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.     

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: time to recognise and treat

Minimal hepatic encephalopathy represents a part of the spectrum of hepatic encephalopathy and is the mildest form. While patients with hepatic encephalopathy have impaired intellectual functioning, personality changes, altered levels of consciousness, and neuromuscular dysfunction, patients with minimal hepatic encephalopathy have no recognisable clinical symptoms of hepatic encephalopathy but have mild cognitive and psychomotor deficits. The prevalence of minimal hepatic encephalopathy has been reported to vary between 30% and 84% in patients with liver cirrhosis and is higher in patients with poor liver function. The diagnosis is usually made by neuropsychological and/or neurophysiological testing in cirrhotic patients who are otherwise normal on neurological examination. Minimal hepatic encephalopathy is a clinically significant disorder that impairs the health-related quality of life, predicts the development of overt encephalopathy and is probably associated with a poor prognosis. Thus screening all patients with cirrhosis for minimal hepatic encephalopathy using psychometric testing is recommended. Pharmacologic therapy is recommended for patients diagnosed with minimal hepatic encephalopathy. The pathogenesis of minimal hepatic encephalopathy is considered similar to that of overt hepatic encephalopathy and ammonia plays a key role. Thus ammonia lowering agents such as lactulose, L-ornithine and L-aspartate that have good safety profiles are recommended. Future studies will better define the role of probiotics, levocarnitine and sodium benzoate.     

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.     

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.     

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.     

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。     

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.     

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.     

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.     

Advances in the Evaluation and Management of Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy (MHE) is a neurocognitive disorder that affects up to 80% of cirrhotic patients. Similar to overt hepatic encephalopathy, ammonia and oxidative stress play key roles in the pathogenesis of MHE. However, MHE is characterized by subtle deficits and psychomotor abnormalities that can only be elicited by specialized psychometric tests. Although no gold standard exists for the diagnosis, MHE remains an important entity for clinicians to recognize because of its negative impact on a patient’s health-related quality of life and association with driving impairment and vehicle accidents. MHE has also been associated with an increased rate in the development of overt hepatic encephalopathy and increased mortality; therefore, identification and treatment should not be delayed. Treatment to date has been focused on reducing serum ammonia levels with agents such as lactulose, probiotics, and synbiotics. MHE is a real and growing problem that is epidemic in cirrhosis, and increasing awareness of this condition is necessary for adequate management of these patients.     

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.     

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.     

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.     

Impairment of Response Inhibition Precedes Motor Alteration in the Early Stage of Liver Cirrhosis: A Behavioral and Electrophysiological Study

Abnormality in movement initiation may partially explain psychomotor delay of cirrhotic patients, even in the absence of overt hepatic encephalopathy (HE). Therefore, the aim of this study was to determine the mechanisms of psychomotor delay observed in patients with cirrhosis in the absence of overt HE. Fourteen patients with nonalcoholic cirrhosis and 12 healthy matched control subjects underwent the lateralized readiness potential (LRP) measurement elicited by a visuospatial compatibility task (Simon task). Stimulus-triggered LRPonset reflects the time in which response is selected, while response-triggered LRP onset reflects motor execution. Cirrhotic patients showed delayed reaction times (RTs) compared to controls, particularly those with trial-making test A (TMT-A) or electroencephalogram (EEG) alterations. Stimulus-triggered LRP onset was found to be delayedin cirrhotic patients compared to controls, with a significant Group-versus-Condition interaction, showing a reduced cognitive ability to cope with interfering codes, even in patients without minimal HE (MHE). Response-triggered LRP was found to be delayed only in the patients with TMT-A or EEG alterations. In conclusion, cirrhotic patients without overt HE display a psychomotor slowing, depending firstlyon response inhibition and only later accompanied by impaired motor execution.     

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.     

Primary prophylaxis of overt hepatic encephalopathy in patients with cirrhosis: an open labeled randomized controlled trial of lactulose versus no lactulose

Background and Aim: Development of overt hepatic encephalopathy (HE) is associated with poor prognosis in patients with cirrhosis. Lactulose is used for the treatment of HE. There is no study on the prevention of overt HE using lactulose in patients who never had HE earlier. Methods: Consecutive cirrhotic patients who never had an episode of overt HE were randomized to receive lactulose (Gp‐L) or no lactulose (Gp‐NL). All patients were assessed by psychometry (number connection test [NCT‐A and B], figure connection test if illiterate [FCT‐A and B], digit symbol test [DST], serial dot test [SDT], line tracing test [LTT]) and critical flicker frequency test (CFF) at inclusion and after 3 months. These patients were followed every month for 12 months for development of overt HE. Results: Of 250 patients screened, 120 (48%) meeting the inclusion criteria were randomized to Gp‐L (n = 60) and Gp‐NL (n = 60). Twenty (19%) of 105 patients followed for 12 months developed an episode of overt HE. Six (11%) of 55 in the lactulose (Gp‐L) group and 14 (28%) of 50 in the Gp‐NL (P = 0.02) developed overt HE. Ten (20%) of 50 patients in Gp‐NL and five (9%) of 55 patients in the Gp‐L group died, P = 0.16. Number of patients with minimal hepatic encephalopathy (MHE) were comparable in two groups at baseline (Gp‐L vs Gp‐NL, 32:36, P = 0.29). Lactulose improved MHE in 66% of patients in Gp‐L. Taking a cutoff < 38 Hz sensitivity and specificity of CFF in predicting HE were 52% and 77% at baseline and 52% and 82% at 3 months of treatment. On multivariate analysis, Child's score and presence of MHE at baseline were significantly associated with development of overt HE. Conclusions: Lactulose is effective for primary prevention of overt hepatic encephalopathy in patients with cirrhosis.     

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.     

Development of a three‐factor neuropsychological approach for detecting minimal hepatic encephalopathy

Background: Minimal hepatic encephalopathy (HE) has profoundly negative effects on daily functioning ad quality of life. However, standard psychometric procedures have not been widely incorporated into efforts to develop a neuropsychological battery for this condition. Aims: To establish the construct and diagnostic validity of a neuropsychological approach for the recognition of minimal HE in patients with cirrhosis. Methods: A comprehensive battery of neuropsychological tests was administered to cirrhotic patients with at most grade 1 HE, recruited from the liver transplant and advanced liver disease clinics. An inflammatory bowel disease comparison group was similarly evaluated, thus controlling for the secondary effects of chronic illness on cognition. Testing results for the cirrhosis group were subjected to principal component analysis to establish the relevant cognitive constructs and associated measures. Factor analysis was applied to the neuropsychological battery of 20 tests to determine the cognitive factors to be used. Age‐adjusted standardized neuropsychological factor scores were then compared for the two groups. Results: Factor analysis revealed that our battery of 20 tests was measuring three cognitive factors. Based on the pattern of factor loadings, we labeled these important cognitive factors: global cognitive function; psychomotor speed; and learning and memory. Logistic regression revealed that only impaired psychomotor speed distinguished cirrhotics with no more than grade 1 HE from medically ill controls. Conclusions: The cirrhosis group was characterized by a pattern of preserved global cognitive functioning, mild memory impairment, and moderate psychomotor speed impairment. Discussion: This distinctive pattern of focal psychomotor speed deficits is suggestive of subcortical pathway involvement in minimal HE.     

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.