Clinics and Research in Hepatology and Gastroenterology (2013) 37, 619—625

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ORIGINAL ARTICLE

Association of Helicobacter pylori infection withhepatic encephalopathy risk: A systematic review

Bang-Li Hu1, Hong-Yu Wang1, Guang-Ye Yang ∗

Guangxi Medical Information Institute, Dong-Ge Road 20-7, Nanning 530022, Guangxi, PR China

Available online 2 July 2013

SummaryBackground: The role of Helicobacter pylori (H. pylori) in the pathogenesis of hepatic encepha-lopathy (HE) is still under debate. We reviewed the available evidence for a pathogenic role ofH. pylori infection in determining HE in cirrhotic patients.Methods: We searched PubMed, EMBASE, and Cochrane Library prior to 2012 for studies thatexplored the role of H. pylori in HE pathogenesis.Results: Twenty studies were eligible for our analysis. Eleven studies investigated the epidemi-ology of H. pylori infection; there is evidence suggesting that the prevalence of H. pylori ishigher in older HE patients. The evidence of nine studies failed to find that blood ammonialevel was higher in H. pylori positive cirrhotic patients than in negative patients. Four studiessuggested that gastric ammonia level was higher in H. pylori positive than H. pylori negativepatients. Eleven studies investigated the effect of H. pylori eradication on the change of bloodammonia levels and the HE improvement. No new reliable evidence was found to support theeffect of H. pylori eradication in reducing blood ammonia levels and improving HE symptoms.Conclusions: Current evidence confirmed the higher prevalence of H. pylori infection in HE

patients. However, no new evidence supported the effect of H. pylori on the increased of bloodammonia level, nor the efficacy of H. pylori eradication in decreasing of blood ammonia leveland improving HE.© 2013 Elsevier Masson SAS. Tous droits réservés.

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Introduction

Hepatic encephalopathy (HE) is a frequent complicationof liver cirrhosis and manifests itself as a wide variety ofneuropsychiatric signs and symptoms [1]. The pathogenic

∗ Corresponding author. Tel.: +86 13607864961;fax: +86 07715867794.

E-mail address: 1808819416@qq.com (G.-Y. Yang).1 Contributed equally to the manuscript.

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2210-7401/$ – see front matter © 2013 Elsevier Masson SAS. All rights rehttp://dx.doi.org/10.1016/j.clinre.2013.05.004

echanisms leading to HE remain unclear, however, plasmaevels of nitrogenous metabolites, in particular ammonia,ither exogenous or endogenous, appear to precipitate HEnset in the presence of specific conditions [2]. Previ-usly, studies have found that Helicobacter pylori (H. pylori)ontributes to hyperammonemia in cirrhosis, and the erad-cation of H. pylori may reduce the blood ammonia [3—6].

owever, other studies failed to find that ammonia levelsignificantly differ between cirrhotic patients with and with-ut H. pylori infection, suggesting that although H. pylorinfection is able to generate ammonia in the stomach, the

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mount appears to be too small to affect blood ammonia lev-ls [7,8]. Some studies claimed that the effect of H. pylorin HE via ammonia production was depending on several fac-ors, such as the number of bacteria and their distribution inhe stomach, gastric membrane permeability to ammonia,nd degree of liver impairment [3,9,10].

Previously, Zullo et al. [11] reviewed the published stud-es that explored the role of H. pylori in HE pathogenesisefore the year 2003. Data of their study indicated thatmmonia production in the stomach by H. pylori ureaseppears to be inadequate to clinically affect ammonia dis-osal in the majority of cirrhotic patients. Since that time,ore studies were conducted to investigate the associa-

ion between H. pylori and HE pathogenesis. We thereforeerformed an update systematic review, by adding stud-es published up until now, to further evaluate the rolef H. pylori in HE pathogenesis, and the effect of H. pyloriradication on HE.

