significant difference in the prevalence of H. pylori infection between cirrhotic patients and controls; five of the studies lacked evidence of difference. This phenomenon could be attributed to the methods selected in the studies, the small sample size, and the rapid clearance of initial infection.
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Cirrhosis and H. pylori Feng et al. 1315
Table 3
Subgroup analysis of the prevalence of H. pylori infection in cirrhotic patients with different etiologies versus controls
References
Origin
Etiology
Cirrhosis with H. pylori (+ / − )
Control with H. pylori (+ / − )
Ram et al. [24] Shapira et al. [25] El-Masry et al. [28] Kim et al. [30] Kim et al. [30] Castéra et al. [31] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36] Ponzetto et al. [36] Shimamoto et al. [37] Siringo et al. [40] Siringo et al. [40] Siringo et al. [40] Wu et al. [41]
Israel France Egypt Korea Korea France Italy Italy Italy Italy Japan Italy Italy Italy Taiwan
PBC PBC Viral Viral Alcoholic Viral PBC Viral Viral Viral Viral Viral Alcoholic PBC Viral
37/31 37/32 50/40 74/100 24/85 5/7 78/71 226/28 40/5 54/16 9/11 74/22 11/4 2/0 45/15
150/235 31/69 26/40 201/121 201/121 4/22 291/328 275/188 183/127 183/127 2/8 422/588 422/588 422/588 33/27
H. pylori, Helicobacter pylori; PBC, primary biliary cirrhosis.
Fig. 6
OR (95% CI)
Weight %
Ram et al. [24]
1.87 (1.11−3.14)
7.53
Shapira et al. [25]
2.57 (1.36−4.86)
7.32
Vergara et al. [6]
1.24 (0.87−1.77)
7.76
Siringo et al. [40]
6.96 (0.33−145.44)
2.60
Subtotal (I2 = 44.1%, P = 0.147)
1.75 (1.15−2.64)
25.20
El-Masry et al. [28]
1.92 (1.01−3.67)
7.30
Kim et al. [30]
0.45 (0.31−0.65)
7.74
Castéra et al. [31]
3.93 (0.82−18.81)
5.15
Pellicano et al. [35]
5.52 (3.57−8.52)
7.66
Ponzetto et al. [36]
5.55 (2.13−14.45)
6.62
Ponzetto et al. [36]
2.34 (1.28−4.28)
7.38
Shimamoto et al. [37]
3.27 (0.55−19.45)
4.66
Siringo et al. [40]
4.69 (2.87−7.67)
7.57
Wu et al. [41]
2.45 (1.13−5.33)
7.03
2.66 (1.24−5.71)
61.10
Kim et al. [30]
0.17 (0.10−0.28)
7.55
Siringo et al. [40]
3.83 (1.21−12.12)
6.15
Subtotal (I2 = 95.8%, P = 0.000)
0.77 (0.04−16.59)
13.70
2.08 (1.14−3.77)
100.00
References PBC
. Viral
2 = 92.0%,
Subtotal (I
P = 0.000)
. Alcoholic
. Overall (I2 = 92.6%, P = 0.000) Note: Weights are from random effects analysis 0.00688
1
145
Subgroup analysis of H. pylori infection according to the etiology of cirrhosis. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio; PBC, primary biliary cirrhosis.
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1316 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 7
References
Total
OR (95% CI)
Weight %
After 2010 Ram et al. [24] Shapira et al. [25] Silva et al. [26]
453 169 126
1.87 (1.11−3.14) 2.57 (1.36−4.86) 11.98 (1.55−92.96) 36.03 (2.00−650.09) 1.92 (1.01−3.67)
5.57 5.36 2.60 1.66 5.34
2.53 (1.49−4.29)
20.53
Chen et al. [27] 50 El-Masry et al. [28] 156 Subtotal (I2 = 46.0%, P = 0.116) . 2000–2009 Ibrişim et al. [29] Kim et al. [30] Abdel-Hady et al. [17] Castéra et al. [31] Nam et al. [32] Konturek et al. [33] Chen et al. [34] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36]
258 610 80 38 63 125 94 768 717 355
Ponzetto et al. [36] 380 Shimamoto et al. [37] 30 Subtotal (I2 = 90.8%, P = 0.000) . Before 2000 Zullo et al. [38] Wang et al. [39] Siringo et al. [40] Wu et al. [41]
256 124 1163 120
Subtotal (I2 = 92.7%, P = 0.000) . Overall (I2 = 89.2%, P = 0.000)
0.48 (0.29−0.79)
5.59
0.48 (0.34−0.68) 3.27 (1.10−9.67)
5.82 4.41
3.93 (0.82−18.81) 1.27 (0.46−3.51) 4.85 (2.10−11.18) 0.69 (0.25−1.91) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 3.27 (0.55−19.45)
3.41 4.56 4.95 4.56 5.80 5.70 4.69 5.42 3.02
1.87 (1.01−3.48)
57.93
2.40 (1.45−3.98)
5.59
0.28 (0.13−0.60) 4.53 (3.05−6.71) 2.45 (1.13−5.33) 1.70 (0.59−4.92)
5.12 5.76 5.08 21.54
2.05 (1.33−3.18)
100.00
Note: Weights are from random effects analysis 0.00154
1
650
Subgroup analysis of H. pylori infection according to publication year. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
Geographical distribution
The prevalence of H. pylori infection ranged from 40 to 55% by geographic region (Asia: 690/1349, 51.15%; Europe: 2357/4424, 53.28%; America: 83/206, 40.29%; Africa 76/156, 48.72%). There was no significant difference in the H. pylori infection rate between cirrhotic patients and controls in Asia. In contrast, in Europe, America, and Africa, H. pylori exposure in patients with cirrhosis was significantly higher. The following reasons may explain the differences: first, almost all negative and unrelated results were concentrated in Asia (6/8); only two unrelated results were seen in Europe. Second, there was a wide range in the data of each region; the study sample size in Europe and Asia was much larger than that of America and Africa. And each set of data came from a different region, with the lack of a global, multicenter
study. There were differences in race, diet, lifestyle, etc, which could have caused the differences in the results. Etiology of cirrhosis distribution
On the basis of the etiology of cirrhosis it was seen that patients with viral cirrhosis and PBC had a higher prevalence of H. pylori infection, compared with those with alcohol cirrhosis. This may be due to two reasons. First, we extracted some data on alcoholic cirrhosis from the literature. Second, some studies that enrolled hepatitis, ulcer or gastritis patients as controls were eliminated for the exclusion criteria. Both led to a small sample size and limited the reliability of the results. Time distribution
The articles on H. pylori infection in cirrhotic patients were concentrated in the decade of 2000–2009. The
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Cirrhosis and H. pylori Feng et al. 1317
Fig. 8
References
Total
