Probiotics For People With Hepatic Encephalopathy (Review) : Cochrane
Probiotics For People With Hepatic Encephalopathy (Review) : Cochrane
Probiotics For People With Hepatic Encephalopathy (Review) : Cochrane
www.cochranelibrary.com
1
Sydney Medical School, Westmead Hospital, Sydney, Australia. 2 Institute of Endocrinology and Diabetes, The Children’s Hospital
at Westmead, Westmead, Australia. 3 Gastrointestinal and Liver Unit, The Prince of Wales, Randwick, Australia. 4 Sydney School of
Public Health, The University of Sydney, Sydney, Australia
Contact address: Richard G McGee, Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Locked Bag 4001,
Westmead, NSW, 2145, Australia. dr.richardmcgee@gmail.com.
Citation: Dalal R, McGee RG, Riordan SM, Webster AC. Probiotics for people with hepatic encephalopathy. Cochrane Database of
Systematic Reviews 2017, Issue 2. Art. No.: CD008716. DOI: 10.1002/14651858.CD008716.pub3.
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic
encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life
and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro-organisms, which when
administered in adequate amounts, may confer a health benefit on the host.
Objectives
To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other
treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis
of hepatic encephalopathy.
Search methods
We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation
Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical
Trials Registry Platform until June 2016.
Selection criteria
We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other
treatment in people with hepatic encephalopathy.
We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random-effects model meta-
analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed
dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI).
Probiotics for people with hepatic encephalopathy (Review) 1
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no
treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group
of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180
days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining
13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias.
We found no effect on all-cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR
0.58, 95% CI 0.23 to 1.44; low-quality evidence). No-recovery (as measured by incomplete resolution of symptoms) was lower for
participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate-quality evidence). Adverse
events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic
encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low-quality evidence), but effects on hospitalisation and
change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very
low-quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low-
quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not
meta-analysed; low-quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705
participants; MD -8.29 µmol/L, 95% CI -13.17 to -3.41; low-quality evidence). There were no reports of septicaemia attributable to
probiotic in any trial.
When probiotics were compared with lactulose, the effects on all-cause mortality were uncertain (2 trials; 200 participants; RR 5.00,
95% CI 0.25 to 102.00; very low-quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very
low-quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR
1.17, 95% CI 0.63 to 2.17; very low-quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very
low-quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low-
quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low-quality
evidence); quality of life (results not meta-analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325
participants; MD -2.93 µmol/L, 95% CI -9.36 to 3.50; very low-quality evidence). There were no reports of septicaemia attributable
to probiotic in any trial.
Authors’ conclusions
The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’).
Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve
recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia
concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic
encephalopathy is uncertain because the quality of the available evidence is very low. High-quality randomised clinical trials with
standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics.
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
M oderate
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; RCT: random ised clinical trial; RR: risk ratio
5
Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Probiotics for people with hepatic encephalopathy (Review)
ef f ects.
6
BACKGROUND in addition to the osmotic effect of lactulose, which encourages
removal of toxic metabolic products such as ammonia, it is also
known to have a bifidogenic effect (De Preter 2006; Bass 2010).
Description of the condition Amongst other potential reasons, one rationale behind the use of
probiotics for hepatic encephalopathy is to reduce the prevalence
Hepatic encephalopathy (also known as portosystemic en-
of harmful ammonia-producing bacteria in the gastrointestinal
cephalopathy) is a reversible neuropsychiatric disorder seen in the
system. Probiotics are thought to reduce blood ammonia levels by
context of either acute or chronic liver failure or portosystemic
several mechanisms including decreasing bacterial urease activity,
shunting, or both (Ferenci 2002). Hepatic encephalopathy is char-
decreasing ammonia absorption by decreasing pH, decreasing in-
acterised by complex cognitive dysfunction, which is indepen-
testinal permeability, and improving nutritional status of gut ep-
dent of sleep dysfunction or problems with overall intelligence
ithelium (Poh 2012).
(Blei 2001). Minimal hepatic encephalopathy is a milder form of
the same condition, which does not have obvious clinical signs
(Stewart 2007; Bajaj 2011). The onset of hepatic encephalopa-
thy indicates a poor prognostic outcome. It may also reduce Why it is important to do this review
quality of life and level of daily functioning (Groeneweg 1998; Hepatic encephalopathy significantly impairs patient’s quality of
Arguedas 2003). The pathophysiology of hepatic encephalopa- life and daily functioning, job performance, and overall mortal-
thy is still uncertain, but the prevailing assumption is that dif- ity (Groeneweg 1998; Arguedas 2003; Stinton 2013). Caring for
ferent toxins, such as false neurotransmitters, natural benzodi- and treating patients with hepatic encephalopathy is a significant
azepines, short-chain fatty acids, and mercaptans enhance the neg- burden on the healthcare system. In 2005, hepatic encephalopa-
ative effects of ammonia on the level of consciousness (Butterworth thy cost the US healthcare system an estimated USD 4676.7
1987; Blei 2001; Vaquero 2003). Current therapeutic options million, increasing to USD 7244.7 million in 2009 (Stepanova
include intensive supportive care, identification and correction 2012). Previous Cochrane Hepato-Biliary Group systematic re-
of the precipitating causes, tailored dietary restrictions, non-ab- views have only shown moderate, and in some cases no ben-
sorbable disaccharides, L-ornithine L-aspartate, and/or oral an- efit for current or proposed therapies for hepatic encephalopa-
tibiotics (Riordan 1997; Blei 2001; Als-Nielsen 2003; Als-Nielsen thy, which include non-absorbable disaccharides, oral antibiotics,
2004a; Als-Nielsen 2004b; Als-Nielsen 2004c; Jiang 2009). branched-chain amino acids, and dopamine (Als-Nielsen 2003;
Als-Nielsen 2004a; Als-Nielsen 2004b; Als-Nielsen 2004c; Junker
2014; Gluud 2015). Based on a preliminary analysis, it is esti-
Description of the intervention mated that the literature on probiotics in hepatic encephalopa-
Probiotics are live micro-organisms, which when administered thy has doubled since this systematic review was last published in
in adequate amounts may confer a health benefit on the host 2011, hence this update will improve the evidence base on the use
(Schrezenmeir 2001). However, the dose needed to confer a health of probiotics in hepatic encephalopathy.