ethods

n order to find all the studies which examined thessociation between H. pylori infection and the risk ofE, we conducted a systematic search on PubMed,MBASE, Cochrane Library, Google scholar, and Chineseational Knowledge Infrastructure (CNKI) prior to May, 2012.he search included the following terms: ‘‘Helicobacterylori’’, ‘‘Ammonia’’ and ‘‘Hepatic encephalopathy’’ with-ut restriction on language or publication status. Weearched the references of all retrieved publications againo trace additional relevant studies. Moreover, the relevanteview articles and their references were checked as well.otentially relevant articles were then screened by at leastwo independent reviewers.

nclusion and exclusion criteria

tudies were eligible if they met the following criteria:tudies have examined the associations between H. pylorinfection and the risk of HE; studies were of observationalesign. In cases of multiple publications of the same or over-apping cohort, only the studies with the largest sample sizeere included. Studies were excluded if: studies were lab-ratory studies, review articles, animal studies; sufficientata were not reported or the related information could note obtained by contacting authors.

ata extraction and quality assessment

wo authors independently conducted data extraction. Theiscrepancy in data extraction was resolved by repeatinghe study review and discussion. The following data werextracted: the first author’s name, patients’ demographics,iagnosis methods of H. pylori infection and HE, etiology ofirrhosis. The quality of included studies was assessed byystematic Appraisal of Quality for Observational Research

SAQOR) criteria [12]. The instrument recorded the fol-owing five criteria: the sample is representative of theopulation from which it was drawn; the source of the sam-le is clearly stated; the sampling method is described; the

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B.-L. Hu et al.

ample size is appropriate to determine statistical signifi-ance for primary outcomes; entry criteria and exclusionsre stated and justified.

esults

he primary literature search retrieved 68 studies that wereonsidered eligible to the analysis. After detailed eval-ation, 48 studies were excluded. The reasons for theirxclusion were: 43 studies were either laboratory studies,eview articles, or irrelevant to the current analysis; in fourtudies the original data could not be obtained after con-acting the authors; one study was duplicated with anothertudy. Consequently, 20 studies [3,7,9,10,13—28] involving148 cirrhotic patients were finally included in the presentystematic review.

haracteristics and quality assessment of studies

he HE type included overt HE and subclinical HE (SHE) orinimal HE (MHE). Most studies used psychometric tests

o detect HE or SHE, however, three studies [15,19,27]sed only clinical examination. All but one study recruitedirrhotic patients of mixed aetiology, mainly chronic viralepatitis B and C and alcohol abuse among several factors;ne study [15] included only patients with alcoholic liver cir-hosis; rapid urease test, histology detection and 14C ureareath test were the commonly used methods for diagnos-ng H. pylori infection. Additional patient demographics ofach included studies were listed in Table 1. The qualityssessment of the included studies was presented in Table 2.

pidemiological studies

ine prospective studies [13,15—22], one cross-sectionaltudy [24] and one case-control study [27] investigatedhe association of H. pylori infection and HE. Eight studies15—18,20—22,27] investigated the association by calculat-ng the rate of H. pylori infection in HE and non-HE patients,he other four studies [13,19,24] by calculating the ratef HE in H. pylori positive and negative patients. The Palue of four studies [15,17,19,22] has been adjusted byonfounding variables. Four studies [13,18,19,27] failed tond the association between H. pylori infection and HE, butther six studies found the existence of such associationTables 3 and 4).

lood and gastric ammonia level

leven studies [7,9,14,16—18,20,22,23,25,28] investigatedhe blood and gastric ammonia level between H. pylori posi-ive and negative patients. Three studies [17,20,22] showedhat blood ammonia level in H. pylori positive was signifi-antly higher than in H. pylori negative patients, whereas

ix studies [7,9,14,23,25,28] did not find any significant dif-erence. Two studies [9,18] showed a correlation betweenncreased gastric ammonia level and H. pylori infection,hereas two other studies [16,23] did not (Table 5).

H.

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HE

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Table 1 Characteristic of included studies.

