Efficacy of Probiotic Therapy in Preventing Overt Hepatic Encephalopathy.

Adam Rahman ; Amindeep Sandhu ; Bandar Al-Judaibi ; Karim Qumosani ; Jeremy Burton ; Gregor Reid

Volume 2016: (1)Page 12-18
DOI: https://doi.org.10.22433/2016/09/4

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  • Rahman, A. (2016). Efficacy of Probiotic Therapy in Preventing Overt Hepatic Encephalopathy.. 2016: (1), 12-18. Retrieved from http://canadianjournalofnutrition.ca/article/efficacy-of-probiotic-therapy-in-preventing-overt-hepatic-encephalopathy/

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Hepatic encephalopathy (HE) is common and is characterized by several neuropsychiatric symptoms ranging from mild impairments in cognitive function to coma, experienced by cirrhotic patients. Advanced encephalopathy or overt hepatic encephalopathy  is associated with poor outcomes including increased mortality, but the consequences of reduced physical and mental function as well as reductions in quality of life can be just as devastating. The cost of hepatic encephalopathy for the healthcare system is exorbitant. While therapies exist for severe encephalopathy, increasingly researchers are aiming to prevent clinically overt hepatic encephalopathy. There is growing interest in the use of probiotic products, which have an excellent physiological basis to reduce the absorption of ammonia, a key neurotoxin in precipitating encephalopathy. The present review discusses hepatic encephalopathy, the various classifications, and reviews literature for probiotics studying the effects on preventing severe encephalopathy. We subsequently postulate on the potential studies and strategies for research studies moving forward.

Ø  The authors declare no conflict of interest

Ø  1Department of Medicine, Division of Gastroenterology, Western University, London, Ontario, Canada. 2 Lawson Health Research Institute, London, Ontario, Canada.

3Department of Surgery, Schulich School of Medicine, Western University. 4Program of Experimental Medicine, Western University Department of Medicine. 5 Department of Microbiology and Immunology, Western University

Ø  Corresponding Author

Adam Rahman MD MSc (EPID) FRCPC 

Assistant Professor of Medicine

Division of Gastroenterology, Western University adam.rahman@sjhc.london.on.ca

268 Grosvenor St. London, Ontario, N6A 4V2 Room B0-689, St. Joseph’s Health Centre

© Rahman et. al. This is an open access journal distributed under the terms of the Creative Common License BY NC


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Hepatic encephalopathy (HE) is condition of a neuropsychiatric symptoms most commonly associated with liver cirrhosis [1].  Clinically overt hepatic encephalopathy is common and develops in 30-45% of cirrhotic patients [1-3]. This severe and clinically apparent form of this type of encephalopathy is termed overt hepatic encephalopathy (OHE) and results in marked limitations in functional status, quality of life and increased mortality [1, 4, 5]. While the pathogenesis of HE is complex, ammonia is the most well described neurotoxin in precipitating HE [6]. The gut is the effectively the only source of ammonia, produced by enterocyte metabolism of glutamine [6] and catabolism of protein and urea by colonic bacteria [6].  In cirrhosis, the liver cannot efficiently metabolize ammonia delivered by portal vein into glutamine, which results in entry of ammonia into the systemic circulation [6]. Subsequently, ammonia crosses the blood brain barrier compromising astrocyte function, a critical component in pathogenesis of HE [6-11] (Figure 1).


Standard Therapy for HE

Lactulose is the standard therapy in clinically overt hepatic encephalopathy [12]. It is disaccharide that cannot be catabolized into individual monosaccharides by the small bowel enterocytes, due to lack of specific disaccharidase activity [13]. Lactulose enters the colon unaltered where colonic bacteria then metabolize it into short chain fatty acids lowering the pH.  The lower pH favors the formation of the ammonium ion NH4+ rather than the absorbable ammonia NH3, consequently reducing plasma ammonia concentrations [12,13].  However, lactulose is not well tolerated [9]. Moreover, a recent systematic review found that the use of lactulose or was ineffective compared to placebo when considering studies of high methodological quality [13,14]. While other therapies including antibiotic therapy exist, many are not available in Canada, such as rifaximin, and are limited by cost [11] and others limited by efficacy [13] (See Table 1).


