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.

Prevalence of minimal hepatic encephalopathy and quality of life evaluations in hospitalized cirrhotic patients in China

AIM:To investigate the prevalence of minimal hepatic encephalopathy(MHE)and to assess corresponding health-related quality of life(HRQoL)in hospitalized cirrhotic patients in China.METHODS:This multi-center cross-sectional study included 16 teaching hospitals,which were members of "Hepatobiliary Cooperation Group,Society of Gastroenterology,Chinese Medical Association",from different areas of China carried out between June and October in 2011.All the eligible hospitalized cirrhotic patients(n = 538)were required to complete triplicate number connection tests combined with one digit symbol test for diagnosing MHE.Patients' clinical examination data were complemented by a modified questionnaire assessing HRQoL.Written informed consent was obtained from each patient.RESULTS:Male was predominant(68.6%)in 519 patients who met the criteria of the study,with a mean age of 49.17 ± 11.02 years.The most common cause of liver cirrhosis was chronic hepatitis B(55.9%).The prevalence of MHE was 39.9% and varied by ChildPugh-Classification score(CPC-A:24.8%,CPC-B:39.4% and CPC-C:56.1%,P < 0.01).MHE(P < 0.01)and higher CPC scores(P < 0.01)were associated with a high HRQoL scores(reflecting poorer quality of life).The prevalence of MHE was proportionate to CPC(P = 0.01)and high quality of life scores(P = 0.01).CONCLUSION:Hospitalized cirrhotic patients have a high prevalence of MHE that is proportionate to the degree of liver function and HRQoL impairment.

Psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in China

AIM:To construct normal values for the tests of the psychometric hepatic encephalopathy score(PHES)and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy(MHE)among Chinese individuals with cirrhosis.METHODS:The five tests of PHES,number connection test-A(NCT-A),number connection test-B,serial dotting test,line tracing test and digit symbol test(DST),were administered to all enrolled subjects in a quiet room with sufficient light.Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination.Based on the nomograms of healthy volunteers,the patients were classified as having MHE when their PHES was less than-4.RESULTS:In total,146 healthy volunteers completed all the PHES tests.Age and education years were confirmed to be predictors of all five tests.In total,53patients with liver cirrhosis completed the PHES.Of the patients with liver cirrhosis,24(45.3%),22(41.5%)and 7(13.2%)had Child-Pugh grades A,B and C,respectively.MHE was diagnosed in 26 patients(49.1%).Compared with compensated cirrhotic patients(Child A),decompensated cirrhotic patients(Child B and C)had a higher proportion of MHE(65.5%vs 29.2%).No differences in age and education years were found between the MHE and non-MHE groups.NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9%and a specificity of 96.3%(AUC=0.866,K=0.735).CONCLUSION:The proportion of MHE is associated with liver function.NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.

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.

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.

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.

Sarcopenia and cognitive impairment in liver cirrhosis: A viewpoint on the clinical impact of minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) represents the mildest type of hepatic encephalopathy (HE). MHE is considered as a preclinical stage of HE and is part of a wide spectrum of typical neurocognitive alterations characteristic of patients with liver cirrhosis, particularly involving the areas of attention, alertness, response inhibition, and executive functions. MHE can be detected by testing the patients’ psychometric performance, attention, working memory, psychomotor speed, and visuospatial ability, as well as by means of electrophysiological and other functional brain measures. MHE is very frequent, affecting from 20% up to 80% of patients tested, depending of the diagnostic tools used. Although subclinical, MHE is considered to be clinically relevant. In fact, MHE has been related to the patients’ falls, fitness to drive, and working ability. As a consequence, MHE affects the patients and caregivers lives by altering their quality of life and even their socioeconomic status. Recently sarcopenia, a very common condition in patients with advanced liver disease, has been shown to be strictly related to both minimal and overt HE. Aim of this review is to summarize the most recently published evidences about the emerging relationship between sarcopenia and cognitive impairment in cirrhotic patients and provide suggestions for future research.

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.

