Hepatic Encephalopathy: Current Thoughts on Pathophysiology and Management.

Deciphering the Spectrum of Low-Grade Hepatic Encephalopathy in Clinical Practice

Efficacy of l-Ornithine l-Aspartate for the Treatment of Hepatic Encephalopathy and Hyperammonemia in Cirrhosis: Systematic Review and Meta-Analysis of Randomized Controlled Trials

Recent pathophysiological models suggest that oxidative stress and hyperammonemia lead to a mild brain oedema in hepatic encephalopathy (HE). Glutathione (GSx) is a major cellular antioxidant and known to be involved in the interception of both. The aim of this work was to study total glutathione levels in covert HE (minimal HE and HE grade 1) and to investigate their relationship with local brain water content, levels of glutamine (Gln), myo-inositol (mI), neurotransmitter levels, critical flicker frequency (CFF), and blood ammonia. Proton magnetic resonance spectroscopy ((1)H MRS) data were analysed from visual and sensorimotor cortices of thirty patients with covert HE and 16 age-matched healthy controls. Total glutathione levels (GSx/Cr) were quantified with respect to creatine. Furthermore, quantitative MRI brain water content measures were evaluated. Data were tested for links with the CFF and blood ammonia. GSx/Cr was elevated in the visual (mHE) and sensorimotor (mHE, HE 1) MRS volumes and correlated with blood ammonia levels (both P<0.001). It was further linked to Gln/Cr and mI/Cr (P<0.01 in visual, P<0.001 in sensorimotor) and to GABA/Cr (P<0.01 in visual). Visual GSx/Cr correlated with brain water content in the thalamus, nucleus caudatus, and visual cortex (P<0.01). Brain water measures did neither show group effects nor correlations with CFF or blood ammonia. Elevated total glutathione levels in covert HE (< HE 2) correlate with blood ammonia and may be a regional-specific reaction to hyperammonemia and oxidative stress. Brain water content is locally linked to visual glutathione levels, but appears not to be associated with changes of clinical parameters. This might suggest that cerebral oedema is only marginally responsible for the symptoms of covert HE.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome complicating acute and chronic liver failure and characterized by a wide range of manifestations, in absence of other brain disease. HE is very frequent in course of cirrhosis and even mild forms involve a great additional burden on patients, their families and health-care resources. Its onset affects subsequent survival of patients. Historically, pathophysiology of HE was connected to several substances (mostly ammonia) produced in the gut and normally metabolized by the liver, but more recently other factors such as inflammation, bacterial translocation and oxidative stress have shown a crucial role. Symptoms are often overt (confusion, asterixis, disorientation, ataxia or coma) but can also be subtle (sleep disturbances, cognitive impairment, mood alterations, impairment of executive decision-making, and psychomotor speed – Minimal HE); the West Haven Criteria are most often used to grade Overt HE (OHE), with grade ranging from 0 to 4 (4 corresponding to coma). Since both Minimal HE and grade 1 HE cannot be diagnosed by clinical examination and need for specific tests, it results practical to combine these entities and name them "Covert" HE (CHE) to aid clinical use. Diagnosis is based on evidence of neurological impairment in presence of liver cirrhosis, only after the exclusion of other brain diseases. Measurement of serum ammonia and electroencephalography are little specific, while brain magnetic resonance and search for portosystemic shunts are important in complex cases. Diagnosis of OHE is often just clinical, while that of CHE requires dedicated psychometric and neurophysiological tests. Although these tests are difficult to be performed in the clinical practice, detection and treatment of CHE are cost-effective and important; indeed, CHE affects patients’ quality of life, socioeconomic status and driving skills, and increases the risk for falls, car accidents, development of OHE, and death. Management of HE includes early diagnosis and prompt treatment of precipitating factors (infection, gastrointestinal bleeding, electrolyte disturbances, dehydration, hypotension, use of benzodiazepines, psychoactive drugs, and/or alcohol). Current treatment is based principally on reducing intestinal ammonia with nonabsorbable disaccharides (lactulose or lactitol); rifaximin, used solely or in addition, is also becoming a first-line treatment.

