Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the mildest form of spectrum of hepatic encephalopathy (HE). Patients with MHE have no recognizable clinical symptoms of HE but have mild cognitive and psychomotor deficits. The prevalence of MHE is high in patients with cirrhosis of liver and varies between 30% and 84%; it is higher in patients with poor liver function. The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests, and treatment of those patients diagnosed to have MHE has been recommended. Ammonia plays a key role in the pathogenesis of MHE, which is thought to be similar to that of overt HE. Thus, ammonia-lowering agents such as lactulose and probiotics have been tried. These agents have been shown to improve cognitive and psychometric deficits, and have good safety profile. Future studies will better define the role of other drugs, such as rifaximin, acetyl L-carnitine and L-ornithine L-aspartate.     

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 eve...     

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 to80% 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.     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy and can affect up to 80% of cirrhotic patients. By definition, it has no obvious clinical manifestation and is characterized by neurocognitive impairment in attention, vigilance and integrative function. Although often not considered to be clinically relevant and, therefore, not diagnosed or treated, MHE has been shown to affect daily functioning, quality of life, driving and overall mortality. The diagnosis of MHE has traditionally been achieved through neuropsychological examination, psychometric tests or the newer critical flicker frequency test. A new smartphone application (EncephalApp Stroop Test) may serve to function as a screening tool for patients requiring further testing. In addition to physician reporting and driving restrictions, medical treatment for MHE includes non-absorbable disaccharides (eg, lactulose), probiotics or rifaximin. Liver transplantation may not result in reversal of the cognitive deficits associated with MHE.     

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.     

Neuropsychological impairment in severe acute viral hepatitis is due to minimal hepatic encephalopathy

Background and Aims: Minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis may have prognostic significance with regard to the development of clinical hepatic encephalopathy (HE) and deterioration in patient quality of life. Its prevalence in acute viral hepatitis (AVH) is not known. Patients and Methods: Consecutive 20 AVH patients (age, 29.9±7.9 years; M:F 18:2, hepatitis A:B:E: 2:16:2) without overt encephalopathy were evaluated for MHE and followed up. All patients underwent number connection tests – A and B, figure connection tests – A and B, digit symbol test and object assembly test and critical flicker frequency (CFF) at baseline and after the resolution of icterus. MHE was diagnosed if two or more psychometric tests were abnormal. Results: Prevalence of MHE (n=5) was 25%, which resolved on follow‐up during the anicteric resolution phase. Five (25%) patients had greater than two abnormal psychometry tests and four (20%) had CFF <38 Hz. CFF alone had sensitivity and specificity of 80 and 100%, respectively, in the diagnosis of MHE. There was significant difference in the performance of CFF during the icteric and resolution phase of AVH (40.6±3.4 vs 41.8±2.1 Hz, P=0.04). Arterial ammonia level were higher in patients with MHE compared with patients without MHE (88.2±23.5 vs 53.8±10.9 μmol/L, P=0.001). On univariate analysis fasting ammonia level at baseline was significantly associated with all the psychometric tests (P=0.001). None of the patients developed HE either in MHE group or in those who did not had MHE at baseline. Conclusions: MHE occurs in 25% of patients with AVH and resolves on follow up with recovery of AVH. Raised arterial ammonia during the icteric phase is associated with development of MHE.     

轻微型肝性脑病诊断研究进展

轻微型肝性脑病常并发于肝硬化及各种门体分流术患者。由于缺乏典型的临床表现及生化异常,只能通过心理智能测试及神经电生理等检查发现,其发病率已升至30%～84%。轻微型肝性脑病可对患者的日常生活造成影响,无干预的轻微型肝性脑病易发展为显性肝性脑病。该病尚无公认的诊断“金标准”。本文介绍了国内外对轻微型肝性脑病的诊断方法。     

轻微肝性脑病的治疗现状

轻微肝性脑病(MHE)是肝性脑病发病的起始阶段,无明显的临床表现,但是对患者的日常生活安全产生了严重的影响,在现代医学中受到越来越多的重视,治疗方法主要包括去除诱因和药物治疗两个部分。介绍了轻微肝性脑病的相关治疗,并对各种治疗方案的疗效进行了客观评价。认为现治疗方案主要是多种治疗方法的联合应用,但没有试验证明联合应用可提高疗效。     

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.     