Minimally invasive treatment of hepatic hemangioma by transcatheter arterial embolization combined with microwave ablation:A case report

BACKGROUND Hepatic hemangioma is the most common benign tumor of the liver.However,patients with large hemangiomas that cause compression symptoms or that are at risk of rupture may need further intervention.It is necessary to explore additional minimally invasive and personalized treatment options for hemangiomas.CASE SUMMARY A 47-year-old woman was diagnosed with a right hepatic hemangioma for more than 10 years.Abdominal contrast-enhanced computed tomography(CT)and contrast-enhanced ultrasound revealed that there was a large hemangioma in the right liver,with a size of approximately 95 mm×97 mm×117 mm.Due to the patient's refusal of surgical treatment,hepatic artery embolization was performed in the first stage.After 25 d of liver protection treatment,the liver function indexes decreased to normal levels.Then,ultrasound-guided microwave ablation of the giant hepatic hemangioma was performed.Ten days after the treatment,hepatobiliary ultrasonography showed that the hemangioma of the right liver was smaller than the previous size(the volume was reduced by approximately 30%).Then the patient was discharged from the hospital.One year after discharge,CT showed that the hepatic hemangioma had shrunk by about 80%CONCLUSION Transcatheter arterial embolization combined with microwave ablation is a safe and effective minimally invasive treatment for hepatic hemangioma.

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.

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.

Role of Serum Zinc Level and P300 Event Related Potential in Detection of Minimal Hepatic Encephalopathy

Background: Minimal hepatic encephalopathy (MHE) is defined as hepatic encephalopathy (HE) without symptoms on clinical/neurological examination, but with deficits in some cognitive areas that can only be measured by neuropsychometric testing. Aim: Our aim was to study serum zinc levels in cirrhotic patients with and without MHE and correlate it with the results of neuropsychological tests and P300 event related potential. Patients and Methods: Fifty-five patients with liver cirrhosis were recruited for the present study. All patients were subjected to full history taking, clinical examination, abdominal ultrasonography, laboratory investigations including liver function tests and serum zinc, psychometric studies (line tracing test and serial dotting test) and P300 event related potential. According to the results of psychometric studies and P300 event related potential, the patients were divided into 3 groups in addition to the control group. Results: Among the 55 patients included in the study, 30 patients had no clinical evidence of HE and 25 patients had overt HE with different grades. In patients with no clinical evidence of HE, psychometric tests and P300 event related potential revealed that 13 patients had MHE, while 17 had no HE. There were significantly lower serum zinc levels in patients with MHE and in cirrhotic patients without HE compared with the healthy controls. Also, zinc levels were significantly lower in higher grades of hepatic encephalopathy. Serum zinc levels showed positive correlation with serum albumin levels and inverse correlation with serial dotting test and P300 latency. Conclusion: Reduced serum zinc level and prolonged P300 latency can serve as predictors of minimal hepatic encephalopathy in cirrhotic patients. Zinc deficiency is common in cirrhotic patients with MHE. These findings may have important prognostic and therapeutic implications in MHE and overt HE patients with zinc deficiency.

Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests

AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy. METHODS: Blood flow(BF) was analyzed by arterial spin labeling(ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy(MHE). Images were collected using a 3 Tesla MR scanner(Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score(PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins(IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated.RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere(P = 0.03) and vermis(P = 0.012) and reduced in occipital lobe(P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE(P = 0.02). Bimanual coordination was impaired in patients without MHE(P = 0.05) and much more in patients with MHE(P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE(P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE(P< 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A(NCT-A), B(NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitric oxide(NO) metabolites. BF in vermis cerebellar also correlates with NO metabolites and with 3-nitrotyrosine. IL-18 in plasma correlates with BF in thalamus and occipital lobe.CONCLUSION: Non invasive BF determination in cerebellum using ASL may detect MHE earlier than the PHES. Altered NO-cGMP pathway seems to be associated to altered BF in cerebellum.

