Liver International ISSN 1478-3223

FIBROSIS, CIRRHOSIS AND THEIR COMPLICATIONS

Probiotics are helpful in hepatic encephalopathy: a meta-analysis of

randomized trials
Sammy Saab1,2, Duminda Suraweera3, Jennifer Au4, Elena G. Saab1, Tori S. Alper1 and Myron J. Tong1,2,5
1 Department of Surgery, University of California at Los Angeles, Los Angeles, CA, USA
2 Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
3 Department of Medicine, Olive View Medical Center, Sylmar, CA, USA
4 Department of Medicine, Albert Einstein Medical Center, Philadelphia, PA, USA
5 Liver Center, Huntington Medical Research Institutes, Pasadena, CA, USA

Liver Int. 2016; 36: 986–993. DOI: 10.1111/liv.13005

Abstract
Background: Hepatic encephalopathy (HE) is a major complication of cirrhosis and is associated with decreased survival and
increased health care utilization. Aim: The aim of this study was to evaluate the efficacy of probiotics in the manage-
ment minimal hepatic encephalopathy HE (MHE) and overt HE (OHE) in comparison to no treatment/placebo and lactu-
lose. Methods: The main outcomes measured were mortality, improvement in MHE, progression to OHE in patients with
MHE and hospitalization. We calculated odds ratios (OR) with 95% confidence intervals (CI). Study heterogeneity was
assessed using the I2 statistic. Results: Fourteen studies totalling 1152 patients were included in the analysis. The use of
probiotics had no impact on the overall mortality when compared to either lactulose (OR: 1.07, 95% CI: 0.47–2.44,
P = 0.88) or no treatment/placebo (OR: 0.69, 95% CI: 0.42–1.14, P = 0.15). When probiotics was compared to no treat-
ment/placebo, it was associated with a significant improvement in MHE (OR: 3.91, 95% CI: 2.25–6.80, P < 0.00001),
decreased hospitalization rates (OR: 0.53, 95% CI: 0.33–0.86, P = 0.01) and decreased progression to overt hepatic
encephalopathy (OR: 0.40, 95% CI: 0.26–0.60, P < 0.0001). However when compared to lactulose, probiotics did not show
a significant difference in improvement of MHE (OR: 0.81, 95% CI: 0.52–1.27, P = 0.35), hospitalization rates (OR: 1.02,
95% CI: 0.52–1.99, P = 0.96) or progression to overt hepatic encephalopathy (OR: 1.24, 95% CI 0.73–2.10,
P = 0.42). Conclusions: Overall the use of probiotics was more effective in decreasing hospitalization rates, improving MHE
and preventing progression to OHE in patients with underlying MHE than placebo, but similar to that seen with lactulose.
The use of probiotics did not affect mortality rates.

Keywords
cirrhosis – hepatic encephalopathy – probiotics

Hepatic encephalopathy (HE) refers to the altered men-
tal status that occurs in the setting of advanced liver
disease (1). There are two forms of HE currently recog-
nized – covert, which included minimal hepatic
encephalopathy (MHE) and Grade 1 HE, and overt HE
(OHE), which includes Grade 2–4 (2). The diagnosis
of covert HE requires specialized instruments (2). In
contrast, patients with OHE present with symptoms
ranging from personality changes to frank coma (2).
The presence of HE increases healthcare utilization and
liver-related mortality, and the ability to learn, which
can persist even after liver transplantation (3–7). The

Abbreviations
CI, confidence interval; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; OHE, overt hepatic encephalopathy; OR, odds ration.
Correspondence
Sammy Saab, MD, MPH, AGAF, FAASLD, UCLA Medical Center, Pfleger Liver Institute, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA
Tel: +310 206 6705
Fax: +310 206 4197
e-mail: ssaab@mednet.ucla.edu
Handling editor: Carmen Berasain
Received 16 September 2015; Accepted 2 November 2015

