Treatment Of Minimal Hepatic Encephalopathy Research Articles

Alterations in gut virome are associated with cognitive function and minimal hepatic encephalopathy cross-sectionally and longitudinally in cirrhosis

ABSTRACT Cognitive dysfunction due to minimal hepatic encephalopathy (MHE) adversely impacts patients with cirrhosis and more precise therapies are needed. Gut-brain axis changes are therapeutic targets, but prior studies have largely focused on bacterial changes. Our aim was to determine linkages between individual cognitive testing results and bacteria with the virome using a cross-sectional and longitudinal approach. We included cross-sectional (n = 138) and longitudinal analyses (n = 36) of patients with cirrhosis tested using three cognitive modalities, which were psychometric hepatic encephalopathy score (PHES), inhibitory control test (ICT), Stroop, and all three. Stool metagenomics with virome and bacteriome were analyzed studied cross-sectionally and in a subset followed for development/reversal of MHE repeated at 6 months (longitudinally only using PHES). Cross-sectional: We found no significant changes in α/β diversity in viruses or bacteria regardless of cognitive testing. Cognitively impaired patients were more likely to have higher relative abundance of bacteriophages linked with Streptococcus, Faecalibacterium, and Lactobacillus, which were distinct based on modality. These were also linked with cognition on correlation networks. Longitudinally, 27 patients remained stable while 9 changed their MHE status. Similar changes in phages that are linked with Streptococcus, Faecalibacterium, and Lactobacillus were seen. These phages can influence ammonia, lactate, and short-chain fatty acid generation, which are neuro-active. In conclusion, we found linkages between bacteriophages and cognitive function likely due to impact on bacteria that produce neuroactive metabolites cross-sectionally and longitudinally. These findings could help explore bacteriophages as options to influence treatment for MHE in cirrhosis.

Comparison of the effects of probiotics, rifaximin, and lactulose in the treatment of minimal hepatic encephalopathy and gut microbiota.

Minimal hepatic encephalopathy (MHE) is an early stage in the pathogenesis of hepatic encephalopathy. Intestinal microbiota is involved in the pathogenesis of hepatic encephalopathy and has become an important therapeutic target. Since there is no unified treatment principle for MHE, this study was conducted to determine the safety and efficacy of different intestinal microecological modulators in the treatment of MHE, and to explore the potential mechanism through intestinal microbiota analysis. Patients with liver cirrhosis were screened for MHE using psychometric hepatic encephalopathy score test. Patients diagnosed with MHE were enrolled and received probiotics, rifaximin, or lactulose for 4 weeks. Adverse events were recorded. The psychometric hepatic encephalopathy score test was performed after treatment. Samples of blood and stool were collected at entry and 4 weeks. Blood samples were analyzed to assess blood ammonia, liver, kidney, and hemostatic functions. Stool microbiota were sequenced to confirm changes in microbial composition. Of 323 patients with liver cirrhosis, 74 patients were diagnosed with MHE. In all, 54 patients were enrolled and 52 who agree to follow-up were included in analysis. The recovery rates of MHE patients received probiotics, rifaximin, and lactulose were 58.8% (20/34), 45.5% (5/11), and 57.1% (4/7), respectively. Probiotics and rifaximin improved liver function in MHE patients to a certain extent. Taxonomic compositions of gut microbiota in MHE patients were distinct from healthy people before treatment; the differences were significantly reduced after treatment, and the gut microbiota gradually resembled the structure of healthy individuals. We found that the relative abundance of specific taxa associated with anti-inflammatory and good cognitive functions was increased in MHE patients after treatment. Accordingly, metabolic pathways in MHE patients were altered before and after treatment. Downregulated pathways after probiotics treatment included glycometabolism and degradation of aromatic compounds. After lactulose treatment, degradation pathways of arginine and ornithine showed a downward trend. Probiotics, rifaximin, and lactulose are safe and effective in the treatment of MHE, and improve the composition of gut microbiota to some extent.

Efficacy of probiotics in the treatment of minimal hepatic encephalopathy: A systematic review and meta-analysis.