ELISA Ram et al. [24] 453 169 Shapira et al. [25] 38 Castéra et al. [31] 125 Konturek et al. [33] 94 Chen et al. [34] Vergara et al. [6] 768 717 Pellicano et al. [35] 355 Ponzetto et al. [36] Ponzetto et al. [36] 380 1163 Siringo et al. [40] Wu et al. [41] 120 Subtotal (I2 = 79.5%, P = 0.000) . H 126 Silva et al. [26] 50 Chen et al. [27] Wang et al. [39] 124 Subtotal (I2 = 91.7%, P = 0.000) . RUT El-Masry et al. [28] 156 Kim et al. [30] 610 Abdel-Hady et al. [17] 80 Nam et al. [32] 63 Subtotal (I2 = 86.8%, P = 0.000) . RUT/H Ibrişim et al. [29] 258 Zullo et al. [38] 256 Subtotal (I2 = 94.9%, P = 0.000) . UBT Shimamoto et al. [37] 30 Subtoal (I2= .%, P= .) . Overall (I2 = 89.2%, P = 0.000)
OR (95% Cl)
Weight %
1.87 (1.11−3.14) 2.57 (1.36−4.86) 3.93 (0.82−18.81) 4.85 (2.10−11.18) 0.69 (0.25−1.91) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 4.53 (3.05−6.71) 2.45 (1.13−5.33) 2.71 (1.80−4.08)
5.57 5.36 3.41 4.95 4.56 5.80 5.70 4.69 5.42 5.76 5.08 56.29
11.98 (1.55−92.96) 36.03 (2.00−650.09) 0.28 (0.13−0.60) 4.22 (0.11−159.49)
2.60 1.66 5.12 9.38
1.92 (1.01−3.67) 0.48 (0.34−0.68) 3.27 (1.10−9.67) 1.27 (0.46−3.51) 1.31 (0.50−3.44)
5.34 5.82 4.41 4.56 20.13
0.48 (0.29−0.79) 2.40 (1.45−3.98) 1.07 (0.22−5.23)
5.59 5.59 11.18
3.27 (0.55−19.45) 3.27 (0.55−19.45)
3.02 3.02
2.05 (1.33−3.18)
100.00
NOTE:Weights are from random effects analysis .00154
1
650
Subgroup analysis of H. pylori infection according to the detection method. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; H, histological assessment; H. pylori, Helicobacter pylori; OR, odds ratio; RUT, rapid urea test; UBT, 13C-urea breath test.
prevalence of H. pylori infection in cirrhotic patients was the highest before 2000, but with no significant difference in comparison with controls [39]. This may be due to selection bias, as histological assessment was used to detect the H. pylori infection in these studies. The prevalence was slightly increased between 2000 and 2009, and then significantly increased after 2010. Method of detection
In this meta-analysis, we performed a stratified analysis according to different detection methods, and found that ELISA showed a significantly high prevalence of H. pylori
infection in cirrhotic patients in comparison with controls, compared with other methods. Anti-H. pylori IgG-ELISA is a method of detection based on the presence of serologic anti-H. pylori IgG antibodies in the patient. It is noninvasive, inexpensive, and well suited to primary care practice, which makes it suitable for large-scale population surveys. It is used as the basic serological test in clinics and has been extensively studied. The USA and Europe recommend only H. pylori IgG testing in guidelines [45,46]. Generally, titers of antiH. pylori IgG could decline ∼50% within 3 months of
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1318 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
infection, and would show a negative result in 60% of patients at 18 months with eradication therapy [47]. However, there may remain a few patients who test positive after eradication therapy. Consequently, using different methods such as UBT to confirm the result is appropriate. Because the 16S rRNA gene is highly conserved in different species of bacteria (16S rDNA), PCR detection of the 16S rRNA of H. pylori in tissue samples is feasible. Histological assessment involves staining the specimens obtained through endoscopy, which has high sensitivity and specificity [48]. RUT is based on the ammonia produced by H. pylori converting urea. However, as the process of obtaining specimens is invasive, it was unsuitable for large-scale population surveys. UBT is a noninvasive method based on the ammonia and carbon dioxide produced by H. pylori converting urea and has high sensitivity and specificity. However, the discrepancy in UBT protocols across different clinical centers caused differences in breath sample collection times and intervals, as well as effects on delaying gastric emptying, which makes it almost impossible to directly compare UBT results [49]. To date, standard H. pylori diagnostic tests have not been established. The results obtained by the different methods cannot be directly compared. However, more accurate and convenient detection methods can be developed through extensive research. Study limitations
First, the inclusion criteria for controls were strictly restricted to healthy individuals; patients with hepatitis, ulcers, or gastritis were excluded, which led to reduced sample sizes. Second, the literature included in this metaanalysis was limited to studies published and listed on PubMed and Embase before Janurary 2014. Some relevant studies that met the inclusion criteria may have been missed, which may have caused some inherent biases. Third, the diagnosis of cirrhosis in each study varied and lacked follow-up studies, which may cause bias in the null hypothesis. Finally, the included articles did not consider the impact of liver function, Child–Pugh grade, and age, which would cause confounding bias.
the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231801). Author contributions: Hao Feng and Xiaoying Zhou collected and analyzed the data, and wrote the first draft of the paper. Guoxin Zhang designed the study and proofread the manuscript. Conflicts of interest
There are no conflicts of interest.
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Conclusion
We found that the prevalence of H. pylori infection in cirrhotic patients has increased significantly worldwide, especially in Europe and America, due to viral cirrhosis and PBC, as per the ELISA method. Because of the limitations of the study, large-scale multicenter studies are needed to prove the further association of cirrhosis and H. pylori infection.