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Saab et al.
Key points
• Probiotics was more effective than placebo in
decreasing hospitalization rates, improving MHE and
preventing progression to overt HE in patients with
underlying MHE.
• The efficacy of probiotics appear similar to that
seen with lactulose.
• The use of probiotics did not affect mortality rates.
• The use of probiotics appeared safe.
development of HE not only affects patients’ quality of
life but also that of their care givers (8, 9).
The management of HE is centred on altering the
bacterial milieu in the intestines (10). Currently, there
are two major pharmacologic interventions in the treat-
ment of HE: lactulose and rifaximin (2, 11). The use of
lactulose is limited by adverse effects including nausea,
anorexia and abdominal cramps (12). Rifaximin is well
tolerated, but is only indicated by the Food and Drug
Administration for reducing of risk of OHE recurrence
(13, 14). There is increasing use of alternative therapies
such as branched chain amino acids and probiotics (15,
16). Probiotics, in particular, are readily available and
may have a role in variety of gastrointestinal disorders
(17–19). The proposed mechanism by which probiotic
use can decrease symptoms of HE is by altering gut
flora, which in turn decreases the production and
absorption of gut derived bacterial toxins (17).
Several studies have suggested a potential benefit in
the use probiotics for the management of hepatic
encephalopathy. However, results have been inconsis-
tent. The objective of the present meta-analysis was to
systematically evaluate the clinical impact of probiotics
on hepatic encephalopathy. Specifically, we were inter-
ested in assessing the impact of probiotics on overall
mortality, hospitalization, treatment of MHE and MHE
progression to OHE.
Methods
Objective
Perform a systematic review of the literature and meta-
analysis to determine the utility of probiotics in the
management of hepatic encephalopathy (Fig. 1).
Selection of trials
Trials that met the following criteria were included: (a)
prospective or retrospective cohort studies as well as
randomized, controlled, open or blinded trials pertinent
to the subject matter and published as an article; (b)
adults (defined as ≥16 years old) with cirrhosis irrespec-
tive of aetiology; (c) use of probiotic in one arm and a
comparative arm receiving either lactulose or placebo or
both and (d) reported measurable clinical outcomes.
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Probiotics and hepatic encephalopathy
219 records identified
Cochrane Review (1)
PubMed (218)
202 studies excluded
because of duplications,
irrelevancy and non-RCT
17 full texts assessed
2 studies excluded as
outcomes of interest were
not measured
15 texts assessed
1 study excluded for low
JDAD score
14 texts included in
meta-analysis
Fig. 1. Flow chart of literature search and trial selection.
Exclusion criteria included studies which used the same
database; nonrandomized, poor quality (JADAD score
<2) studies, the use of concurrent antibiotics, no
reported follow up, a lack of information on the pres-
ence or severity of cirrhosis, publications only as
abstracts and non-English manuscripts (20). Disagree-
ments were resolved by consensus.
Search strategy
A comprehensive search of the MEDLINE database and
the Cochrane Database of Systematic Reviews was per-
formed to identify studies published before 1 May 2015,
which investigated the use of probiotics in management
of hepatic encephalopathy. We used combinations of the
keywords: probiotics, hepatic encephalopathy, minimal
hepatic encephalopathy, subclinical hepatic encephalopa-
thy and cirrhosis. We also manually searched manuscript
references to identify additional studies that may have
been missed with a MEDLINE-assisted strategy.
Data extraction
Studies were subjected to inclusion and exclusion crite-
ria. Two reviewers (D. S. and J. A.) independently and
in duplicate assessed the eligibility and quality of trials.
987
Probiotics and hepatic encephalopathy Saab et al.