Patients with minimal hepatic encephalopathy (MHE) have no recognizable clinical symptoms of hepatic encephalopathy (HE), but the mild cognitive and psychomotor deficits have been shown to negatively affect their daily functioning and quality of life. Treatment with probiotics has shown benefit in some clinical trials. This review aimed to systematically analyze the efficacy of probiotics in the treatment of MHE. A systematic search of the electronic databases PubMed, Science Direct, and Cochrane Library was conducted for randomized controlled trials (RCTs) in adult patients with MHE who had been given probiotics intervention. The primary outcomes were reversal of MHE and improvement of neuropsychometric tests, while the secondary outcome was the reduction of serum ammonia. Nine RCTs involving 776 MHE patients were included, consisting of 311 patients receiving probiotics and 465 patients receiving comparator (placebo or no treatment, lactulose, L-ornithine L-aspartate [LOLA], or rifaximin). The meta-analysis showed that probiotics significantly reversed MHE (OR = 3.95, p < 0.0001, 95% CI: 2.05 to 7.60) compared with placebo or no treatment. Probiotics also significantly reduced serum ammonia compared with placebo (pooled mean difference -25.94, p = 0.04, 95% CI: -50.21 to -1.66). However when compared to lactulose and LOLA, probiotics did not show a significant difference in reversal of MHE or reduction of serum ammonia levels. Probiotics were more effective in reversal of MHE and reduced serum ammonia levels in patients with MHE compared to placebo or no treatment, but not more effective than lactulose or LOLA.

Minimal Hepatic Encephalopathy Affects Daily Life of Cirrhotic Patients: A Viewpoint on Clinical Consequences and Therapeutic Opportunities

Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of "overt" HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.

Comparison of the Efficacy of Lactobacillus rhamnosus GG and Lactulose Treatments in Minimal Hepatic Encephalopathy

Objective: Minimal hepatic encephalopathy is a condition characterized by decreased perception and consequently deterioration in quality of life, and there is still limited data on its treatment. The aim of this study is to compare the efficacy of lactulose and Lactobacillus rhamnosus GG treatments by critical flicker frequency test in minimal hepatic encephalopathy patients. Methods: Patients with a critical flicker frequency test result of &lt;39 Hz were considered to have minimal hepatic encephalopathy. Eighty-four minimal hepatic encephalopathy patients were divided into 3 groups as lactulose, Lactobacillus rhamnosus GG, and control group. Critical flicker frequency control was performed 4 weeks after treatment. Critical flicker frequency values before and after treatment were compared according to the treatment groups and evaluated. Results: Minimal hepatic encephalopathy was detected in 84 (54.5%) of 154 cirrhosis patients. Of the patients with minimal hepatic encephalopathy, 31 (36.9%) received lactulose, 31 (36.9%) Lactobacillus rhamnosus GG treatment, and 22 (26.2%) did not receive any treatment. In patients with minimal hepatic encephalopathy compared to those without minimal hepatic encephalopathy, there were statistically significant differences in terms of age (P=.003), body mass index (BMI) (P=.019), albumin (P &lt; .001), sodium (P = .010), model for end-stage liver diseases score (P &lt; .001), and Child Pugh Classification (CHILD) score (P &lt; .001).There was no significant difference between cirrhosis etiology and treatment response (P=.535). Statistically significant increase was found in critical flicker frequency values in the lactulose (P=.011) and Lactobacillus rhamnosus GG (P=.007) groups after treatment. No statistically significant difference was found in the placebo group (P=.804). There was no statistically significant difference between lactulose and Lactobacillus rhamnosus GG (P=.576). Conclusion: In the treatment of minimal hepatic encephalopathy, Lactobacillus rhamnosus GG treatment is as effective like lactulose treatment and can be used safely

Current approach to treatment of minimal hepatic encephalopathy in patients with liver cirrhosis.

Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of hepatic encephalopathy (HE). MHE does not present clinically detectable neurological-psychiatric abnormalities but is characterized by imperceptible neurocognitive alterations detected during routine clinical examination via neuropsychological or psychometrical tests. MHE may affect daily activities and reduce job performance and quality of life. MHE can increase the risk of accidents and may develop into overt encephalopathy, worsening the prognosis of patients with liver cirrhosis. Despite a lack of consensus on the therapeutic indication, interest in finding novel strategies for prevention or reversion has led to numerous clinical trials; their results are the main objective of this review. Many studies address the treatment of MHE, which is mainly based on the strategies and previous management of overt HE. Current alternatives for the management of MHE include measures to maintain nutritional status while avoiding sarcopenia, and manipulation of intestinal microbiota with non-absorbable disaccharides such as lactulose, antibiotics such as rifaximin, and administration of different probiotics. This review analyzes the results of clinical studies that evaluated the effects of different treatments for MHE.

Retraction

“Efficacy of different drugs in the treatment of minimal hepatic encephalopathy: A network meta‐analysis involving 826 patients based on 10 randomized controlled trials,” by Xiao‐Jun Cai, Lei Wang, and Chun‐Mei Hu, J Cell Biochem. 2018; 8336–8345: The above article, published online on June 22, 2018 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/full/10.1002/jcb.26886), has been retracted by agreement between the journal's Editor in Chief, Prof. Dr. Christian Behl, and Wiley Periodicals LLC.The retraction has been agreed after the authors found that the experimental methods were flawed and the results are not reliable. The authors collaborated in the investigation initially, but were not available for a final confirmation of the retraction.

Bifidobacterium longum W11: Uniqueness and individual or combined clinical use in association with rifaximin.

Strains belonging to bifidobacteria have been documented as being helpful in adults with intestinal dysbiosis conditions, like those related to irritable bowel syndrome (IBS). This review aims to present the most relevant evidence regarding the efficacy of Bifidobacterium longum W11, a Bifidobacterium used in clinical settings for conditions such as IBS and inflammatory bowel disease. The following electronic databases were systematically searched up to August 2020: MEDLINE (via PubMed), EMBASE, Cochrane Central Database of Controlled Trials (via CENTRAL), Google Scholar, and Clinicaltrials.gov. Data arising from pooled analysis, 7 invitro/pharmacological studies, 7 clinical trials including 1 randomized, double-blind and placebo-controlled, showed that the probiotic strain B.longum W11 has been extensively studied for its efficacy in subjects with IBS with constipation, leading to a significant reduction in symptoms. In particular, its role in alleviating constipation was also confirmed in subjects for whom a low-calorie weight-loss diet led to the slowing down of gut motility. The probiotic characteristics of B. longum W11 were further demonstrated in the treatment of minimal hepatic encephalopathy and hepatic disease. The most remarkable trait of B. longum W11 is its non-transmissible antibiotic resistance, due to a nucleotide polymorphism mutation in the rpoB gene, making it resistant to antibiotics of the rifampicin group, including rifaximin. The co-administration of B. longum W11 and rifaximin in patients with symptomatic uncomplicated diverticular disease brought about a further significant improvement in the clinical condition compared to patients treated with rifaximin alone. B. longum W11 is a probiotic which could synergize with rifaximin as an adjuvant to antibiotic treatment. Taken altogether these findings demonstrate the clinical role of the strain W11 both in some functional and in some inflammatory bowel diseases.

Thrombopoietin Receptor Agonist Eltrombopag Alleviates Cognitive Impairment in Minimal Hepatic Encephalopathy &lt;i&gt;via&lt;/i&gt; Activating NRG1/ErbB4 Signaling

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairments. Thrombopoietin (TPO) has been shown to be neuroprotective. This study aimed to explore the therapeutic effect of Thrombopoietin receptor agonist eltrombopag (ELT) on MHE and the involvement of NRG1 signaling using primary rat neurons and a MHE rat model. The results showed that ELT stimulation activated NRG1/ErbB4 signaling and enhanced synaptic protein expression in the primary rat neurons via sirtuin 1. An anti-NRG1 antibody, ErbB4 inhibitor, or knockdown of NRG1 or ErbB4 could significantly abolish ELT-induced upregulation of synaptic protein expression in the primary rat neurons. MHE rats had significantly decreased cerebral ELT expression compared with normal rats. ELT activated NRG1/ErbB4 signaling in MHE rat brains. Administration or overexpression of ELT or TPO promoted synapse formation and alleviated cognitive impairments in MHE rats. These data suggest that ELT promotes synapse formation in vitro and in vivo via activating NRG1/ErbB4 signaling, serving as a promising therapeutic agent for MHE treatment. Funding Statement: This study was supported by Natural Science Foundation of Zhejiang province (LY21H030012), Basic Scientific Research Projects of Wenzhou city (Y20180076) and Natural Science Foundation of China (81671042, 81300308). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by Institutional Animal Care and Use Committee of Wenzhou Medical University (Wenzhou, Zhejiang, China).