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Acknowledgements This work was supported by National Natural Science Foundation of China (No. 81270476 and 81470830) and
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Association between cirrhosis and Helicobacter pylori infection: a meta-analysis Hao Fenga,b,*, Xiaoying Zhoua,* and Guoxin Zhanga Cirrhosis is a severe threat to public health. Some studies have suggested that cirrhosis is associated with Helicobacter pylori infection, but the results remain controversial. This meta-analysis was conducted to quantify the association between cirrhosis and H. pylori infection. Published articles on H. pylori prevalence in patients with cirrhosis were collected to assess the potential associations between H. pylori infection and cirrhosis risk. Twenty-one eligible studies were included for the analysis. Data on publication year, geographic region, and etiology were summarized. Metaregression models and subgroup analyses were established to screen the factors for heterogeneity. Of the 322 articles retrieved, 21 met the inclusion criteria. These studies involved 6135 cases, with a total H. pylori infection rate of 52.26%. This meta-analysis showed significant difference in H. pylori infection between patients with cirrhosis and controls [odd ratio (OR) = 2.05, 95% confidence interval (CI): 1.33–3.18, P < 0.0001]. The subgroup analysis revealed, in contrast to Asia (OR = 0.90, 95% CI: 0.48–1.66, P < 0.0001), Europe (OR = 2.98, 95% CI: 2.02–4.39, P < 0.0001), and America (OR = 4.75, 95% CI: 1.42–15.95, P = 0.249), a significantly higher prevalence of H. pylori infection in patients with cirrhosis. On the basis of
etiology, there was a higher prevalence of H. pylori infection due to primary biliary cirrhosis (OR = 1.75, 95% CI: 1.15–2.64, P = 0.147) and viral cirrhosis (OR = 2.66, 95% CI: 1.24–5.71, P < 0.0001) compared with alcohol cirrhosis (OR = 0.77, 95% CI: 0.04–16.59, P < 0.0001). The pooled data suggest that there is a significantly high prevalence of H. pylori infection in patients with cirrhosis. Large-scale and multicenter studies are needed to further investigate the relation between cirrhosis and H. pylori infection. Eur J Gastroenterol Hepatol 26:1309–1319 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Introduction
cirrhosis has attracted a lot of attention [16]. Many studies have suggested that H. pylori infection has an important role in the pathogenesis of PU in cirrhotic patients and contributes to the development of HE and hyperammonemia [17]. HE is a complex neuropsychiatric syndrome caused by brain function disorder mainly due to chronic liver failure. It was established that H. pylori separates urea into ammonia and carbon dioxide, and plasma ammonia levels were firmly related to HE [18]. A systematic review has shown that eradication therapy in H. pylori-positive cirrhotic patients may have a beneficial effect on hyperammonemia and (minimal) hepatic encephalopathy [(M)HE] [19]. Concerned with the relationship between H. pylori infection and cirrhosis, many observational studies have been conducted, revealing the relationship, but large differences exist among them. Some studies that included case reports proved the high prevalence of H. pylori infection in patients with cirrhosis, but others found no relationship.
Cirrhosis is a severe threat to public health all over the world. It can develop into hepatocellular carcinoma [1,2]. Patients with cirrhosis are more likely to develop gastrointestinal mucosal lesions. The previous study based on endoscopy screening showed that the frequency of peptic ulcer (PU) disease in liver cirrhosis patients was increased to ∼ 5–20% compared with 2–4% in the general population [3–7]. Because of the high rate of life-threatening complications like PU, hepatic encephalopathy (HE), and upper gastrointestinal hemorrhage, the medical history of cirrhotic patients was frequently punctuated and caused a heavy burden on the National Health Service [8,9]. As a microphilic, Gram-negative bacterium [10], Helicobacter pylori is mainly associated with PU disease, gastric mucosa-associated lymphoid tissue lymphoma, chronic gastritis, and gastric cancer [11,12]. Furthermore, some reports have focused on the effects between H. pylori and the host [13] and found that H. pylori infection could cause extragastrointestinal diseases such as cardiovascular, liver, and biliary diseases [14,15]. However, the role of H. pylori infection in these diseases is still unclear. The relationship of H. pylori with liver 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
European Journal of Gastroenterology & Hepatology 2014, 26:1309–1319 Keywords: cirrhosis, Helicobacter pylori, meta-analysis a Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, First Clinical Medical College of Nanjing Medical University and b Nanjing Jiangbei People’s Hospital, Nanjing, China
Correspondence to Guoxin Zhang, PhD, MD, Department of Gastroenterology, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China Tel: + 86 25 83718836 x6973; fax: + 86 25 83674636; e-mail: [email protected] *Hao Feng and Xiaoying Zhou contributed equally to the writing of this article. Received 14 May 2014 Accepted 4 September 2014
The aim of this meta-analysis was to summarize the epidemiologic evidence on the association between H. pylori and cirrhosis. Strong existence of a correlation between H. pylori infection and cirrhosis may benefit the DOI: 10.1097/MEG.0000000000000220
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1310 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
clinic with a more in-depth understanding of the mechanisms of H. pylori infection in cirrhosis patients and aid in prevention.
Materials and methods Literature search
Our meta-analysis was conducted following the guidelines of PRISMA and MOOSE [20]. Two independent investigators (Hao Feng and Xiaoying Zhou) launched a systematic literature search and summarized their results from the PubMed and Embase database from inception to February 2014 at medical science information centers affiliated to Nanjing Medical University. The search strategy was as follows: First, the following combinations were used as search keywords – Helicobacter pylori OR H. pylori AND cirrhosis, Helicobacter pylori OR H. pylori AND cirrhotic. The search was repeated three times at different time points, with the last search taking place on 21 February 2014. Second, searches were expanded by reviewing the corresponding reference lists of every article that met our inclusion criteria. When further information was required for a potentially relevant paper, we contacted the article’s corresponding author. All findings were categorized as review articles or original papers (see the flowchart in Fig. 1). Inclusion criteria
(1) The studies had to be case–control or cross-sectional in design. (2) Raw data on H. pylori infection in both the cirrhosis group and the control group had to be available. (3) H. pylori infection had been detected by means of the 13 C-urea breath test (UBT), rapid urea test (RUT), PCR, histological assessment, or enzyme-linked immunosorbent assay (ELISA). At least one positive test result was regarded as confirmation of infection.
