Nutritional therapy for persistent cognitive impairment after resolution of overt hepatic encephalopathy in patients with cirrhosis: A double-blind randomized controlled trial.

BACKGROUND AND AIM: Minimal hepatic encephalopathy (MHE) reflects cognitive impairment in patients with liver cirrhosis and is associated with poor prognosis. We assessed the effects of nutritional therapy on cognitive functions, health-related quality of life (HRQOL), anthropometry, endotoxins, and inflammatory markers in cirrhotic patients with MHE. METHODS: In a double-blind randomized controlled trial, cirrhotic patients with MHE were randomized to nutritional therapy (group I: 30-35 kcal/kg/day and 1.0-1.5 g of protein/kg/day) and no nutritional therapy (group II: diet as patients were taking before) for 6 months. MHE was diagnosed based on psychometric hepatic encephalopathy score (PHES). Anthropometry, ammonia, endotoxins, inflammatory markers, myostatin, and HRQOL were assessed at baseline and after 6 months. Primary endpoints were improvement or worsening in MHE and HRQOL. RESULTS: A total of 150 patients were randomized to group I (n = 75, age 46.3 ± 12.5 years, 58 men) and group II (n = 75, age 45.2 ± 9.3 years, 56 men). Baseline PHES (-8.16 ± 1.42 vs -8.24 ± 1.43; P = 0.54) was comparable in both groups. Reversal of MHE was higher in group I (73.2% vs 21.4%; P = 0.001) than group II. Improvement in PHES (Δ PHES 4.0 ± 0.60 vs -4.18 ± 0.40; P = 0.001), HRQOL (Δ Sickness Impact Profile 3.24 ± 3.63 vs 0.54 ± 3.58; P = 0.001), anthropometry, ammonia, endotoxins, cytokines, and myostatin levels was also significantly higher in group I than group II. Overt hepatic encephalopathy developed in 6 patients in group I and 13 in group II (P = 0.04). CONCLUSIONS: Nutritional therapy is effective in treatment of MHE and associated with improvement in nutritional status, HRQOL, ammonia, endotoxins, inflammatory markers, and myostatin levels.

[Study on HBV-related acute-on-chronic liver failure risk factors and novel predictive survival model].

Objective: To identify the predisposing factors, clinical characteristics, and risk factors of disease progression to establish a novel predictive survival model and evaluate its application value for hepatitis B virus-related acute-on-chronic liver failure. Methods: 153 cases of HBV-ACLF were selected according to the guidelines for the diagnosis and treatment of liver failure (2018 edition) of the Chinese Medical Association Hepatology Branch. Predisposing factors, the basic liver disease stage, therapeutic drugs, clinical characteristics, and factors affecting survival status were analyzed. Cox proportional hazards regression analysis was used to screen prognostic factors and establish a novel predictive survival model. The receiver operating characteristic curve (ROC) was used to evaluate predictive value with the Model for End-Stage Liver Disease (MELD) and the Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF). Results: 80.39% (123/153) based on hepatitis B cirrhosis had developed ACLF. HBV-ACLF's main inducing factors were the discontinuation of nucleos(t)ide analogues (NAs) and the application of hepatotoxic drugs, including Chinese patent medicine/Chinese herbal medicine, non-steroidal anti-inflammatory drugs, anti-tuberculosis drugs, central nervous system drugs, anti-tumor drugs, etc. 34.64% of cases had an unknown inducement. The most common clinical symptoms at onset were progressive jaundice, poor appetite, and fatigue. The short-term mortality rate was significantly higher in patients complicated with hepatic encephalopathy, upper gastrointestinal hemorrhage, hepatorenal syndrome, and infection (P < 0.05). Lactate dehydrogenase, albumin, the international normalized ratio, the neutrophil-to-lymphocyte ratio, hepatic encephalopathy, and upper gastrointestinal bleeding were the independent predictors for the survival status of patients. The LAINeu model was established. The area under the curve for evaluating the survival of HBV-ACLF was 0.886, which was significantly higher than the MELD and CLIF-C ACLF scores (P < 0.05), and the prognosis was worse when the LAINeu score ≥ -3.75. Conclusion: Discontinuation of NAs and the application of hepatotoxic drugs are common predisposing factors for HBV-ACLF. Hepatic decompensation-related complications and infection accelerate the disease's progression. The LAINeu model can predict patient survival conditions more accurately.

