Effects of Probiotic Therapy on

Hepatic Encephalopathy in
Patients with Liver Cirrhosis: an
Updated Meta-Analysis of Six
Randomized Controlled Trials
Pembimbing:
dr. Meliana, Sp.PD

Presentan:
Welly Surya
Background
Liver cirrhotic patients with hepatic encephalopathy have poor
prognosis.

Probiotics alter the intestinal microbiota and reduce the production

of ammonia

Aim: to asses the effect of probiotic therapies on HE in liver cirrhotic

patients.
Introduction
Hepatic encephalopathy (HE) is a serious disorder in patients with
cirrhosis.
Overt HE is estimated to occur in 30%-45% of patients with cirrhosis
Reported studies showed that bowel movement disorders exist in
liver cirrhotic pastiens, which may delay orocecal transit time,
enhance the growth of pathogenic bacteria, and the absorption of
gut toxins. All of these trigger or aggravate HE.
Introduction
Ammonia plays a vital role in etiology and pathogenesis of HE.
Ammonia is released into the portal vein after the absorption by
intestinal epithelium
Then, the ammonia is converted into urea by the liver then excreted
through urine
Intestinal flora produces toxins such as benzodiazepine-like
substances and mercaptans, which may aggravate the development
of HE by increasing the toxicity of ammonia
Methods
Literature Search
All literature that relevant between January 1 1990 and February 21
2014 from databases of PubMed, EMBASE, and the Cochrane Central
Register of Controlled Trials.

The keywords: probiotics, synbiotics, prebiotics, and lactulose.

Criteria
Inclusion
Treatment comparisons were made of outcomes between probiotics and
controls which included no therapy or placebo
At least one of the outcomes mentioned below was included
If the studies were from the same institution and/or authors, the patient must
be different
For dual or multiple publications from the same institution and/or authors,
either the one of higher quality or the latest publication was included.
Criteria
Exclusion
The outcomes and parameters of patient were not clearly reported
itisimpossibletoextracttheappropriate data from the published
results
there is overlap betweenauthorsorcentersinthepublishedliterature
nocomparisonbetweenprobioticandplacebo/ nointervention.
Outcomes of Interest and Data Extraction
Assess the effets of probiotics on clinical indicators, such as:
Serum ammonia
Development of overt HE
Mortality
Constipation

Tworeviewers(XJandMR)independentlyextracted the following

parameters from each study:
first author and year of publication;
study population characteristics;
numberofsubjectswhowereincluded instudies,
clinicalindicatorsincluded
Statistical Analysis
Themeta-analysiswasperformedusingtheRevMan software, (version
5.2, Cochrane collaboration, http://
ims.cochrane.org/revman/download)andSTATA(version
12.0,StataCorp,CollegeStation,TX,USA).
analyzeddichotomousvariablesusingestimationofoddsratio (OR)
with95%confidenceinterval(CI)
Funnel plots with Egger's testandBeggs test were used to evaluate the
publication bias
Ifplotswereasymmetrical,thentrimandfillanalyseswereperformedt
oevaluatethestabilityofoveralleffects.Pvalue<0.05wasconsideredst
atistically significant.
Results
Literature Search
Studycharacteristicsandqualityassessment
The6studiesareallRCTsincludingatotalof496patients:258int
heprobioticsgroupand238in thecontrolgroup. (4 from India, 1
from America, and 1 from Israel).
Sample sized varied from 25-160 patients
Patients matched for age, gender, levels os serum ammonia, overt
HE development, mortality, and constipation.
Thelevelofserumammonia
Probioticshadnosignificanteffectonserumammonia(WMD[95%
CI]:-3.67[-15.71,8.37],P=0.55)
asub- analysis of patients on arterial and venous ammonia
and found that probiotics tend to reduce the arterial
ammonialevels.However,thiseffectwasnotpronounced
invenousammonia
OvertHEdevelopment
The data showed that probiotics significantly reduced overt HE
development (OR [95% CI]: 0.42 [0.26, 0.70], P=0.0007)
Mortality
4 RCTs didnotfindasignificant difference in mortality between
the probiotics group and control group (OR [95% CI]: 0.73
[0.38, 1.41], P=0.35)
Constipation
ThreeRCTs comparedtheeffectofprobioticswith
placeboonconstipationinlivercirrhoticpatients.There
wasnosignificantdifference(OR[95%CI]:0.67[0.29,1.56],
P=0.35)
Discussion
 HE occurs in about 30%-45% of patients with liver cirrhosis,
10%-50% with a transjugular intrahepatic portosystemicshunt
and25%-80%withminimal HE without overt HE. Minimal HE
has the risk of progressiontoovertHE
Probioticsinhibitsthegrowthofpathogenicbacteria
throughacidifyingthegutlumen,competingfornutrients,
andproducingantibacterialsubstances
 Ithasbeen shown that the administration of probiotics to
liver cirrhoticpatientsresultedinamodulationofthegutflora
withasignificantreductionofthequantityofseveral
bacterialpathogensinfecalbacteriologicalanalysis
Probiotics may be beneficial intheprevention and treatment of the
complications of liver cirrhosis.
Probioticsalterthegutfloraanddecreasethe ammonia
production
 30-day administration of probiotic bacteria to liver cirrhotic patients
with minimal HE results in 50% reversal of encephalopathy.
Anotherstudyassessedtheefficacyofa3monthadministrationof
Bifidobacterium longumplusfructo-oligosaccharides in 60 liver
cirrhotic patients with minimal HE.
This combination significantly improved the results of biochemical
and neurophysiological test in minimal HE.
 This analysis also demonstrated that probiotics
therapysignificantlyreducedthenumberofdevelopment
ofovertHEinpatientswithcirrhosis(OR[95%CI]: 0.42 [0.26,
0.70], P=0.0007).
Probiotic did not improve mortality, levels of serum ammonia and
constipation (mortality:OR[95%CI]:0.73[0.38,1.41],
P=0.35;serumammonia:WMD[95%CI]:-3.67[-15.71,
8.37],P=0.55);constipation:OR[95%CI]:0.67[0.29,
1.56],P=0.35).
 probioticsreducesserumlevelsofbilirubinandalanineaminotran
sferaseandimprovestheChild-Pughfunctionalclass,whichmay
contribute tothepreventionofovertHEdevelopment.
Conclusions
The results of this meta-analysis of 496 patients showed that
probiotics are effective in preventing overt HE development in
patients with liver cirrhosis