Statistical analysis
The meta-analysis consisted of two parts. One part was an epidemiological description of H. pylori prevalence in patients with cirrhosis. The other comprised a description of the publication year, origin, etiology, and the methods used to test the bacterium. The prevalence rate and odds ratio (OR) were the two main parameters. Choice between the random-effects model and the fixedeffects model was decided on the basis of heterogeneity between studies. Heterogeneity was determined by the I2 statistic test, which considered heterogeneity to indicate low, medium, and high by the values of 25, 50, and 75%. The Q statistics test was also used to determine heterogeneity and P values less than 0.10 were considered indicative of significant heterogeneity. The fixed-effects model was used if I2 values were less than 50%, indicating no significant heterogeneity; otherwise, the random-effects model was used [21]. All reported P values are two sided, and P values less than 0.05 were regarded as indicating statistical significance. We used the OR with the 95% confidence interval (CI) as the summary statistic to carry out the calculation of dichotomous variables. In addition, the Mantel–Haenszel method was used to combine ORs for the outcome parameters. Yates’s correction was used in studies containing a ‘zero’ value in each group [22]. Egger’s unweighted regression asymmetry test was used to test the degree of asymmetry. Publication bias was tested by the rank correlation coefficient from Begg’s test to a value of 1, or to the slope parameter from Egger’s regression [23]. Data manipulation and statistical analyses were carried out using the STATA statistical software package, version 12.0 (STATA Corp., College Station, Texas, USA).
Results Exclusion criteria
Description of studies
(1) The studies had only case reports with no control groups. (2) The control group comprised patients with hepatitis, ulcers, or gastritis, instead of healthy individuals. (3) The articles were review articles, laboratory studies, or studies on animals.
A total of 322 articles were retrieved and 21 studies published between 1990 and 2014 met the inclusion criteria and were selected for the meta-analysis (Table 1 and Fig. 2) [6,17,24–35,37–43]. These studies included a total of 6135 cases, and the total H. pylori infection rate was 52.26% (3206/6135). The cumulative sample size of the cirrhosis group was 1941, and 1151 were H. pylori positive (59.30%). Of the total number of 4194 controls, 2055 (49.00%) were H. pylori positive.
Data extraction
The two investigators who launched the literature search also performed the data extraction independently, but in agreement. The following data were collected for each included study: first author, year and origin of the study, etiology, and methods of H. pylori detection. The numbers of H. pylori-positive and H. pylori-negative patients in each study’s cirrhosis group and control group were recorded. When data from the same study were reported in different papers, only one was included in the metaanalysis.
With respect to the origin of studies, 10 studies were from Europe, eight were from Asia, two were from America, and one was from Africa. The prevalence of H. pylori infection in cirrhotic patients was the highest in European patients (88.98%) and the lowest in Asian patients (31.85%). Compared with Asia (43.73%), the prevalence of H. pylori infection in cirrhotic patients was demonstrated to be significantly higher in European (72.12%) and American (45.78%) patients.
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Cirrhosis and H. pylori Feng et al. 1311
Fig. 1
Records identified through “Helicobacter pylori” OR “H . pylori” AND “cirrhosis” searching (n=311)
Records identified through “Helicobacter pylori” OR “H . pylori” AND “cirrhotic” searching (n=322)
Records after duplicates removed (n=322)
Records after articles not in English or English abstract removed (n=301)
Records excluded on the basis of an assessment of title and abstract (n=254)
Records screened (n=301)
Full-text articles excluded, (reviews, comments, without control studies, animal models (n=12)
Full-text articles assessed for eligibility (n=47)
Prospective studies included in qualitative synthesis (n=35)
Flowchart.
Table 1
Characteristics of studies on H. pylori infection in cirrhosis patients and controls
References Ram et al. [24] Shapira et al. [25] Silva et al. [26] Chen et al. [27] El-Masry et al. [28] Ibrişim et al. [29] Kim et al. [30] Abdel-Hady et al. [17] Castéra et al. [31] Nam et al. [32] Konturek et al. [33] Chen et al. [34] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36] Ponzetto et al. [36] Shimamoto et al. [37] Zullo et al. [38] Wang et al. [39] Siringo et al. [40] Wu et al. [41]
Origin
Cirrhosis with H. pylori (+ / − )
Age (years)
Sex (M/F)
Control with H. pylori (+ / − )
Age (years)
Sex (M/F)
Detection
Europe Europe America Asia Africa Asia Asia America Europe Asia Europe Asia Europe Europe Europe Europe Asia Europe Asia Europe Asia
37/31 37/32 41/65 14/16 50/40 43/92 101/187 35/25 5/7 19/11 50/10 43/15 78/71 226/28 40/5 54/16 9/11 88/47 19/30 117/36 45/15
ND ND 49.6 ± 13.4 ND ND 46.04 ± 10.79 49.3 ± 11.1 ND 60 ± 11 ND 53.35 ± 11.84 65.5 ± 0.8 58.2 ± 11 ND 57.1 ± 6.5 ND ND ND 57.5 ± 10.5 57.6 ± 12.8 ND
ND ND 58/48 ND 58/32 64/71 229/59 33/27 5/7 ND 40/20 43/15 10/139 127/127 45/0 ND 17/3 ND 26/23 99/54 ND
150/235 31/69 1/19 0/20 26/40 61/62 201/121 6/14 4/22 19/14 33/32 29/7 291/328 275/188 183/127 183/127 2/8 53/68 52/23 422/588 33/27
ND ND 32.9 ± 13.4 ND ND 46.99 ± 11.06 49 ± 10 ND 49 ± 12 ND 40.62 ± 11.9 63.7 ± 11 47 ± 5.3 ND ND ND ND ND 53.8 ± 10.7 44.2 ± 9.2 ND
ND ND 10/4 ND 31/35 59/64 259/63 13/7 13/13 ND 22/43 29/7 523/96 254/209 ND ND 8/2 ND 47/28 559/451 ND
ELISA ELISA PCR PCR RUT RUT/H RUT RUT ELISA RUT ELISA ELISA ELISA ELISA ELISA ELISA UBT RUT/H H ELISA ELISA
ELISA, enzyme-linked immunosorbent assay; F, female; H, histological assessment; H. pylori, Helicobacter pylori; M, male; ND, no data; RUT, rapid urea tests; UBT, 13 C-urea breath test.
