Rapid Communication
Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Mar 28, 2008; 14(12): 1914-1918
Published online Mar 28, 2008. doi: 10.3748/wjg.14.1914
Effect of H pylori infection and its eradication on hyperammo-nemia and hepatic encephalopathy in cirrhotic patients
Shu-Jie Chen, Liang-Jing Wang, Qin Zhu, Jian-Ting Cai, Tao Chen, Jian-Min Si
Shu-Jie Chen, Qin Zhu, Jian-Min Si, Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, Zhejiang Province, China
Liang-Jing Wang, Jian-Ting Cai, Tao Chen, Department of Gastroenterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
Author contributions: Chen SJ and Wang LJ contributed equally to this work.
Correspondence to: Liang-Jing Wang, Department of Gastro-enterology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China. wanglj2001@tom.com
Telephone: +86-571-86006788
Fax: +86-571-86006788
Received: October 24, 2007
Revised: December 30, 2007
Published online: March 28, 2008

Abstract

AIM: To investigate the relationship between H pylori infection, blood ammonia concentration and hepatic encephalopathy (HE), and the effect of H pylori eradication in cirrhotic patients.

METHODS: From July 2003 to January 2005, 457 cirrhotic patients in five regions of Zhejiang Province were enrolled. Patients were evaluated for demographics, number connection test, H pylori infection, liver impairment, blood ammonia concentration and HE. Patients with H pylori infection were given 1 wk therapy with omeprazole plus clarithromycin and tinidazole. 14C urea breath test was performed and mental symptoms and blood ammonia level were reassessed after bacterium eradication.

RESULTS: Overall H pylori infection rate was 60.6%, and HE occurred in 47.5% of cirrhotic patients. Subclinical HE (SHE) was detected in 55 of 117 cirrhotic patients. Blood ammonia concentration in H pylori negative (n = 180) and positive (n = 277) cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 &mgr;mol/L, respectively (P < 0.01), which was significantly reduced to 53.5 ± 37.7 &mgr;mol/L after bacterium eradication (n = 126) (P < 0.01). Blood ammonia was 97.5 ± 81.0 &mgr;mol/L in H pylori-positive cirrhotic patients, and this did not significantly change in those with persistent infection after H pylori eradication (n = 11). HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). H pylori prevalence significantly differed among cirrhotic patients with HE (74.4%), SHE (69.1%), and those without HE (53.2%) (P < 0.05). Blood ammonia level was significantly different among cirrhotic patients with HE (94.5 ± 75.6 &mgr;mol/L), SHE (59.9 ± 49.2 &mgr;mol/L), and without HE (47.3 ± 33.5 &mgr;mol/L) (P < 0.05). Logistic regression analysis showed that blood ammonia concentration, Child-Pugh stage, upper gastrointestinal bleeding, electrolyte disturbance, and urea nitrogen were risk factors for HE.

CONCLUSION: H pylori infection is an important factor for inducing high blood ammonia concentration and HE in cirrhotic patients. H pylori eradication may be helpful for treatment and prevention of HE.

Key Words: Cirrhosis, Helicobacter Pylori, Hepatic encephalopathy, Hyperammonemia



INTRODUCTION

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis. Although the pathogenesis is unclear, ammonia is one of the key factors involved. Recently, it has been suggested H pylori contributes to hyperammonemia in cirrhosis, and bacterium eradication decreases blood ammonia concentration in these patients[18]. However, the literature contains conflicting data, with several other studies showing ammonia levels do not significantly differ between cirrhotic patients with and without H pylori infection. Ammonia production in the stomach by H pylori urease appears to be inadequate to clinically affect ammonia disposal in the majority of cirrhotic patients[2913]. The possible role of H pylori in the pathogenesis of HE deserves further investigation.

