Clinics and Research in Hepatology and Gastroenterology (2013) 37, 619625

Available online at
www.sciencedirect.com

ORIGINAL ARTICLE

Association of Helicobacter pylori infection with

hepatic encephalopathy risk: A systematic review
Bang-Li Hu 1, Hong-Yu Wang 1, Guang-Ye Yang
Guangxi Medical Information Institute, Dong-Ge Road 20-7, Nanning 530022, Guangxi, PR China
Available online 2 July 2013

Summary
Background: The role of Helicobacter pylori (H. pylori) in the pathogenesis of hepatic encephalopathy (HE) is still under debate. We reviewed the available evidence for a pathogenic role of
H. pylori infection in determining HE in cirrhotic patients.
Methods: We searched PubMed, EMBASE, and Cochrane Library prior to 2012 for studies that
explored the role of H. pylori in HE pathogenesis.
Results: Twenty studies were eligible for our analysis. Eleven studies investigated the epidemiology of H. pylori infection; there is evidence suggesting that the prevalence of H. pylori is
higher in older HE patients. The evidence of nine studies failed to nd that blood ammonia
level was higher in H. pylori positive cirrhotic patients than in negative patients. Four studies
suggested that gastric ammonia level was higher in H. pylori positive than H. pylori negative
patients. Eleven studies investigated the effect of H. pylori eradication on the change of blood
ammonia levels and the HE improvement. No new reliable evidence was found to support the
effect of H. pylori eradication in reducing blood ammonia levels and improving HE symptoms.
Conclusions: Current evidence conrmed the higher prevalence of H. pylori infection in HE
patients. However, no new evidence supported the effect of H. pylori on the increased of blood
ammonia level, nor the efcacy of H. pylori eradication in decreasing of blood ammonia level
and improving HE.
2013 Elsevier Masson SAS. Tous droits rservs.

Introduction
Hepatic encephalopathy (HE) is a frequent complication
of liver cirrhosis and manifests itself as a wide variety of
neuropsychiatric 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.

mechanisms leading to HE remain unclear, however, plasma

levels of nitrogenous metabolites, in particular ammonia,
either exogenous or endogenous, appear to precipitate HE
onset in the presence of specic conditions [2]. Previously, studies have found that Helicobacter pylori (H. pylori)
contributes to hyperammonemia in cirrhosis, and the eradication of H. pylori may reduce the blood ammonia [36].
However, other studies failed to nd that ammonia levels
signicantly differ between cirrhotic patients with and without H. pylori infection, suggesting that although H. pylori
infection is able to generate ammonia in the stomach, the

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

620
amount appears to be too small to affect blood ammonia levels [7,8]. Some studies claimed that the effect of H. pylori
on HE via ammonia production was depending on several factors, such as the number of bacteria and their distribution in
the stomach, gastric membrane permeability to ammonia,
and degree of liver impairment [3,9,10].
Previously, Zullo et al. [11] reviewed the published studies that explored the role of H. pylori in HE pathogenesis
before the year 2003. Data of their study indicated that
ammonia production in the stomach by H. pylori urease
appears to be inadequate to clinically affect ammonia disposal in the majority of cirrhotic patients. Since that time,
more studies were conducted to investigate the association between H. pylori and HE pathogenesis. We therefore
performed an update systematic review, by adding studies published up until now, to further evaluate the role
of H. pylori in HE pathogenesis, and the effect of H. pylori
eradication on HE.

Methods
In order to nd all the studies which examined the
association between H. pylori infection and the risk of
HE, we conducted a systematic search on PubMed,
EMBASE, Cochrane Library, Google scholar, and Chinese
National Knowledge Infrastructure (CNKI) prior to May, 2012.
The search included the following terms: Helicobacter
pylori, Ammonia and Hepatic encephalopathy without restriction on language or publication status. We
searched the references of all retrieved publications again
to trace additional relevant studies. Moreover, the relevant
review articles and their references were checked as well.
Potentially relevant articles were then screened by at least
two independent reviewers.

B.-L. Hu et al.
sample size is appropriate to determine statistical signicance for primary outcomes; entry criteria and exclusions
are stated and justied.

Results
The primary literature search retrieved 68 studies that were
considered eligible to the analysis. After detailed evaluation, 48 studies were excluded. The reasons for their
exclusion were: 43 studies were either laboratory studies,
review articles, or irrelevant to the current analysis; in four
studies the original data could not be obtained after contacting the authors; one study was duplicated with another
study. Consequently, 20 studies [3,7,9,10,1328] involving
2148 cirrhotic patients were nally included in the present
systematic review.