On the basis of the year of publication, studies were divided into three groups surrounding the years 2000–2010: studies published before 2000 (4), those published between 2000 and 2010 (12), and those
published after 2010 (5). Although the proportion of H. pylori-positive patients in each cirrhotic group was decreasing (67.76 vs. 59.53 vs. 49.31%), the result showed no statistical significance.
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1312 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 2
References
Total
OR (95%CI)
Weight %
Ram et al. [24]
453
1.87 (1.11−3.14)
5.57
Shapira et al. [25]
169
2.57 (1.36−4.86)
5.36
Silva et al. [26]
126
11.98 (1.55−92.96)
2.60
Chen et al. [27]
50
36.03 (2.00−650.09) 1.66
El-Masry et al. [28]
156
1.92 (1.01−3.67)
5.34
Ibrişim et al. [29]
258
0.48 (0.29−0.79)
5.59
Kim et al. [30]
610
0.48 (0.34−0.68)
5.82
Abdel-Hady et al. [17]
80
3.27 (1.10−9.67)
4.41
Castéra et al. [31]
38
3.93 (0.82−18.81)
3.41
Nam et al. [32]
63
1.27 (0.46−3.51)
4.56
Konturek et al. [33]
125
4.85 (2.10−11.18)
4.95
Chen et al. [34]
94
0.69 (0.25−1.91)
4.56
Vergara et al. [6]
768
1.24 (0.87−1.77)
5.80
Pellicano et al. [35]
717
5.52 (3.57−8.52)
5.70
Ponzetto et al. [36]
355
5.55 (2.13−14.45)
4.69
Ponzetto et al. [36]
380
2.34 (1.28−4.28)
5.42
Shimamoto et al. [37]
30
3.27 (0.55−19.45)
3.02
Zullo et al. [38]
256
2.40 (1.45−3.98)
5.59
Wang et al. [39]
124
0.28 (0.13−0.60)
5.12
Siringo et al. [40]
1163
4.53 (3.05−6.71)
5.76
Wu et al. [41]
120
2.45 (1.13−5.33)
5.08
2.05 (1.33−3.18)
100.00
2=
Overall (I
89.2%, P= 0.000)
Note: Weights are from random effects analysis 0.00154
1
650
Association between H. pylori infection and cirrhosis risk (ORs). Eight studies that adopted control groups were selected for the analysis of H. pylori infection and cirrhosis risk. The random-effects model was chosen to estimate the ORs after pooling, because of the high heterogeneity among these studies (I2 = 89.2%, P < 0.0001). CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
Several methods were used in these studies to detect H. pylori infection: 11 studies used anti-H. pylori IgGELISA alone to detect the presence of H. pylori; two studies tested H. pylori infection by PCR; four studies used RUT; two studies used RUT and/or histological assessment; and one study used UBT or histological assessment. The method of ELISA was used the most (4382/6135) and yielded a positive rate for H. pylori infection in cirrhosis patients of 73.35%. The etiology of cirrhosis was viral in nine studies, primary biliary cirrhosis (PBC) in two, and alcoholic in two. The prevalence of H. pylori infection in cirrhotic patients was significantly higher in viral cirrhosis (70.70%) and PBC patients (54.68%) than in alcoholic cirrhotic patients (28.22%). The random-effects model was chosen on the basis of estimated OR (I2 = 89.2%, P < 0.0001) (Fig. 2). H. pylori infection was associated with a 1.05-fold (95% CI:
1.33–3.18) increased cirrhosis risk, which indicates that the prevalence of H. pylori infection was significantly different between cirrhotic patients and controls (Begg’s test, P = 0.545). Egger’s test (P = 0.144, 95% CI: − 0.39 to 2.49) was used to measure publication bias and show insignificance (Figs 3 and 4). Subgroup analysis of H. pylori infection prevalence
We performed a subgroup analysis to investigate the factors influencing the overall results (Table 2). Geographic distribution and the etiology of cirrhosis were determined to have the most influence on the results. Stratification analysis by geographic region showed that in Europe and America the level of H. pylori infection was significantly higher in patients with cirrhosis than in controls, in contrast to Asia (Table 2 and Fig. 5). The ORs were 2.98 (95% CI: 2.02–4.39, P < 0.0001) in the 10 studies conducted in Europe, 4.75 (95% CI: 1.42–15.92, P = 0.249) in the two studies from America, 0.90 (95% CI:
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Cirrhosis and H. pylori Feng et al. 1313
0.48–1.66, P < 0.0001) in the eight studies from Asia, and 1.92 (95% CI: 1.01–3.67) in the study from Africa.
Fig. 3
Begg′s funnel plot with pseudo 95% confidence limits 400
var6
200
0
−200 0
50
100
150
SE of: var6 Publication bias estimated by Begg’s test.
With regard to the study publication year, we divided all studies into three groups surrounding the years 2000–2010 (Table 2 and Fig. 6), and found that the level of H. pylori infection in cirrhosis had gradually increased. The ORs were 1.70 (95% CI: 0.59–4.92, P < 0.001) for four studies before 2000, 1.87 (95% CI: 1.01–3.48, P < 0.001) for 12 studies between 2000 and 2010, and 2.53 (95% CI: 1.49–4.29, P = 0.116) for five studies after 2010 (Table 2 and Fig. 7).
Fig. 4
Egger′s publication bias plot
Standardized effect
8 6 4
Using stratified analysis based on different methods, the pooled data showed that the prevalence of H. pylori was increased significantly by using ELISA (OR = 2.71, 95% CI: 1.80–4.08, P < 0.001) and PCR (OR = 17.31, 95% CI: 3.25–92.12, P = 0.542), but it was not statistically significant difference in other groups (Table 2 and Fig. 8).
2 0 0
0.1 Precision
0.2
Discussion Current studies on the association between cirrhosis and H. pylori infection give conflicting results. This article
Publication bias estimated by Egger’s test.