Potential Role for Probiotics in HE

The need for better, well-tolerated and cost effective therapies have turned the attention of researchers to probiotics. In the most basic definition, are live microorganisms that when given in adequate amounts provide benefit to the host (WHO) these are usually laboratory designed and clinically tested formulations of non pathogenic commensal or food related microorganisms that have beneficial properties for the host [13]. Probiotics offer a powerful pathophysiologic mechanism of meaningful alterations gut flora that may reduce portal vein ammonia absorption by favoring colonization of acid-resistant, non-urease producing bacteria [15].

Last year, researchers from India have completed an open label randomized control trial where they enrolled cirrhotic patients with subtle findings of encephalopathy, appropriately termed minimal hepatic encephalopathy, or MHE. The patients who received commercially available probiotics experienced substantively lower rates of overt hepatic encephalopathy [16]. Buoyed by this recent study, we set to review hepatic encephalopathy, the differences and relationship between minimal hepatic encephalopathy and overt hepatic encephalopathy, and to make recommendations about further research in this important field.

Minimal Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric complication occurring in the context of acute or chronic liver dysfunction, porto-systemic shunting or any combination of those entities [17].  HE is subcategorized into two separate primary components: overt HE (OHE) and minimal HE (MHE).  OHE manifests through a constellation of commonly recognized symptoms, ranging from lack of awareness, shortened attention span and euphoria (grade I) to a coma (grade IV) [17] (Table 2).


More difficult to diagnose is MHE, often termed “subclinical encephalopathy”.  It is characterized by distinct abnormalities on psychometric examination with a normal neuropsychiatric examination [17].  The prevalence of MHE is approximated at 55% in the setting of cirrhosis [18].  MHE increases the risk of the development of OHE and may have negative consequences on survival [3].  Diminished psychometric performance, evidence of subtle cognitive decline and correlations with driving impairment and increased motor vehicle collisions have been documented with MHE [19-21].  In addition, negative effects on quality of life, decreased executive functioning, impaired memory and sleep disturbances have also been demonstrated with MHE [22-24]. The annual rate of progression from no MHE to MHE in cirrhotic patients is 19% [25].

The diagnosis of MHE can be difficult, and several diagnostic methods have been described, including that of neuropsychological tests, computerized tests and other experimental methods but no ideal test for MHE currently exists.  Given this heterogeneity in diagnosis, a Working Party at the 11th World Congress of Gastroenterology recommended that the diagnosis require a normal mental status and impairment in performance in at least two psychometric tests, including Number Connection Test A and B (NCT-A, NCT-B), Block Design Test (BST) and Digit Symbol Test (DST) [17].  Recommendations were also made to include additional psychometric testing and electroencephalography testing when possible [26].

Given the increasing body of literature demonstrating the negative outcomes in MHE and the potential of conversion to OHE (estimated up to 23% over a one year period [27]), various treatment modalities have been suggested, most of which are aimed at reducing blood ammonia levels.  However, MHE is often not treated outside of clinical trials given the difficulty of diagnosis and lack of overt symptomatology.  Non-absorbable disaccharides, such as lactulose, have some empiric evidence in improving psychometric tests and possible health-related quality of life (HRQOL) in MHE [28].  Compliance-related side effects often limit the effectiveness of such interventions, due to gastrointestinal complaints and self-titration of therapy to achieve the 2 to 3 bowel movements per day.  There is limited randomized data exists documenting the efficacy and cost effectiveness of antibiotics, including rifampin, in MHE.

Impact of Encephalopathy

The burden of hepatic encephalopathy is substantial to both the patient and the healthcare system [29]. Overt hepatic encephalopathy is the second most common reason for hospitalization of cirrhotic patients, and is the most cause for readmission to hospital [30]. Estimates of cost to the healthcare system in Canada are not available but estimates in the United States of America range up to $7 billion per year [31-33].  Moreover, hospital stays are longer (8 days vs. 6.8 days). Even on dischagre, cirrhotics with OHE require more primary care visits (18.2 vs. 8.7 contacts per patient year) when compared to cirrhotic patients without HE [32]. This is particularly relevant as encephalopathy is potentially preventable. The true economic costs may be considerable greater when one considers the effect on employment, managing finances, and resultant burden, both financial and otherwise, on family members and caregivers [33].  Overall, overt hepatic encephalopathy (OHE) is associated with a significant increase in mortality (58.1% vs. 32.4%), when compared to cirrhotics with a similar degree of liver dysfunction [33]. This is reflected in the Child-Pugh-Turcotte score which incorporates OHE as a predictor of poor outcomes, and was previously the dominant scoring system utilized in stratifying need for liver transplant [34] (Table 3).  The effects of MHE are more subtle. There is a growing body of literature suggesting that MHE has a substantial effect on quality of life, particularly in activities of daily living requiring motor skills, detailed attention and three dimensional visual-spatial ability [35]. MHE can affect driving ability and several experts recommend assessment of driving history in patients with MHE [20].


