Role of gut microbiota in the pathogenesis and therapeutics of minimal hepatic encephalopathy via the gut-liver-brain axis

Minimal hepatic encephalopathy(MHE) is a frequent neurological and psychiatric complication of liver cirrhosis. The precise pathogenesis of MHE is complicated and has yet to be fully elucidated. Studies in cirrhotic patients and experimental animals with MHE have indicated that gut microbiota dysbiosis induces systemic inflammation, hyperammonemia, and endotoxemia, subsequently leading to neuroinflammation in the brain via the gut-liver-brain axis. Related mechanisms initiated by gut microbiota dysbiosis have significant roles in MHE pathogenesis. The currently available therapeutic strategies for MHE in clinical practice, including lactulose, rifaximin, probiotics, synbiotics, and fecal microbiota transplantation, exert their effects mainly by modulating gut microbiota dysbiosis. Microbiome therapies for MHE have shown promised efficacy and safety;however, several controversies and challenges regarding their clinical use deserve to be intensively discussed. We have summarized the latest research findings concerning the roles of gut microbiota dysbiosis in the pathogenesis of MHE via the gut-liver-brain axis as well as the potential mechanisms by which microbiome therapies regulate gut microbiota dysbiosis in MHE patients.

Discrimination for minimal hepatic encephalopathy based on Bayesian modeling of default mode network

In order to classify the minimal hepatic encephalopathy （MHE） patients from healthy controls, the independent component analysis （ICA） is used to generate the default mode network （DMN） from resting-state functional magnetic resonance imaging （fMRI）. Then a Bayesian voxel- wised method, graphical-model-based multivariate analysis （GAMMA）, is used to explore the associations between abnormal functional integration within DMN and clinical variable. Without any prior knowledge, five machine learning methods, namely, support vector machines （SVMs）, classification and regression trees （ CART ）, logistic regression, the Bayesian network, and C4.5, are applied to the classification. The functional integration patterns were alternative within DMN, which have the power to predict MHE with an accuracy of 98%. The GAMMA method generating functional integration patterns within DMN can become a simple, objective, and common imaging biomarker for detecting MIIE and can serve as a supplement to the existing diagnostic methods.

Minimal hepatic encephalopathy matters in daily life

Minimal hepatic encephalopathy is a neuro-cognitive dysfunction which occurs in an epidemic proportion of cirrhotic patients,estimated as high as 80% of the population tested. It is characterized by a specific,complex cognitive dysfunction which is independent of sleep dysfunction or problems with overall intelligence. Although named "minimal",minimal hepatic encephalopathy(MHE) can have a far-reaching impact on quality of life,ability to function in daily life and progression to overt hepatic encephalopathy. Importantly,MHE has a profound negative impact on the ability to drive a car and may be a significant factor behind motor vehicle accidents. A crucial aspect of the clinical care of MHE patients is their driving history,which is often ignored in routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of care in patients with MHE. The lack of specific signs and symptoms,the preserved communication skills and lack of insight make MHE a difficult condition to diagnose. Diagnostic strategies for MHE abound,but are usually limited by financial,normative or time constraints. Recent studies into the inhibitory control and critical flicker frequency tests are encouraging since these tests can increase the rates of MHE diagnosis without requiring a psychologist. Although testing for MHE and subsequent therapy is not standard of care at this time,it is important to consider this in cirrhotics in order to improve their ability to live their life to the fullest.

Effect of probiotic treatment on cirrhotic patients with minimal hepatic encephalopathy: A meta-analysis