benefit is unknown for many conditions. Probiotics commonly
come from two groups of bacteria, Lactobacillus or Bifidobacterium.
Within each group, there are different species (e.g. Lactobacillus
acidophilus and Bifidobacterium bifidus), and within each species, OBJECTIVES
different strains (or varieties). A few common probiotics, such as
To determine the beneficial and harmful effects of probiotics in
Saccharomyces boulardii, are yeasts, which are different from bac-
any dosage, compared with placebo or no intervention or with
teria. Therapeutic effects may be strain specific, and so caution
any other treatment for people with any grade of acute or chronic
must be exerted in generalising results from one species to another.
hepatic encephalopathy. This review did not consider the primary
While probiotics are generally considered safe, adverse events have
prophylaxis of hepatic encephalopathy.
been attributed to their use (Besselink 2008).
Outcomes Anticipated absolute effects* (95% CI) Relative effect No of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; RCT: random ised clinical trial; RR: risk ratio
The high response in the control groups of this review reflects the
natural history of hepatic encephalopathy, with its spontaneously
AUTHORS’ CONCLUSIONS fluctuating nature and possibility for spontaneous remission. Fu-
ture trials should take this into account when assessing the efficacy
Implications for practice of interventions. It is also important that those conducting trials
Due to the very low overall quality of the evidence, there is lim- also account for the time of day in which assessments are made.
ited evidence for the use of probiotics compared with lactulose. Consideration should be given to the type of placebo used, for ex-
Compared with placebo or no intervention, probiotics probably ample inactivated probiotic. All trials should at a minimum assess
improve recovery and may lead to improvements in the develop- important outcomes such as mortality, quality of life, and adverse
ment of overt hepatic encephalopathy, quality of life, and plasma events. Trials should also be designed according to Standard Pro-
ammonia concentrations, but may lead to little or no difference tocol Items: Recommendations for Interventional Trials (SPIRIT)
in mortality. Statement (www.spirit-statement.org/) and reported following the
CONSORT Statement (www.consort-statement.org/).
Implications for research Future systematic reviews on this topic ought to search also
Hepatic encephalopathy has a poor clinical outcome and is a sig- databases of regulatory authorities. Review authors should also use,
nificant burden on the healthcare system. Current treatment op- for example, Trial Sequential Analysis to control risks of random
tions are of limited efficacy. Probiotics represent an inexpensive errors.
Cochrane Review Group funding acknowledgement: The Dan- Sign-off editor: Christian Gluud, Denmark.
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Probiotics for people with hepatic encephalopathy (Review) 25
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cumulative meta-analysis. Journal of Clinical Epidemiology McGee 2011
2008; Vol. 61, issue 1:64–75. [0895–4356] McGee RG, Bakens A, Wiley K, Riordan SM, Webster
Wood 2008 AC. Probiotics for patients with hepatic encephalopathy.
Wood L, Egger M, Gluud LL, Schulz KF, Jüni P, Altman Cochrane Database of Systematic Reviews 2011, Issue 11.
GD, et al. Empirical evidence of bias in treatment effect [DOI: 10.1002/14651858.CD008716.pub2; 1361–6137]
∗
estimates in controlled trials with different interventions Indicates the major publication for the study
Bajaj 2008
7. Venous ammonia.
8. IL-6 and TNF-alpha levels.
Notes Contacted Professor JS Bajaj on 14 October 2010, who provided additional information
Funding source: “The General Clinical Research Center at the Medical College of Wis-
consin sponsored by the NIH supported this study”. This study declared the funding
source and was deemed to be independently funded
Allocation concealment High risk The treatment allocation was not concealed
from the principal investigator
Selective outcome reporting Low risk All outcomes mentioned in the methods
(minimal hepatic encephalopathy reversal,
overt hepatic encephalopathy development,
and adherence) were described in the results
at baseline, after 30 days, and after 60 days.
Personal communication with the author re-
vealed no other outcomes were assessed
Funding source Low risk The General Clinical Research Center at the
Medical College of Wisconsin sponsored by
the NIH supported this study
Bajaj 2014a
Interventions Lactobacillus GG AT strain 53103, 3 batches of LGG and placebo were used. Each LGG
batch had > 50 billion CFU/g (51, 61, and 53, respectively), without any other organisms.
No live organisms were detected in the placebo batches
Notes This study was carried out under the IND mechanism of Center for Biologics Evalua-
tion and Research (CBER) of the Food and Drug Administration (FDA) (IND number
BB13870)
Contacted Professor JS Bajaj on 14 March 2015, who provided additional information
Funding source: “JSB received funding from NCCAM, NIH grant U01AT004428 for
this trial. No other personal or funding interests exist. Writing and preparation of this
paper was performed by the authors”. This study declared the funding source and was
deemed to be independently funded
Selective outcome reporting Unclear risk “Blood was collected for MELD score, am-
monia, serum albumin and pre-albumin,
and the dietician met with them to con-
firm continued adherence on the prescribed
diet. If there were no adverse events requir-
Funding source Low risk “JSB received funding from NCCAM, NIH
grant U01AT004428 for this trial. No other
personal or funding interests exist. Writing
and preparation of this paper was performed
by the authors.”