Study on HBV-related acute-on-chronic liver failure risk factors and novel predictive survival model / 中华肝脏病杂志

Objective: To identify the predisposing factors, clinical characteristics, and risk factors of disease progression to establish a novel predictive survival model and evaluate its application value for hepatitis B virus-related acute-on-chronic liver failure. Methods: 153 cases of HBV-ACLF were selected according to the guidelines for the diagnosis and treatment of liver failure (2018 edition) of the Chinese Medical Association Hepatology Branch. Predisposing factors, the basic liver disease stage, therapeutic drugs, clinical characteristics, and factors affecting survival status were analyzed. Cox proportional hazards regression analysis was used to screen prognostic factors and establish a novel predictive survival model. The receiver operating characteristic curve (ROC) was used to evaluate predictive value with the Model for End-Stage Liver Disease (MELD) and the Chronic Liver Failure Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF). Results: 80.39% (123/153) based on hepatitis B cirrhosis had developed ACLF. HBV-ACLF's main inducing factors were the discontinuation of nucleos(t)ide analogues (NAs) and the application of hepatotoxic drugs, including Chinese patent medicine/Chinese herbal medicine, non-steroidal anti-inflammatory drugs, anti-tuberculosis drugs, central nervous system drugs, anti-tumor drugs, etc. 34.64% of cases had an unknown inducement. The most common clinical symptoms at onset were progressive jaundice, poor appetite, and fatigue. The short-term mortality rate was significantly higher in patients complicated with hepatic encephalopathy, upper gastrointestinal hemorrhage, hepatorenal syndrome, and infection (P < 0.05). Lactate dehydrogenase, albumin, the international normalized ratio, the neutrophil-to-lymphocyte ratio, hepatic encephalopathy, and upper gastrointestinal bleeding were the independent predictors for the survival status of patients. The LAINeu model was established. The area under the curve for evaluating the survival of HBV-ACLF was 0.886, which was significantly higher than the MELD and CLIF-C ACLF scores (P < 0.05), and the prognosis was worse when the LAINeu score ≥ -3.75. Conclusion: Discontinuation of NAs and the application of hepatotoxic drugs are common predisposing factors for HBV-ACLF. Hepatic decompensation-related complications and infection accelerate the disease's progression. The LAINeu model can predict patient survival conditions more accurately.

Methylene blue and photobiomodulation recover cognitive impairment in hepatic encephalopathy through different effects on cytochrome c-oxidase.

Mitochondrial dysfunction plays a central role in hepatic encephalopathy (HE), due to changes in enzyme cytochrome c-oxidase (CCO), causing a decline in brain metabolism. We used an HE animal model and applied intracranial administration of methylene blue (MB) and transcranial photobiomodulation (PBM), both targeting CCO, to determine their differential effects on recovering cognition. Five groups of rats were used: sham-operated group + saline (SHAM + SAL, n = 6), hepatic encephalopathy + SAL (HE + SAL, n = 7), SHAM + methylene blue (SHAM + MB, n = 7), HE + MB (n = 7), HE + PBM (n = 7). PBM animals were exposed transcranially to 670 +/- 10 nm LED light at a dose of 9 J/cm2 once a day for 7 days, and the MB and SAL groups were injected with 2.2 µg/0.5 µL in the accumbens. Cognitive dysfunction was evaluated on a striatal stimulus-response task using the Morris water maze. Our results showed cognitive improvement in the HE group when treated with MB. This improvement was accompanied by a decrease in CCO activity in the prefrontal cortex, dorsal striatum, and dorsal hippocampus. When comparing MB and PBM, we found that, although both treatments effectively improved the HE-memory deficit, there was a differential effect on CCO. A general decrease in CCO activity was found in the prefrontal and entorhinal cortices, dorsal striatum, and hippocampus when PBM, compared to MB, was applied. Our results suggest that mitochondrial dysfunction and brain metabolic decline in HE might involve CCO alteration and can be improved by administering MB and PBM.

Changes in the Body Composition and Nutritional Status after Long-term Rifaximin Therapy for Hyperammonemia in Japanese Patients with Hepatic Encephalopathy.