MATERIALS AND METHODS
Subjects

From July 2003 to January 2005, 457 cirrhotic patients in 18 hospitals from five regions of Zhejiang Province in China were enrolled in this prospective study. Diagnosis of liver cirrhosis was carried out by history, clinical examination, laboratory findings, and radiological findings according to the principles established by Chinese Hepatology Association in 2002. The main exclusion criteria included: (1) Severe cardiac, pulmonary, cerebral and renal disorders; (2) severe HE of grades III and IV; (3) currently receiving H pylori eradication therapy; (4) currently undergoing surgery, (5) active gastrointestinal bleeding where non-surgical therapy is ineffective; (6) psychological disorders other than HE; and (7) current alcohol or sedative-drug abuse.

Patients were evaluated for demographic checklists, number connection test (NCT), H pylori infection, liver impairment (according to Child-Pugh classification, including the total score of HE, ascites, prothrombin time, albumin concentration and bilirubin level, which ranked as Child-Pugh class A, B and C), blood ammonia concentration, and HE status. All patients received a low-salt, low-protein diet, and lactulose was given to all patients to induce two to four bowel movements a day. Protein intake was restricted to about 20-40 g daily. One hundred and thirty-seven patients with H pylori infection were given 1 wk eradication therapy. Mental symptoms and blood ammonia levels were reassessed 1 mo after eradication therapy.

Detection of H pylori infection

Gastric specimens were taken from the antrum when performing endoscopic biopsies, which were assessed by rapid urease test, histology (Giemsa staining) or H pylori culture. The presence of H pylori was detected by 14C urea breath test in those who did not undergo biopsy. Subjects who had H pylori were identified by at least one of the above tests showing a positive result.

Ammonia measurement

Fasting venous blood samples were obtained from each patient to measure ammonia concentration (&mgr;mol/L), according to the manufacturer’s instructions.

NCT

The NCT (part A) was performed to detect subclinical HE. Subjects were required to connect numbers printed on paper consecutively from 1 to 25, as quickly as possible. NCT abnormality was defined as taking > 66 s to fulfill this task.

HE stage

HE stage was established by clinical characteristics, electroencephalography (EEG) and NCT results. Patients were classified as cirrhotic without HE, with subclinical HE (SHE), and with HE. SHE was characterized by normal traditional clinical evaluation with definite and quantifiable neuropsychological defects (NCT abnormality).

H pylori eradication therapy

The 137 cirrhotic patients with H pylori infection received 7 d dual eradication therapy (omeparazole 20 mg b.i.d plus clarythromicin 500 mg b.i.d plus tinidazole 500 mg b.i.d). One month after completion of treatment, a 14C-urea breath test was performed to reassess H pylori status.

Statistical analysis

Statistics were calculated using SPSS ver. 11.0. Qualitative variables were expressed by means of frequency and percentiles, and were analyzed using the χ2 test. Quantitative results are expressed as means ± SD. Groups were compared by using Student’s t test or ANOVA. Risk factors for HE were analyzed using logistic multiple regression. Odds ratio (OR) values were calculated from 95% CI, and OR > 1.00 was considered a significant risk factor. Statistical significance was established at P < 0.05.

RESULTS
Effect of H pylori infection on blood ammonia and HE

Overall H pylori infection rate was 60.6% (277/457). There were 137 H pylori-positive patients who received eradication therapy, among whom the eradication rate was 91.4% (126/137). HE occurred in 47.5% of cirrhotic patients (217/457), and SHE was detected in 47.0% (55/117) of those without HE. There was no significant difference in liver impairment (Child-Pugh class), and complications (upper gastrointestinal bleeding, hepatorenal syndrome, and ascites) between H pylori positive and negative groups (Table 1). Blood ammonia concentration in H pylori negative and positive cirrhotic patients was 53.8 ± 51.4 and 78.4 ± 63.6 &mgr;mol/L, respectively (P < 0.01). Blood ammonia was 78.4 ± 63.6 &mgr;mol/L in H pylori-positive cirrhotic patients before treatment (n = 137), and 97.5 ± 81.0 &mgr;mol/L in those with persistent infection after treatment (n = 11). Blood ammonia was significantly reduced to 53.5 ± 37.7 &mgr;mol/L (P < 0.01) in the H pylori eradication group (n = 126). HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). Data are shown in Table 2.