Dhiman 2013a
Interventions 40 participants received probiotic (1 sachet of VSL#3 (CD Pharma India Pvt. Ltd, New
Delhi), at a dose of 900 billion bacteria daily, and 40 participants received placebo
Liu 2004
Sequence generation High risk 1 sachet was randomly drawn from a pool
for each participant, which is equivalent to
drawing lots. We feel that this does not rep-
resent best practise for randomisation, and
so have judged this category as high risk of
bias according to our predefined criteria
Allocation concealment Low risk Sachets were coded and contents unknown
to investigators when drawn
Loguercio 1987
Notes Additional information on ’Risk of bias’ criteria provided by the author. Contacted Pro-
fessor C Loguercio on 15 October 2010
Funding source: “Gipharmex (Milan, Italy) supported this study”. This study declared the
funding source and was deemed to be industry funded
Incomplete outcome data High risk All participants completed the treatment
All outcomes period. 5 participants given lactulose and
4 given Enterococcus SF68 did not arrive
for post-treatment follow-up. On day 15, 2
participants given lactulose were withdrawn
from the study because of marked hyperam-
monaemia and a worsening of hepatic en-
cephalopathy
Interventions Participants entered a 15-day run-in period. 1 group of participants took, after main meals,
2 capsules containing a total of 150 million Enterococcus faecium strain SF68 3 times a day
for 4 weeks; the participants in the lactulose treatment branch ingested, after main meals,
30 mL (20 g) oral lactulose 3 times a day for the same time span. The treatment was
repeated for three 4-week periods, each separated by a 2-week wash-out interval. During
the 2-week wash-out period participants were treated as during the run-in period
Sequence generation Low risk “After the basal evaluation, the patients
enrolled in the study were assigned to
one of two treatments according the Broc
Plan computerised randomisation scheme
(kindly provided by the Biometrics Division
of Bracco SPA).”
Lunia 2014
Interventions Cirrhotic patients with MHE were divided into: group 1 (probiotics, n = 42, VSL#3) and
group 2 (control, n = 39)
Outcomes All participants underwent psychometric tests, critical flicker frequency, glucose hydrogen
breath test for SIBO and lactulose hydrogen breath test for OCTT.
Primary endpoint was reversal of MHE.
Mortality.
Arterial ammonia.
Small intestinal bowel overgrowth.
Orocaecal transit time.
Malaguarnera 2010
Mittal 2009
• Electrolyte impairment (serum sodium < 130 or > 150 meq/dL, serum potassium <
3.0 or > 5.5 meq/dL).
• Recent alcohol use (< 6 wk) as reported by the person, recent use of antibiotic,
lactulose, or LOLA (< 6 wk), use of psychotropic drugs in last 6 weeks.
• TIPS, shunt surgery.
• Hepatocellular carcinoma.
• Severe comorbidity such as congestive heart failure, pulmonary disease,
neurological and psychiatric problems impairing quality of life, or poor vision
precluding neuropsychiatric assessment.
Notes Author provided additional information on ’Risk of bias’ criteria. Contacted Professor BC
Sharma on 14 October 2010.
Author provided unpublished data.
Funding source: not stated
Allocation concealment Low risk “The sequences were concealed until a de-
cision to enroll a patient was taken after as-
sessment for eligibility and after receiving
informed consent.”
Mouli 2014
Interventions Participants were randomised to receive either lactulose (Lark Laboratories; Rajasthan,
India) or probiotics (VSL#3; Sun Pharmaceutical, Mumbai, India) for a period of 2
months. Lactulose was given at a dose of 30 to 60 mL/day orally to ensure 2 to 3 soft stools
per day. VSL#3 was given at a dose of 4 capsules (2 twice a day) per day, amounting to a total
of 450 billion CFU/day; each capsule contained 112.5 billion viable lyophilised bacteria of
4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei
DSM 24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium
(B longum DSM 24736, B breve DSM 24732, B infantis DSM 24737), and 1 strain of
Streptococcus (S thermophilus DSM 24731).
Outcomes The primary outcome measure was improvement of MHE, which was defined as the
normalisation of the prior abnormal neuropsychometric/neurophysiological tests. The
secondary outcome measure was change in venous ammonia level with study intervention.
The study endpoints were: (i) completion of 2 months of treatment; (ii) development of
overt HE; and (iii) death
Blinding Low risk The objective nature of the tests for MHE
Outcome assessors would likely limit the effect of bias on MHE
recovery outcomes and venous ammonia
Incomplete outcome data Unclear risk “60 patients each were randomized into the
All outcomes lactulose and probiotics groups. Four pa-
tients were dropouts and 19 were lost to
follow up, two patients died and 22 devel-
oped overt encephalopathy, and hence dis-
continued with the trial drugs due to differ-
ent management protocols for overt HE. At
the end of intervention (i.e. at 2 months)
, 40 patients in the lactulose group and 33
patients in the probiotics group were taken
for analysis who had completed the study
medications.”