Objective Rifaximin has become available for treating hyperammonemia in patients with hepatic encephalopathy. This study analyzed the changes in the body composition and nutritional status after long-term rifaximin therapy. Methods Twenty-one patients who underwent rifaximin therapy at 1,200 mg/day for more than 24 weeks were evaluated for the changes in the controlling nutritional status (CONUT) scores for the nutritional assessment, albumin-bilirubin (ALBI) scores for the liver function assessment, and skeletal muscle index (SMI) for the body composition assessment. Results There were 17 men and 4 women, with a mean age of 67.14±8.32 years. Eleven cases had a portosystemic shunt (52.3%), and 10 had hepatocellular carcinoma (47.6%). The Child-Pugh class was A in 9 cases (42.9%), B in 9 cases (42.9%), and C in 3 cases (14.2%). The blood ammonia levels in the rifaximin group improved significantly upon rifaximin therapy, from 124.76±28.68 µg/dL at baseline to 47.00±14.43 µg/dL after 2 weeks (p<0.001) and 49.81±15.02 µg/dL after 24 weeks (p<0.001). The CONUT scores improved significantly during rifaximin therapy, from 6.47±3.25 at baseline to 3.33±2.65 after 24 weeks (p=0.0007). The ALBI scores also improved significantly from -0.39±1.89 at baseline to -2.20±0.55 after 24 weeks (p=0.0002). The SMI scores showed that the body composition had been maintained in response to rifaximin therapy (50.20±7.67 at baseline and 51.29±7.62 after 24 weeks). Conclusion Rifaximin administration for hepatic encephalopathy improved the CONUT and ALBI scores. It may have a secondary effect on the improvement in the nutritional status and hepatic reserve.

Disturbance of thalamic metabolism and its association with regional neural dysfunction and cognitive impairment in minimal hepatic encephalopathy.

PURPOSE: To conduct the first investigation on thalamic metabolic alterations in minimal hepatic encephalopathy (MHE) and elucidate their association with intrinsic neural activity change and cognitive dysfunction. METHODS: Thirty-eight cirrhotic patients [18 with MHE, 20 without MHE (NHE)] and 21 healthy controls (HC) were included, all of whom underwent 1H-magnetic resonance spectroscopy, resting-state functional magnetic resonance imaging (fMRI), as well as cognitive assessment based on the Psychometric Hepatic Encephalopathy Score (PHES). Metabolite ratios in the thalamus were measured, including N-acetyl aspartate (NAA)/creatine (Cr), glutamate plus glutamine (Glx)/Cr, choline (Cho)/Cr, and myo-inositol (mI)/Cr. Intrinsic neural activity was evaluated based on frequency-specific amplitude of low-frequency fluctuations (ALFF) using fMRI signals. RESULTS: MHE patients showed an increase in Glx/Cr and a decrease in Cho/Cr and mI/Cr, compared with HC. These changes were aggravated from NHE to MHE. Cho/Cr and mI/Cr were positively correlated with regional ALFF derived from the frequency-specific band (0.01-0.027 Hz) and PHES. Receiver operating characteristic curve analysis showed that Cho/Cr and mI/Cr measurements exhibited moderate discrimination ability between NHE and MHE. CONCLUSION: Our findings provide evidence that MHE is associated with disturbed metabolism in the thalamus, which may contribute to the altered neural activity and underlie the mechanisms of cognitive impairments. MRS measurements in the thalamus could serve as the potential biomarker for diagnosing MHE among cirrhotic patients.

Zinc supplementation in patients with cirrhosis and hepatic encephalopathy: a systematic review and meta-analysis.

BACKGROUND: Low serum zinc level is associated with hepatic encephalopathy (HE), but the efficacy of zinc supplementation remains uncertain. This study aimed to investigate the effects of zinc supplementation on HE treatment in patients with cirrhosis. METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (Cochrane CENTRAL) and Scopus from inception to December 2018; without publication date or language restrictions. Randomized controlled trials of zinc supplementation versus placebo or other treatment for the management of HE in adult patients with cirrhosis were selected. The primary outcome was the degree of HE as assessed by clinical signs or specialized psychometric tests. The secondary outcomes included serum ammonia levels, adverse events, or the length of hospital stay and costs. We carried out a meta-analysis with random effects model and summarized continuous outcomes using standardized mean differences (SMD) or mean differences (MD) with 95% confidence intervals (95% CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of evidence for each outcome was evaluated with the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: Four trials with 247 patients were included. In patients with cirrhosis who had mild HE (≤ grade II), the available evidence suggested that the combination treatment of zinc supplementation and lactulose over 3 to 6 months significantly improved performance in the number connection test (SMD: -0.97; 95% CI: - 1.75 to - 0.19; P = 0.01; moderate certainty), reported in three trials (n = 227). However, compared with lactulose therapy alone, additional zinc supplementation demonstrated no significant difference in the digit symbol test (SMD: 0.44; 95% CI: - 0.12 to 1.00; P = 0.12; very low certainty) or serum ammonia levels (MD: -10.86; 95% CI: - 25.73 to 4.01; P = 0.15; very low certainty), reported in two trials (n = 137). None of the included trials reported adverse events or effects on hospitalization. CONCLUSIONS: In conclusion, a combination of zinc supplementation and lactulose over 3 to 6 months may improve the number connection test in cirrhotic patients with low grade HE, compared with lactulose only. TRIAL REGISTRATION: PROSPERO: CRD42017080955 . Registered 23 November 2017.