Background: The dietary protein restriction that was commonly recommended to hepatic encephalopathy (HE) patients, often leads to malnutrition, whereas malnutrition can deteriorate cirrhosis prognosis. The aims of this study were to find out encephalopathy improvement that was measured by critical flicker frequency (CFF) test and nutritional status by measuring prealbumin level after L-Ornithine L-Aspartate (LOLA) treatment with adequate calories and protein intake in patients with HE. Method: Patients with liver cirrosis who visited Cipto Mangunkusumo hospital on June-October 2009 was evaluated by CFF test using HEPAtonormTM device. Encephalopathy was defined when CFF < 39 Hz. Nutritional status was measured by the mid-arm muscle circumference (MAMC) and was stated as malnutrition when the MAMC was below the 15th percentile. Patients had been treated by 3 x 6 mg LOLA granules for 2 weeks, and adequate calories and protein intake with branched-chain amino acid (BCAAs) substitution. The change of encephalopaty was evaluated by the CFF test and the nutritional status by measuring prealbumin blood level. Results: There were 17 patients with liver cirrhosis who fulfilled the inclusion criteria. The mean CFF Result increased from 34.1 ± 2.5 Hz to 36.5 ± 2.9 Hz after LOLA treatment with the adequate calories and protein intake including BCAAs substitution, which was statistically significant (p < 0.001) compared to before treatment. The prealbumin level also increased significantly compared before treatment, i.e. from 5.4 ± 2.1 mg/dL to 6.4 ± 2.6 mg/dL, p = 0.008. Conclusion: HE patients with malnutrition could be given adequate calorie and protein with BCAAs substitution to improve their nutritional status, and LOLA granules for the improvement of HE. Keywords: minimal hepatic encephalopathy, malnutrition, CFF, LOLA, prealbumin, BCAAs

Hepatic encephalopathy (HE)-associated brain edema is a common cause of death in acute liver failure (ALF). Molecular Adsorbent Recirculating System (MARS) albumin dialysis detoxifies endogenous and exogenous toxins from blood and improves HE. In this study we assessed the effect of MARS on increasing the length of time available while waiting for liver graft. Thirty-seven patients with ALF who received a high-urgent liver transplant (LTx) were divided into three groups according to the amount of histological necrosis in the explanted liver: group I = 100% necrosis; group II = 80-99% necrosis; group III = less than 80% necrosis. MARS was used continuously until LTx. Median time (range) on MARS treatment prior to LTx in groups I-III was 7 days (2-26), 6 days (1-17), and 5 days (1-15), and the median time on the waiting list was 5 days (1-11), 3 days (0-13), and 1 day (0-12), respectively. The HE grade prior to and after MARS was similar in all groups. In two patients the HE grade decreased during MARS treatment, even though the explanted liver showed a complete lack of viable cells. Overall 30-day and one-year survival were 97% and 92%, respectively, without differences between the three groups. In ALF patients the liver cell damage progressed to total or near total necrosis of the liver when the waiting time was prolonged. Yet, with MARS treatment some patients with total hepatic necrosis showed an absence of encephalopathy. With MARS treatment some patients might be able to wait longer for a LTx with good results.