Hepatic Encephalopathy: Diagnosis and Management.

Type C hepatic encephalopathy (HE) is a brain dysfunction caused by severe hepatocellular failure or presence of portal-systemic shunts in patients with liver cirrhosis. In its subclinical form, called “minimal hepatic encephalopathy (MHE), only psychometric tests or electrophysiological evaluation can reveal alterations in attention, working memory, psychomotor speed and visuospatial ability, while clinical neurological signs are lacking. The term “covert” (CHE) has been recently used to unify MHE and Grade I HE in order to refer to a condition that is not unapparent but also non overt. “Overt” HE (OHE) is characterized by personality changes, progressive disorientation in time and space, acute confusional state, stupor and coma. Based on its time course, OHE can be divided in Episodic, Recurrent or Persistent. Episodic HE is generally triggered by one or more precipitant factors that should be found and treated. Unlike MHE, clinical examination and clinical decision are crucial for OHE diagnosis and West Haven criteria are widely used to assess the severity of neurological dysfunction. Primary prophylaxis of OHE is indicated only in the patient with gastrointestinal bleeding using non-absorbable antibiotics (Rifaximin) or non-absorbable disaccharides (Lactulose). Treatment of OHE is based on the identification and correction of precipitating factors and starting empirical ammonia-lowering treatment with Rifaximin and Lactulose (per os and enemas). The latter should be used for secondary prophylaxis, adding Rifaximin if HE becomes recurrent. In recurrent/persistent HE, the treatment options include fecal transplantation, TIPS revision and closure of eventual splenorenal shunts. Treatment of MHE should be individualized on a case-by-case basis.

Minimal Hepatic Encephalopathy in Indians: Psychometric Hepatic Encephalopathy Score and Inhibitory Control Test for Diagnosis and Rifaximin or Lactulose for Its Reversal.

Background and Aims: Psychometric hepatic encephalopathy score (PHES) is used widely for diagnosis of minimal hepatic encephalopathy (MHE). This prospective study aimed to determine the utility of the inhibitory control test (ICT) for the diagnosis of MHE. Additionally, the efficacy of rifaximin and lactulose for reversal of MHE was evaluated.Methods: A total of 180 eligible cirrhotic patients underwent testing for MHE. When PHES was ≤ −5 and ICT lures were ≥ 14, MHE was diagnosed. The 108 patients with MHE were randomized to three groups for treatment with either lactulose, rifaximin, or placebo. Treatment outcomes were measured at the end of 3 months.Results: The 108 patients with MHE diagnosed by PHES and/or ICT accounted for 60%. The diagnosis of MHE was made by both ICT and PHES positivity in 56 patients, by abnormal ICT and normal PHES in 37 patients, and by abnormal PHES and normal ICT in 15 patients. For diagnosis of MHE, ICT had sensitivity of 78.87%, specificity of 66.06% with 60.22% positive predictive value and 82.76% negative predictive value. An area under the curve value of 0.724 (95% CI: 0.653–0.788) was obtained for diagnosis of MHE. Reversal of MHE was seen in 71.42%, 70.27% and 11.11% of patients in the rifaximin, lactulose and placebo arms (p < 0.001). Rifaximin showed better tolerability compared to lactulose.Conclusions: For the diagnosis of MHE, ICT is a simple tool but has lower sensitivity and better specificity than PHES. Rifaximin is as efficacious as lactulose in the treatment of MHE and better tolerated.