Table 1 Clinical characteristics of H pylori-positive and -negative patients.
H pylori (+)H pylori (-)P value
Sex (male/female)196/81141/390.045
Age (yr)57.6 ± 12.756.9 ± 13.40.604
Child-Pugh class
A/B/C67/124/8655/77/480.309
Upper gastrointestinal155950.263
hemorrhage
Hepatorenal syndrome19110.448
Ascites1971360.208
Table 2 Effect of H pylori infection on blood ammonia concentration and HE.
H pylori infectionnAmmonia concentration (&mgr;mol/L)HE rate
H pylori (–)18053.8 ± 51.4bd55 (30.6%)bd
H pylori (+)27778.4 ± 63.6162 (58.5%)
Eradicated12653.5 ± 37.7bd43 (34.1%)bd
Failed to eradicate1197.5 ± 81.06 (54.5%)
Relationship between HE and H pylori infection and blood ammonia

H pylori prevalence differed significantly between cirrhotic patients with HE (74.4%), those with SHE (69.1%), or without HE (53.2%) (P < 0.05). Blood ammonia level differed significantly between cirrhotic patients with HE (94.5 ± 75.6 &mgr;mol/L), those with SHE (59.9 ± 49.2 &mgr;mol/L), or without HE 47.3 ± 33.5 &mgr;mol/L) (P < 0.05). Liver impairment of Child-Pugh class B and C in patients with HE and SHE were 87.6% and 83.6%, respectively. Child-Pugh class A and B accounted for 88.7% of cirrhotic patients without HE (Table 3).

Table 3 Relationship between HE and H pylori infection and blood ammonia.
HE (n = 217)SHE (n = 55)Cirrhotic (n = 62)P valueχ2
H pylori infection74.4%69.1%53.2%< 0.019.999
Child–Pugh class< 0.0129.154
A/B/C27/100/909/30/1622/33/7
Ammonia94.5 ± 75.6b59.9 ± 49.247.3 ± 33.5
concentration (&mgr;mol/L)
Risk factors for HE

Through logistic multiple regression analysis, we found blood ammonia concentration (P = 0.000, OR = 4.701), Child-Pugh class (P = 0.000, OR = 3.416), H pylori infection (P = 0.007, OR = 2.113), gastrointestinal hemorrhage (P = 0.048, OR = 1.798), electrolyte disturbance (P = 0.045, OR = 1.875), and blood urea nitrogen (P = 0.041, OR = 1.854) were risk factors for HE. Sex, age, ascites, spontaneous bacteria peritonitis infection, hemoglobin, white blood count, platelet count and creatinine were not significantly associated with HE (Table 4).

Table 4 Risk factors for HE analyzed by logistic multiple regression.
P valueOR value95% CI
Sex0.3410.7510.416-1.354
Age0.8810.9590.555-1.657
Etiology0.1251.5640.883-2.769
H pylori infection0.0072.1131.222-3.654
Blood ammonia level0.0004.7012.773-7.970
Child-Pugh class0.0003.4161.823-6.398
Ascites0.2771.3950.765-2.541
Hemorrhage0.0481.7981.004-3.218
Infections0.9341.0270.546-1.932
Electrolyte disturbance0.0451.8571.015-3.398
Leukocyte count0.8401.0560.625-1.782
Hemoglobin0.5921.1920.626-2.270
Platelet count0.4301.2790.694-2.356
Creatinine0.4890.7680.364-1.621
Blood urea nitrogen0.0411.8541.025-3.353
DISCUSSION