Study Year/Country

Studydesign

Cirrhoticpatients (n)

Malen (%)

Age(yrs)

Child-Pughclass B/Cn (%)

HE type(n)

Diagnosisof HE

Etiologyofcirrhosis

H. pyloritest

Agrawal A [20] 2011/India Prospective 65 55 (84.6) 35.7 27 (79.4) MHE FCT, NCT HCV, HBV, alcohol,others

R

Chen SJ [17] 2008/China Prospective 457 337 (73.7) 57.6 335 (73.3) HE/SHE NCT, EEG HCV, HBV, alcohol,others

R + H + 14C

Shavakhi A [26] 2008/Iran Cross-sectional 42 16 (38.1) 48 NA HE FCT, NCT HBV, HCV IgGAbdel-Hady H [21] 2007/Egypt Prospective 60 33 (55) 48 40 (66.7) HE Clinical

examination,NCT, EEG

HCV, schistosoma,HBV

R + IgG

Rekha C [28] 2007/India Prospective 47 35 (76.1) 40 24 (52.2) SHE NCT, EEG NA RYang CS [22] 2007/China Prospective 368 266 (72.3) 56.4 281 (76.4) HE/SHE NCT, EEG HCV, HBV, alcohol,

othersR + H + 14C + IgG

Nam YJ [23] 2004/Korea Case-control 29 NA 51 22 (81.5) NA NCT HBV, alcohol, HCV RSethar GH [24] 2004/Pakistan Cross-sectional 76 48 (63.2) 17—85 73 (96.1) HE NA HBV, HCV IgGChakrabarti P [18] 2002/India and

ItalyProspective 46 39 (60.0) 59 29 (87.9) HE/SHE NCT HBV, HCV, alcohol,

Wilson disease,cryptogenic

R + H

Calvet X [19] 2001/Spain Prospective 205 135 (65.9) 55 NA HE Clinicalexamination

HCV, alcohol, others IgG

Demiturk L [3] 2001/Turkey Prospective 27 27 (100) 57 22 (59.5) SHE Visual evokedpotentials

HCV, HBV,schistosoma

R + H

Kini D [14] 2001/India Prospective 58 54 (93.1) 35.5 28 (48.3) HE/SHE FCT, NCT Alcohol, HCV, HBV,HBV & HCV, others

R + H + 14C

Miquel J [7] 2001/Spain Prospective 37 28 (75.7) 59 35 (94.6) SHE NCT, EEG Alcohol, HCV, HBV,others

14C

Scotiniotis IA [13] 2001/USA Prospective 69 47 (68.1) 49 25 (36.2) SHE CPT, NCT, EEG HCV, HBV, Alcohol,others

14C

Shrimali L [27] 2001/India Case-control 75 NA NA NA HE Clinicalexamination

Alcohol, others IgG

Vásconez C [25] 1999/USA Prospective 62 36 (58) 61 14 (21.9) HE/SHE FCT, NCT, EEG HCV, HBV, alcohol 14CZullo A [10] 1999/Italy Prospective 47 30 (39.0) 62.9 7 (33.3) HE/SHE NCT, DST HBV, alcohol, HCV,

cryptogenicR + H

Dasani BM [16] 1998/USA Prospective 55 55 (100) 61.1 NA HE NCT Alcohol, cryptogenic,HBV, HCV

R + H

Miyaji H [9] 1997/Japan Prospective 50 31 (62.0) 63.3 31 (62.0) NA NA NA HGubbins GP [15] 1993/USA Prospective 273 273 (100) 51 NA HE Clinical

examinationAlcohol IgG

HE: hepatic encephalopathy; SHE: subclinical hepatic encephalopathy; NA: not available; R: rapid urease test; H: histology staining and culture; 14C: 14C urea breath test; IgG: IgGantibodies; EEG: electroencephalogram; NCT: number connection test; DST: digit symbol test; FCT: figure connection test.

622 B.-L. Hu et al.

Table 2 Quality assessment according to SAQOR criteria.