or moderate if the I2 was less than 25% and 50% respec-

Statistical analysis
We used the statistical package RevMan version 5.2. The
Mantel-Haenszel procedure for binary data was used to
determine the clinical significance of effect. Sensitivity
analysis was two-tailed and set at P ≤ 0.05. A random-
effects model was employed because of the anticipated
variability between trials in terms of patient popula-
tions, interventions and concomitant interventions.
Heterogeneity between trials was assessed by the chi-
squared test with significance set at P ≤ 0.10. The
approximate proportion of total variability in point esti-
mates attributed to heterogeneity was calculated by use
of the I2 statistic. Heterogeneity was thought to be mild
tively (21).
Results
Fourteen studies were included in the meta-analysis and
are summarized in Table 1. Four studies compared the
use of probiotics with lactulose (22–25) and seven stud-
ies compared the use of probiotics with placebo (26–
32). In three studies, there were multiple comparisons
using probiotics, lactulose and placebo (33–35). Most of
the studies were conducted in India (23, 25, 27, 29, 30,
32–34) (Table 2). The remaining studies were con-
ducted in China, Italy, USA, Israel, Egypt and Iran (22,

Table 1. Characteristics of randomized clinical studies included in the meta-analysis

Treatment
Study Study Design JDAD Cohort Intervention N D Disease aetiology Child–Pugh duration
Loguercio (22) Open label 3 HE Probiotic 14 7 ALD 10, other 11 NA 3 months
Lactulose 12 7 ALD 11, other 8 NA 3 months
Liu (26) Open label 3 MHE Probiotic 20 0 ALD 4, HBV 14, other 2 A 3 BC 17 1 month
Placebo 35 0 ALD 7, HBV 25, HCV 2, A 5 BC 30 1 month
other 1
Sharma (23) Open label 3 MHE Probiotic 31 4 ALD 78, HBV 70, HCV 54 A 12 B 14 C 9 1 month
Lactulose 31 4 AIH 3, PBC 1, other 14, A 14 B 10 C 11 1 month
(includes probiotic+
lactulose arm)
Bajaj (31) Open label 3 MHE Probiotic 17 0 HCV 12, PSC 1, AIH 2, A 15 B 2 C 0 2 months
other 3
No treatment 8 0 HCV 5, PSC 1, other 2 A7B1C0 2 months
Mittal (33) Open label 3 MHE Probiotic 40 0 ALD 18, viral 13, other 9 8 3 months
Lactulose 40 0 ALD 17, viral 14, other 9 7.5 3 months
No treatment 40 0 ALD 14, viral 14, other 12 8 3 months
Sanji (27) Double blinded 5 MHE Probiotic 21 0 ALD 34, HBV 2, HCV 1 NA 1 month
Placebo 22 0 cryptogenic 3 NA 1 month
Pereg (28) Double blinded 5 MHE Probiotic 18 0 HCV 9, other 9 A 13 B 5 C 0 6 months
& HE Placebo 18 0 HCV 10, other 8 A 14 B 4 C 0 6 months
Agrawal (34) Open label 3 HE Probiotic 64 NA 10.5 12 months
Lactulose 68 NA 10.1 12 months
No treatment 65 NA 10 12 months
Ziada (35) Open label 3 MHE Probiotic 26 NA A 3 B 14 C 9 1 month
Lactulose 24 NA A 2 B 14 C 8 1 month
Placebo 25 NA A 3 B 13 C 9 1 month
Dhiman (29) Double blinded 5 HE Probiotic 66 ALD 50, HCV 9, HBV 4, A 5 B 20 C 41 6 months
other 7
Placebo 64 ALD 44, HCV 4, HBV 4, A 3 B 20 C 41 6 months
other 13
Shavakhi (24) Open label 3 MHE Probiotic 20 viral 16, AIH 2, other 2 A 2 B 14 C 4 2 months
Lactulose 21 viral 15, AIH 5, other 1 A 3 B 12 C 6 2 months
Mouli (25) Open label 3 MHE Probiotic 60 ALD 24, viral 24, other 12 A 14 B 24 C 22 2 months
Lactulose 60 ALD 21, viral 24, other 15 A 15 B 30 C 15 2 months
Lunia (32) Open label 3 None Probiotic 86 ALD 42, HBV 18, HCV 6, A 12 B 26 C 44 3 months
other 20
No treatment 74 ALD 40, HBV 13, HCV 5, A 9 B 25 C 40 3 months
other 16
Sharma (30) Open label 2 MHE Probiotic 32 ALD 4, HCV 7, HBV 5 A 6 B 21 C 5 2 months
Placebo- Placebo 30 ALD 10, HCV 4, HBV 7 A 10 B 8 C 12 2 months

N, population size; D, dropouts; HE, hepatic encephalopathy; MHE, minimal hepatic encephalopathy; ALD, alcohol related liver disease; HCV, hepati-
tis C virus; HBV, hepatitis B virus; AIH, autoimmune hepatitis.