EncephalApp Stroop Test validation for the screening of minimal hepatic encephalopathy in Brazil

Introduction and objectivesThe EncephalApp Stroop Test was developed to more easily diagnose minimal hepatic encephalopathy (MHE). A cut-off of >274.9sec (ONtime+OFFtime) reached a 78% sensitivity and 90% specificity in the validation study, but it has been poorly studied in Brazil. We aim to analyze the usefulness of this diagnostic method and to describe a cut-off value to screen MHE in Brazil.MethodsIn this cross-sectional and single-center study, three positive psychometric tests defined the diagnosis of MHE as the gold standard. We evaluated gender, age, education, familiarity with smartphones, etiology of cirrhosis, Child-Pugh/MELD scores, and previous hepatic encephalopathy (HE). Healthy controls and patients without HE were compared for the task validation. The Chi-square and Mann-Whitney tests, logistic regression analysis, and ROC curves were used for statistical evaluation.ResultsWe included 132 patients with cirrhosis (61% male) and 42 controls (62% male) around 51y. Sixty-three were diagnosed with MHE on psychometric tests and 23 had clinical HE. Viral hepatitis (38%) was the major etiology of cirrhosis. The median MELD was 10 and Child-Pugh A was more frequent (70%). There was no significant difference in test results between controls and patients without HE. There was also no influence of gender, age, education, and familiarity with smartphones in the test results. Child-Pugh A was associated with MHE (p=0.0106). A cut-off of >269.8sec (ONtime+OFFtime) had an 87% sensitivity and 77% specificity to detect MHE (p=0.002).ConclusionThis is a valid and reliable tool for screening MHE. However, optimal cut-off values need to be validated locally.     

Predictors of nonresponse to lactulose for minimal hepatic encephalopathy in patients with cirrhosis

Background/Aims: 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. However, not all patients respond to lactulose. We evaluated predictors of nonresponse to lactulose. Patients and methods: Consecutive 110 cirrhotic patients without HE were evaluated for MHE by psychometry, P300 auditory event‐related potential (P300ERP), venous ammonia and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry and P300ERP (>2 SD). MHE patients were treated with lactulose for 1 month. Response was defined by normalization of the abnormal test parameters (both psychometric tests and P300ERP). Results: Sixty patients (54.5%) were diagnosed as having MHE: 17/39 (44%) in Child's A, 21/42 (50%) Child's B and 22/29 (76%) in Child's C. There was a significant difference between Child's C's vs Child's A's and B's (P<0.05). Abnormal psychometric tests and abnormal P300ERP were seen in 74 (67%) and 74 (67%) patients respectively. Of 60 patients with MHE, after treatment, psychometry remained abnormal in 22 (36.6%) and P300ERP in 21 (35%) patients. CFF was<38 Hz in 34 (57%) and 11 (18%) patients, respectively, before and after treatment in MHE patients. There was a significant difference between the baseline serum sodium level (134.7±2.6 vs 131.1±2.2 mmol/L, P=0.001) and the venous ammonia level (76.6±20.7 vs 113.4±22.8 μmol/L, P=0.001) between responders vs nonresponders. Receiver operating characteristic analysis was performed to identify the cutoff for venous ammonia [cutoff 93.5 mmol/L, area under the curve (AUC) 0.892 (0.814–0.970)] and for the serum sodium level [cutoff 132.5 mmol/L, AUC 0.874 (0.779–0.998)]. Taking a cutoff of 93.5 mmol/L for ammonia patient had a sensitivity of 88.5% and a specificity of 79.4%, respectively, and a cutoff of 132.5 mmol/L for serum sodium patient had a sensitivity of 76.5% and a specificity of 88.5% for nonresponse to lactulose. On univariate analysis and multivariate analysis, serum sodium and venous ammonia were the only two parameters associated with nonresponse to lactulose. Conclusion: The prevalence of MHE was 55% and MHE improved in 57% patients with lactulose. Baseline low serum sodium and high venous ammonia were highly predictive of nonresponse to lactulose therapy.     