Background: Minimal hepatic encephalopathy(MHE) is an early and reversible form of hepatic encephalopathy. The documentations on the treatment with probiotics are inconsistent. The present meta-analysis was to verify the role of probiotics in the treatment of cirrhotic patients with MHE.Data sources: Seven electronic databases were searched for relevant randomized controlled trials(RCTs)published until July 2015. The effects of probiotics on serum ammonia, endotoxin, and MHE were evaluated.Results: A total of 14 RCTs(combined n = 1132) were included in the meta-analysis. When probiotics were compared to placebo or no treatment, probiotics were more likely to reduce values in the number connection test(NCT; week 4: MD =-30.25, 95% CI:-49.85 to-10.66), improve MHE(week 4: OR = 0.18,95% CI: 0.07 to 0.47; week 12: OR = 0.15, 95% CI: 0.07 to 0.32), and prevent overt HE progression(week4: OR = 0.22, 95% CI: 0.07 to 0.67) in patients with liver cirrhosis. When probiotics was compared to lactulose, probiotics tended to reduce serum ammonia levels(week 4: MD =-0.33 μmol/L, 95% CI:-5.39 to 4.74; week 8: MD = 6.22 μmol/L, 95% CI:-24.04 to 36.48), decrease NCT(week 8: MD = 3.93, 95% CI:-0.72 to 8.58), improve MHE(week 4: OR = 0.93, 95% CI: 0.45 to 1.91; week 12: OR = 0.73, 95% CI: 0.35 to 1.51) and prevent the development of overt HE(week 4: OR = 0.96, 95% CI: 0.17 to 5.44; week 12:OR = 2.7, 95% CI: 0.50 to 14.64) in patients with liver cirrhosis. However, lactulose appears to be more effective in reducing NCT values as compared to probiotics(week 4: MD = 6.7, 95% CI: 0.58 to 12.82).Conclusion: Probiotics can decrease serum ammonia and endotoxin levels, improve MHE, and prevent overt HE development in patients with liver cirrhosis.

Assessment of health-related quality of life in Chinese patients with minimal hepatic encephalopathy

AIM:To evaluate the health-related quality of life (HRQOL) based on the Chinese version of SF-36 and Chronic Liver Disease Questionnaire (CLDQ) in subjects with chronic hepatitis B,liver cirrhosis,including patients with minimal hepatic encephalopathy (MHE). METHODS:The SF-36 and CLDQ were administered to 160 healthy volunteers,20 subjects with chronic hepatitis B and 106 patients with cirrhosis (33 cases exhibited MHE). HRQOL scores were compared among the different study groups. The SF-36 includes eight health concepts:physical functioning,role-physical,body pain,general health,vitality,social functioning,role-emotion,and mental health. Six domains of CLDQ were assessed:abdominal symptoms,fatigue,systemic symptoms,activity,emotional function and worry. RESULTS:Compared with healthy controls (96.9 ± 4.5,86.6 ± 18.4,90.1 ± 12.5,89.0 ± 5.7,87.5 ± 4.3,95.8 ± 7.1,88.5 ± 15.9,88.7 ± 5.2 in SF-36 and 6.7 ± 0.5,6.1 ± 0.6,6.3 ± 0.6,6.5 ± 0.5,6.3 ± 0.5,6.8 ± 0.4 in CLDQ),patients with chronic hepatitis B (86.3 ± 11.0,68.8 ± 21.3,78.9 ± 14.4,60.8 ± 10.5,70.8 ± 8.6,76.1 ± 12.6,50.0 ± 22.9,72.2 ± 10.6 and 5.5 ± 1.0,4.5 ± 1.0,5.2 ± 1.1,5.3 ± 0.9,4.8 ± 0.9,4.9 ± 1.0) and cirrhosis (52.8 ± 17.4,32.8 ± 27.9,61.6 ± 18.9,30.2 ± 18.3,47.9 ± 20.1,54.0 ± 19.2,28.9 ± 26.1,51.1 ± 17.8 and 4.7 ± 1.2,3.9 ± 1.2,4.7 ± 1.2,4.7 ± 1.3,4.7 ± 1.0,4.4 ± 1.1) had lower HRQOL on all scales of the SF-36 and CLDQ (P < 0.01 for all). Increasing severity of liver cirrhosis (based on the Child-Pugh score/presence or absence of MHE) was associated with a decrease in most components of SF-36 and CLDQ,especially SF-36.CONCLUSION:The Chinese version of SF-36 along with CLDQ is a valid and reliable method for testing MHE in patients with liver cirrhosis. Cirrhosis and MHE are associated with decreased HRQOL.