Materials and methods

The focus of this article is reviewing the literature regarding the use of probiotics both as a treatment of MHE but more importantly, as a prophylactic measure in preventing OHE.  We chose to study the effects of probiotics on MHE rather than all cirrhotic patients given the high rates of progression of MHE to OHE. Probiotics may be efficacious in HE by altering intrinsic gut flora via the colonization of non-urease-producing organisms, which could subsequently alter levels of gut-derived toxins in the blood.  This may include decreasing ammonia levels in portal circulation [25]. With that said, measuring MHE reliably and being able to demonstrate improvement in MHE status is difficult, as discussed above. Hence, the potential role of probiotics in study is whether or nor probiotics can decrease the rate of progression of MHE to OHE.

We performed an electronic literature search regardless of language was conducted on electronic databases including The Cochrane CENTRAL Register for Controlled Trials (2014), EMBASE (1980+), Scopus (1990 present), EBSCO host (1960 to 2014), PUBMED / MEDLINE (1966 to 2014), OVID (1950 to 2014). The search strategy used to search was for PUBMED search was modified to search other electronic databases. We only studied randomized control trials, meta-analyses and COCHRANE reviews that evaluated the use of probiotics in MHE [36-44].  The results of this literature are summarized in Table 4. Although probiotics were the predominant form of intervention evaluated in MHE, these should be differentiated from prebiotics and synbiotics, which have also been used in various trials [45].   Prebiotics refers to non-digestible ingredients that stimulate the growth and activity of select bacteria in the gut to improve host health, such as fermentable fiber [45].  Probiotics are a live microbial supplement that selectively improves intestinal microbial balance.  Synbiotics are a combination of probiotics and prebiotics [45].


In the past decade, numerous randomized trials have documented the efficacy of probiotics in MHE [36-41] and OHE [44,46-48].  Bajaj et al. [37] studied non-alcoholic cirrhotic patients in 25 patients and demonstrated a 71% reversal Of MHE with probiotics vs. 0% in the control group.  No patient in the interventional arm developed OHE, as opposed to 25% in the untreated group.  They observed excellent adherence to the probiotic regimen.  Mittal et al. [38] compared probiotics, lactulose and L-ornithine L-aspartate (LOLA), a stable salt derivative that may benefit both OHE and MHE [49], to placebo.  Their robust trial with 160 patients demonstrated all three treatment arms were similarly efficacious at significantly improving MHE and HRQOL versus placebo.  In 2014, Sharma et al. [43] examined 124 cirrhotic patients with MHE and the probiotic arm of the study demonstrated 50% improvement of MHE via improved psychometric scoring, significantly higher that of placebo, but comparable to LOLA and rifaximin.  Based on these and other randomized trials listed in Table 4, certainly there is a significant amount of data to suggest that there is a role of probiotics in the treatment of MHE.  No significant adverse events were reported with such therapy and compliance was often excellent, which is often in stark contrast to other therapies like lactulose.

McGee et al. [42] in 2011 completed a COCHRANE review amassing randomized trials comparing probiotics to placebo or no treatment.  They included both OHE and MHE and analyzed a vast array of outcomes.  Of the seven trials meeting the inclusion criteria, five assessed MHE.  There were no significant differences in all-cause mortality, adverse events, symptom resolution or quality of life when probiotics were compared with both placebo (or no intervention) and lactulose.  The authors did not mention specifically how those with MHE improved on probiotics, with respect to psychometric scores.  Overall, the quality of evidence was poor with respect to sample size, consistency of reported outcomes, trial populations, and variations in duration of therapy.  Thus, meaningful conclusions regarding the benefits and risks of probiotic therapy, specifically in MHE, could not be drawn from this review.  Most of the probiotics studied were products from cultured milk products [13].  The list of microorganisms is extensive and includes species and strains of lactic acid bacilli including Lactobacillus and Bifidobacterium, as well as those strains with a shorter history of therapeutic use in humans, such as Escherichia coli, Clostridium butyricum, Streptococcus salivarius, and Saccharomyces boulardii.  The most tested species for hepatic encephalopathy appear to be from the Lactobacillus and Bifidobacterium genera [13].