Selective outcome reporting Low risk Outcomes were reported as per protocol
found registered at ClinicalTrials.gov iden-
tifier NCT01008293
Funding source Low risk “We thank the Indian Council of Medical
Research (ICMR) for providing a research
grant and CD Pharmaceuticals India for
providing probiotic VSL#3 and lactulose”
Nair 2008
Participants Setting: Study was conducted in Department of Neurology, Medical College Calicut, in
collaboration with Department of Gastroenterology
Country: India
Age range (years): range unspecified, mean 49.5 ± 8.05 SD
Interventions Group A was given probiotic preparation in a dose of 1-gram sachet containing not less
than 1.25 billion cells of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium
longum, and Saccharomyces boulardii 3 times daily after meals, and group B was given
placebo powder in identically looking sachet in a similar dose
Outcomes Number Connection Test-A, arterial ammonia, auditory evoked response tests, visual
evoked response tests
Notes Contacted Dr R Nair on 22 December 2014, full manuscript provided, awaiting additional
information from author
Funding source: “Sachets of drug as well as placebo were supplied by Aristo pharmaceuticals
Pvt. Ltd. No financial aid of any form was received from any source for the purpose of
conducting this trial”. This study declared the funding source and was deemed to be
independently funded
Sequence generation Low risk Randomisation was done using random ta-
ble allocation.
Allocation concealment Low risk Treatment allocation was concealed from in-
dividual who did the allocation
Funding source Low risk Sachets of drug as well as placebo were sup-
plied by Aristo Pharmaceuticals Pvt. Ltd
No financial aid of any form was received
from any source for the purpose of conduct-
ing this trial
Pereg 2011
Blinding Unclear risk Only stated in the title that the trial was dou-
Participants ble-blinded - no specific details provided on
who was blinded or how blinding was con-
ducted
Blinding Unclear risk Only stated in the title that the trial was dou-
Personnel ble-blinded - no specific details provided on
who was blinded or how blinding was con-
ducted
Blinding Unclear risk Only stated in the title that the trial was dou-
Outcome assessors ble-blinded - no specific details provided on
who was blinded or how blinding was con-
ducted
Incomplete outcome data High risk Four participants “dropped out”, no further
All outcomes details provided
Interventions Control group was given compound vitamin B tablets, 2 tablets each time, 3 times a day.
Treatment group was given bifid triple viable, 2 tablets each time, 3 times a day
Outcomes Outcome measurements: Blood ammonium, ALT, and NCT were measured 1 day before
treatment and again 1 day after treatment. NCT used the NCT-A version, where the
patient orders the numbers 1 to 25 and the time it takes to complete the test is recorded,
including time spent correcting any mistakes. NCT was measured in seconds; longer time
to complete indicates abnormality
Saji 2011
Interventions Group A received probiotic preparation in a dose of 1-gram sachet containing not less than
1.25 billion spores of Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium
longum, and Saccharomyces boulardii, 3 times daily after meals. Group B received placebo
powder in identical-looking sachet 3 times daily after meals. The duration of treatment
was 4 weeks
Outcomes At the end of 4 weeks, participants’ symptoms were recorded and a thorough examination
was done for any features of overt encephalopathy. Investigations were done to reassess
the Child’s score. Arterial ammonia, NCT -A, and evoked responses were repeated
Notes Both sachets of probiotics and placebo were supplied by Aristo Pharmaceuticals Pvt. Ltd
Mumbai
Contacted Dr S Saji on 14 March 2015, awaiting additional information from author
Funding source: not stated
Sequence generation Low risk “Randomization was done using random ta-
ble allocation.”
Incomplete outcome data Low risk “There were 3 drop-outs, one in the probi-
All outcomes otic group and two in the placebo group.”
“The data reported are only for the intent-
to-treat population.”
Selective outcome reporting Low risk “At the end of 4 weeks patients symptoms
were recorded and a thorough examina-
tion was done for any features of overt en-
cephalopathy. Investigations were done to
reassess the Child’s score. Arterial ammonia,
number connection test-A and evoked re-
sponses were repeated.”
All of the above outcomes except the Child’s
score were reported
Allocation concealment High risk Trial personnel were able to view the alloca-
tion sequence.
Incomplete outcome data High risk 13 participants in the control group and 5
All outcomes participants in the lactulose plus probiotic
group were lost to follow-up. Reasons are
unclear
Selective outcome reporting Low risk All outcomes reported in the methods (psy-
chometric tests outcomes, P300 auditory
event-related potential, venous ammonia
level, and Child-Pugh classification) were
measured and discussed on baseline and af-
ter 1 month. Personal communication with
the author revealed that no other outcomes
were assessed
Sharma 2014
Interventions After the diagnosis of MHE was made, the participants were randomised into 4 groups:
DRUG 1 (l-ornithine l-aspartate (LOLA), 2 sachets 3 g each thrice a day) n = 31, DRUG
2 (tab rifaximin 400 mg thrice a day) n = 31, DRUG 3 (cap Velgut (5 billion CFUs of
Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus aci-
dophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus
thermophilus, Saccharomyces boulardii)1 capsule twice a day) n = 32, and DRUG 4 (placebo
twice a day) n = 30
Outcomes 1. Death.
2. Recovery from MHE.
3. Overt HE.
4. CFF.
Sequence generation Low risk “the block randomization method was uti-
lized for random allocation of drugs.”
Allocation concealment Low risk “The sequence remained concealed from the
investigator and the generator of the ran-
dom blocks did not participate in screening,
enrolment, or drug delivery.”