Value of the critical flicker frequency in patients with minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is mainly diagnosed using psychometric tests such as the psychometric hepatic encephalopathy score (PHES). Despite the clinical and social relevance of MHE, psychometric testing is not widespread in routine clinical care. We assessed the usefulness of the critical flicker frequency (CFF), for the diagnosis of MHE and for the prediction of the development of overt episodes of HE. The normal range of PHES in the Spanish population was evaluated in a control group. Subsequently, 114 patients with cirrhosis and 103 healthy controls underwent both PHES and CFF tests. A diagnosis of MHE was made when the PHES was lower than -4 points. Patients were followed-up every 6 months for a total of 1 year. CFF did not correlate with age, education, or sex in the control group. The mean CFF was significantly lower in patients with MHE versus non-MHE or controls. Mean CFF correlated with individual psychometric tests as well as PHES (r = 0.54; P < 0.001). CFF <38 Hz was predictive of further bouts of overt HE (log-rank: 14.2; P < 0.001). There was a weak correlation between mean CFF and Child-Pugh score but not with model for end-stage liver disease score. In multivariate analysis using Cox regression, CFF together with Child-Pugh score was independently associated with the development of overt HE. CONCLUSION: CFF is a simple, reliable, and accurate method for the diagnosis of MHE. It is not influenced by age or education and could predict the development of overt HE.     

门冬氨酸鸟氨酸治疗显性和轻微型肝性脑病

检索2000年至2010年期间在国内外发表的有关门冬氨酸鸟氨酸治疗显性肝性脑病（HE）和轻微型肝性脑病（MHE）的文献,并进行分析综述。结果显示,门冬氨酸鸟氨酸的治疗机制是直接降低血氨,疗效可靠,无明显不良反应,其对显性HE的疗效已得到公认,对MHE的疗效也在国内外研究中得到初步证实。     

Chinese guidelines on management of hepatic encephalopathy in cirrhosis

The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy in cirrhosis based on the published evidence and the panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy(HE) including minimal hepatic encephalopathy(MHE) and overt hepatic encephalopathy, emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and timely treatment are the key to improve the prognosis of HE. The principles of treatment include prompt removal of the cause, recovery of acute neuropsychiatric abnormalities to baseline status, primary prevention, and secondary prevention as soon as possible.     

Management options for minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is a neurocognitive dysfunction that is present in the majority of patients with cirrhosis. MHE has a characteristic cognitive profile that cannot be diagnosed clinically. This cognitive dysfunction is independent of sleep dysfunction or problems with overall intelligence. MHE has a significant impact on quality of life, the ability to function in daily life and progression to overt hepatic encephalopathy. Driving ability can be impaired in MHE and this 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 during routine care and can add a vital dimension to the overall disease assessment. Driving history should be an integral part of the care of patients with MHE. The preserved communication skills and lack of specific signs and insight make MHE difficult to diagnose. The predominant strategies for MHE diagnosis are psychometric or neurophysiological testing. These are usually limited by financial, normative or time constraints. Studies into inhibitory control, cognitive drug research and critical flicker frequency tests are encouraging. These tests do not require a psychologist for administration and interpretation. Lactulose and probiotics have been studied for their potential use as therapies for MHE, but these are not standard-of-care practices at this time. Therapy can improve the quality of life in MHE patients but the natural history, specific diagnostic strategies and treatment options are still being investigated.     

隐匿性肝性脑病的诊疗进展

隐匿性肝性脑病(minimal hepatic encephalopa-thy,MHE)又称亚临床肝性脑病(subclinicalhepatic encephalopathy,SHE),是慢性肝病和肝硬化最常见的严重并发症,是一种具有渐进性、可逆性的神经精神病学异常和运动功能失调特点的疾病.尽管其发病机制仍未明确,血清和中枢神经系统(central nervoussystem,CNS)血氨升高仍被认为是肝性脑病(hepatic encephalopathy,HE)的致病机制和治疗核心,并受血脑屏障改变、神经递质紊乱、氨基丁酸和苯二氮异常等因素影响.因此明确其诱发因素是HE治疗的关键.治疗药物包括抗生素、二糖类、益生菌、门冬氨酸鸟氨酸(L-ornithine-L-aspartate,LOLA)、苯甲/苯乙酸盐等.因此,对MHE的发病机制、临床诊断和治疗研究进展进行归纳,为临床诊疗提供前沿性、系统性信息,具有重要意义.     