There is even less literature focusing on the prevention of OHE in the setting of MHE.   Of the more robust and recent trials, Lunia et al. in 2014 [44] published an open-labeled, non-blinded, randomized controlled trial with adult cirrhotic patients with MHE and no previous history of OHE, who were assigned to probiotics (N = 86) versus their control (N = 74).  The psychometric hepatic encephalopathy score (PHES) was used to diagnose MHE, which utilizes a variety of psychometric testing to come to the diagnosis.  Their study demonstrated a significant decrease in the number of patients with MHE following 3 months of therapy in the probiotic group as documented by improved psychometry, in addition to a reduction in the incidence of small intestinal bacterial overgrowth (SIBO) and reduction of arterial ammonia in the treatment arm.  They used commercially available VSL#3 (mixture of non urease-producing organisms including Streptococcus thermophilus, and species of Bifidobacterium and Lactobacillus). The probiotic group also demonstrated a significant reduction in the development of OHE at 8.8% in the probiotic group vs. 20.3% in the control, with a number needed to treat (NNT) of 4.2 (i.e. roughly four patients with cirrhosis and MHE need to be treated with probiotics to prevent one episode of OHE).  On multivariate analysis, MHE, the Child-Turcotte-Pugh score correlated significantly with the development of OHE [44].



We cannot conclude probiotics would be effective in altering progression of MHE to OHE, based on the absence of quality randomized control data to date. However, there are strong literature pointing to positive signals in improvement of outcomes in reducing progression of MHE to OHE and improvement in MHE with probiotic therapy [44].

We argue that the target population for further studies in probiotics should target patients with MHE. This is because of the high rates of progression of MHE to OHE, which is reported as high as 23% per year [28].  In the most recent trial by Lunia et al., there was a similar progression rate was reported at 20.3% at 40 weeks [44].  While one could argue to target all cirrhotic patients, the need for feasible sample sizes mandate further study in MHE patients only. We would also contend that future studies must target patients with higher Child Pugh scores. The Child Pugh classification includes overt hepatic encephalopathy as a defining of the most severe classification, Child Pugh class C. Several studies have demonstrated that advanced Child Pugh score (i.e. class B versus class A) is an independent predictor of progression to overt hepatic encephalopathy [3].

We would also defend our assertion that future studies be powered to primarily determine if OHE can be prevented rather than to determine if improvements in MHE can be achieved with probiotic therapy.  While the burden of MHE cannot be ignored, the modalities utilized to diagnose and monitor MHE are difficult to perform, time consuming and subject to considerable inter-observer variability [14].  Changes in on neuro-psychometric testing do not necessary correlate to improved quality of life or other functional measures in terms of activities of daily living. Moreover, well-formed treatment algorithms do not exist currently. Thus, studies only directed at reducing MHE, will be difficult to design and perform, and interpret. However, what is not in question in that OHE which is clearly defined, easily recognizable with clearly profound consequences for patients, caregivers, and the healthcare system [29,30].

Further study of probiotics is particularly important given the absence of any documented evidence pointing to adverse effects [9] and the devastating short-term and long-term consequences of OHE, as discussed above.

The chose of probiotic to use in a study may be controversial given the heterogeneity of probiotics used, and their may a class effect. However, based on the Lunia study and the results of previous reviews we would recommend probiotic products that contain Lactobacilli and Bifidobacteria [13].


Minimal hepatic encephalopathy poses numerous hazards to the cirrhotic patient, namely that of conversion to OHE and other risks, including that of driving impairment and cognitive decline.  Based on the aforementioned literature, there is a growing body of literature supporting the use of probiotics in MHE.  Multiple randomized studies have demonstrated improved psychometric scoring and resolution of MHE with such therapy.  There is less, but very promising, literature documenting the use of probiotics as prophylaxis against conversion of MHE to OHE.  Probiotics have had no significant documented adverse effects and compliance appears to be excellent, which is often not the case with alternative therapies such as lactulose.  Ultimately, further randomized and blinded studies with larger sample sizes would help to reinforce the practical use of probiotics in the prophylaxis of progression of MHE to OHE.


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