Reversibility of minimal hepatic encephalopathy following liver transplantation in Egyptian cirrhotic patients

AIMTo evaluate the reversibility of minimal hepatic encephalopathy (MHE) following liver transplantation (LT) in Egyptian cirrhotic patients. METHODSThis prospective study included twenty patients with biopsy-proven liver cirrhosis listed for LT and twenty age- and sex-matched healthy control subjects. All underwent neuro-psychiatric examination, laboratory investigations, radiological studies and psychometric tests including trail making test A (TMT A), TMT B, digit symbol test and serial dotting test. The psychometric hepatic encephalopathy score (PHES) was calculated for patients to diagnose MHE. Psychometric tests were repeated six months following LT in the cirrhotic patient group. RESULTSBefore LT, psychometric tests showed highly significant deficits in cirrhotic patients in comparison to controls (P P P P = 0.005). More patients in whom reversal of MHE was observed had a pre-transplant MELD score CONCLUSIONReversal of MHE in cirrhotic patients could be achieved by LT, especially in those with a MELD score

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.

Comparison of probiotics and lactulose in the treatment of minimal hepatic encephalopathy in rats

AIM: To compare the efficacy of probiotic preparation Golden Bifid and lactulose on rat experimental model of minimal hepatic encephalopathy (MHE) induced by thioactamide (TAA).METHODS: MHE was induced by intraperitoneal injection of TAA (200 mg/kg) every 24 h for two consecutive days.Thirty-six male MHE models were then randomly divided into 3 groups: TAA group (n = 12) received tap water ad libitum only; lactulose group (n = 12) and probiotics group (n = 12) were gavaged, respectively with 8 mL/kg of lactulose and 1.5 g/kg of probiotic preparation Golden Bifid (highly concentrated combination of probiotic)dissolved in 2 mL of normal saline, once a day for 8 d (from the 5th d before the experiment to the 3rd d of the experiment). The latency of brainstem auditory evoked potentials (BAEP) I was used as an objective index of MHE. The incidence of MHE, the level of serum endotoxin,ammonia, liver function and histological grade of hepatic injury of rats were examined individually.RESULTS: There were no overt HE and rat deaths in 3groups. The incidence of MHE, the levels of blood ammonia and endotoxin in TAA group, which were 83.3% (10/12),168.33±15.44 mg/dL and 0.36±0.04 EU/mL, respectively,were significantly higher than those in lactulose group,which were 33.3% (4/12), 110.25±7.39 mg/dL and 0.19±0.02 EU/mL, and probiotics group, which were 33.3% (4/12), 108.58±10.24 mg/dL and 0.13±0.03 EU/mL respectively (P ＜0.001). It showed that either probiotics or lactulose could significantly lower the level of hyperammonemia and hyper-endotoxemia, lighten centrolobular necrotic areas as well as inflammatory reaction in the liver of rats, normalize the latency of BAEP,and decrease the incidence of MHE. However, no significant differences were observed between these two groups (P ＞0.05).CONCLUSION: Probiotic compound Golden Bifid is at least as useful as lactulose for the prevention and treatment of MHE. Probiotic therapy may be a safe, natural, well-tolerated therapy appropriate for the long-term treatment of MHE.

Critical flicker frequency for diagnosis and assessment of recovery from minimal hepatic encephalopathy in patients with cirrhosis