Table 2
Subgroup analysis of the prevalence of H. pylori infection in cirrhotic patients versus controls
Category Origin
Publication calendar period
Method
The subgroup analysis on the etiology of cirrhosis revealed that 12 articles had provided a clear etiology for cirrhosis as well as the number of patients enrolled, whereas two studies had included different cirrhotic diseases and had provided the respective number of patients. All reports had three groups on the basis of etiology (Table 3 and Fig. 6) and had found that the prevalence of H. pylori infection in PBC and viral cirrhosis was significantly elevated compared with control (OR = 1.75, 95% CI: 1.15–2.64, P = 0.147 and OR = 2.66, 95% CI: 1.24–5.71, P < 0.0001). In contrast, the prevalence of H. pylori infection in alcohol cirrhosis was not significantly different compared with control (OR = 0.77, 95% CI: 0.04–16.59, P < 0.001).
Subcategory
Number of studies
H. pylori (+ ) in alcoholic cirrhosis group
H. pylori (+ ) in control group
Total Europe Asia America Africa Total
21 10 8 2 1 21
1511/1941 732/1015 293/670 76/166 50/90 1511/1941
2055/4194 1625/3409 397/679 7/40 26/66 2055/4194
2.05 2.98 0.90 4.75 1.92 2.05
(1.33–3.18) (2.02–4.39) (0.48–1.66) (1.42–15.92) (1.01–3.67) (1.33–3.18)
< 0.0001 < 0.0001 < 0.0001 0.249 – < 0.0001
Before 2000 2000–2009 After 2010 Total ELISA RUT RUT/H PCR UBT H
4 12 5 21 11 4 2 2 1 1
269/397 703/1181 179/363 1511/1941 732/998 205/468 131/270 55/136 9/20 19/49
560/1266 1287/2337 208/591 2055/4194 1634/3384 252/441 114/244 1/40 2/10 52/75
1.70 1.87 2.53 2.05 2.71 1.31 1.07 17.31 3.27 0.28
(0.59–4.92) (1.01–3.48) (1.49–4.29) (1.33–3.18) (1.80–4.08) (0.50–3.44) (0.22–5.23) (3.52–92.12) (0.55–19.45) (0.13–0.60)
< 0.0001 < 0.0001 0.116 < 0.0001 < 0.0001 < 0.0001 < 0.0001 0.542 – –
OR (95% CI)
P value
CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; H, histological assessment; H. pylori, Helicobacter pylori; OR, odds ratio; RUT, rapid urea tests; UBT, C-urea breath test.
13
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1314 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 5
References
Total
Europe 453 Ram et al. [24] Shapira et al. [25] 169 Castéra et al. [31] 38 Konturek et al. [33] 125 768 Vergara et al. [6] 717 Pellicano et al. [35] 355 Ponzetto et al. [36] 380 Ponzetto et al. [36] 256 Zullo et al. [38] 1163 Siringo et al. [40] Subtotal (I2= 78.6%, P = 0.000) . America Silva et al. [26] 126 Abdel-Hady et al. [17] 80 Subtotal (I2= 24.7%, P = 0.249) . Asia Chen et al. [27] 50 258 Ibrişim et al. [29] Kim et al. [30] 610 Nam et al. [32] 63 94 Chen et al. [34] 30 Shimamoto et al. [37] Wang et al. [39] 124 Wu et al. [41] 120 Subtotal (I2= 78.8%, P = 0.000) . Africa 156 El-Masry et al. [28] Subtotal . Overall (I2= 89.2%, P = 0.000)
OR (95% CI)
Weight %
1.87 (1.11−3.14) 2.57 (1.36−4.86) 3.93 (0.82−18.81) 4.85 (2.10−11.18) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 2.40 (1.45−3.98) 4.53 (3.05−6.71) 2.98 (2.02−4.39)
5.57 5.36 3.41 4.95 5.80 5.70 4.69 5.42 5.59 5.76 52.24
11.98 (1.55−92.96) 3.27 (1.10−9.67) 4.75 (1.42−15.95)
2.60 4.41 7.01
36.03 (2.00−650.09) 0.48 (0.29−0.79) 0.48 (0.34−0.68) 1.27 (0.46−3.51) 0.69 (0.25−1.91) 3.27 (0.55−19.45) 0.28 (0.13−0.60) 2.45 (1.13−5.33) 0.90 (0.48−1.66)
1.66 5.59 5.82 4.56 4.56 3.02 5.12 5.08 35.41
1.92 (1.01−3.67) 1.92 (1.01−3.67)
5.34 5.34
2.05 (1.33−3.18)
100.00
Note: Weights are from random effects analysis 0.00154
1
650
Subgroup analysis of H. pylori infection according to geographic region. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
investigated the potential relationship between cirrhosis and H. pylori infection through the published evidence in previous studies. The meta-analysis of 21 studies across the globe indicated that the prevalence of H. pylori infection is significantly higher in cirrhosis patients in comparison with controls, which could be explained as follows. First, there was a big difference in the prevalence of H. pylori infection in patients with cirrhosis [25,26]; some authors found that the prevalence of H. pylori infection in cirrhotic patients was significantly higher than that in controls [29,30], whereas others did not. Some studies that enrolled PU or hepatitis patients as controls were excluded to reduce selected bias, and it led to a reduction in the sample size. Second, H. pylori
infection may occur during childhood, and the infection is much less in adulthood [43,44]. Our study did not analyze the subject by age and this may have caused collection bias. Finally, several methods were used to detect H. pylori infection in this study and this may have led to a high level of heterogeneity in this study. Sixteen studies in this meta-analysis showed significant difference in the prevalence of H. pylori infection between cirrhotic patients and controls; five of the studies lacked evidence of difference. This phenomenon could be attributed to the methods selected in the studies, the small sample size, and the rapid clearance of initial infection.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Cirrhosis and H. pylori Feng et al. 1315
Table 3
Subgroup analysis of the prevalence of H. pylori infection in cirrhotic patients with different etiologies versus controls
References
Origin
Etiology
Cirrhosis with H. pylori (+ / − )
Control with H. pylori (+ / − )
Ram et al. [24] Shapira et al. [25] El-Masry et al. [28] Kim et al. [30] Kim et al. [30] Castéra et al. [31] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36] Ponzetto et al. [36] Shimamoto et al. [37] Siringo et al. [40] Siringo et al. [40] Siringo et al. [40] Wu et al. [41]
Israel France Egypt Korea Korea France Italy Italy Italy Italy Japan Italy Italy Italy Taiwan
PBC PBC Viral Viral Alcoholic Viral PBC Viral Viral Viral Viral Viral Alcoholic PBC Viral
37/31 37/32 50/40 74/100 24/85 5/7 78/71 226/28 40/5 54/16 9/11 74/22 11/4 2/0 45/15
150/235 31/69 26/40 201/121 201/121 4/22 291/328 275/188 183/127 183/127 2/8 422/588 422/588 422/588 33/27