Authors The sample isrepresentative of thepopulation fromwhich it was drawn

The source ofthe sample isclearly stated

The samplingmethod isdescribed

The sample size is appropriateto determine statisticalsignificance for primaryoutcomes

Entry criteriaand exclusionsare stated andjustified

Agrawal A [20] Yes Yes Yes Yes YesChen SJ [17] NA Yes Yes Yes NAShavakhi A [26] Yes Yes Yes NA YesAbdel-Hady H [21] NA NA Yes Yes NARekha C [28] Yes Yes Yes Yes YesYang CS [22] Yes Yes Yes Yes YesNam YJ [23] Yes Yes Yes Yes YesSethar GH [24] Yes Yes Yes Yes YesChakrabarti P [18] Yes Yes Yes Yes YesCalvet X [19] Yes Yes No Yes YesDemiturk L [3] Yes Yes Yes NA YesKini D [14] Yes Yes Yes Yes YesMiquel J [7] Yes Yes Yes NA YesScotiniotis IA [13] Yes Yes Yes Yes YesShrimali L [27] NA Yes No Yes YesVásconez C [25] Yes Yes Yes Yes YesZullo A [10] Yes Yes Yes NA YesDasani BM [16] Yes Yes Yes Yes YesMiyaji H [9] NA Yes Yes Yes YesGubbins GP [15] No Yes No Yes Yes

Table 3 Prevalence of H. pylori in hepatic encephalopathy (HE) and non-HE patients.

Study HE, n (%) Non-HE, n (%) OR (95% CI) P value

Agrawal A [20] 22 (63) 12 (37) 2.92 (0.95—9.09) < 0.01Chen SJ [17] 161 (74.4) 33 (53.2) 2.113 (1.222—3.654) 0.007*

Yang CS [22] 154 (81.5) 50 (53.9) NA < 0.05*

Abdel-Hady H [21] 29 (74) 6 (29) 7.25 (1.93—28.72) < 0.01Chakrabarti P [18] 5 (33) 4 (29.4) 2.39 (0.39—25.69) > 0.05Shrimali L [27] 39 (78) 14 (56) 2.78 (0.86—8.85) 0.048Dasani BM [16] 27 (67) 5 (33) 7.02 (1.72—30.92) 0.002Gubbins GP [15] 92 (76.8) 44 (62) 2.4 (1.2—4.8) < 0.01*

* P value was calculated from logistic regression.

Table 4 Prevalence of hepatic encephalopathy (HE) in H. pylori positive and negative patients.

Study H. pylori (+), n (%) H. pylori (−), n (%) P value

Sethar GH [24] 59 (77.6) 17 (22.4) < 0.01Calvet X [19] 26 (22) 13 (12) > 0.05*

Scotiniotis IA [13] 5 (36) 22 (40) 0.769

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* P value from logistic regression analysis.

ffect of H. pylori eradication

ive studies [7,9,17,20,22] showed that blood ammonia

evel was significantly reduced after H. pylori eradication,hree studies [3,10,25] failed to show significant reduction.our studies [7,10,13,25] showed that the number con-ection test (NCT) was significantly improved; the other

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ix studies [3,9,16,20,22,26] failed to find any significanthange (Table 6).

iscussion

ubbins et al. [15] initially investigated the role of H. pylorinfection in the pathogenesis of HE and found that H. pylori

H. pylori and HE 623

Table 5 Blood and gastric ammonia level of H. pylori positive and negative patients.

Study Patients (+/−) Blood ammonia level P value Patients (+/−) Gastric ammonia level P value

H. pylori (+) H. pylori (−) H. pylori (+) H. pylori (−)

Agrawal A [20] 22/12 1.80 ± 0.34 1.39 ± 0.14 < 0.01 NA NA NA —Chen SJ [17] 277/180 78.4 ± 63.6 53.8 ± 51.4 < 0.01 NA NA NA —Yang CS [22] 258/110 79.3 ± 61.8 52.7 ± 49.8 < 0.01 NA NA NA —Nam YJ [23] 12/7 51.8 ± 23.6 82.6 ± 51.9 > 0.05 15/5 3.8 ± 2.1 2.0 ± 0.9 > 0.05Chakrabarti P [18] 10/36 37.7 ± 18.6 37.6 ± 18.8 > 0.05 10/36 2.3 ± 1.9 0.9 ± 0.6 < 0.01Miquel J [7] 22/37 62.05 ± 33 62.5 ± 33 > 0.05 NA NA NA —Kini D [14] 31/27 29 (18—47) 34 (15—48) > 0.05 NA NA NA —Vásconez C [25] 30/32 47 ± 24 43 ± 22 > 0.05 NA NA NA —Rekha C [28] 23/24 56.75 61.04 > 0.05 NA NA NA —Dasani BM [16] NA NA NA — 13/4 4.9 ± 0.4 2.9 ± 0.5 0.05