Characteristics and quality assessment of studies

The HE type included overt HE and subclinical HE (SHE) or
minimal HE (MHE). Most studies used psychometric tests
to detect HE or SHE, however, three studies [15,19,27]
used only clinical examination. All but one study recruited
cirrhotic patients of mixed aetiology, mainly chronic viral
hepatitis B and C and alcohol abuse among several factors;
one study [15] included only patients with alcoholic liver cirrhosis; rapid urease test, histology detection and 14 C urea
breath test were the commonly used methods for diagnosing H. pylori infection. Additional patient demographics of
each included studies were listed in Table 1. The quality
assessment of the included studies was presented in Table 2.

Epidemiological studies
Inclusion and exclusion criteria
Studies were eligible if they met the following criteria:
studies have examined the associations between H. pylori
infection and the risk of HE; studies were of observational
design. In cases of multiple publications of the same or overlapping cohort, only the studies with the largest sample size
were included. Studies were excluded if: studies were laboratory studies, review articles, animal studies; sufcient
data were not reported or the related information could not
be obtained by contacting authors.

Nine prospective studies [13,1522], one cross-sectional

study [24] and one case-control study [27] investigated
the association of H. pylori infection and HE. Eight studies
[1518,2022,27] investigated the association by calculating the rate of H. pylori infection in HE and non-HE patients,
the other four studies [13,19,24] by calculating the rate
of HE in H. pylori positive and negative patients. The P
value of four studies [15,17,19,22] has been adjusted by
confounding variables. Four studies [13,18,19,27] failed to
nd the association between H. pylori infection and HE, but
other six studies found the existence of such association
(Tables 3 and 4).

Data extraction and quality assessment

Two authors independently conducted data extraction. The
discrepancy in data extraction was resolved by repeating
the study review and discussion. The following data were
extracted: the rst authors name, patients demographics,
diagnosis methods of H. pylori infection and HE, etiology of
cirrhosis. The quality of included studies was assessed by
Systematic Appraisal of Quality for Observational Research
(SAQOR) criteria [12]. The instrument recorded the following ve criteria: the sample is representative of the
population from which it was drawn; the source of the sample is clearly stated; the sampling method is described; the

Blood and gastric ammonia level

Eleven studies [7,9,14,1618,20,22,23,25,28] investigated
the blood and gastric ammonia level between H. pylori positive and negative patients. Three studies [17,20,22] showed
that blood ammonia level in H. pylori positive was signicantly higher than in H. pylori negative patients, whereas
six studies [7,9,14,23,25,28] did not nd any signicant difference. Two studies [9,18] showed a correlation between
increased gastric ammonia level and H. pylori infection,
whereas two other studies [16,23] did not (Table 5).

Characteristic of included studies.

Study

Year/
Country

Study
design

Agrawal A [20]

2011/India

Prospective

Chen SJ [17]

2008/China

Prospective

Shavakhi A [26]
2008/Iran
Abdel-Hady H [21] 2007/Egypt

Cross-sectional
Prospective

Rekha C [28]
Yang CS [22]

Prospective
Prospective

2007/India
2007/China

Nam YJ [23]
2004/Korea
Case-control
Sethar GH [24]
2004/Pakistan Cross-sectional
Chakrabarti P [18] 2002/India and Prospective
Italy

Cirrhotic
patients (n)

Male
n (%)

Age
(yrs)

Child-Pugh
class B/C
n (%)

HE type
(n)

Diagnosis
of HE

Etiology
of
cirrhosis

H. pylori
test

65

55 (84.6)

35.7

27 (79.4)

MHE

FCT, NCT

457

337 (73.7)

57.6

335 (73.3)

HE/SHE

NCT, EEG

42
60

16 (38.1)
33 (55)

48
48

NA
40 (66.7)

HE
HE

47
368

35 (76.1)
266 (72.3)

40
56.4

24 (52.2)
281 (76.4)

SHE
HE/SHE

FCT, NCT
Clinical
examination,
NCT, EEG
NCT, EEG
NCT, EEG

HCV, HBV, alcohol,

others
HCV, HBV, alcohol,
others
HBV, HCV
HCV, schistosoma,
HBV

29
76
46

NA
48 (63.2)
39 (60.0)

51
22 (81.5)
1785 73 (96.1)
59
29 (87.9)

NA
HE
HE/SHE

NCT
NA
NCT

135 (65.9)

55

NA

HE

Calvet X [19]

2001/Spain

Prospective

205

Demiturk L [3]

2001/Turkey

Prospective

27

27 (100)

57

22 (59.5)