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Saab et al. Probiotics and hepatic encephalopathy

Table 2. Probiotic formulation and country of origin

Study Country of origin Probiotic used
Loguercio (22) Italy Bioflorin (Enterococcus SF68)
Liu (26) China Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei, Lactobacillus plantarum
Sharma (23) India Streptococcus faecalis, Clostridium butyricum, Bacillus mesentricus, lactic acid bacillus
Bajaj (31) USA Probiotic yogurt with lactobacillus
Mittal (33) India 110 billion CFU
Sanji (27) India 1.25 billion Lactobacillus acidophilus, rhamnosus, Bifidobacterium longum and sacchromyces
Pereg (28) Israel Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum
Agrawal (34) India VSL#3 (4 strains of Lactobacilli, 3 strains of Bifidobacteria, 1 strain Streptococcus thermophilus)
Ziada (35) Egypt Lactobacillus acidophilus
Dhiman (29) India VSL#3 (4 strains of Lactobacilli, 3 strains of Bifidobacteria, 1 strain Streptococcus thermophilus)
Shavakhi (24) Iran Balance (L. casei, L. rhamnosus, L. acidophilus, L. bulgaricus, B. breve, B. longum, S. thermophilus)
Mouli (25) India VSL#3 (4 strains of Lactobacilli, 3 strains of Bifidobacteria, 1 strain S. thermophilus)
Lunia (32) India VSL#3 (4 strains of Lactobacilli, 3 strains of Bifidobacteria, 1 strain S. thermophilus)
Sharma (30) India Velgut (4 stratins of Lactobacillus, 3 strains of Bifidobacterium, Sacchromyce boulardi, S. thermophilus)

Source Probiotic No treatment/placebo Weight (%) Risk Ratio, (95% CI)

Bajaj 2008 12 17 0 8 1.5% 38.64 [1.88, 794.36]
Liu 2004 10 20 12 35 33.0% 1.92 [0.63, 5.88]
Mittal 2011 14 40 4 40 19.7% 4.85 [1.43, 16.42]
Pereg 2011 0 18 0 18 Not estimable
Sanji 2011 0 21 0 22 Not estimable
Sharma 2014 16 32 9 30 35.1% 2.33 [0.82, 6.63]
Ziada 2013 14 26 3 25 10.7% 8.56 [2.04, 35.81]

Total (95% CI) 174 178 100.0% 3.91 [2.25, 6.80]

Total events 66 28

Heterogeneity: I 2 = 33%

Test for overall effect: Z = 4.84 (P < 0.00001)

Fig. 2. Forest plot on improvement on minimal hepatic encephalopathy comparing probiotics and no treatment/placebo. CI, confidence
interval; M-H, Mantel-Haenszel.