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infection was an independent risk factor for HE. However,this result was subject to some limitations, such as the sin-gle etiology (only alcohol abusers) of cirrhosis and the singledetective method (only by serology) of H. pylori infection[29,30]. Recently, two large studies [17,22] reported thatH. pylori infection was associated with HE, their results havebeen calculated from multivariate regression by adjustingconfounding variables, in addition, they included cirrhoticpatients of various aetiology and the diagnosis of H. pyloriinfection was made with accurate direct detection methods.Although three early studies [13,18,19] initially failed tofind an association between H. pylori infection and the pres-ence of HE, this was shown to exist by later investigations.However, the mean age of cirrhotic patients in those stud-ies was over 60 years. In a study including younger patients[11], H. pylori infection was independently associated withHE only in patients with decompensated cirrhosis youngerthan 60 years of age.

Hyperammonemia blood ammonia plays an essential role

in the pathogenesis of HE, and treatment or preventionrelies on dietary or pharmacological strategies that lowerblood ammonia levels [2]. The mechanism of H. pyloriinfection leads to hyperammonemia and aggravates HE via

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Table 6 Change of ammonia and number connection test (NCT) b

Study Patients Blood ammonia level

Before After

Agrawal A [20] 22 1.8 ± 0.34 1.18 ± 0.27

Chen SJ [17] 277 78.4 ± 63.6 53.5 ± 37.7

Shavakhi A [26] 30 NA NA

Yang CS [22] 258 79.3 ± 61.8 52.6 ± 36.5

Demiturk L [3] 27 44 ± 19 41 ± 20

Miquel J [7] 22 62.05 ± 33 52.37 ± 29

Scotiniotis IA [13] 4 NA NA

Zullo A [10] 21 81 ± 33 80 ± 19

Vásconez C [25] 32 47 ± 24 48 ± 26

Dasani BM [16] 14 NA NA

Miyaji H [9] 18 89 ± 28 17 ± 11

a Number and rate of HE.

12/20 5.9 ± 2.5 1.6 ± 0.4 < 0.05

hanging urease activity or serum zinc level [17,31,32]. Therease activity of H. pylori is many times more potent thanhat of enterobacteria [33,34]. H. pylori urease hydrolyzesrea present in the gastric juice into ammonia and carbonioxide, and the amount of ammonia produced in the gas-ric mucosa could increase blood ammonia levels in cirrhoticatients, due to the severe impairment of liver function,nd the reduction of blood ammonia levels by anti-H. pylorireatment can improve the symptoms of HE [35,36].

Nam et al. [23] showed that the gastric ammonia levelas higher in H. pylori infection cirrhotic patients than

hose without infection, however, this study was case-ontrol design of just 19 cirrhotic patients. However, otherhree prospective studies [9,16,18] enrolled more cir-hotic patients to further confirm the association betweenlevated gastric ammonia level and H. pylori infection.herefore, we supposed that the presence of H. pylori infec-ion will increase the gastric ammonia level. In regard tohe blood ammonia level, in the three positive studies

17,20,22], over 70% of the patients belonged to the B/Child-Pugh’s classes, whereas in the five negative studies7,14,18,23,25], only 30% belonged to those advanced Child-ugh’s classes. These evidences suggest that liver function

efore and after H. pylori eradication.