SHE

Kini D [14]

2001/India

Prospective

58

54 (93.1)

35.5

28 (48.3)

HE/SHE

Clinical
examination
Visual evoked
potentials
FCT, NCT

Miquel J [7]

2001/Spain

Prospective

37

28 (75.7)

59

35 (94.6)

SHE

NCT, EEG

Scotiniotis IA [13]

2001/USA

Prospective

69

47 (68.1)

49

25 (36.2)

SHE

CPT, NCT, EEG

Shrimali L [27]

2001/India

Case-control

75

NA

NA

NA

HE

Vsconez C [25]
Zullo A [10]

1999/USA
1999/Italy

Prospective
Prospective

62
47

36 (58)
30 (39.0)

61
62.9

14 (21.9)
7 (33.3)

HE/SHE
HE/SHE

Clinical
examination
FCT, NCT, EEG
NCT, DST

Dasani BM [16]

1998/USA

Prospective

55

55 (100)

61.1

NA

HE

NCT

Miyaji H [9]
Gubbins GP [15]

1997/Japan
1993/USA

Prospective
Prospective

50
273

31 (62.0)
273 (100)

63.3
51

31 (62.0)
NA

NA
HE

NA
Clinical
examination

NA
HCV, HBV, alcohol,
others
HBV, alcohol, HCV
HBV, HCV
HBV, HCV, alcohol,
Wilson disease,
cryptogenic
HCV, alcohol, others

R + H + 14 C
IgG
R + IgG

R
R + H + 14 C + IgG
R
IgG
R+H

IgG

HCV, HBV,
schistosoma
Alcohol, HCV, HBV,
HBV & HCV, others
Alcohol, HCV, HBV,
others
HCV, HBV, Alcohol,
others
Alcohol, others

R+H

HCV, HBV, alcohol

HBV, alcohol, HCV,
cryptogenic
Alcohol, cryptogenic,
HBV, HCV
NA
Alcohol

14
C
R+H

14 C: 14 C

R + H + 14 C
14

14

IgG

R+H
H
IgG

urea breath test; IgG: IgG

621

HE: hepatic encephalopathy; SHE: subclinical hepatic encephalopathy; NA: not available; R: rapid urease test; H: histology staining and culture;
antibodies; EEG: electroencephalogram; NCT: number connection test; DST: digit symbol test; FCT: gure connection test.

H. pylori and HE

Table 1

622

B.-L. Hu et al.

Table 2

Quality assessment according to SAQOR criteria.

Authors

The sample is
representative of the
population from
which it was drawn

The source of
the sample is
clearly stated

The sampling
method is
described

The sample size is appropriate

to determine statistical
signicance for primary
outcomes

Entry criteria
and exclusions
are stated and
justied

Agrawal A [20]
Chen SJ [17]
Shavakhi A [26]
Abdel-Hady H [21]
Rekha C [28]
Yang CS [22]
Nam YJ [23]
Sethar GH [24]
Chakrabarti P [18]
Calvet X [19]
Demiturk L [3]
Kini D [14]
Miquel J [7]
Scotiniotis IA [13]
Shrimali L [27]
Vsconez C [25]
Zullo A [10]
Dasani BM [16]
Miyaji H [9]
Gubbins GP [15]

Yes
NA
Yes
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
NA
Yes
Yes
Yes
NA
No

Yes
Yes
Yes
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No

Yes
Yes
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
NA
Yes
NA
Yes
Yes
Yes
NA
Yes
Yes
Yes

Yes
NA
Yes
NA
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Table 3

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

Study

HE, n (%)

Agrawal A [20]
Chen SJ [17]
Yang CS [22]
Abdel-Hady H [21]
Chakrabarti P [18]
Shrimali L [27]
Dasani BM [16]
Gubbins GP [15]
*

22
161
154
29
5
39
27
92

12
33
50
6
4
14
5
44

(37)
(53.2)
(53.9)
(29)
(29.4)
(56)
(33)
(62)

OR (95% CI)

P value

2.92 (0.959.09)
2.113 (1.2223.654)
NA
7.25 (1.9328.72)
2.39 (0.3925.69)
2.78 (0.868.85)
7.02 (1.7230.92)
2.4 (1.24.8)

< 0.01
0.007*
< 0.05*
< 0.01
> 0.05
0.048
0.002
< 0.01*

P value was calculated from logistic regression.