P: 70 Quality of Life Assessment May Aid in the Diagnosis of Minimal Hepatic Encephalopathy and Prediction of Overt Hepatic Encephalopathy

BACKGROUND: Minimal hepatic encephalopathy (MHE) impinges on quality of life (QoL), is associated with a high risk of overt hepatic encephalopathy (OHE) and is often treatable by simple means. Still, MHE is rarely systematically diagnosed and treated likely because dedicated psychometric tests give the impression of being resource heavy and thus scare off many clinicians. Simple, patient-administered QoL questionnaires e.g. sickness impact profile (SIP), could improve diagnostic rates. This approach was tested in a US-based study introducing SIPCHE score (formula of 4 SIP statements, gender and age). We here aim at externally validate SIPCHE score in a cirrhotic cohort using continuous reaction time (CRT) test and portosystemic hepatic encephalopathy score (PHES) for MHE diagnosis. METHODS: 110 cirrhotic patients without OHE (age 60 years, MELD 11.4, 80% blue-collar) completed cognitive testing and SIP. Abnormal CRT and/or PHES diagnosed MHE. SIP consists of 136 questions inquiring about QoL and standardized QoL scores were compared in MHE and non-MHE patients. The SIPCHE (US cut point &gt;0) was applied and predictive values were calculated. We followed the patients for 2.7 years on average and registered OHE episodes. RESULTS: The SIPCHE was abnormal in 82/110 patients and was in agreement with the psychometric tests in 73/110 cases (66%). The SIPCHE indicated MHE in 58/71 of the patients with MHE according to 2-test psychometry (positive predictive value = 71%, sensitivity = 82%, AUUROC 0.63). The SIPCHE was false positive in 24/39 non-MHE patients (specificity 38%, NPV 53%). A normal SIPCHE did not exclude MHE in our population as 13/28 (46%) with a normal SIPCHE score had MHE according to the CRT and PSE tests. In our cohort using a cut point of &gt;−0.40, in stead of &gt;0, sligthly improved correct classification to 72% of patients. Only 4/28 (14%) with a normal baseline SIPCHE experienced OHE, while 29/82 (35%) with abnormal SIPCHE experienced OHE (P = 0.05). Accordingly, the SIPCHE positive predictive value for a future HE episode is this 87% (likelihood ratio 2.4). CONCLUSIONS: In conclusion, the idea of a patient-reported outcome score as an addition to standard psychometry is appealing. The US derived SIPCHE score is able to identify the majority of patients with MHE and future OHE episodes, but lacks diagnostic specificity. We suggest that development of regional SIPCHE scores could be useful. In future studies using the SIPCHE as a measure of patients-experienced effect of MHE treatment would be of interest.

Lactulose Management of Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy has been shown to increase risk of involvement in road traffic accidents and alter quality of life. This systematic review focused on the role of nonabsorbable disaccharides for the management of minimal hepatic encephalopathy. Randomized clinical trials that evaluated medical management of minimal hepatic encephalopathy were considered for inclusion. Individual studies compared lactulose with usual care and lactulose with probiotics and L-ornithine-L-aspartate. The outcome for examination was the neuropsychiatric test for cognitive function. Search strategies outlined by the Johanna Briggs Institute were used, and articles and references of selected articles were reviewed according to that methodology. Meta-analyses and narrative synthesis of the included studies were undertaken. Treatment of minimal hepatic encephalopathy with lactulose, probiotics, or L-ornithine-L-aspartate was seen to be equally effective in reducing abnormal tests at 1, 3, and 12 months post-treatment. All patients with minimal hepatic encephalopathy should be screened using a neuropsychiatric test and receive treatment as needed. Treatment can delay or eliminate risky automobile accidents and harm to self. Lactulose, probiotics, and L-ornithine-L-aspartate are a low-cost alternative compared with antibiotic treatment.

Quality of life in patients with minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) represents the mildest type of hepatic encephalopathy (HE). This condition alters the performance of psychometric tests by impairing attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients, depending of the diagnostic tools used for the diagnosis. MHE is related to falls, to an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life (QoL) and their socioeconomic status. MHE is detected in clinically asymptomatic patients through appropriate psychometric tests and neurophysiological methods which highlight neuropsychological alterations such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency evoked cognitive potentials and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment such as non-absorbable disaccharides, poorly absorbable antibiotics such rifaximin, probiotics and branched chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, to date the treatment of MHE is not routinely recommended apart from on a case-by-case basis. Aim of this review is analyze the burden of MHE on QoL of patients and provide a brief summary of therapeutic approaches.