P value NCT P value

Before After

< 0.01 86 ± 15 75 ± 15 < 0.01< 0.01 NA NA —— 2.06 ± 0.9 0.52 ± 0.59 0.038< 0.01 154 (59.6%)a 51 (32.8)a < 0.01> 0.05 NA NA < 0.05< 0.01 71 ± 26 69 ± 32 > 0.05— 38 ± 2 43 ± 6 > 0.05> 0.05 55 ± 26 52 ± 20 > 0.05> 0.05 2.2 ± 1.2 2.3 ± 1.2 > 0.05— 62 ± 8 46 ± 4 0.011< 0.01 NA NA 0.001

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emains the main determinant of HE even in patients with. pylori infection. However, the results should be inter-reted with caution, because other potential confoundingactors were not presented in the studies, making it a ques-ionable comparison between their results.

In view of the association of H. pylori infection withyperammonemia and HE, bacterium eradication may, inheory, reduce ammonia level in cirrhotic patients. In theresent study, successful H. pylori eradication was achievedn the great majority of the cirrhotic patients treated in alltudies attempting to correlate eradication with a reduc-ion in HE severity (data not shown). However, three studies3,10,25] failed to show that the blood ammonia level wasignificantly reduced, and four studies [7,10,13,25] did nothow that the NCT value improved after H. pylori eradica-ion. In the Yang et al. [22] study, the blood ammonia levelas reduced and the NCT was improved significantly after. pylori eradication. On the contrary, the Vásconez et al.

25] study showed that neither blood ammonia level norhe NCT was changed significantly. In addition, Demiturkt al. [3] showed a significant reduction of blood ammo-ia levels, but no significant improvement in visual evokedotentials recordings occurred. These results do not sup-ort the hypothesis that H. pylori eradication would helpmproving HE. The effect of eradication of H. pylori on bloodmmonia is likely to be non-specific, perhaps due to antibi-tic therapy rather than an effect of the eradication ofhe organism. Furthermore, another factor, such as proteinntake with the diet, seems to be the main determinantffecting blood ammonia level after H. pylori eradication. Inrder to provide a reliable assessment of this effect, a largeandomized controlled trial would certainly be of great help;eanwhile there is no evidence for using different criteria

or searching and eradicating H. pylori infection in cirrhoticatients compared to the general population.

Since the last systematic review on the subject, our paperas included eight new published studies [14,17,20—24,27]n an attempt to give a state-of-the-art view that mayuide further investigations. We have found that the lim-tations highlighted by the earlier review are still there.irst, no randomized controlled studies have yet beenarried out, thus making unreliable any attempt to a meta-nalysis approach of the available results. Second, theaseline characteristics of cirrhotic patients are hetero-eneous across the studies, such as the age, Child-Pughlass and gender, thus making any comparison difficulto interpret. Third, HE was diagnosed solely accord-ng to clinical findings in three studies [15,19,27] and. pylori infection was determined according to a positiveerology in five studies [15,19,24,26,27] thus, the diag-ostic accuracy of both conditions may not be optimaln these studies due to the intrinsic limitations of theethods. Therefore, well-designed prospective randomized

ontrolled studies are warranted in order to provide a morerecise estimation by taking potential confounders intoccount.

In conclusion, the present systematic review provided annsight on the currently available evidence. The prevalence

f H. pylori infection was higher in HE patients than non-HEatients, particular the older patients. However, there areo strong evidences for an effect of H. pylori on increasinglood ammonia level, nor there is strong evidence to support

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B.-L. Hu et al.

he hypothesis that H. pylori eradication can reduce bloodmmonia level and improve HE symptoms.

isclosure of interest

he authors declare that they have no conflicts of interestoncerning this article.

Source of funding: this study was supported by Guangxicientific research and technology development programNo. 01-108-18).

cknowledgements

his work benefitted from the helpful comments of thenonymous reviewers.

eferences

[1] Amodio P, Montagnese S, Gatta A, Morgan MY. Character-istics of minimal hepatic encephalopathy. Metab Brain Dis2004;19:253—67.

[2] Riordan SM, Williams R. Treatment of hepatic encephalopathy.N Engl J Med 1997;337:473—9.

[3] Demirturk L, Yazgan Y, zci O, Ozel M, Togrol E, Gultepe M,et al. The effect of Helicobacter pylori eradication on gastricjuice and blood ammonia concentrations and on visual evokedpotentials in cirrhotics. Helicobacter 2001;6:325—30.