Most currently available therapies for prevention of HE focus on reducing blood ammonia concentration[1415]. H pylori is known to produce copious amounts of ammonia due to its strong urease activity. Ammonia produced by H pylori has a role in the pathogenesis of hyperammonemia when this organism is widely distributed and present in large numbers in the stomach, particularly in the presence of liver cirrhosis[1619]. We did not find a significant difference in age, liver impairment and complication rate (upper gastrointestinal bleeding, hepatorenal syndrome and ascites) between H pylori-positive and -negative groups. However, blood ammonia concentration in H pylori-positive patients was significantly higher than that in H pylori-negative patients (P < 0.01). This suggested that H pylori infection was associated with hyperammonemia in cirrhotic patients. It has previously been shown ammonia concentration in portal and venous blood significantly increased after the instillation of 1010 CFU/L H pylori in the stomach of cirrhotic rats[20]. Oral administration of acetohydroxamic acid significantly reduced blood ammonia levels in cirrhotic patients with H pylori infection, compared with those without infection[21]. We have previously reported that ammonia level in portal vein blood of cirrhotic patients with H pylori infection is significantly higher than that in patients without infection[22].

In the present study, HE was more frequently observed in patients with H pylori infection than in those without (58.5% vs 30.6%, P < 0.01), which was consistent with that reported elsewhere[2325].The hypothesis that H pylori infection plays a pathogenic role in HE was initially devised by Gubbins et al[26]. In their study, seroprevalence for H pylori was detected in 78.6% of 117 alcoholic liver disease patients with HE, and in 62% of 71 patients without (P = 0.013). H pylori was detected only by serology, which has been reported to be inaccurate in cirrhotic patients. Therefore, the results of that study should be interpreted with caution. In a study of 55 cirrhotic patients, Dasani et al[17] detected H pylori infection more frequently in those with HE compared with those without (67% vs 33%, P = 0.004). However, conflicting data are available in the literature. Several studies have shown that ammonia levels do not significantly differ between cirrhotic patients with and without H pylori infection, which suggests that although H pylori infection is able to generate ammonia in the stomach, the amount appears to be too small to affect arterial ammonia levels in patients with cirrhosis[291431]. The contribution of ammonia produced by H pylori to HE may depend on the number of bacteria and their distribution in the stomach, gastric pH, gastric membrane permeability to ammonia, liver impairment, and portal vein branch circulation. We suppose H pylori may increase blood ammonia concentration and induce HE when the bacterium is widely distributed in the stomach, and in the presence of severe liver impairment (Child-Pugh class B or C) with abundant portal vein branch circulation. Through logistic multiple regression analysis, we found blood ammonia, Child-Pugh class, upper gastrointestinal bleeding, electrolyte disturbance, and urea nitrogen were significantly associated with HE. Dasani et al[17] have documented that risk factors associated with HE include older age (P = 0.001), lower albumin (P = 0.001), H pylori infection (P = 0.004), greater ascites score (P = 0.01), and greater Child-Pugh class (P = 0.001).

In view of the association of H pylori infection with hyperammonemia and HE, bacterium eradication may theoretically reduce ammonia concentration in cirrhotic patients[272932]. Ito et al[30] initially gave H pylori eradication therapy to cirrhotic patients, and found reduced ammonia concentration and recovery from HE after eradication, without relapse in the following 5 mo. In our study, blood ammonia concentration in H pylori-positive cirrhotic patients was significantly reduced by bacterium eradication (P < 0.01). HE rate significantly dropped to 34.1% after H pylori eradiation (P < 0.01). However, several investigators have questioned whether the effect of eradication therapy on hyperammonemia is due to the non-specific effect of antibiotic therapy on the ammonia-producing gut flora. In Miyaji and Ito’s study[16], all patients were given lactulose, branched-chain enriched amino acid solution, low-protein diet, and kanamycin for 2 wk before H pylori eradication therapy, to reduce the effect of the gut flora on hyperammonemia. The blood ammonia concentration in patients with diffuse distribution of H pylori in the stomach was significantly reduced after bacterium eradication compared with the concentration after conventional treatment to reduce the gut flora. The ammonia concentration at 12 wk after eradication treatment was still significantly lower than that before. Therefore, eradication of H pylori to reduce bacterial ammonia production in the stomach is effective in patients with hyperammonemia with diffuse H pylori infection in the stomach, even after conventional therapy with a low-protein diet, antibiotics, lactulose and branched-chain enriched amino acid solution[11617]. H pylori eradication may be helpful for the treatment and prevention of HE. However, further studies are warranted to evaluate the arguments for and against the role of H pylori in the pathogenesis of HE.