Minimal hepatic encephalopathy: Consensus statement of a working party of the Indian National Association for Study of the Liver

Hepatic encephalopathy (HE) is a major complication that develops in some form and at some stage in a majority of patients with liver cirrhosis. Overt HE occurs in approximately 30–45% of cirrhotic patients. Minimal HE (MHE), the mildest form of HE, is characterized by subtle motor and cognitive deficits and impairs health‐related quality of life. The Indian National Association for Study of the Liver (INASL) set up a Working Party on MHE in 2008 with a mandate to develop consensus guidelines on various aspects of MHE relevant to clinical practice. Questions related to the definition of MHE, its prevalence, diagnosis, clinical characteristics, pathogenesis, natural history and treatment were addressed by the members of the Working Party.     

Motor vehicle accidents: How should cirrhotic patients be managed?

Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs. Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit, which frequently occurs in cirrhotic patients independent of severity of liver disease. Although MHE is known as a risk factor for MVAs, the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown. Recently, Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT), and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs. Besides the ICT and lactulose, there are various diagnostic tools and therapeutic strategies for MHE. In this commentary, we discussed a current issue of diagnostic tools for MHE, including neuropsychological tests. We also discussed the advantages of the other therapeutic strategies for MHE, such as intake of a regular breakfast and coffee, and supplementation with zinc and branched chain amino acids, on the MVA-related societal costs.     

肝硬化患者轻微肝性脑病临床相关危险因素分析

目的评估肝硬化人群中轻微型肝性脑病（MHE）发生的相关因素.方法在121例肝硬化患者,分别进行心理肝性脑病得分（PHES）和临界闪烁频率（CFF）测定,并评估肝功能分级状态.结果在121例肝硬化患者中,检出MHE者70例（57.9%）.性别、受教育程度、肝病病因、肝功能Child-Pugh分级、血浆氨浓度等因素对肝硬化患者发生MHE无统计学意义（P〉0.05）;经Logistic多因素回归分析,仅发现年龄为MHE发生的危险因素（P=0.041, OR=1.035）,而MHE发生与性别、教育程度、肝病病因、肝功能Child-Pugh分级和血浆氨浓度无关（P〉0.05）.结论在肝硬化患者中MHE发生率较高,年龄增长是肝硬化患者发生MHE的危险因素.     

Minimal Hepatic Encephalopathy in Patients with Cirrhosis by Measuring Liver Stiffness and Hepatic Venous Pressure Gradient

Background/Aim:

Transient elastography (TE) of liver and hepatic venous pressure gradient (HVPG) allows accurate prediction of cirrhosis and its complications in patients with chronic liver disease. There is no study on prediction of minimal hepatic encephalopathy (MHE) using TE and HVPG in patients with cirrhosis.

Patients and Methods:

Consecutive cirrhotic patients who never had an episode of hepatic encephalopathy (HE) were enrolled. All patients were assessed by psychometry (number connection test (NCT-A and B), digit symbol test (DST), serial dot test (SDT), line tracing test (LTT)), critical flicker frequency test (CFF), TE by FibroScan and HVPG. MHE was diagnosed if there were two or more abnormal psychometry tests (± 2 SD controls).

Results:

150 patients with cirrhosis who underwent HVPG were screened; 91 patients (61%, age 44.0 ± 11.4 years, M:F:75:16, Child''s A:B:C 18:54:19) met the inclusion criteria. Fifty three (58%) patients had MHE (Child A (7/18, 39%), Child B (32/54, 59%) and Child C (14/19, 74%)). There was no significant difference between alanine aminotranferease (ALT), aspartate aminotransferase (AST) and total bilirubin level in patients with MHE versus non MHE. Patients with MHE had significantly lower CFF than non MHE patients (38.4 ± 3.0 vs. 40.2 ± 2.2 Hz, P = 0.002). TE and HVPG in patients with MHE did not significantly differ from patients with no MHE (30.9 ± 17.2 vs. 29.8 ± 18.2 KPas, P = 0.78; and 13.6 ± 2.7 vs. 13.6 ± 3.2 mmHg, P = 0.90, respectively).There was significant correlation of TE with Child''s score (0.25, P = 0.01), MELD (0.40, P = 0.001) and HVPG (0.72, P = 0.001) while no correlation with psychometric tests, CFF and MHE.

Conclusion:

TE by FibroScan and HVPG cannot predict minimal hepatic encephalopathy in patients with cirrhosis.