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.     

肝性脑病临床诊治的进展

肝性脑病（HE）是在各种急慢性及终末期肝病的基础上出现的以代谢紊乱为主要特征的神经、精神、功能失调综合征。目前一致认为,由于氨中毒及感染使星型胶质细胞肿胀及脑水肿,从而导致这些症状的出现。然而,导致脑部形态学改变的细胞学机制尚未明确。我们可以通过多种方法来诊断及评估不同程度的HE。HE的治疗主要是去除诱因,同时根据有效的经验用药来明确诊断。HE的经验用药主要是使用利福昔明及乳果糖以减少肠道内氨的产生与吸收。     

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy

Hepatic encephalopathy(HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE(CHE) and overt HE(OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis.     

单胺类神经递质在大鼠急性肝性脑病发生中的作用

目的:阐明单胺类神经递质在大鼠急性肝性脑病发生中的作用。方法:采用硫代乙酰胺所致大鼠(n=10)急性肝功能衰竭模型,测定血浆及脑组织中单胺类神经递质与血浆内毒素含量,并与正常组(n=5)进行比较。结果:在肝性脑病进入Ⅲ-Ⅳ期时,脑组织中仅5-羟色胺含量明显升高(5 139±48.0比394.7±43.8ng/g),血浆5-羟色胺升高幅度是脑组织中的两倍并伴严重内毒素血症。结论:5-羟色胺可能是肝性脑病时昏迷的因素,脑组织中升高的5-羟色胺部分源于血浆。     

Original research: Nationwide analysis of incidence and predictors of 30-day readmissions in patients with decompensated cirrhosis

Background and objectiveCirrhosis is the number one cause of non-cancer deaths among gastrointestinal diseases and is responsible for significant morbidity and healthcare utilisation. The objectives were to measure the 30-day readmissions rate following index hospitalisation, to determine the predictors of readmission, and to estimate the cost of 30-day readmission in patients with decompensated cirrhosis.MethodsWe performed a retrospective cohort study of patients with decompensated cirrhosis using 2014 Nationwide Readmission Database from January to November. Decompensated cirrhosis was identified based on the presence of at least one of the following: ascites, hepatic encephalopathy, variceal bleeding, spontaneous bacterial peritonitis and hepatorenal syndrome. We excluded patients less than 18 years of age, pregnant patients, patients with missing length of stay data, and those who died during the index admission.ResultsAmong 57 305 unique patients with decompensated cirrhosis, the 30-day readmission rate was 23.2%. The top three predictors of 30-day readmission were leaving against medical advice (AMA), ascites and acute kidney injury, which increased the risk of readmission by 47%, 22% and 20%, respectively. Index admission for variceal bleeding was associated with a lower 30-day readmission rate by 18%. The estimated total cost associated with 30-day readmission in our study population was US$234.4 million.ConclusionIn a nationwide population study, decompensated cirrhosis is associated with a 30-day readmission rate of 23%. Leaving AMA, ascites and acute kidney injury are positively associated with readmission. Targeted interventions and quality improvement efforts should be directed toward these potential risk factors to reduce readmissions.     

Spectral and dynamic electroencephalogram abnormalities are correlated to psychometric test performance in hepatic encephalopathy

Abstract

Objective. Alterations of the electroencephalogram (EEG) have been reported in patients with hepatic encephalopathy (HE). However, previous methods have not assessed transient phenomena in the EEG signal (dynamics) and associations to psychometric test performance have in general been poor. The aims were to quantify spectral and dynamic EEG abnormalities in patients with HE and to correlate putative findings to psychometric test performances. Methods. Multichannel EEG (64 electrodes) was recorded in 24 cirrhotic patients with various grades of HE and 26 healthy volunteers. Spectral and dynamic EEG indices were quantified by continues wavelet analysis. In addition, the psychometric hepatic encephalopathy score (PHES), continues reaction time, and biochemical profile were assessed. Results. Compared with healthy volunteers, patients had progressively slowing of the EEG (all p ≤ 0.004) (spectral EEG indices) and increased variability in the alpha [7.5–13.5 Hz] (p = 0.001) and beta bands [13.5–32 Hz] (p = 0.02) (dynamic EEG indices). In addition, anteriorization and dissociation of the basic posterior alpha rhythm, along with dissociation of frontal delta activities [1–3.5 Hz] were seen with worsening of HE. Spectral EEG indices (all frequency bands) as well as dynamic EEG indices (alpha and beta bands) were correlated to PHES scores (all p < 0.05). Conclusion. EEG analysis, based on continues wavelet transform, provides quantifiable information on static as well as dynamic features of the EEG in patients with HE. EEG abnormalities were correlated to psychometric test performance and may provide valuable clinical biomarkers for surveillance, prognostication and treatment of this entity.     