COMMENTS
Background

Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis. Although the pathogenesis is unclear, ammonia is one of the key factors involved. Recently, it has been suggested H pylori contributes to hyperammonemia in cirrhotic patients and bacterium eradication decreases blood ammonia concentration. However, several other studies have shown ammonia levels do not significantly differ between cirrhotic patients with and without H pylori infection. The possible role of H pylori in the pathogenesis of HE merits further investigation.

Research frontiers

Recent research has focused on determining the relationship between H pylori infection, blood ammonia concentration and HE status in prospective and multicenter studies, and on investigating the effect of H pylori eradication on blood ammonia level and HE in cirrhotic patients.

Innovations and breakthroughs

We designed this prospective study to evaluate the effects of H pylori infection and eradication on hyperammonemia and HE in 457 cirrhotic patients in five regions of Zhejiang Province, China. We observed blood ammonia concentration was significantly higher and HE was more frequent in patients with H pylori infection than in those without. Moreover, eradication of H pylori infection resulted in reduction in both blood ammonia concentration and frequency of HE.

Applications

H pylori infection is an important factor for inducing high blood ammonia concentration and HE in cirrhotic patients. H pylori eradication may be helpful for treatment and prevention of HE.

Terminology

SHE is characterized by normal, traditional clinical evaluation with definite and quantifiable neuropsychological defects.

Peer review

This study evaluated the relationship between H pylori infection, blood ammonia concentration and HE, and determined the effect of H pylori eradication on blood ammonia level and HE in cirrhotic patients. This study is of important clinical significance and should be of interest to readers of the journal.

Footnotes

Peer reviewers: Xian-Ming Chen, MD, Associate Professor, Department of Medical Microbiology and Immunology, Creighton University, 2500 California Plaza, Omaha NE 68178, United States; Harry HX Xia, PhD, MD, Novartis Pharmaceuticals Corporation, One Health Plaza, East Hanover, NJ 07936-1080, United States