H. pylori, Helicobacter pylori; PBC, primary biliary cirrhosis.
Fig. 6
OR (95% CI)
Weight %
Ram et al. [24]
1.87 (1.11−3.14)
7.53
Shapira et al. [25]
2.57 (1.36−4.86)
7.32
Vergara et al. [6]
1.24 (0.87−1.77)
7.76
Siringo et al. [40]
6.96 (0.33−145.44)
2.60
Subtotal (I2 = 44.1%, P = 0.147)
1.75 (1.15−2.64)
25.20
El-Masry et al. [28]
1.92 (1.01−3.67)
7.30
Kim et al. [30]
0.45 (0.31−0.65)
7.74
Castéra et al. [31]
3.93 (0.82−18.81)
5.15
Pellicano et al. [35]
5.52 (3.57−8.52)
7.66
Ponzetto et al. [36]
5.55 (2.13−14.45)
6.62
Ponzetto et al. [36]
2.34 (1.28−4.28)
7.38
Shimamoto et al. [37]
3.27 (0.55−19.45)
4.66
Siringo et al. [40]
4.69 (2.87−7.67)
7.57
Wu et al. [41]
2.45 (1.13−5.33)
7.03
2.66 (1.24−5.71)
61.10
Kim et al. [30]
0.17 (0.10−0.28)
7.55
Siringo et al. [40]
3.83 (1.21−12.12)
6.15
Subtotal (I2 = 95.8%, P = 0.000)
0.77 (0.04−16.59)
13.70
2.08 (1.14−3.77)
100.00
References PBC
. Viral
2 = 92.0%,
Subtotal (I
P = 0.000)
. Alcoholic
. Overall (I2 = 92.6%, P = 0.000) Note: Weights are from random effects analysis 0.00688
1
145
Subgroup analysis of H. pylori infection according to the etiology of cirrhosis. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio; PBC, primary biliary cirrhosis.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1316 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
Fig. 7
References
Total
OR (95% CI)
Weight %
After 2010 Ram et al. [24] Shapira et al. [25] Silva et al. [26]
453 169 126
1.87 (1.11−3.14) 2.57 (1.36−4.86) 11.98 (1.55−92.96) 36.03 (2.00−650.09) 1.92 (1.01−3.67)
5.57 5.36 2.60 1.66 5.34
2.53 (1.49−4.29)
20.53
Chen et al. [27] 50 El-Masry et al. [28] 156 Subtotal (I2 = 46.0%, P = 0.116) . 2000–2009 Ibrişim et al. [29] Kim et al. [30] Abdel-Hady et al. [17] Castéra et al. [31] Nam et al. [32] Konturek et al. [33] Chen et al. [34] Vergara et al. [6] Pellicano et al. [35] Ponzetto et al. [36]
258 610 80 38 63 125 94 768 717 355
Ponzetto et al. [36] 380 Shimamoto et al. [37] 30 Subtotal (I2 = 90.8%, P = 0.000) . Before 2000 Zullo et al. [38] Wang et al. [39] Siringo et al. [40] Wu et al. [41]
256 124 1163 120
Subtotal (I2 = 92.7%, P = 0.000) . Overall (I2 = 89.2%, P = 0.000)
0.48 (0.29−0.79)
5.59
0.48 (0.34−0.68) 3.27 (1.10−9.67)
5.82 4.41
3.93 (0.82−18.81) 1.27 (0.46−3.51) 4.85 (2.10−11.18) 0.69 (0.25−1.91) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 3.27 (0.55−19.45)
3.41 4.56 4.95 4.56 5.80 5.70 4.69 5.42 3.02
1.87 (1.01−3.48)
57.93
2.40 (1.45−3.98)
5.59
0.28 (0.13−0.60) 4.53 (3.05−6.71) 2.45 (1.13−5.33) 1.70 (0.59−4.92)
5.12 5.76 5.08 21.54
2.05 (1.33−3.18)
100.00
Note: Weights are from random effects analysis 0.00154
1
650
Subgroup analysis of H. pylori infection according to publication year. CI, confidence interval; H. pylori, Helicobacter pylori; OR, odds ratio.