Table 4

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

Study
Sethar GH [24]
Calvet X [19]
Scotiniotis IA [13]
*

(63)
(74.4)
(81.5)
(74)
(33)
(78)
(67)
(76.8)

Non-HE, n (%)

H. pylori (+), n (%)

59 (77.6)
26 (22)
5 (36)

H. pylori (), n (%)

17 (22.4)
13 (12)
22 (40)

P value
< 0.01
> 0.05*
0.769

P value from logistic regression analysis.

Effect of H. pylori eradication

Five studies [7,9,17,20,22] showed that blood ammonia
level was signicantly reduced after H. pylori eradication,
three studies [3,10,25] failed to show signicant reduction.
Four studies [7,10,13,25] showed that the number connection test (NCT) was signicantly improved; the other

six studies [3,9,16,20,22,26] failed to nd any signicant

change (Table 6).

Discussion
Gubbins et al. [15] initially investigated the role of H. pylori
infection in the pathogenesis of HE and found that H. pylori

H. pylori and HE
Table 5

623

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

Study

Patients (+/) Blood ammonia level

P value Patients (+/) Gastric ammonia level

H. pylori (+) H. pylori ()

Agrawal A [20]
Chen SJ [17]
Yang CS [22]
Nam YJ [23]
Chakrabarti P [18]
Miquel J [7]
Kini D [14]
Vsconez C [25]
Rekha C [28]
Dasani BM [16]
Miyaji H [9]

22/12
277/180
258/110
12/7
10/36
22/37
31/27
30/32
23/24
NA
NA

1.80 0.34
78.4 63.6
79.3 61.8
51.8 23.6
37.7 18.6
62.05 33
29 (1847)
47 24
56.75
NA
NA

1.39 0.14
53.8 51.4
52.7 49.8
82.6 51.9
37.6 18.8
62.5 33
34 (1548)
43 22
61.04
NA
NA

H. pylori (+) H. pylori ()

< 0.01
< 0.01
< 0.01
> 0.05
> 0.05
> 0.05
> 0.05
> 0.05
> 0.05

infection was an independent risk factor for HE. However,

this result was subject to some limitations, such as the single etiology (only alcohol abusers) of cirrhosis and the single
detective method (only by serology) of H. pylori infection
[29,30]. Recently, two large studies [17,22] reported that
H. pylori infection was associated with HE, their results have
been calculated from multivariate regression by adjusting
confounding variables, in addition, they included cirrhotic
patients of various aetiology and the diagnosis of H. pylori
infection was made with accurate direct detection methods.
Although three early studies [13,18,19] initially failed to
nd an association between H. pylori infection and the presence of HE, this was shown to exist by later investigations.
However, the mean age of cirrhotic patients in those studies was over 60 years. In a study including younger patients
[11], H. pylori infection was independently associated with
HE only in patients with decompensated cirrhosis younger
than 60 years of age.
Hyperammonemia blood ammonia plays an essential role
in the pathogenesis of HE, and treatment or prevention
relies on dietary or pharmacological strategies that lower
blood ammonia levels [2]. The mechanism of H. pylori
infection leads to hyperammonemia and aggravates HE via

Table 6

NA
NA
NA
15/5
10/36
NA
NA
NA
NA
13/4
12/20

NA
NA
NA
3.8 2.1
2.3 1.9
NA
NA
NA
NA
4.9 0.4
5.9 2.5

NA
NA
NA
2.0 0.9
0.9 0.6
NA
NA
NA
NA
2.9 0.5
1.6 0.4

> 0.05
< 0.01

0.05
< 0.05

changing urease activity or serum zinc level [17,31,32]. The

urease activity of H. pylori is many times more potent than
that of enterobacteria [33,34]. H. pylori urease hydrolyzes
urea present in the gastric juice into ammonia and carbon
dioxide, and the amount of ammonia produced in the gastric mucosa could increase blood ammonia levels in cirrhotic
patients, due to the severe impairment of liver function,
and the reduction of blood ammonia levels by anti-H. pylori
treatment can improve the symptoms of HE [35,36].
Nam et al. [23] showed that the gastric ammonia level
was higher in H. pylori infection cirrhotic patients than
those without infection, however, this study was casecontrol design of just 19 cirrhotic patients. However, other
three prospective studies [9,16,18] enrolled more cirrhotic patients to further conrm the association between
elevated gastric ammonia level and H. pylori infection.
Therefore, we supposed that the presence of H. pylori infection will increase the gastric ammonia level. In regard to
the blood ammonia level, in the three positive studies
[17,20,22], over 70% of the patients belonged to the B/C
Child-Pughs classes, whereas in the ve negative studies
[7,14,18,23,25], only 30% belonged to those advanced ChildPughs classes. These evidences suggest that liver function

Change of ammonia and number connection test (NCT) before and after H. pylori eradication.