Efficacy of different drugs in the treatment of minimal hepatic encephalopathy: A network meta-analysis involving 826 patients based on 10 randomized controlled trials.

Minimal hepatic encephalopathy (MHE), a complex neuropsychological complication of cirrhosis, is characterized by delayed reaction time and the inhibition of abnormal response. This network meta-analysis (NMA) was adopted to compare the efficacy of five drugs including lactulose, probiotics, rifaximin, acetyl-L-carnitine (ALC), and L-Ornithine L-aspartate (LOLA) in the treatment of MHE. The Cochrane Library, PubMed, and Embase databases were searched for any existing entail on these five drugs from the inception to February 2018, including Randomized controlled trials (RCTs). The NMA of the five drugs, accounting for both direct and indirect comparisons to assess WMD (weighted mean difference) and SUCRA (surface under the cumulative ranking curves) was conducted. In total, 10 RTCS with 826 MHE patients met the inclusion criteria and were included in the NMA. The meta-analysis revealed that compared with placebo, lactulose, and probiotics had better efficacy in reducing ammonia serum levels and total SIP (Sickness Impact Profil) score; ALC had better efficacy in lowering serum level of ammonia and increasing the serum level of albumin; rifaximin and LOLA had better efficacy in reducing total SIP score. The results from SUCRA revealed that in terms of ammonia and albumin serums, ALC presented with the highest rankings when it comes to efficacy (serum ammonia: 87.2%; serum albumin: 92.25%). Hence, the key findings from the present study highly suggested that ALC had the best efficacy in the treatment of MHE patients.

Role of probiotics in the treatment of minimal hepatic encephalopathy in patients with HBV-induced liver cirrhosis.

ObjectiveThis study was performed to investigate the role of probiotics (Clostridium butyricum combined with Bifidobacterium infantis) in the treatment of minimal hepatic encephalopathy (MHE) in patients with hepatitis B virus (HBV)-induced liver cirrhosis.MethodsSixty-seven consecutive patients with HBV-induced cirrhosis without overt hepatic encephalopathy were screened using the number connection test and digit symbol test. The patients were randomized to receive probiotics (n = 30) or no probiotics (n = 37) for 3 months. At the end of the trial, changes in cognition, intestinal microbiota, venous ammonia, and intestinal mucosal barriers were analyzed using recommended systems biology techniques.ResultsThe patients’ cognition was significantly improved after probiotic treatment. The predominant bacteria (Clostridium cluster I and Bifidobacterium) were significantly enriched in the probiotics-treated group, while Enterococcus and Enterobacteriaceae were significantly decreased. Probiotic treatment was also associated with an obvious reduction in venous ammonia. Additionally, the parameters of the intestinal mucosal barrier were obviously improved after probiotic treatment, which might have contributed to the improved cognition and the decreased ammonia levels.ConclusionTreatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis.

Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials

l-Ornithine l-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its' efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE. Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI). 10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10-1.69), p=0.005), OHE (RR: 1.19, 95% CI of 1.01-1.39, test for overall effect: Z=2.14, p=0.03), MHE (RR: 2.15 (1.48-3.14), p<0.0001) and for lowering of blood ammonia (MD: -17.50μmol/l (-27.73 to (-7.26)), p=0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE. LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.

JianPi HuaZhuo XingNao formula (Chinese herbal medicine) for the treatment of minimal hepatic encephalopathy: a protocol for a randomized, placebo-controlled pilot trial.