24, 26, 28, 31, 35). The most common probiotic used in
the studies wasVSL#3 (25, 29, 32, 35). VSL#3 contains
four strains of lactobacilli, three strains of Bifidobacteria
and 1 strain Streptococcus thermophilus. The rest of the
studies used unique probiotic combinations, usually
with lactobacillus (22, 24, 26, 28, 31, 35) (Table 2).
The duration of treatment varied from 1 to
12 months. In most studies, patients were treated for
3 months or less (22–27, 30–33, 35). Treatment dura-
tion was 6 months in two studies (28, 29) and
12 months in one study (34).
Mortality
Information on mortality comparing probiotic vs pla-
cebo/no treatment or lactulose was available in 10 stud-
ies (22, 24, 25, 29–35). Overall there was no difference
in survival. For instance, OR was 1.07 (95% CI: 0.47–
2.44, P = 0.88) in the analysis of six studies comparing
the use of probiotics with lactulose (22, 24, 25, 33–35).
There was no significant heterogeneity in the analysis
(P = 0.27, I2 = 17%). Similarly, in the seven studies
comparing the use probiotics with no treatment/pla-
cebo, the OR was 0.699 (95% CI: 0.42–1.14, P = 0.15)
(29–35). Again there was no significant heterogeneity in
the analysis (P = 0.97, I2 = 0%).
Minimal hepatic encephalopathy
Improvement in MHE was generally assessed through a
combination of instruments and psychometric tests in
nine studies (23, 25–28, 30, 31, 33, 35). The authors of
several studies utilized alternative tests if patients were
illiterate (30, 33). Although there was no difference
between patients treated with probiotics vs lactulose
(OR: 0.81, 95% CI: 0.52–1.27, P = 0.35) (23, 25, 27, 35),
there was a significantly greater likelihood of MHE
improvement with probiotics vs no treatment/placebo
(OR: 3.91, 95% CI: 2.25–6.80, P < 0.00001; Fig. 2) (23,
25–28, 30, 31, 33, 35). In the seven studies comparing

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Probiotics and hepatic encephalopathy Saab et al.

the use of the probiotics to no treatment, 38% (66/174)

of the patients who received probiotics had improve-
ment of MHE in contrast to 16% (28/178) in the pla-
cebo arm. There was no significant heterogeneity in the
analysis (P = 0.20, I2 = 33%).
Hospitalizations
Five studies compared hospitalization rates between
patients who were treated with probiotics vs no treat-
ment/placebo or lactulose (24, 28, 29, 33, 34). Reasons
for admission were generally liver related, but not neces-
sarily because of hepatic encephalopathy. The odds of
hospitalization were significant when comparing probi-
otics and no treatment/placebo (OR: 0.53, 95% CI: 0.33
to 0.86, P = 0.01; Fig. 3) (28, 29, 33, 34). The hospital-
ization rate was 22% (41/188) in the probiotic group,
and 33% (62/187) in the placebo group. There was no
significant heterogeneity in the analysis (P = 0.69,
I2 = 0%). In contrast, there was no difference in hospi-
talization between the probiotic and lactulose groups
(OR: 1.02, 95% CI: 0.52–1.99, P = 0.96) (24, 33, 34).
Progression to overt hepatic encephalopathy
Ten studies assessed the progression to OHE in patients
with minimal encephalopathy (22, 24, 25, 28, 29, 31–
35). The definition of OHE differed among the studies.
Most studies based the diagnosis from objective criteria
such as PHES scoring or the West Haven criteria (24,
25, 29, 32, 34). One study did not specifically mention
the criteria utilized to diagnose OHE (33). The differ-
ence in the likelihood of progression to OHE in patients
with MHE or worsening OHE in patients with existing
diagnosis was statistically significant in the analyses
comparing probiotics and no treatment/placebo (OR:
0.40, 95% CI: 0.26–0.60, P < 0.0001; Fig. 4) (28, 29, 31–
35); 17% (55/317) and 32% (95/294) of the patients
treated with probiotics and placebo or no treatment,
respectively, developed OHE. There was no significant
heterogeneity in the analysis (P = 0.82, I2 = 0%). How-
ever, the likelihood of progression to or worsening OHE
was similar when comparing the probiotic and lactulose
groups (OR: 1.24, 95% CI: 0.73–2.10, P = 0.42) (22, 24,
25, 33–35); 17% (38/224) of the patient treated with

Source Probiotic No treatment/placebo Weight (%) Risk Ratio, (95% CI)

Agrawal 2012 21 64 28 65 41.1% 0.65 [0.32, 1.32]
Dhiman 2014 16 66 29 64 49.1% 0.39 [0.18, 0.82]
Mittal 2011 1 40 2 40 4.3% 0.49 [0.04, 5.60]
Pereg 2011 3 18 3 18 5.5% 1.00 [0.17, 5.77]

Total (95% CI) 188 187 100.0% 0.53 [0.33, 0.86]

Total events 41 62

Heterogeneity: I 2 = 0%

Test for overall effect: Z = 2.57 (P = 0.01)

Fig. 3. Forest plot on hospitalization comparing probiotics and no treatment/placebo. CI, confidence interval; M-H, Mantel-Haenszel.