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

AIM To evaluate the reversibility of minimal hepatic encephalopathy(MHE) following liver transplantation(LT) in Egyptian cirrhotic patients. METHODS This prospective study included twenty patients with biopsy-proven liver cirrhosis listed for LT and twenty ageand 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. RESULTS Before LT, psychometric tests showed highly significant deficits in cirrhotic patients in comparison to controls(P < 0.001). There was a statistically significant improvement in test values in the patient group after LT; however, their values were still significantly worse than those of the controls(P < 0.001). The PHES detected MHE in 16 patients(80%) before LT with a median value of -7 ± 3.5. The median PHES value was significantly improved following LT, reaching-4.5 ± 5(P < 0.001), and the number of patients with MHE decreased to 11(55%). The pre-transplant model for end-stage liver disease(MELD) score ≥ 15 was significantly related to the presence of post-transplant MHE(P = 0.005). More patients in whom reversal of MHE was observed had a pre-transplant MELD score < 15.CONCLUSION Reversal of MHE in cirrhotic patients could be achieved by LT, especially in those with a MELD score < 15.

Correlation between the Degree of Liver Fibrosis and Driving Test Alterations as an Indicator of Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy is a subclinical disorder in patients with liver cirrhosis that may have an impact upon driving capacity. This study in highly selected patients without other confounding factors examines whether there is a relationship between the degree of liver fibrosis as determined by Fibroscan exploration and the driving test scores. Using the ASDE DRIVER-TEST N-845 system, validated for obtaining the driving license in Spain, we assessed the calculation of distances and time, bimanual visual-motor coordination, reaction time to different stimuli, concentrated attention, and resistance to monotony. The data were processed using the SPSS statistical package, with an analysis of the correlation between the degree of fibrosis and the test scores based on the Spearman statistic and the comparison of means (Mann-Whitney U-test). We found no alterations in driving capacity in patients diagnosed of hepatitis C with different degrees of early stage fibrosis or cirrhosis.

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.

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

AIM To apply the Frontal Assessment Battery to cirrhotic patients with or without overt hepatic encephalopathy(OHE) and controls. METHODS The 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 Ant?nio de Moraes University Hospital(Hospital Universitário Cassiano Ant?nio de Moraes- HUCAM), Espírito Santo, Brazil.RESULTS The average FAB score was lower for the cirrhotic than for the non-cirrhotic patients(10.6 ± 3.67 vs 12.25 ± 2.72, P = 0.015). The FAB score was lower for the cirrhotic patients with OHE than for the patients without OHE(8.25 ± 4.55 vs 11.14 ± 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 ± 3.25 vs 12.25 ± 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 ± 0.93 vs 2.2 ± 0.85, P = 0.011).CONCLUSION The present study indicates that the FAB is a promising tool for outpatient minimal HE screening and the assessment of HE severity.

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.

Pituitary hormone circadian rhythm alterations in cirrhosis patients with subclinical hepatic encephalopathy

AIM:To analyze pituitary hormone and melatonin circadian rhythms, and to correlate hormonal alterations with clinical performance, hepatic disease severity and diagnostic tests used for the detection of hepatic encephalopathy in cirrhosis. METHODS:Twenty-six patients with cirrhosis were enrolled in the study. Thirteen patients hospitalized for systemic diseases not affecting the liver were included as controls. Liver disease severity was assessed by the Child-Pugh score. All patients underwent detailed neurological assessment, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), assays of pituitary hormone, cortisol and melatonin, and complete blood chemistry evaluation. RESULTS: Pituitary hormone and melatonin circadian patterns were altered in cirrhosis patients without clinical encephalopathy. Circadian hormone alterations were different in cirrhosis patients compared with controls. Although cortisol secretion was not altered in any patient with cirrhosis, the basal cortisol levels were lowand correlated with EEG and brain MRI abnormalities. Melatonin was the only hormone associated with the severity of liver insufficiency. CONCLUSION: Abnormal pituitary hormone and melatonin circadian patterns are present in cirrhosis before the development of hepatic encephalopathy. These abnormalities may be early indicators of impending hepatic encephalopathy. Factors affecting the human biologic clock at the early stages of liver insufficiency require further study.