Incomplete outcome data Unclear risk A total of 20 participants could not be fol-
All outcomes lowed up to the end of the study: 10 were
lost to follow-up, 6 went into overt HE, and
4 expired. Of the total 10 participants lost
to follow-up, the most were in the LOLA
group (4 cases) followed by the placebo
group (3 cases). The largest number of dete-
riorations in clinical state, i.e. development
of overt HE, occurred in the placebo group
(3 cases). Of the total 4 deaths, 2 were in
the placebo group and 1 each was in the ri-
faximin and Velgut groups. There were no
deaths in the LOLA group
Shavakhi 2014
Participants Setting: The study was conducted on adults with MHE referred consecutively to the
gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and
October 2012
Country: Iran
Age range (years): range not given, mean age (SD) 38.4 (9.6) years
Total numbers randomised: total (Gp-LPr/Gp-L): 46 (23/23)
Sex (M/F): 48/12
Language: unspecified
Stage/severity of hepatic encephalopathy: minimal hepatic encephalopathy; Child-Pugh
score A/B/C: 8/37/14 (data missing for 1 participant)
Cause of hepatic encephalopathy: viral/autoimmune/other: 44/11/5
Inclusions: The study was conducted on adults with MHE referred consecutively to the
gastroenterology clinic of a university hospital in Isfahan city (Iran) between June and
October 2012. Cirrhosis was diagnosed histologically (unless biopsy was contraindicated)
and on clinical and radiological grounds. Diagnosis of MHE was based on the Conn’s
modification of the Parsons-Smith classification (grade 1 and above)
Exclusions: People with overt HE, known brain lesions, active gastrointestinal bleeding,
active ongoing infection, renal impairment (serum creatinine > 2 mg/dL), electrolyte
abnormalities (serum sodium < 130 or > 150 meq/dL, serum potassium < 3.0 or > 5.5
meq/dL), and those who had received HE treatments such as lactulose and antibiotics or
consumed benzodiazepines, narcotics, opioids, or alcohol in the preceding 8 weeks were
not included in the trial
Interventions Participants were randomised into 2 groups: lactulose + probiotic (Gp-LPr) and lactulose
+ placebo (Gp-L). Another non-randomised group of participants who received probiotic
alone (Gp-Pr) were included separately for further comparisons; this group received neither
placebo nor lactulose.
All participants received routine treatment for cirrhosis, including diuretics, β-blockers,
endoscopic treatment, and a salt-restricted diet but not protein-restricted diet in those
with ascites. For Gp-LPr and Gp-L, lactulose syrup was administered as 30 to 60 mL/day
in divided doses for a stool frequency of 2 to 3 soft defecations per day. For Gp-LPr and
Gp-Pr, a multistrain probiotics compound, Balance (Protexin Co., Somerset, UK), was
administered twice daily after meal. Balance capsules contain 7 bacteria species including
Lactobacillus strains (L casei, L rhamnosus, L acidophilus, and L bulgaricus), Bifidobacterium
strains (B breve and B longum), and Streptococcus thermophilus. Total viable count is 1 × 108
CFU per capsule. Other ingredients are fructo-oligosaccharides as prebiotic, magnesium
stearate, and hydroxypropyl methyl cellulose. These interventions were continued for 14
consecutive days, and compliance was assessed with pill and bottle count
Outcomes Primary endpoint was improvement in MHE status, which was assessed by applying the
PHES at baseline, 14 days after start of the intervention (14th day), and then at 8 weeks’
follow-up (10th week). The PHES is a set of neuropsychological tests including the Line-
Tracing Test, Digit Symbol Test, Serial Dotting Test, and Number Connection Test.
These tests are used in the diagnosis and grading of MHE and examine visual perception,
visuospatial orientation, visual construction, motor speed and accuracy, concentration,
attention, and memory. Participants could achieve between +6 and −18 points.
Secondary outcomes were development of overt HE, admission to hospital for any other
complication of cirrhosis, or death
Notes The study was also registered at Iranian Registry of Clinical Trials
(IRCT201211012417N9)
Contacted Dr A Shavakhi on 14 March 2015, received no response
Funding source: “Source of Support: Isfahan University of Medical Sciences, Potential
competing interests: None declared”. This study declared the funding source and was
deemed to be independently funded
Blinding Unclear risk Although the trial was not blinded, the ob-
Outcome assessors jective nature of the tests for MHE would
likely limit the effect of bias on MHE re-
covery outcomes
Incomplete outcome data Low risk “After randomization, two patients from the
All outcomes Gp-L, four patients from the Gp-LPr, and
three patients from the Gp-Pr declined to
receive intervention. Finally, 60 adult pa-
tients with cirrhosis (80% male, mean age
38.4 ± 9.6 years) started the trial and com-
pleted the intervention.”
“During the follow-up period, one patient
from each of the Gp-LPr and Gp-L was lost
to follow-up.”
Selective outcome reporting Unclear risk The outcomes to be measured were not
clearly specified in trial as registered at Ira-
nian Registry of Clinical Trials (trial num-
ber IRCT201211012417N9)
Interventions 72 participants were equally randomised into Lactobacillus plantarum 299v at a dose of
1010 units per sachet (Lp299v) or identical placebo, given twice a day for a period of 12
weeks
Zhao 2013
Interventions Standard treatment of liver cirrhosis (control) compared to both lactulose (twice daily, 30
to 60 mL with soft stools 2 to 3 times daily) and probiotic (110 million CFU twice daily
for 1 month) groups
Zhitai 2013
Interventions Treatment group: routine liver protection against hepatic coma therapy, oral or nasal
feeding of live Bacillus cereus capsules
Control group: conventional liver protection against hepatic coma therapy, oral or nasal
feeding of lactulose
Interventions Group A received lactulose (30 to 60 mL/day); group B received a probiotic (1 capsule
containing 106 Lactobacillus acidophilus 3 times/day); and group C was the control.