亚临床性肝性脑病智能测试与体表感觉诱发电位相关性的研究

目的了解亚临床性肝性脑病（ＳＨＥ）心理智能测试和诱发电位检查之间是否有相关性。方法 ６０例非酒精性肝硬化ＳＨＥ患者同时接受数字连接试验（ＮＣＴ）、数字符号试验（ＤＳ）与体表感觉诱发电位（ＳＳＥＰ）检查。结果ＮＣＴ、ＤＳ与ＳＳＥＰ检查的Ｎ２、Ｎ３、Ｐ３潜伏期之间无相关性。结论ＮＣＴ、ＤＳ与ＳＳＥＰ检查之间不能互相替代。     

Proton Magnetic Resonance Spectroscopy in Portal-Systemic Encephalopathy

Localized proton magnetic resonance spectroscopy (MRS) with short echo times provides unique information of human cerebral metabolism. Studies on patients with portal-systemic encephalopathy (PSE) have been performed to clarify the pathogenesis of this disease and to find a method which allows an objective diagnosis. Spectra of patients with PSE show typical abnormalities. Regional variations of these spectral changes are observed. The metabolic changes correlate with the grade of encephalopathy but the dependence on the Child-Pugh score is controversial. No causal dependence between MRS findings and abnormalities in magnetic resonance imaging is evident. Differences in magnetic resonance spectra in patients compared to controls vanish after liver transplantation, but increase after TIPS. The results of proton magnetic resonance spectroscopy are important for an understanding of the pathogenesis of PSE, but do not aid in the diagnosis of subclinical hepatic encephalopathy.     

Lack of therapeutic effects of gabexate mesilate on the hepatic encephalopathy in rats with acute and chronic hepatic failure

Background and Aim: Inflammation plays a pivotal role in liver injury. Gabexate mesilate (GM, a protease inhibitor) inhibits inflammation by blocking various serine proteases. This study examined the effects of GM on hepatic encephalopathy in rats with acute and chronic liver failure. Methods: Acute and chronic liver failure (cirrhosis) were induced by intraperitoneal TAA administration (350 mg/kg/day for 3 days) and common bile duct ligation, respectively, in male Sprague‐Dawley rats. Rats were randomized to receive either GM (50 mg/10 mL/kg) or saline intraperitoneally for 5 days. Severity of encephalopathy was assessed by the Opto‐Varimex animal activity meter and hemodynamic parameters, mean arterial pressure and portal pressure, were measured (only in chronic liver failure rats). Plasma levels of liver biochemistry, ammonia, nitrate/nitrite, interleukins (IL) and tumor necrosis factor (TNF)‐α were determined. Results: In rats with acute liver failure, GM treatment significantly decreased the plasma levels of alanine aminotransferase (P = 0.02), but no significant difference of motor activity, plasma levels of ammonia, IL‐1β, IL‐6, IL‐10 and TNF‐α or survival was found. In chronic liver failure rats, GM significantly lowered the plasma TNF‐α levels (P = 0.04). However, there was no significant difference of motor activity, other biochemical tests or survival found. GM‐treated chronic liver failure rats had higher portal pressure (P = 0.04) but similar mean arterial pressure in comparison with saline‐treated rats. Conclusions: Chronic GM treatment does not have a major effect on hepatic encephalopathy in rats with TAA‐induced acute liver failure and rats with chronic liver failure induced by common bile duct ligation.     

Efficacy of Lactulose in Cirrhotic Patients with Subclinical Hepatic Encephalopathy

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.     

Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B

Background: Background: We carried out a study to predict the prognosis of acute hepatic failure in patients with chronic hepatitis B. Methods: We studied 25 consecutive patients with severe acute hepatitis. Severe acute hepatitis was defined as the development of acute hepatitis with a total serum bilirubin level of more than 15 mg/dl, prolonged prothrombin time (PT) of more than 5 s, and hepatic encephalopathy (HE). All patients were assessed for King's criteria. Positivity for King's criteria was defined as PT more than 100 s, or any three of the following: (age < 10 years or >40 years; cryptogenic or drug-induced hepatitis; jaundice for more than 7 days before the onset of HE; PT > 50 s; and serum bilirubin > 17.5 mg/dl). All but 1 patient had serial serum alpha-fetoprotein (AFP) levels measured every 1–2 weeks. Results: Eleven of 17 patients who died during the study met the King's criteria, whereas none of the surviving patients met the criteria. The sensitivity was 64.7% and the specificity, 100% for King's criteria in predicting a poor prognosis. In 16 of the 17 deceased patients, the AFP levels were reduced while their jaundice increased (sensitivity, 94.1%; specificity, 87.5%). All 17 deceased patients met the King's criteria and/or had reduced AFP levels while their jaundice increased (sensitivity, 100%; specificity, 87.5%). Conclusions: Our observations suggest that the combined use of follow-up AFP levels and King's criteria is helpful in predicting the poor prognosis of severe acute hepatitis superimposed on chronic hepatitis B. Received: August 20, 2001 / Accepted: December 27, 2001     

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.     

Original research: Serum ammonia use: unnecessary,frequent and costly

Background/objectiveWhile ammonia plays a role in the complex pathophysiology of hepatic encephalopathy (HE), serum ammonia is unreliable for both diagnosis of, and correlation with, neurological symptoms in patients with cirrhosis. We aimed to quantify ordering, cost and appropriate use of serum ammonia in a major Midwestern healthcare system.Design/methodSerum ammonia ordering in adult patients presenting to a large Midwestern health system was evaluated from 1 January 2015 to 31 December 2019.ResultsSerum ammonia ordering was prevalent, with 20 338 tests ordered over 5 years. There were no differences in the number of inappropriate serum ammonia tests per 100 000 admissions for chronic liver disease over time (Pearson’s correlation coefficient=−0.24, p=0.70). As a proportion of total ammonia tests ordered, inappropriate tests increased over time (Pearson’s correlation coefficient=0.91, p=0.03). Inappropriate ordering was more common at community hospitals compared with the academic medical centre (99.3% vs 87.6%, p<0.001).ConclusionDespite evidence that serum ammonia levels are unreliable for the diagnosis of HE and are not associated with severity of HE in individuals with cirrhosis, ordering remains prevalent, contributing to waste and potential harm.