[4] Queiroz DM, Rocha AM, Rocha GA, Cinque SM, Oliveira AG,Godoy A, et al. Association between Helicobacter pylori infec-tion and cirrhosis in patients with chronic hepatitis C virus. DigDis Sci 2006;51:370—3.

[5] Shimamoto C, Hirata I, Katsu K. Breath and blood ammonia inliver cirrhosis. Hepatogastroenterology 2000;47:443—5.

[6] Nandakumar R, Naik AS, Pandit B, Kamat R, Bhatia SJ. Effectof Helicobacter pylori eradication on serum ammonia levelsin patients with chronic liver disease. Indian J Gastroenterol2003;22:221—3.

[7] Miquel J, Barcena R, Boixeda D, Fernandez J, SanRoman AL,Martin-de-Argila C, et al. Role of Helicobacter pylori infectionand its eradication in patients with subclinical hepatic ence-phalopathy. Eur J Gastroenterol Hepatol 2001;13:1067—72.

[8] Huber M, Rossle M, Siegerstetter V, Ochs A, Haag K, KistM, et al. Helicobacter pylori infection does not correlatewith plasma ammonia concentration and hepatic encepha-lopathy in patients with cirrhosis. Hepatogastroenterology2001;48:541—4.

[9] Miyaji H, Ito S, Azuma T, Ito Y, Yamazaki Y, Ohtaki Y, et al.Effects of Helicobacter pylori eradication therapy on hyperam-monaemia in patients with liver cirrhosis. Gut 1997;40:726—30.

10] Zullo A, Rinaldi V, Meddi P, Hassan C, Winn S, Attili AF.Helicobacter pylori infection, plasma ammonia levels, and psy-chometric testing in cirrhotic patients. Am J Gastroenterol1999;94:2214—8.

11] Zullo A, Hassan C, Morini S. Hepatic encephalopathy and Heli-cobacter pylori: a critical reappraisal. J Clin Gastroenterol2003;37:164—8.

12] Ross LE, Grigoriadis S, Mamisashvili L, Koren G, Steiner M, Den-nis CL, et al. Quality assessment of observational studies inpsychiatry: an example from perinatal psychiatric research. IntJ Methods Psychiatr Res 2011;20:224—34.

13] Scotiniotis IA, Lucey MR, Metz DC. Helicobacter pylori infection

is not associated with subclinical hepatic encephalopathy instable cirrhotic patients. Dig Dis Sci 2001;46:2744—51.

14] Kini D, Aggarwal R, Saraswat VA, Naik SR. Role of Helicobacterpylori infection in hyperammonemia and subclinical hepatic

[

[

[

[

[

[

[

[

[

[

H. pylori and HE

encephalopathy in cirrhosis of liver. Indian J Gastroenterol2001;20:237—40.

[15] Gubbins GP, Moritz TE, Marsano LS, Talwalkar R, McClain CJ,Mendenhall CL. Helicobacter pylori is a risk factor for hepaticencephalopathy in acute alcoholic hepatitis: the ammoniahypothesis revisited. The Veterans Administration Cooper-ative Study Group No. 275. Am J Gastroenterol 1993;88:1906—10.

[16] Dasani BM, Sigal SH, Lieber CS. Analysis of risk factors forchronic hepatic encephalopathy: the role of Helicobacterpylori infection. Am J Gastroenterol 1998;93:726—31.

[17] Chen SJ, Wang LJ, Zhu Q, Cai JT, Chen T, Si JM. Effect ofH. pylori infection and its eradication on hyperammo-nemiaand hepatic encephalopathy in cirrhotic patients. World J Gas-troenterol 2008;14:1914—8.

[18] Chakrabarti P, Zullo A, Hassan C, Pandit A, Chowdhury A,Santra A, et al. Helicobacter pylori, gastric juice, and arterialammonia levels in patients with cirrhosis. J Clin Gastroenterol2002;34:578—81.