Source Probiotic No treatment/placebo Weight (%) Risk Ratio, (95% CI)

Agrawal 2012 22 64 37 65 33.6% 0.40 [0.19, 0.81]
Bajaj 2008 0 17 2 8 4.5% 0.07 [0.00, 1.76]
Dhiman 2014 23 66 33 64 30.5% 0.50 [0.25, 1.02]
Lunia 2014 7 86 14 74 19.3% 0.38 [0.14, 1.00]
Mittal 2011 2 40 4 40 5.3% 0.47 [0.08, 2.75]
Pereg 2011 0 18 0 18 Not estimable
Ziada 2013 1 26 5 25 6.8% 0.16 [0.02, 1.48]

Total (95% CI) 317 294 100.0% 0.40 [0.26, 0.60]

Total events 55 95

Heterogeneity: I 2 = 0%

Test for overall effect: Z = 4.33 (P < 0.0001)

Fig. 4. Forest plot on improvement on progression or worsening hepatic encephalopathy comparing probiotics and no treatment/placebo.
CI, confidence interval. M-H, Mantel-Haenszel.

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Saab et al. Probiotics and hepatic encephalopathy

probiotics and 15% (38/225) treated with lactulose pro-
gressed to OHE.
Further subgroup analysis of the use of probiotics as
primary prophylaxis in preventing patients from devel-
oping OHE was also assessed. The odds of developing
OHE were significantly decreased when patients were
treated with probiotics as compared to no treatment/
placebo (OR: 0.31, 95% CI: 0.15–0.67, P = 0.003;
Fig. 5) (31–33, 35). There was no significant hetero-
geneity in the analysis (P = 0.68, I2 = 0%). However no
significant difference was seen when comparing the use
of probiotics to lactulose (OR: 1.16, 95% CI: 0.54–2.52,
P = 0.70) (24, 25, 33, 35).
Discussion
The results of our meta-analysis indicate that the use of
probiotics may have an important role in the manage-
ment of hepatic encephalopathy. In several analyses, the
clinical impact of probiotic use was similar to that of
lactulose, but better than the use of placebo (Table 3).
For instance, the use of probiotics was found to be effec-
tive for preventing progression of MHE to OHE, and
decreased hospitalization rated when compared to pla-
cebo, but not any more effective than the use of lactu-
lose. Also, the use of probiotics did not affect mortality
rates.
Lactulose is very unpalatable. It is sweet, thick syrup
associated with a number of adverse effects including
anorexia, nausea, abdominal cramps and diarrhoea.
Tolerability is limited, and indeed lactulose noncompli-
ance is the most preventable reason for admission
because of hepatic encephalopathy (12). The use of pro-
biotics is an attractive potential alternative to lactulose.
Not only are probiotics better tolerated, but in our
meta-analysis, they are also as efficacious when com-
pared to no treatment/placebo. MHE has been associ-
ated with a reduced 5 year survival rate in those with
cirrhosis (36) and probiotics may play a role in
management of these patients who have yet to develop
OHE.
Probiotics are defined by the World Health Organiza-
tion as ‘life microorganisms, which when administered
in sufficient quantities can confer a health benefit’
(FAO/WHO). A number of studies have indeed demon-
strated the possible health benefits of probiotics. But the

Source Probiotic No treatment/placebo Weight (%) Risk Ratio, (95% CI)

Bajaj 2008 0 17 2 8 12.6% 0.07 [0.00, 1.76]
Lunia 2014 7 86 14 74 53.7% 0.38 [0.14, 1.00]
Mittal 2011 2 40 4 40 14.7% 0.47 [0.08, 2.75]
Ziada 2013 1 26 5 25 19.0% 0.16 [0.02, 1.48]

Total (95% CI) 169 147 100.0% 0.31 [0.15, 0.67]

Total events 10 25

Heterogeneity: I 2 = 0%

Test for overall effect: Z = 3.01 (P = 0.003)

Fig. 5. Forest plot on effectiveness of probiotics as primary prophylaxis in preventing hepatic encephalopathy comparing probiotics and no
treatment/placebo. CI, confidence interval; M-H, Mantel-Haenszel.