Structural change of thalamus in cirrhotic patients with or without minimal hepatic encephalopathy and the relationship between thalamus volume and clinical indexes related to cirrhosis.

Aberrant brain structural change in cirrhotic patients with or without hepatic encephalopathy is one of the most typical cases in voxel-based morphometry (VBM) studies. However, there exist inconsistent results regarding to the volume change of the thalamus. Furthermore, the relationship between thalamus structural change and cirrhotic symptoms has not yet been fully elucidated. To address these two issues, we repeated two VBM analyses in SPM and FreeSurfer and compared the two measurements with manually measured thalamic volumes. We also correlated the VBM results with clinical indexes related to cirrhosis to further investigate the relationship between thalamic structural change and liver cirrhosis. The inconsistent result of thalamic structural change was successfully reproduced in regard to the volume measurements of SPM and FreeSurfer. The manually measured results demonstrate an increase in the volume of the thalamus in cirrhotic patients compared to healthy controls, which differs from the results of FreeSurfer. The structural change of thalamus closely correlated with the blood biochemical indexes, including albumin levels, blood coagulation time, and AST/ALT ratio. All of these biochemical indexes are closely related to the severity of liver cirrhosis. Beyond all the results, this study also provides a good demonstration of the difference between multiple VBM measurements for clinicians.

[Portal-systemic encephalopathy with bilateral thalamic and internal capsule lesions using diffusion-weighted MRI in a super-aged patient].

We describe the case of a 90-year-old woman who was hospitalized in July 2016 and subsequently experienced a sudden decline in consciousness level resulting in a state of deep coma. Involuntary movements were not observed, and bilateral Babinski signs were inconclusive. Diffusion-weighted MRI (DWI) of the brain showed bilateral hyperintensity in the thalamus and internal capsule, laboratory testing detected high levels of plasma ammonia, and an electroencephalogram showed delta waves and triphasic waves predominantly in the frontal lobe. Based on these results, treatment for hepatic encephalopathy was administered, which led to an improvement in consciousness level, a decrease in plasma ammonia levels, and a normalization in the DWI scan. Abdominal computed tomography scan showed no abnormality in the liver, but revealed an abnormal blood vessel leading from the ileocolic vein to the inferior vena cava; the patient was diagnosed with portal-systemic encephalopathy. In deep coma patients, acute encephalopathy with hyperammonemia is important for differential diagnosis when DWI shows high-density legions in the thalamus and internal capsule.

Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice.

BACKGROUND: Acute liver failure is associated with numerous systemic consequences including neurological dysfunction, termed hepatic encephalopathy, which contributes to mortality and is a challenge to manage in the clinic. During hepatic encephalopathy, microglia activation and neuroinflammation occur due to dysregulated cell signaling and an increase of toxic metabolites in the brain. Fractalkine is a chemokine that is expressed primarily in neurons and through signaling with its receptor CX3CR1 on microglia, leads to microglia remaining in a quiescent state. Fractalkine is often suppressed during neuropathies that are characterized by neuroinflammation. However, the expression and subsequent role of fractalkine on microglia activation and the pathogenesis of hepatic encephalopathy due to acute liver failure is unknown. METHODS: Hepatic encephalopathy was induced in mice via injection of azoxymethane (AOM) or saline for controls. Subsets of these mice were implanted with osmotic minipumps that infused soluble fractalkine or saline into the lateral ventricle of the brain. Neurological decline and the latency to coma were recorded in these mice, and brain, serum, and liver samples were collected. Neurons or microglia were isolated from whole brain samples using immunoprecipitation. Liver damage was assessed using hematoxylin and eosin staining and by measuring serum liver enzyme concentrations. Fractalkine and CX3CR1 expression were assessed by real-time PCR, and proinflammatory cytokine expression was assessed using ELISA assays. RESULTS: Following AOM administration, fractalkine expression is suppressed in the cortex and in isolated neurons compared to vehicle-treated mice. CX3CR1 is suppressed in isolated microglia from AOM-treated mice. Soluble fractalkine infusion into the brain significantly reduced neurological decline in AOM-treated mice compared to saline-infused AOM-treated mice. Infusion of soluble fractalkine into AOM-treated mice reduced liver damage, lessened microglia activation, and suppressed expression of chemokine ligand 2, interleukin-6, and tumor necrosis factor alpha compared to saline-infused mice. CONCLUSIONS: These findings suggest that fractalkine-mediated signaling is suppressed in the brain following the development of hepatic encephalopathy. Supplementation of AOM-treated mice with soluble fractalkine led to improved outcomes, which identifies this pathway as a possible therapeutic target for the management of hepatic encephalopathy following acute liver injury.