References
1.  Demirturk L, Yazgan Y, zci O, Ozel M, Togrol E, Gultepe M, Gurbuz AK, Yildirim S. The effect of Helicobacter pylori eradication on gastric juice and blood ammonia concentrations and on visual evoked potentials in cirrhotics. Helicobacter. 2001;6:325-330.  [PubMed]  [DOI]
2.  Zullo A, Hassan C, Morini S. Hepatic encephalopathy and Helicobacter pylori: a critical reappraisal. J Clin Gastroenterol. 2003;37:164-168.  [PubMed]  [DOI]
3.  Queiroz DM, Rocha AM, Rocha GA, Cinque SM, Oliveira AG, Godoy A, Tanno H. Association between Helicobacter pylori infection and cirrhosis in patients with chronic hepatitis C virus. Dig Dis Sci. 2006;51:370-373.  [PubMed]  [DOI]
4.  Shimamoto C, Hirata I, Katsu K. Breath and blood ammonia in liver cirrhosis. Hepatogastroenterology. 2000;47:443-445.  [PubMed]  [DOI]
5.  Nandakumar R, Naik AS, Pandit B, Kamat R, Bhatia SJ. Effect of Helicobacter pylori eradication on serum ammonia levels in patients with chronic liver disease. Indian J Gastroenterol. 2003;22:221-223.  [PubMed]  [DOI]
6.  Lee OJ, Lee EJ, Kim HJ. Correlations among gastric juice pH and ammonia, Helicobacter pylori infection and gastric mucosal histology. Korean J Intern Med. 2004;19:205-212.  [PubMed]  [DOI]
7.  Abdel-Hady H, Zaki A, Badra G, Lotfy M, Selmi C, Giorgini A, El-Sayed M, Badr R. Helicobacter pylori infection in hepatic encephalopathy: Relationship to plasma endotoxins and blood ammonia. Hepatol Res. 2007;37:1026-1033.  [PubMed]  [DOI]
8.  Yang CS, Cao SY, He XJ, Wang YX, Zhang YL. Study of correlation between helicobacter pylori infection and hyperammonemia and hepatic encephalopathy in cirrhotic patients. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2007;19(7):422-424.  [PubMed]  [DOI]
9.  Huber M, Rossle M, Siegerstetter V, Ochs A, Haag K, Kist M, Blum HE. Helicobacter pylori infection does not correlate with plasma ammonia concentration and hepatic encephalopathy in patients with cirrhosis. Hepatogastroenterology. 2001;48:541-544.  [PubMed]  [DOI]
10.  Miquel J, Barcena R, Boixeda D, Fernandez J, SanRoman AL, Martin-de-Argila C, Ramosa F. Role of Helicobacter pylori infection and its eradication in patients with subclinical hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2001;13:1067-1072.  [PubMed]  [DOI]
11.  DuBois S, Eng S, Bhattacharya R, Rulyak S, Hubbard T, Putnam D, Kearney DJ. Breath ammonia testing for diagnosis of hepatic encephalopathy. Dig Dis Sci. 2005;50:1780-1784.  [PubMed]  [DOI]
12.  Zullo A, Sanchez-Mete L, Hassan C, Diana F, Festuccia F, Attili AF, Morini S. Helicobacter pylori density and cagA status in cirrhotic patients: a case-control study. J Gastroenterol Hepatol. 2004;19:1174-1178.  [PubMed]  [DOI]
13.  Calvet X, Nogueras C, Roque M, Sanfeliu I. Helicobacter pylori is not a risk factor for hepatic encephalopathy. Dig Liver Dis. 2001;33:414-419.  [PubMed]  [DOI]
14.  Romero-Gomez M, Grande L, Camacho I, Benitez S, Irles JA, Castro M. Altered response to oral glutamine challenge as prognostic factor for overt episodes in patients with minimal hepatic encephalopathy. J Hepatol. 2002;37:781-787.  [PubMed]  [DOI]
15.  Nam YJ, Kim SJ, Shin WC, Lee JH, Choi WC, Kim KY, Han TH. Gastric pH and Helicobacter pylori infection in patients with liver cirrhosis. Korean J Hepatol. 2004;10:216-222.  [PubMed]  [DOI]
16.  Miyaji H, Ito S, Azuma T, Ito Y, Yamazaki Y, Ohtaki Y, Sato F, Hirai M, Kuriyama M, Kohli Y. Effects of Helicobacter pylori eradication therapy on hyperammonaemia in patients with liver cirrhosis. Gut. 1997;40:726-730.  [PubMed]  [DOI]