Geographical distribution
The prevalence of H. pylori infection ranged from 40 to 55% by geographic region (Asia: 690/1349, 51.15%; Europe: 2357/4424, 53.28%; America: 83/206, 40.29%; Africa 76/156, 48.72%). There was no significant difference in the H. pylori infection rate between cirrhotic patients and controls in Asia. In contrast, in Europe, America, and Africa, H. pylori exposure in patients with cirrhosis was significantly higher. The following reasons may explain the differences: first, almost all negative and unrelated results were concentrated in Asia (6/8); only two unrelated results were seen in Europe. Second, there was a wide range in the data of each region; the study sample size in Europe and Asia was much larger than that of America and Africa. And each set of data came from a different region, with the lack of a global, multicenter
study. There were differences in race, diet, lifestyle, etc, which could have caused the differences in the results. Etiology of cirrhosis distribution
On the basis of the etiology of cirrhosis it was seen that patients with viral cirrhosis and PBC had a higher prevalence of H. pylori infection, compared with those with alcohol cirrhosis. This may be due to two reasons. First, we extracted some data on alcoholic cirrhosis from the literature. Second, some studies that enrolled hepatitis, ulcer or gastritis patients as controls were eliminated for the exclusion criteria. Both led to a small sample size and limited the reliability of the results. Time distribution
The articles on H. pylori infection in cirrhotic patients were concentrated in the decade of 2000–2009. The
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Cirrhosis and H. pylori Feng et al. 1317
Fig. 8
References
Total
ELISA Ram et al. [24] 453 169 Shapira et al. [25] 38 Castéra et al. [31] 125 Konturek et al. [33] 94 Chen et al. [34] Vergara et al. [6] 768 717 Pellicano et al. [35] 355 Ponzetto et al. [36] Ponzetto et al. [36] 380 1163 Siringo et al. [40] Wu et al. [41] 120 Subtotal (I2 = 79.5%, P = 0.000) . H 126 Silva et al. [26] 50 Chen et al. [27] Wang et al. [39] 124 Subtotal (I2 = 91.7%, P = 0.000) . RUT El-Masry et al. [28] 156 Kim et al. [30] 610 Abdel-Hady et al. [17] 80 Nam et al. [32] 63 Subtotal (I2 = 86.8%, P = 0.000) . RUT/H Ibrişim et al. [29] 258 Zullo et al. [38] 256 Subtotal (I2 = 94.9%, P = 0.000) . UBT Shimamoto et al. [37] 30 Subtoal (I2= .%, P= .) . Overall (I2 = 89.2%, P = 0.000)
OR (95% Cl)
Weight %
1.87 (1.11−3.14) 2.57 (1.36−4.86) 3.93 (0.82−18.81) 4.85 (2.10−11.18) 0.69 (0.25−1.91) 1.24 (0.87−1.77) 5.52 (3.57−8.52) 5.55 (2.13−14.45) 2.34 (1.28−4.28) 4.53 (3.05−6.71) 2.45 (1.13−5.33) 2.71 (1.80−4.08)
5.57 5.36 3.41 4.95 4.56 5.80 5.70 4.69 5.42 5.76 5.08 56.29
11.98 (1.55−92.96) 36.03 (2.00−650.09) 0.28 (0.13−0.60) 4.22 (0.11−159.49)
2.60 1.66 5.12 9.38
1.92 (1.01−3.67) 0.48 (0.34−0.68) 3.27 (1.10−9.67) 1.27 (0.46−3.51) 1.31 (0.50−3.44)
5.34 5.82 4.41 4.56 20.13
0.48 (0.29−0.79) 2.40 (1.45−3.98) 1.07 (0.22−5.23)
5.59 5.59 11.18
3.27 (0.55−19.45) 3.27 (0.55−19.45)
3.02 3.02
2.05 (1.33−3.18)
100.00
NOTE:Weights are from random effects analysis .00154
1
650
Subgroup analysis of H. pylori infection according to the detection method. CI, confidence interval; ELISA, enzyme-linked immunosorbent assay; H, histological assessment; H. pylori, Helicobacter pylori; OR, odds ratio; RUT, rapid urea test; UBT, 13C-urea breath test.
prevalence of H. pylori infection in cirrhotic patients was the highest before 2000, but with no significant difference in comparison with controls [39]. This may be due to selection bias, as histological assessment was used to detect the H. pylori infection in these studies. The prevalence was slightly increased between 2000 and 2009, and then significantly increased after 2010. Method of detection
In this meta-analysis, we performed a stratified analysis according to different detection methods, and found that ELISA showed a significantly high prevalence of H. pylori
infection in cirrhotic patients in comparison with controls, compared with other methods. Anti-H. pylori IgG-ELISA is a method of detection based on the presence of serologic anti-H. pylori IgG antibodies in the patient. It is noninvasive, inexpensive, and well suited to primary care practice, which makes it suitable for large-scale population surveys. It is used as the basic serological test in clinics and has been extensively studied. The USA and Europe recommend only H. pylori IgG testing in guidelines [45,46]. Generally, titers of antiH. pylori IgG could decline ∼50% within 3 months of
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1318 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 12
infection, and would show a negative result in 60% of patients at 18 months with eradication therapy [47]. However, there may remain a few patients who test positive after eradication therapy. Consequently, using different methods such as UBT to confirm the result is appropriate. Because the 16S rRNA gene is highly conserved in different species of bacteria (16S rDNA), PCR detection of the 16S rRNA of H. pylori in tissue samples is feasible. Histological assessment involves staining the specimens obtained through endoscopy, which has high sensitivity and specificity [48]. RUT is based on the ammonia produced by H. pylori converting urea. However, as the process of obtaining specimens is invasive, it was unsuitable for large-scale population surveys. UBT is a noninvasive method based on the ammonia and carbon dioxide produced by H. pylori converting urea and has high sensitivity and specificity. However, the discrepancy in UBT protocols across different clinical centers caused differences in breath sample collection times and intervals, as well as effects on delaying gastric emptying, which makes it almost impossible to directly compare UBT results [49]. To date, standard H. pylori diagnostic tests have not been established. The results obtained by the different methods cannot be directly compared. However, more accurate and convenient detection methods can be developed through extensive research. Study limitations
First, the inclusion criteria for controls were strictly restricted to healthy individuals; patients with hepatitis, ulcers, or gastritis were excluded, which led to reduced sample sizes. Second, the literature included in this metaanalysis was limited to studies published and listed on PubMed and Embase before Janurary 2014. Some relevant studies that met the inclusion criteria may have been missed, which may have caused some inherent biases. Third, the diagnosis of cirrhosis in each study varied and lacked follow-up studies, which may cause bias in the null hypothesis. Finally, the included articles did not consider the impact of liver function, Child–Pugh grade, and age, which would cause confounding bias.
the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (JX10231801). Author contributions: Hao Feng and Xiaoying Zhou collected and analyzed the data, and wrote the first draft of the paper. Guoxin Zhang designed the study and proofread the manuscript. Conflicts of interest
There are no conflicts of interest.
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Conclusion
We found that the prevalence of H. pylori infection in cirrhotic patients has increased significantly worldwide, especially in Europe and America, due to viral cirrhosis and PBC, as per the ELISA method. Because of the limitations of the study, large-scale multicenter studies are needed to prove the further association of cirrhosis and H. pylori infection.
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Acknowledgements This work was supported by National Natural Science Foundation of China (No. 81270476 and 81470830) and
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