Table 3. Comparison in clinical outcomes with probiotics

Probiotic Comparison Odds ratio
Comparison Events/total patients Events/total patients (95%) confidence interval P value
Mortality
Lactulose 13/224 13/225 1.07 (0.47–2.44) 0.88
No treatment/placebo 32/331 42/306 0.69 (0.42–1.14) 0.15
Improvement in minimal HE
Lactulose 67/157 74/155 0.81 (0.52–1.27) 0.35
No treatment/placebo 66/174 28/178 3.91 (2.25–6.80) <0.0001
Hospitalizations
Lactulose 22/124 23/129 1.02 (0.52–1.99) 0.96
No treatment/placebo 41/188 62/187 0.53 (0.33–0.86) 0.01
Progression to or worsening of HE
Lactulose 38/224 33/225 1.24 (0.73–2.10) 0.42
No treatment/placebo 55/317 95/294 0.40 (0.26–0.60) <0.0001

HE, hepatic encephalopathy.

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Probiotics and hepatic encephalopathy
health benefits may be disease particular as well as speci-
fic bacterial strains and dose dependent (37). Although
the results of our study demonstrate a favourable impact
of probiotics in the management of hepatic
encephalopathy, there are a number of practical consid-
erations such as optimal treatment duration, dose and
viability of mircoorganisms (38). Serious adverse effects,
including death, have been reported with the use of pro-
biotics, believed from contamination (39, 40). The Food
and Drug Administration does not regulate probiotics
since manufacturers propose structure/function claims,
rather than specific health claims (41).
There are a number of important limitations to our
meta-analysis. First, most studies in our meta-analysis
were conducted in India and it therefore may be diffi-
cult to extrapolate the results to all parts of the world.
Environmental and dietary factors may contribute to
the efficacy of probiotics in the treatment of hepatic
encephalopathy. Another limitation is the variability in
probiotics used in the studies analysed. Probiotics differ
in the amount and bacteria strains used (42). Indeed, a
variety of probiotics were used in the studies of our
meta-analysis. These probiotics may potentially be
harmful to patients who are immune-suppressed or -
compromised. The benefits seen in our meta-analysis
may not be generalizable to patients who have severe
hepatic decompensation. Equally important, the major-
ity of trials were open labelled. Thus, the benefits of pro-
biotics may have been unintentionally overestimated.
Heterogeneity is always a concern when conducting
misanalyses, however, no significant heterogeneity was
present in comparisons made in this meta-analysis.
Several meta-analyses have been published compar-
ing the use probiotics to lactulose or placebo (43–47).
Our study is the most up to date meta-analysis com-
prised of many references not previous included in pre-
viously published meta-analysis (43–45). We included
14 randomized control trials and assessed the efficacy of
probiotics compared to both placebo and lactulose. Our
meta-analysis assessed several outcomes not consistently
measured by others such as mortality (44, 45, 47) and
hospitalization (45, 46). In one meta-analysis, reduction
in plasma ammonia was found with the use of probi-
otics but no improvement in clinical outcomes was
noted (43).
In conclusion, probiotics may be useful as part of an
armamentarium against hepatic encephalopathy. The
findings of this meta-analysis provide evidence that pro-
biotics are more effective than no treatment/placebo in
decreasing hospitalization rates, and preventing progres-
sion to OHE in patients with underlying MHE. How-
ever, the use of probiotics had no impact on mortality
rates.
Acknowledgements
The authors thank Melissa Saletel, RD and Lauren Hal-
liburton, MD, RD, CSNC for the review and comments.
992
Saab et al.
Financial support: None.
Conflict of interest: The authors do not have any dis-
closures to report.
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