Blinding Low risk Although the trial was not blinded, the ob-
Outcome assessors jective nature of the tests for MHE would
likely limit the effect of bias on MHE re-
covery outcomes
Funding source Unclear risk “The authors declared that there is no con-
flict of interest”
ALT = alanine aminotransferase; BAEP = brainstem auditory evoked potentials; CFF = critical flicker frequency; CFU = colony forming
unit; CNS = central nervous system; CT = computed tomography; CTP = Child-Turcotte-Pugh; DST = digit symbol test; FCT =
figure connection test; GI = gastrointestinal; HBV = hepatitis B virus; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus;
HE = hepatic encephalopathy; HRQOL = health-related quality of life; IL-6 = interleukin 6; LOLA = L-ornithine-L-aspartate; MCS
= Mental Component summary; MELD = Model for End-Stage Liver Disease; MHE = minimal hepatic encephalopathy; MRS =
Magnetic resonance spectroscopy; NASH = non-alcoholic steatohepatitis;
NCT = Number Connection Test; NIH = National Institutes of Health; NPT = neuropsychological testing; OCTT = orocaecal transit
time;
OHE = overt hepatic encephalopathy; PHES = psychometric hepatic encephalopathy score; QOL= quality of life; SD = standard
deviation; SDT = serial dotting test; SF-36 = 36-Item Short Form Health Survey; SIBO = small intestinal bacterial overgrowth; TIPS
= transjugular intrahepatic portosystemic shunt; TNF alpha = tumour necrosis factor-alpha; USG = ultrasonography
ACTRN12610001021066
fibres: * 2.5 g oat bran; * 2.5 g pectin; * 2.5 g resistant starch; * 2.5 g inulin. Probiotic bacteria: * Lactobacillus paracasei
ssp paracasei 10 x 10¹¹; * Lactobacillus plantarum 10 x 10¹¹; * Leuconostoc mesenteroides 10 x 10¹¹; * Pediococcus
pentosaceus 10 x 10¹¹ (Medipharm). Dose is 1 sachet/day mixed with juice, jam, or honey according to participant’s
tolerance. Duration of supplementation is 56 days
Branched-chain amino acid preparation is HepatAmine (Nutricia), which is a mixture of branched-chain amino acids
+ sugars. Dose is 1 sachet at night mixed with 200 mL lemonade or fruit juice. Duration of supplementation is 56
days
Placebo for synbiotics is 10 g crystalline starch packaged similarly to Synbiotic 2000 Forte. Dose is 1 sachet/day
mixed with juice, jam, or honey according to participant’s tolerance. Duration of supplementation is 56 days. Placebo
for BCAAs is 29 g glucose + 15 g Vitafresh. Dose is 1 sachet at night mixed with 200 mL lemonade or fruit juice.
Duration of supplementation is 56 days
Notes Data obtained from trial registry www.anzctr.org.au/, trial ID: ACTRN12610001021066.
IRCT201211012417N9
Outcomes Consiousness level. (Time point: beginning and 14 days postintervention. Method of measurement: questionnaire.)
NCT01798329
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 All-cause mortality 7 404 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.23, 1.44]
1.1 2 weeks 1 46 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 1 month 1 80 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.01, 7.95]
1.3 2 months 3 117 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.11, 4.66]
1.4 3 months 2 161 Risk Ratio (M-H, Random, 95% CI) 0.57 [0.19, 1.74]
2 No recovery (incomplete 10 574 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.56, 0.79]
resolution of clinical
symptoms)
2.1 1 month 4 228 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.58, 0.96]
2.2 2 months 3 117 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.38, 1.10]
2.3 3 months 3 229 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.43, 0.78]
3 Adverse events 11 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Overt hepatic 10 585 Risk Ratio (M-H, Random, 95% CI) 0.29 [0.16, 0.51]
encephalopathy
3.2 Infection 1 37 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.3 Hospitalisation 3 163 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.11, 4.00]
3.4 Intolerance leading to 1 37 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
discontinuation
3.5 Change of/or withdrawal 9 551 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.46, 1.07]
from treatment
4 Quality of life 3 Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 SF-36 Physical 1 20 Mean Difference (IV, Random, 95% CI) 0.0 [-5.47, 5.47]
4.2 SF-36 Mental 1 20 Mean Difference (IV, Random, 95% CI) -4.0 [-9.82, 1.82]
4.3 Change in Total SIP Score 2 95 Mean Difference (IV, Random, 95% CI) -3.66 [-7.75, 0.44]
4.4 Change in SIP 2 95 Mean Difference (IV, Random, 95% CI) -3.54 [-4.95, -2.12]
Psychological Score
4.5 Change in SIP Physical 2 95 Mean Difference (IV, Random, 95% CI) -2.94 [-4.44, -1.44]
Score
5 Plasma ammonia concentration 10 705 Mean Difference (IV, Random, 95% CI) -8.29 [-13.17, -3.41]
(final and change scores)
(µmol/L)
5.1 1 month 5 357 Mean Difference (IV, Random, 95% CI) -5.55 [-10.67, -0.42]
5.2 2 months 4 211 Mean Difference (IV, Random, 95% CI) -5.11 [-14.56, 4.34]
5.3 3 months 1 73 Mean Difference (IV, Random, 95% CI) -6.79 [-10.39, -3.19]
5.4 6 months 1 64 Mean Difference (IV, Random, 95% CI) -31.08 [-40.50, -21.