Background:Minimal hepatic encephalopathy (MHE) is a subclinical state of hepatic encephalopathy with the possibility of developing into overt hepatic encephalopathy (OHE) and having adverse outcomes. However, no preventative medicine for MHE has been recommended so far. The aim is to evaluate the therapeutic effect of the JianPi HuaZhuo XingNao formula (JPHZXN) on MHE, specifically whether JPHZXN decreases OHE occurrence, through a randomized controlled trial.Method:Seventy-two patients with MHE are enrolled and allocated in a 1:1 ratio in an experimental group and a control group. JPHZXN granules and placebos are dispatched to the experimental group and control group, respectively, for 24 weeks. The primary outcome is the incidence of developing OHE. The secondary outcomes are the patients’ performances in number connection test A and the digital sign test as well as results from the health survey and chronic liver disease questionnaire.Results:This study will provide proof regarding the therapeutic effect of JPHZXN among patients with MHE.Conclusion:The outcomes could grant clinicians an alternative choice when treating potentially progressive patients with MHE.

Factors associated with non-response to lactulose therapy in cirrhotic patients with minimal hepatic encephalopathy

Background and objectives: Minimal hepatic encephalopathy (MHE) impairs health related quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients. Lactulose is effective in the treatment of MHE. But the response to lactulose treatment depends on several factors. This study was aimed to find out the contributing factors to non-response to lactulose therapy.Materials and methods: The study was carried out at the BIRDEM general hospital from September, 2013 to March, 2015. Sixty patients were enrolled to assess the response of lactulose therapy in cirrhotic patients with MHE. MHE was diagnosed based on abnormal psychometric tests namely, number connection test (NCT), digit symbol test (DST) and high serum ammonia level. A daily dose of 30-60 ml of lactulose was given to all patients for one month. The response to treatment with regard to MHE was determined after one month using defined criteria. The response was graded as responder and non-responder.Results: The mean age of the study population was 57.0±10.3 years. Out of 60 cases, 46 (77%) were male and 39 (65%) had diabetes. Out of 60 enrolled MHE cases, 16 (27%) had Child-Turcotte-Pugh-A (CTP-A) score and 44 (73%) belonged to CTP-B &amp; C category. Out of 60 MHE cases, 23 (38.3%) showed improvement in their MHE status based on normalization of psychometric tests and reduction of serum ammonia level to ≤32 μmol/L. Age, gender and diabetes were not associated with the response to lactulose therapy. Low baseline arterial pressure was significantly (p=0.003) associated with non-response to lactulose treatment. The mean baseline ammonia level was higher significantly among the nonresponders compared to the responders (83.6±21.4 μmol/L vs 58.8±19.8 μmol/L, p&lt;0.001). Compared to responders, low serum sodium and potassium and raised serum bilirubin levels of non-responders at baseline were found significantly (p&lt;0.05) associated with non-response to one month of lactulose treatment. Initial hemoglobulin, peripheral leucocyte and platelet counts did not have any effect on the response to lactulose treatment in MHE cases.Conclusions: The status of MHE in patients with cirrhosis improved by one-month treatment with lactulose. Baseline low arterial pressure, hyperammonemia, hypokalemia and hyponatremia were major contributors to non-response to lactulose therapy. The findings of the study would be useful in treating patients of cirrhosis with MHE.IMC J Med Sci 2018; 12(1): 15-21

The burden of minimal hepatic encephalopathy: from diagnosis to therapeutic strategies.

Minimal hepatic encephalopathy (MHE) is the mildest form of hepatic encephalopathy (HE). It affects the performance of psychometric tests focused on attention, working memory, psychomotor speed, and visuospatial ability, as well as electrophysiological and other functional brain measures. MHE is a frequent complication of liver disease, affecting up to 80% of tested patients. By being related to falls, an impairment in fitness to drive and the development of overt HE, MHE severely affects the lives of patients and caregivers by altering their quality of life and their socioeconomic status. MHE is detected in clinically asymptomatic patients using appropriate psychometric tests and neurophysiological methods that highlight neuropsychological alterations, such as video-spatial orientation deficits, attention disorders, memory, reaction times, electroencephalogram slowing, prolongation of latency-evoked cognitive potentials, and reduction in the critical flicker frequency. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics such as rifaximin, probiotics and branched-chain amino acids. However, because of the multiple diagnosis methods, the various endpoints of treatment trials and the variety of agents used in trials, the treatment of MHE is not currently recommended as routine, but only on a case-by-case basis.