BACKGROUND:Minimal hepatic encephalopathy (MHE) impairs quality of life and predicts overt hepatic encephalopathy (HE) in cirrhotic patients.Diagnosis of MHE requires cumbersome tests.Lactulose is effective in the treatment of MHE.This study aimed to evaluate the use of critical flicker frequency (CFF) for the diagnosis of MHE in cirrhotic patients after treatment.METHODS:One hundred and ten patients were evaluated by psychometry (number connection tests A,B or figure connection tests A,B),P300 auditory event related potential (P300ERP),venous ammonia,and CFF for MHE.MHE was diagnosed by abnormal psychometry (>2SD age matched controls) and P300ERP.MHE patients were treated with lactulose for one month.Response was defined by normalization (<2SD of matched controls) of both psychometry and P300ERP.RESULTS:Of the 110 patients [Child Turcott Pugh score A:B:C 39:42:29,(age 41.6±11.6 years,M:F 82:28)],75 (68%) had abnormal results of psychometric tests,and 74 (67%) had prolonged P300ERP.Fifteen (20%) patients with abnormal results of psychometric tests had normal P300ERP.Thus sixty (54.5%) patients were diagnosed as having MHE.After treatment for one month,34 (57%) recovered while 26 (43%) continued to have abnormal resents of psychometric or P300ERP tests.CFF was <39 Hz in 72 (65.4%) patients before treatment and in 20 (33.3%) after treatment.CFF sensitivity,specificity,positive predictive value,negative predictive value,and diagnostic accuracy for the assessment of recovery of MHE were 65%,91%,85%,77% and 80%,respectively.CONCLUSION:CFF is a simple,relatively reliable,and accurate test without any dependence on age or literacy in the diagnosis and assessment of recovery of patients with MHE.

Frontal assessment battery: A tool for screening minimal hepatic encephalopathy?

AIMTo apply the Frontal Assessment Battery to cirrhotic patients with or without overt hepatic encephalopathy (OHE) and controls. METHODSThe frontal assessment battery (FAB) was applied to 87 patients with liver cirrhosis (16 with and 71 without OHE) and 40 control subjects without cirrhosis treated at the alcohol and liver outpatient clinics and the gastroenterology ward of the Cassiano Antônio de Moraes University Hospital (Hospital Universit&aacute;rio Cassiano Antônio de Moraes - HUCAM), Esp&iacute;rito Santo, Brazil. RESULTSThe average FAB score was lower for the cirrhotic than for the non-cirrhotic patients (10.6 &plusmn; 3.67 vs 12.25 &plusmn; 2.72, P = 0.015). The FAB score was lower for the cirrhotic patients with OHE than for the patients without OHE (8.25 &plusmn; 4.55 vs 11.14 &plusmn; 3.25, P = 0.027). The total FAB score was lower for the cirrhotic patients without OHE than for the non-cirrhotic patients, although this difference was not significant (11.14 &plusmn; 3.25 vs 12.25 &plusmn; 2.72, P = 0.067). Nevertheless, the difference in the scores on the subtest that assessed the ability to inhibit a response previously conditioned to a stimulus was significant (1.72 &plusmn; 0.93 vs 2.2 &plusmn; 0.85, P = 0.011). CONCLUSIONThe present study indicates that the FAB is a promising tool for outpatient minimal HE screening and the assessment of HE severity.

Novel computerized psychometric tests as primary screening tools for the diagnosis of minimal hepatic encephalopathy

Minimal hepatic encephalopathy(MHE)is a critical neurocognitive complication of decompensated liver cirrhosis and portosystemic shunting,which results in a wide range of cognitive deficits including impairments in working attention,psychomotor speed,and executive function.Current guidelines have recommended paper-and-pencil psychometric tests for the diagnosis of MHE.Most high-risk cirrhotic patients are required to be examined;however,paperand-pencil psychometric tests are neither convenient nor rapid to perform in the clinic.Recently,novel computerized psychometric tests,including the inhibitory control test,EncephalApp Stroop App,and critical flicker frequency,have been proven to be rapid,effective,and convenient methods for screening MHE in clinical practice and for identifying high-risk cirrhotic patients for further validation using rigid neuropsychometric examinations.However,diagnostic accuracy of these tests is influenced by educational background,age,and cultural differences.This review summarizes clinical evidence of the application of novel computerized psychometric tests for screening MHE.