66]
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 All-cause mortality 2 200 Risk Ratio (M-H, Random, 95% CI) 5.00 [0.25, 102.00]
1.1 1 month 1 80 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
1.2 2 months 1 120 Risk Ratio (M-H, Random, 95% CI) 5.00 [0.25, 102.00]
2 No recovery (incomplete 7 430 Risk Ratio (M-H, Random, 95% CI) 1.01 [0.85, 1.21]
resolution of clinical
symptoms)
2.1 1 month or less 5 255 Risk Ratio (M-H, Random, 95% CI) 0.94 [0.75, 1.20]
2.2 2 months 1 95 Risk Ratio (M-H, Random, 95% CI) 0.98 [0.65, 1.47]
2.3 3 months 1 80 Risk Ratio (M-H, Random, 95% CI) 1.24 [0.85, 1.80]
3 Adverse events 7 Risk Ratio (M-H, Random, 95% CI) Subtotals only
3.1 Overt hepatic 6 420 Risk Ratio (M-H, Random, 95% CI) 1.17 [0.63, 2.17]
encephalopathy
3.2 Infection 0 0 Risk Ratio (M-H, Random, 95% CI) 0.0 [0.0, 0.0]
3.3 Hospitalisation 1 80 Risk Ratio (M-H, Random, 95% CI) 0.33 [0.04, 3.07]
3.4 Intolerance leading to 3 220 Risk Ratio (M-H, Random, 95% CI) 0.35 [0.08, 1.43]
discontinuation
3.5 Change of/or withdrawal 7 490 Risk Ratio (M-H, Random, 95% CI) 1.27 [0.88, 1.82]
from treatment
4 Health-related quality of life 1 Mean Difference (IV, Random, 95% CI) Subtotals only
4.1 Change in Total SIP Score 1 69 Mean Difference (IV, Random, 95% CI) 0.65 [-1.13, 2.43]
4.2 Change in SIP 1 69 Mean Difference (IV, Random, 95% CI) 0.48 [-1.04, 2.00]
Psychological Score
4.3 Change in SIP Physical 1 69 Mean Difference (IV, Random, 95% CI) 0.38 [-0.61, 1.37]
Score
5 Plasma ammonia concentration 6 325 Mean Difference (IV, Random, 95% CI) -2.93 [-9.36, 3.50]
(final and change scores)
(µmol/L)
5.1 1 month or less 5 248 Mean Difference (IV, Random, 95% CI) -4.30 [-13.17, 4.56]
5.2 3 months 1 77 Mean Difference (IV, Random, 95% CI) 1.16 [-1.96, 4.28]
1 2 weeks
Shavakhi 2014 0/23 0/23 Not estimable
1 1 month
Liu 2004 10/20 10/20 6.0 % 1.00 [ 0.54, 1.86 ]
Mean Mean
Study or subgroup Probiotic No intervention Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 SF-36 Physical
Bajaj 2008 14 -39 (5) 6 -39 (6) 100.0 % 0.0 [ -5.47, 5.47 ]
Mittal 2009 34 -6.24 (3.4) 31 -1.05 (2.6) 65.0 % -5.19 [ -6.65, -3.73 ]
Mittal 2009 34 -4.69 (3.5) 31 -1.13 (2.4) 95.3 % -3.56 [ -5.01, -2.11 ]
Mittal 2009 34 -3.21 (2.1) 31 0.05 (2) 85.1 % -3.26 [ -4.26, -2.26 ]
-10 -5 0 5 10
Favours probiotic Favours control
Mean Mean
Study or subgroup Probiotic No intervention Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 1 month
Sharma 2008 30 68.7 (28.4) 31 69.3 (33.3) 5.8 % -0.60 [ -16.11, 14.91 ]
Ziada 2013 26 52.47 (21.72) 25 74.54 (23.33) 7.4 % -22.07 [ -34.45, -9.69 ]
Malaguarnera 2010 63 66.2 (28.8) 62 71.45 (29.8) 8.7 % -5.25 [ -15.53, 5.03 ]
Zhao 2013 40 72.87 (15.84) 40 76.35 (10.23) 11.7 % -3.48 [ -9.32, 2.36 ]
Liu 2004 20 38.6 (3.9) 20 41.5 (5.2) 13.4 % -2.90 [ -5.75, -0.05 ]
Bajaj 2014a 14 29.3 (13.7) 16 43.4 (19.7) 7.6 % -14.10 [ -26.13, -2.07 ]
Malaguarnera 2010 63 55.9 (15.5) 62 65.25 (22.3) 11.1 % -9.35 [ -16.09, -2.61 ]
1 1 month
Zhao 2013 0/40 0/40 Not estimable
1 1 month or less
Loguercio 1995 3/18 8/19 2.4 % 0.40 [ 0.12, 1.26 ]
Mean Mean
Study or subgroup Probiotic Lactulose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
-4 -2 0 2 4
Favours probiotic Favours lactulose
Mean Mean
Study or subgroup Probiotic Lactulose Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
1 1 month or less
Sharma 2008 31 75.7 (33) 31 69.3 (33.3) 9.9 % 6.40 [ -10.10, 22.90 ]
Loguercio 1995 14 57.3 (19.8) 11 62.7 (17.3) 11.6 % -5.40 [ -19.96, 9.16 ]
Ziada 2013 26 52.47 (21.72) 24 55.64 (28.1) 12.2 % -3.17 [ -17.17, 10.83 ]
Loguercio 1987 16 58.72 (5.87) 15 76.33 (17.62) 17.9 % -17.61 [ -26.98, -8.24 ]
Zhao 2013 40 72.87 (15.84) 40 71.56 (16.17) 21.4 % 1.31 [ -5.70, 8.32 ]
-50 -25 0 25 50
Favours probiotic Favours lactulose
ADDITIONAL TABLES
Table 1. Types of probiotics used across studies
Mouli 2014 VSL#3 (4 strains of Lactobacillus (L acidophilus DSM 24735, L plantarum DSM 24730, L paracasei DSM
24733, L delbrueckii subsp. bulgaricus DSM 24734), 3 strains of Bifidobacterium (B longum DSM 24736,
B breve DSM 24732, B infantis DSM 24737), and 1 strain of Streptococcus (S thermophilus DSM 24731))