The clinical classification of hepatic encephalopathy is largely subjective, which has led to difficulties in designing trials in this field. To review the current classification of hepatic encephalopathy and to develop consensus guidelines on the design and conduct of future clinical trials. A round table was convened at the 14th International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) meeting. Key discussion points were the nomenclature of hepatic encephalopathy and the selection of patients, standards of care and end-points for assessing the treatment and secondary prevention of hepatic encephalopathy. It was generally agreed that severity assessment of hepatic encephalopathy in patients with cirrhosis, whether made clinically or more objectively, should be continuous rather than categorical, and a system for assessing the SONIC (Spectrum of Neuro-cognitive Impairment in Cirrhosis) was proposed. Within this system, patients currently classified as having minimal hepatic encephalopathy and Grade I hepatic encephalopathy would be classified as having Covert hepatic encephalopathy, whereas those with apparent clinical abnormalities would continue to be classified as overt hepatic encephalopathy. Some aspects of the terminology require further debate. Consensus was also reached on the patient populations, standards of care and endpoints to assess clinical trial outcomes. However, some compromises had to be made as there is considerable inter- and intravariability in the availability of some of the more objective surrogate performance markers. The objectives of the round table were met. Robust, defendable guidelines for the conduct of future studies into hepatic encephalopathy have been provided. Outstanding issues are few and will continue to be discussed.

BACKGROUND: Minimal hepatic encephalopathy (MHE) is associated with structural and functional connectivity abnormalities in the brain which correlate with cognitive dysfunction. The default mode network (DMN) comprises functionally interconnected brain regions responsible for attention and may explain cognitive deficits in MHE. While L-ornithine L-aspartate (LOLA) may improve MHE, its mechanism of action is not well characterised in controlled studies. METHODS: We performed a double-blind, randomised trial comparing the impact of oral L-ornithine L-aspartate (LOLA) 6g three times per day with placebo on 34 individuals with MHE (defined by PHES) for 12 weeks. Fourteen subjects received LOLA, 20 patients received placebo for the study duration. Subjects underwent functional MRI (fMRI) of the brain while performing motor and cognitive tasks and resting state studies at baseline (before starting on LOLA) or placebo, and at 12 weeks. The motor and cognitive task data in the LOLA arm (vs placebo) were analysed by comparing the sum total of fMRI activation at baseline with data collected at 12 weeks. For resting state data, the level of functional connectivity within a network was compared between baseline and 12 weeks for LOLA against placebo. Results: Groups were matched for age, sex, baseline educational level, weekly alcohol consumption, baseline PHES score, CogstateTM computerised psychometric testing, WTAR and SF36 scores. Color-naming subtest of the Stroop task was significantly impaired at baseline in LOLA receivers (P = 0.0179) For group averaged whole-brain data, there was no significant difference in activation for both motor and cognitive tasks or in resting state in all 34 patients at baseline and 12 weeks. Group differences by region of interest (see Table 1 below): the choice reaction time task in the default mode network (DMN) demonstrated significant treatment (P = 0.026) advantage after 12 weeks of LOLA. Of the 12 resting state networks studied, visual area 2 showed a significant treatment (P = 0.021) benefit after 12 weeks of LOLA. Conclusion: In the first RCT of LOLA combined with modern brain imaging analysis, a significant treatment benefit with LOLA on task activation was noted in the DMN. A significant treatment advantage of LOLA on resting-state fMRI in the visual network is consistent with this, this may be a compensatory mechanism in early MHE. Future studies could stratify patients who may benefit from LOLA based on base-line fMRI characterisation.

Management of Covert Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome showing a wide spectrum and one of the serious complications seen in patients with acute and chronic liver disease or spontaneous portal-systemic shunting. Recently, HE has been classified into two categories: covert HE, which involves minimal HE and is identified solely through psychometric or neurological tests, and overt HE (coma grade II-IV). Although recent therapies based on evidence-based results have improved the therapeutic outcomes of HE patients, repeat recurrent or resistant HE is often seen, and the prognosis in patients with severe liver dysfunction is still poor. In this issue, we discuss the therapeutic strategies and current management, except liver transplantation and interventional procedures for portal-systemic shunting, in cirrhotic patients with HE.