[19] Calvet X, Nogueras C, Roque M, Sanfeliu I. Helicobacter pyloriis not a risk factor for hepatic encephalopathy. Dig Liver Dis2001;33:414—9.

[20] Agrawal A, Gupta A, Chandra M, Koowar S. Role of Helicobacterpylori infection in the pathogenesis of minimal hepatic ence-phalopathy and effect of its eradication. Indian J Gastroenterol2011;30:29—32.

[21] Abdel-Hady H, Zaki A, Badra G, Lotfy M, Selmi C, Giorgini A,et al. Helicobacter pylori infection in hepatic encephalopathy:relationship to plasma endotoxins and blood ammonia. HepatolRes 2007;37:1026—33.

[22] Yang CS, Cao SY, He XJ, Wang YX, Zhang YL. [Study ofcorrelation between Helicobacter pylori infection and hyper-ammonemia and hepatic encephalopathy in cirrhotic patients].Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2007;19:422—4.

[23] Nam YJ, Kim SJ, Shin WC, Lee JH, Choi WC, Kim KY, et al.[Gastric pH and Helicobacter pylori infection in patients with

liver cirrhosis]. Korean J Hepatol 2004;10:216—22.

[24] Sethar GH, Ahmed R, Zuberi BF, Afsar S. Frequency of Heli-cobacter pylori antibodies in porto-systemic encephalopathy.J Coll Physicians Surg Pak 2004;14:530—3.

[

[

625

25] Vasconez C, Elizalde JI, Llach J, Gines A, de la Rosa C, Fer-nandez RM, et al. Helicobacter pylori, hyperammonemia andsubclinical portosystemic encephalopathy: effects of eradica-tion. J Hepatol 1999;30:260—4.

26] Shavakhi A, Shariatifar B, Chuloo SA, Minakari M, Somi MH.Effect of Helicobacter pylori eradication on hepatic encepha-lopathy. Hepat Mon 2008;8:121—4.

27] Shrimali L, Chadda VS, Singh VB, Soni PK, Nayak KC, GuptaBK. Study of prevalence of H. pylori in hepatic encephalopathydue to various liver diseases. Indian Acad Clin Med 2001;2:195—7.

28] Rekha C, Phanidhar S, Sagar AV, Revathi A, Asra WA. Role of Heli-cobacter pylori and hyperammonemia in subclinical hepaticencephalopathy in cirrhosis of liver. Indian J Clin Biochem2007;22:136—9.

29] Nardone G, Coscione P, D’Armiento FP, Del Pezzo M, PontilloM, Mossetti G, et al. Cirrhosis negatively affects the efficiencyof serologic diagnosis of Helicobacter pylori infection. Ital JGastroenterol 1996;28:332—6.

30] Taylor-Robinson SD, Jackson N, Buckley C. Helicobacter pylori,ammonia and the brain. Gut 1997;40:805—6.

31] Riggio O, Ariosto F, Merli M, Caschera M, Zullo A, Balducci G,et al. Short-term oral zinc supplementation does not improvechronic hepatic encephalopathy. Results of a double-blindcrossover trial. Dig Dis Sci 1991;36:1204—8.

32] Riggio O, Merli M, Capocaccia L, Caschera M, Zullo A, PintoG, et al. Zinc supplementation reduces blood ammonia andincreases liver ornithine transcarbamylase activity in experi-mental cirrhosis. Hepatology 1992;16:785—9.

33] Dunn BE, Campbell GP, Perez-Perez GI, Blaser MJ. Purificationand characterization of urease from Helicobacter pylori. J BiolChem 1990;265:9464—9.

34] Turbett GR, Nandapalan N, Campbell IG, Nikoletti SM, Mee BJ.Characterisation of the urease from Helicobacter pylori andcomparison with the ureases from related spiral gastric bacte-ria. FEMS Microbiol Immunol 1991;3:19—24.

35] Vilstrup H. Cirrhosis and bacterial infections. Rom J Gastroen-terol 2003;12:297—302.

36] Ponzetto A, Fagoonee S, Pellicano R. Helicobacter pylori andliver: an actor with three roles. Dig Liver Dis 2001;33: 399—401.