The thalamus in cirrhotic patients with and without hepatic encephalopathy: a volumetric MRI study.

BACKGROUND & AIMS: The thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. METHODS: Neuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. RESULTS: Thalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child-Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r=0.659, P=0.001; r=-0.577, P=0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P=0.001). CONCLUSIONS: A significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients.

Preventive effect of N-acetyl-L-cysteine on oxidative stress and cognitive impairment in hepatic encephalopathy following bile duct ligation.

Oxidative stress caused by ammonia toxicity is known to play a key role in the pathogenesis of hepatic encephalopathy (HE). The present study was designed to evaluate the protective effect of N-acetyl-L-cysteine (NAC) supplementation in a bile duct ligation (BDL)-induced model of HE. Three weeks after BDL, rats developed biliary fibrosis which was supported by liver function tests, ammonia levels, and hydroxyproline content. Impaired cognitive and motor functions were observed along with decreased acetylcholinesterase activity in the brain of BDL rats. Cerebral cortex and cerebellum of BDL animals showed an increase in lipid peroxidation and reduction in total and nonprotein thiols along with reduction in antioxidant enzymes. Histopathological examination of cortex and cerebellum of BDL rats showed astrocytic swelling, inflammation, necrosis, and white matter edema. One week after BDL surgery, animals administered with NAC at a daily dose 100 mg/kg for 2 weeks showed significant improvement in the activity of liver marker enzymes and restored structural morphology of liver. NAC was able to ameliorate spatial memory and motor coordination deficits observed in BDL rats. NAC supplementation decreased lipid peroxidation and was also able to restore the activity of antioxidant enzymes as well as structural deficits observed in the cortex and cerebellum of BDL animals. The results clearly demonstrate that the protective effect of NAC in an experimental model of HE is mediated through attenuation of oxidative stress, suggesting a therapeutic role for NAC in individuals withHE.

[Nutritional support in patients with liver cirrhosis]. / Soporte nutricional en el paciente con cirrosis hepática.

Given the liver's multiple synthetic, regulatory and detoxifying functions, one of the characteristics accompanying severe hepatocellular dysfunction is the presence of malnutrition. This disorder is highly frequent in liver cirrhosis, even in the relatively early stages of the disease. Independently of the cause of the cirrhosis, poor nutritional status is associated with a worse prognosis and therefore early intervention to correct nutrient deficiency can prolong life expectancy, improve quality of life, reduce complications and increase the probability of successful transplantation. The present article reviews current knowledge of the diagnosis and management of malnutrition in patients with cirrhosis. Special attention is paid to the concept of the late evening snack and its characteristics, composition and probable benefits in the course of the disease.

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.

Current and emerging strategies for treating hepatic encephalopathy.

Hepatic encephalopathy (HE) is caused by liver impairment and has a multitude of symptoms in affected patients, including change in level of consciousness, intellectual function, and neuromuscular function. Pharmacologic therapy includes use of nonabsorbable disaccharides (lactulose and lactitol), and antibiotics such as neomycin, paromycin, metronidazole, and rifaximin. Probiotics, acarbose, and drugs such as L-carnitine and flumazenil, may also be helpful in treating HE.

Conventional diet therapy for hyperammonemia is risky in the treatment of hepatic encephalopathy associated with citrin deficiency.