Pereg 2011 Lactobacillus acidophilus, Lactobacillus bulgaricus, Bifidobacterium bifidum, Streptococcus thermophilus (Bio
Plus, Supherb, Israel)
Sharma 2014 Velgut ERIS Pharmaceuticals, Ahmadabad, India (Lactobacillus acidophilus,Lactobacillus rhamnosus,Lacto-
bacillus plantarum,Lactobacillus casei,Bifidobacterium longum,Bifidobacterium infantis,Bifidobacterium breve,
Saccharomyces boulardii,Streptococcus thermophilus)
Shavakhi 2014 Balance (Protexin Co., Somerset, UK) Lactobacillus strains (L casei,L rhamnosus,L acidophilus,L bulgaricus)
,Bifidobacterium strains (B breve, B longum), andStreptococcus thermophilus
The Cochrane Hepato-Biliary Group Con- August 2015 (probiot* OR lactobacil* OR bifidobacter*) AND (’hepatic en-
trolled Trials Register cephalopath*’ OR (liver AND (diseas* OR cirrhosis*)))
Cochrane Central Register of Controlled 2016, Issue 5. #1 LIVER CIRRHOSIS explode all trees (MeSH)
Trials (CENTRAL) in the Cochrane Li- #2 (liver cirrhosis):ti,ab,kw
brary #3 HEPATIC ENCEPHALOPATHY explode all trees (MeSH)
#4 (hepatic encephalopathy):ti,ab,kw
#5 (liver next cirrhosis)
#6 (hepatic next encephalopathy)
#7 (#1 or #2 or #3 or #4 or #5 or #6)
#8 probiotics explode all trees (MeSH)
#9 (probiotics):ti,ab,kw
#10 lactobacillus explode all trees (MeSH)
#11 (lactobacillus):ti,kw,ab
#12 bifidobacterium explode all trees (MeSH)
#13 (bifidobacterium):ti,kw,ab
#14 (#8 or #9 or #10 or #11 or #12 or #13)
#15 (#7 and #14)
MEDLINE Ovid 1946 to June 2016. #1 randomised controlled trial.pt. [#1 randomized controlled
trial.pt. in 2015 update]
#2 controlled clinical trial.pt.
#3 randomized.ab.
#4 placebo.ab.
#5 drug therapy.fs.
#6 randomly.ab.
#7 trial.ab.
#8 groups.ab.
#9 or/1-8
#10 animals.sh.
#11 9 not 10
#12 exp hepatic encephalopathy/
#13 hepatic encephalopathy.tw
#14 exp liver cirrhosis/
#15 liver cirrhosis.tw
#16 12 or 13 or 14 or 15
#17 exp probiotics/
#18 probiotic.tw
#19 exp lactobacillus/
#20 lactobacillus.tw
#21 exp bifidobacterium/
#22 bifidobacterium.tw
#23 17 or 18 or 19 or 20 or 21 or 22
#24 11 and 16 and 23
Science Citation Index Expanded (Web of 1900 to June 2016. # 1 TS=(probiotic OR probiot* OR lactobacil* OR bifidobacter*)
Science) # 2 TS=(hepatic encephalopath* OR liver diseas*)
# 3 #1 AND #2
# 4 TS=(random* OR blind* OR placebo*)
# 5 #3 AND #4
WHAT’S NEW
Last assessed as up-to-date: 14 June 2016.
14 June 2016 New citation required and conclusions have changed The conclusions changed from “While probiotics appear
to reduce plasma ammonia concentration when compared
with placebo or no intervention, we are unable to conclude
that probiotics are efficacious in altering clinically relevant
outcomes” (McGee 2011), to “Overall, probiotics appear to
help symptom resolution, reduce plasma ammonia concen-
trations, and result in less overt hepatic encephalopathy com-
pared with no treatment, although we consider the evidence
to be of low quality”
14 June 2016 New search has been performed June 2016 search update: Seven new trials added. The review
is now based on 21 trials with a total of 1420 participants
DECLARATIONS OF INTEREST
RD: is a recipient of a scholarship from The University of Sydney. This scholarship had no influence on the conduct of this review.
RMG: none to declare.
SMR: is an author of a trial included in the review. SMR had no influence on its inclusion or data extraction and analysis.
ACW: none to declare.
SOURCES OF SUPPORT
Internal sources
• No financial support was received for the conduct of this review, Australia.
External sources
• No financial support was received for the conduct of this review, Australia.
• The search terms used have been updated to keep the search strategy up to date.
• The outcome adverse events, which previously reported “number of adverse events”, has been expanded to include overt hepatic
encephalopathy, infections, hospitalisations, intolerance leading to discontinuation, and change of/or withdrawal from treatment.
• The previous outcome “change of/or withdrawal from treatment” is now a subgroup of adverse events.
• Final and change scores have been combined into the same analysis for plasma ammonia concentration.