Prevalence and risk factors for minimal hepatic encephalopathy in cirrhotic patients with different etiologies

Aims:Minimal hepatic encephalopathy(MHE)significantly affects the prognosis of patients with cirrhosis.This study was performed to determine whether there is a difference in the prevalence of MHE among patients with cirrhosis of different etiologies and whether the etiology directly influences the occurrence of MHE.Methods:This multicenter,cross-sectional study enrolled 1879 patients with confirmed cirrhosis at 40 hospitals from October 25,2021,to January 10,2023(Trial registration:https://clinicaltrials.gov/[NCT05140837]).The patients'demographics,etiologies of cirrhosis,and laboratory test results were collected.The psychometric hepatic encephalopathy score(PHES)was determined in all patients to screen for MHE.Multivariate logistic analyses were performed to identify the risk factors for MHE.Results:In total,736 patients with cirrhosis were analyzed.The prevalence of MHE was 42.0%(n=309).The primary etiology among all patients was hepatitis B virus(HBV)-related cirrhosis(71.9%[529/736]).The prevalence of MHE was significantly higher in patients with alcoholic cirrhosis(57.1%[40/70])than in those with HBV-related cirrhosis(40.6%[215/529],p=0.009)or hepatitis C virus(HCV)-related cirrhosis(38.2%[26/68],p=0.026).Age(odds ratio[OR],1.042;95%confidence interval[CI],1.024-1.059;p<0.001),duration of education(OR,0.935;95%CI,0.899-0.971;p=0.001),etiology(OR,1.740;95%CI,1.028-2.945;p=0.039),and high MELD-Na scores(OR,1.038;95%CI,1.009-1.067;p=0.009)were independent risk factors for MHE.When patients with cirrhosis of different etiologies were analyzed separately,the results showed that age(OR,1.035;95%CI,1.014-1.057;p=0.001)and duration of education(OR,0.924;95%CI,0.883-0.966;p=0.001)were risk factors for MHE among patients with HBV-related cirrhosis,whereas age(OR,1.138;95%CI,1.033-1.254;p=0.009)and creatinine concentration(OR,16.487;95%CI,1.113-244.160;p=0.042)were risk factors for MHE in patients with HCV-related cirrhosis.No risk factors for MHE were found in patients with autoimmune cirrhosis.For patients with alcoholic cirrhosis,the platelet count(OR,1.014;95%CI,1.000-1.027;p=0.045)was a risk factor for MHE.The PHES subtest results were inconsistent among patients who had MHE with cirrhosis of different etiologies.Patients with HBV-related cirrhosis performed better on Number Connection Test B and the serial dotting test than those with alcoholic cirrhosis(p=0.007 and p<0.001),better on Number Connection Test B than those with HCV-related cirrhosis(p=0.020),and better on the line tracing test than those with autoimmune cirrhosis(p=0.037).Conclusion:The etiology of cirrhosis affected the prevalence of MHE and risk factors for MHE.The domains of major cognitive impairment varied among patients with cirrhosis of different etiologies.Further studies are required to verify these findings.

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 encephalop-athy 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 abnor-mal 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 treat-ment of MHE and better tolerated.

Hepatic encephalopathy: Ever closer to its big bang

Hepatic encephalopathy(HE) is a neuropsychiatric disorder that commonly complicates the course of patients with liver disease. Despite the fact that the syndrome was probably first recognized hundreds of years ago, the exact pathogenesis still remains unclear. Minimal hepatic encephalopathy(MHE) is the earliest form of HE and is estimated to affect more that 75% of patients with liver cirrhosis. It is characterized by cognitive impairment predominantly attention, reactiveness and integrative function with very subtle clinical manifestations. The development of MHE is associated with worsen in driving skills, daily activities and the increase of overall mortality. Skeletal muscle has the ability to shift from ammonia producer to ammonia detoxifying organ. Due to its large size, becomes the main ammonia detoxifying organ in case of chronic liver failure and muscular glutaminesynthase becomes important due to the failing liver and brain metabolic activity. Gut is the major glutamine consumer and ammonia producer organ in the body. Hepatocellular dysfunction due to liver disease, results in an impaired clearance of ammonium and in its interorgan trafficking. Intestinal bacteria, can also represent an extra source of ammonia production and in cirrhosis, small intestinal bacterial overgrowth and symbiosis can be observed. In the study of HE, to get close to MHE is to get closer to its big bang; and from here, to travel less transited roads such as skeletal muscle and intestine, is to go even closer. The aim of this editorial is to expose this road for further and deeper work.