Citrin deficiency caused by SLC25A13 gene mutations develops into adult-onset type II citrullinemia (CTLN2) presenting with hepatic encephalopathy. Recent studies have suggested that excessive loading of carbohydrates is harmful in citrin-deficient individuals. Here we report a CTLN2 patient who showed further deterioration of encephalopathy after the employment of conventional low-protein diet therapy for chronic liver failure. Owing to the high carbohydrate content, the conventional low-protein diet therapy should be avoided in patients with hepatic encephalopathy associated with citrin deficiency. In addition, our observation may suggest that carbohydrate-restricted diet in which the content of carbohydrate is below 50% of daily energy intake can have therapeutic efficacy in CTLN2 patients.

Cannabidiol ameliorates cognitive and motor impairments in mice with bile duct ligation.

BACKGROUND/AIMS: The endocannabinoid system in mice plays a role in models of human cirrhosis and hepatic encephalopathy (HE), induced by a hepatotoxin. We report now the therapeutic effects of cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, on HE caused by bile duct ligation (BDL), a model of chronic liver disease. METHODS: CBD (5mg/kg; i.p.) was administered over 4weeks to mice that had undergone BDL. RESULTS: Cognitive function in the eight arm maze and the T-maze tests, as well as locomotor function in the open field test were impaired by the ligation and were improved by CBD. BDL raised hippocampal expression of the TNF-alpha-receptor 1 gene, which was reduced by CBD. However, BDL reduced expression of the brain-derived neurotrophic factor (BDNF) gene, which was increased by CBD. The effects of CBD on cognition, locomotion and on TNF-alpha receptor 1 expression were blocked by ZM241385, an A(2)A adenosine receptor antagonist. BDL lowers the expression of this receptor. CONCLUSIONS: The effects of BDL apparently result in part from down-regulation of A(2)A adenosine receptor. CBD reverses these effects through activation of this receptor, leading to compensation of the ligation effect.

Preliminary report of the Hepatic Encephalopathy Assessment Driving Simulator (HEADS) score.

INTRODUCTION: Audiovisual simulations of real-life driving (ie, driving simulators) have been used to assess neurologic dysfunction in a variety of medical applications. However, the use of simulated driving to assess neurologic impairment in the setting of liver disease (ie, hepatic encephalopathy) is limited. OBJECTIVES: The aim of this analysis was to develop a scoring system based on simulated driving performance to assess mild cognitive impairment in cirrhotic patients with hepatic encephalopathy. METHODS: This preliminary analysis was conducted as part of the Hepatic Encephalopathy Assessment Driving Simulator (HEADS) pilot study. Cirrhotic volunteers initially underwent a battery of neuropsychological tests to identify those cirrhotic patients with mild cognitive impairment. Performance during an audiovisually simulated course of on-road driving was then compared between mildly impaired cirrhotic patients and healthy volunteers. A scoring system was developed to quantify the likelihood of cognitive impairment on the basis of data from the simulated on-road driving. RESULTS: Mildly impaired cirrhotic patients performed below the level of healthy volunteers on the driving simulator. Univariate logistic regression and correlation models indicated that several driving simulator variables were significant predictors of cognitive impairment. Five variables (run time, total map performance, number of collisions, visual divided attention response, and average lane position) were incorporated into a quantitative model, the HEADS scoring system. The HEADS score (0-9 points) showed a strong correlation with cognitive impairment as measured by area under the receiver-operator curve (.89). CONCLUSION: The HEADS system appears to be a promising new tool for the assessment of mild hepatic encephalopathy.

The role of nutrition in hepatic encephalopathy.

PURPOSE OF REVIEW: Protein-calorie malnutrition may be observed in all clinical stages of liver disease. Nutritional management in these patients is imperative. It is crucial that protein intake is not restricted ad hoc. Administration of vegetable proteins for patients who cannot tolerate standard proteins and, if necessary, branched-chain amino acid-enriched formulae can be an option to these patients. This issue, however, remains controversial. RECENT FINDINGS: This study is an update on the nutritional management of hepatic encephalopathy based on several studies of the last decades, involving dietary protein intake and branched-chain amino acid supplementation. SUMMARY: Malnutrition is a common complication of liver disease and it adversely affects patient outcome. Inadequate dietary protein intake has a very deleterious effect on hepatic encephalopathy, nutritional status, and clinical outcome in these patients and must be avoided. The administration of branched-chain amino acids stimulates hepatic protein synthesis, reduces postinjury catabolism and therefore improves nutritional status. Conflicting results in various different trials, however, exist, and this issue remains unclear.