Patients with cirrhosis commonly experience hepatic encephalopathy (HE), a condition associated with alterations in behavior, cognitive function, consciousness, and neuromuscular function of varying severity. HE occurring before liver transplant can have a substantial negative impact on posttransplant outcomes, and preoperative history of HE may be a predictor of posttransplant neurologic complications. Even with resolution of previous episodes of overt or minimal HE, some patients continue to experience cognitive deficits after transplant. Because HE is one of the most frequent pretransplant complications, improving patient HE status before transplant may improve outcomes. Current pharmacologic therapies for HE, whether for the treatment of minimal or overt HE or for prevention of HE relapse, are primarily directed at reducing cerebral exposure to systemic levels of gut-derived toxins (e.g., ammonia). The current mainstays of HE therapy are nonabsorbable disaccharides and antibiotics. The various impacts of adverse effects (such as diarrhea, abdominal distention, and dehydration) on patient's health and nutritional status should be taken into consideration when deciding the most appropriate HE management strategy in patients awaiting liver transplant. This paper reviews the potential consequences of pretransplant HE on posttransplant outcomes and therapeutic strategies for the pretransplant management of HE.

To explore the spatial patterns of the amplitude of low-frequency fluctuation (ALFF) in patients with hepatic encephalopathy (HE) of varying severity and to correlate these fluctuations with clinical markers of HE. This study was approved by the local ethics committee, and written informed consent was obtained from all participants. Twenty-nine patients with HE (15 with overt and 14 with minimal HE) and 17 healthy control subjects underwent resting-state functional magnetic resonance (MR) imaging. The ALFF, an index reflecting the amplitudes of spontaneous brain activity, was compared among patients with overt HE, patients with minimal HE, and control subjects with analysis of variance tests and t tests between each pair. Pearson correlation analysis was performed between the ALFF and the venous blood ammonia level and Child-Pugh score of all patients with HE. Compared with control subjects, patients with overt and minimal HE showed decreased ALFF mainly in regions within the default-mode network (DMN) and increased ALFF in the cerebellum and middle temporal gyrus. Compared with patients with minimal HE, those with overt HE showed decreased ALFF in DMN regions and increased ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Both the venous blood ammonia levels and Child-Pugh scores of individual patients with HE showed negative correlation with ALFF within some DMN regions, whereas they showed positive correlation with ALFF in the posterior insular cortex (P<.05, corrected for multiple comparisons). Patients with HE have diffuse abnormalities in intrinsic brain activity. The levels of decreased ALFF in the DMN and increased ALFF in the posterior insular cortex are dependent on the severity of HE, suggesting continuous impairment of the DMN and a compensatory role of the insula during the progression of HE. Resting-state functional MR imaging with ALFF analysis may be a noninvasive modality with which to detect the progression of HE.

BACKGROUND: In daily clinical practice, the detection of HE is still less represented but strongly required. Therefore, we assessed the EncephalApp (Stroop-Test) in a German population by standard diagnostic procedures such as the Critical Flicker Frequency (CFF) and the PHES-Test (Psychometric Hepatic Encephalopathy Score). One of the purposes of the trial was finding a Cut-Off value for the EncephalApp in the German population. METHODS: 81 patients with liver cirrhosis underwent the testing of the CFF, the PHES-Test and the EncephalApp. A control group of 25 healthy subjects were examined in the same manner. The CFF was considered pathological with &lt;39 Hz and the PHES-Test with &lt; - 4 value points. The On-plus-Off Time of the EncephalApp was compared to the results of the CFF and the PHES-Test. Different Cut-Offs of the On-plus-Off Time were analyzed. Within these HE groups, the mean values of the PHES-Test, the CFF and the On-plus-Off Time of the EncephalApp were compared and the ROC Analysis (receiver operating characteristic) was conducted. Laboratory parameters, clinical data, and further imaging techniques were also included and compared. RESULTS: The study group (n = 81) included 52 men and 29 women (62.8 years ± 12.5). For the evaluation of the EncephalApp, different Cut-Off values were determined and their specificity and sensitivity were calculated. The comparative parameter was the result of the PHES-Test. Through the creation of a ROC curve, the AUC (area under the curve) showed that the Cut-Off time of &gt;224 sec with 0.803 is the most efficient with better sensitivity (79%) and specificity (82%). Other Cut-Off values showed lower sensitivities and higher false negative values. CONCLUSIONS: After evaluating the specificity, sensitivity and AUC the most efficient Cut-Off value for the On-plus-Off Time in the EncephalApp is &gt;224 sec. In comparison with the CFF and the PHES testing, most of the patient withdrawals (especially in higher grade HE) within the study were registered by the EncephalApp. The EncephalApp is a valid and quick method to diagnose minimal HE but has its limitations in the grading between HE grade 1 and 2.