17.  Dasani BM, Sigal SH, Lieber CS. Analysis of risk factors for chronic hepatic encephalopathy: the role of Helicobacter pylori infection. Am J Gastroenterol. 1998;93:726-731.  [PubMed]  [DOI]
18.  Seckin Y, Harputluoglu MM, Batcioglu K, Karincaoglu M, Yildirim B, Oner RI, Uyumlu B, Aydogdu N, Hilmioglu F. Gastric tissue oxidative changes in portal hypertension and cirrhosis. Dig Dis Sci. 2007;52:1154-1158.  [PubMed]  [DOI]
19.  Cylwik B, Dlugosz JW, Kemona A, Szmitkowski M. The effect of intragastric ammonia production on titratable gastric acid output in Helicobacter pylori-infected patients with chronic gastritis. Dig Dis Sci. 2005;50:2094-2099.  [PubMed]  [DOI]
20.  Suto H, Azuma T, Ito S, Ohtani M, Dojo M, Ito Y, Kohli Y, Kuriyama M. Helicobacter pylori infection induces hyperammonaemia in Mongolian gerbils with liver cirrhosis. Gut. 2001;48:605-608.  [PubMed]  [DOI]
21.  Zullo A, Rinaldi V, Hassan C, Folino S, Winn S, Pinto G, Attili AF. Helicobacter pylori and plasma ammonia levels in cirrhotics: role of urease inhibition by acetohydroxamic acid. Ital J Gastroenterol Hepatol. 1998;30:405-409.  [PubMed]  [DOI]
22.  Si J, Cao Q, Gao M, Fang L, Qian G, Wang Y. Changes in serum ammonia concentration in cirrhotic patients with Helicobacter pylori infection. Chin Med J (Engl). 2000;113:1080-1081.  [PubMed]  [DOI]
23.  Abdel-Hady H, Zaki A, Badra G, Lotfy M, Selmi C, Giorgini A, El-Sayed M, Badr R. Helicobacter pylori infection in hepatic encephalopathy: Relationship to plasma endotoxins and blood ammonia. Hepatol Res. 2007;37:1026-1033.  [PubMed]  [DOI]
24.  Scotiniotis IA, Lucey MR, Metz DC. Helicobacter pylori infection is not associated with subclinical hepatic encephalo-pathy in stable cirrhotic patients. Dig Dis Sci. 2001;46:2744-2751.  [PubMed]  [DOI]
25.  Zullo A, Rinaldi V, Meddi P, Hassan C, Winn S, Attili AF. Helicobacter pylori infection, plasma ammonia levels, and psychometric testing in cirrhotic patients. Am J Gastroenterol. 1999;94:2214-2218.  [PubMed]  [DOI]
26.  Gubbins GP, Moritz TE, Marsano LS, Talwalkar R, McClain CJ, Mendenhall CL. Helicobacter pylori is a risk factor for hepatic encephalopathy in acute alcoholic hepatitis: the ammonia hypothesis revisited. The Veterans Administration Cooperative Study Group No. 275. Am J Gastroenterol. 1993;88:1906-1910.  [PubMed]  [DOI]
27.  Udayakumar N, Subramaniam K, Umashankar L, Verghese J, Jayanthi V. Predictors of mortality in hepatic encephalopathy in acute and chronic liver disease: a preliminary observation. J Clin Gastroenterol. 2007;41:922-926.  [PubMed]  [DOI]
28.  Hong L, Zhao Y, Han Y, Guo W, Wang J, Li X, Han Y, Fan D. Reversal of migraine symptoms by Helicobacter pylori eradication therapy in patients with hepatitis-B-related liver cirrhosis. Helicobacter. 2007;12:306-308.  [PubMed]  [DOI]
29.  Chakrabarti P, Zullo A, Hassan C, Pandit A, Chowdhury A, Santra A, Hazra B, Morini S, Roy T. Helicobacter pylori, gastric juice, and arterial ammonia levels in patients with cirrhosis. J Clin Gastroenterol. 2002;34:578-581.  [PubMed]  [DOI]
30.  Ito S, Miyaji H, Azuma T, Li Y, Ito Y, Kato T, Kohli Y, Kuriyama M. Hyperammonaemia and Helicobacter pylori. Lancet. 1995;346:124-125.  [PubMed]  [DOI]
31.  Scotiniotis IA, Lucey MR, Metz DC. Helicobacter pylori infection is not associated with subclinical hepatic encephalopathy in stable cirrhotic patients. Dig Dis Sci. 2001;46:2744-2751.  [PubMed]  [DOI]
32.  Demirturk L, Yazgan Y, zci O, Ozel M, Togrol E, Gultepe M, Gurbuz AK, Yildirim S. The effect of Helicobacter pylori eradication on gastric juice and blood ammonia concentrations and on visual evoked potentials in cirrhotics. Helicobacter. 2001;6:325-330.  [PubMed]  [DOI]