Study

Agrawal A [20]
Chen SJ [17]
Shavakhi A [26]
Yang CS [22]
Demiturk L [3]
Miquel J [7]
Scotiniotis IA [13]
Zullo A [10]
Vsconez C [25]
Dasani BM [16]
Miyaji H [9]
a

P value

Patients

22
277
30
258
27
22
4
21
32
14
18

Number and rate of HE.

Blood ammonia level

Before

After

1.8 0.34
78.4 63.6
NA
79.3 61.8
44 19
62.05 33
NA
81 33
47 24
NA
89 28

1.18 0.27
53.5 37.7
NA
52.6 36.5
41 20
52.37 29
NA
80 19
48 26
NA
17 11

P value

< 0.01
< 0.01

< 0.01
> 0.05
< 0.01

> 0.05
> 0.05

< 0.01

NCT

P value

Before

After

86 15
NA
2.06 0.9
154 (59.6%)a
NA
71 26
38 2
55 26
2.2 1.2
62 8
NA

75 15
NA
0.52 0.59
51 (32.8)a
NA
69 32
43 6
52 20
2.3 1.2
46 4
NA

< 0.01

0.038
< 0.01
< 0.05
> 0.05
> 0.05
> 0.05
> 0.05
0.011
0.001

624
remains the main determinant of HE even in patients with
H. pylori infection. However, the results should be interpreted with caution, because other potential confounding
factors were not presented in the studies, making it a questionable comparison between their results.
In view of the association of H. pylori infection with
hyperammonemia and HE, bacterium eradication may, in
theory, reduce ammonia level in cirrhotic patients. In the
present study, successful H. pylori eradication was achieved
in the great majority of the cirrhotic patients treated in all
studies attempting to correlate eradication with a reduction in HE severity (data not shown). However, three studies
[3,10,25] failed to show that the blood ammonia level was
signicantly reduced, and four studies [7,10,13,25] did not
show that the NCT value improved after H. pylori eradication. In the Yang et al. [22] study, the blood ammonia level
was reduced and the NCT was improved signicantly after
H. pylori eradication. On the contrary, the Vsconez et al.
[25] study showed that neither blood ammonia level nor
the NCT was changed signicantly. In addition, Demiturk
et al. [3] showed a signicant reduction of blood ammonia levels, but no signicant improvement in visual evoked
potentials recordings occurred. These results do not support the hypothesis that H. pylori eradication would help
improving HE. The effect of eradication of H. pylori on blood
ammonia is likely to be non-specic, perhaps due to antibiotic therapy rather than an effect of the eradication of
the organism. Furthermore, another factor, such as protein
intake with the diet, seems to be the main determinant
affecting blood ammonia level after H. pylori eradication. In
order to provide a reliable assessment of this effect, a large
randomized controlled trial would certainly be of great help;
meanwhile there is no evidence for using different criteria
for searching and eradicating H. pylori infection in cirrhotic
patients compared to the general population.
Since the last systematic review on the subject, our paper
has included eight new published studies [14,17,2024,27]
in an attempt to give a state-of-the-art view that may
guide further investigations. We have found that the limitations highlighted by the earlier review are still there.
First, no randomized controlled studies have yet been
carried out, thus making unreliable any attempt to a metaanalysis approach of the available results. Second, the
baseline characteristics of cirrhotic patients are heterogeneous across the studies, such as the age, Child-Pugh
class and gender, thus making any comparison difcult
to interpret. Third, HE was diagnosed solely according to clinical ndings in three studies [15,19,27] and
H. pylori infection was determined according to a positive
serology in ve studies [15,19,24,26,27] thus, the diagnostic accuracy of both conditions may not be optimal
in these studies due to the intrinsic limitations of the
methods. Therefore, well-designed prospective randomized
controlled studies are warranted in order to provide a more
precise estimation by taking potential confounders into
account.
In conclusion, the present systematic review provided an
insight on the currently available evidence. The prevalence
of H. pylori infection was higher in HE patients than non-HE
patients, particular the older patients. However, there are
no strong evidences for an effect of H. pylori on increasing
blood ammonia level, nor there is strong evidence to support

B.-L. Hu et al.
the hypothesis that H. pylori eradication can reduce blood
ammonia level and improve HE symptoms.

Disclosure of interest
The authors declare that they have no conicts of interest
concerning this article.
Source of funding: this study was supported by Guangxi
scientic research and technology development program
(No. 01-108-18).

Acknowledgements
This work benetted from the helpful comments of the
anonymous reviewers.

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