The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experiments using different albumin concentrations and dialysate flow rates were performed. In each experiment, 1000 ml human donor plasma, spiked with 250 mg unconjugated bilirubin, 200 mg sulfobromophthalein (BSP) and 115 mg glycocholic acid (N-[3alpha,7alpha,12alpha-trihydroxy-24-oxycholan-24-yl]glycine) - a conjugated bile acid (BA), circulated in a closed loop with 150 ml/min and was dialysed against albumin solution. These substances are bound to the different binding sites of albumin and have different association constants. For the comparison, the standard MARS experiment was performed using the same plasma flow rate of 150 ml/min. Moreover, the clearances of bilirubin for MARS and SPAD during clinical treatments were calculated using own data and those reported by Seige, Kreymann, Jeschke, et al. in Transplant Proc 1999; 31: 1371-5. The concentrations of bilirubin, BSP and BA were measured in plasma and dialysate and for these substances clearances (Cl) were calculated. It is known that the elimination rate of bilirubin is not very high during albumin dialysis in comparison to other substances, like bile acids, due to the high association constant. An increase of albumin concentration or the flow rate improved the efficacy but also raised the costs substantially. In this study, we have shown that MARS is the more effective kind of albumin dialysis for the important substances like bile acids. By SPAD an improvement of efficacy can be reached only by dramatic increase of the costs. Also, the earlier experiments showed that MARS is safer because of the removal of the stabilizers, which are normally included in the commercial albumin solutions.

Background: Covert hepatic encephalopathy (CHE) is underdiagnosed and is difficult to detect. The EncephalApp Stroop test is validated for its screening. The aim of the study was to define Tunisian norms for the test based on healthy controls norms and to estimate the prevalence of CHE in cirrhotic Tunisian patients.Methods: A prospective, multicenter, cross‐sectional study was conducted. Ambulatory or hospitalized cirrhotic patients aged 40 years and over were recruited at 11 centers. Healthy subjects aged 40 years and over were recruited at 8 centers. We used a translated Arabic version of the streamlined EncephalApp Stroop test. The task has two components: “Off” and “On” state depending on the discordance or concordance of the stimuli.Results: 142 patients were included. The mean age was 57.26 years [40–86]. 40 (28.17%) of cirrhotic patients who were included were diagnosed as having a minimal hepatic encephalopathy or CHE. Among the ineligible patients, 22 had overt hepatic encephalopathy. If we consider these patients, the overall prevalence rate of CHE was around 24.39% in cirrhotic patients. It was more frequent in women (34.21%vs 25.96%), and in patients whose level of school education is between 6 and 13 years. Its prevalence does not appear to be affected by gender, MELD score, etiology of cirrhosis and age group of patients, as these variables were independent with respective p according to the chi-square test 0.413; 0.736; 0.663 and 0.1. The stroop times (On / Off and On + Off) correlated significantly with each other, are associated significantly and positively with age (respective Pearson coefficients: 0.578; 0.567 and 0.6). The more the age increases, the more the stroop response times increases (p > 10-3).Conclusions: EncephalApp Stroop test was an efficient screening tool for CHE in Tunisian cirrhotic patients.