Hepatic Encephalopathy In Cirrhosis Research Articles

Infection, inflammation and hepatic encephalopathy from a clinical perspective.

Hepatic encephalopathy (HE) is a syndrome that is associated with both acute and chronic liver injury. It manifests as a wide spectrum of neuropsychological abnormalities, ranging from subtle impairments in executive higher functions observed in cirrhosis, through to coma in acute liver failure. In acute liver failure, the central role of ammonia in the development of brain oedema has remained undisputed for 130 years. It latterly became apparent that infection and inflammation were profound determinants for the development of severe hepatic encephalopathy, associated with the development of cerebral oedema and intracranial hypertension. The relationship of the development of hepatic encephalopathy with blood ammonia levels in cirrhosis is less clear cut and the synergistic interplay of inflammation and infection with ammonia has been identified as being fundamental in the development and progression of hepatic encephalopathy. A perturbed gut microbiome and the presence of an impaired gut epithelial barrier that facilitates translocation of bacteria and bacterial degradation products into the systemic circulation, inducing systemic inflammation and innate and adaptive immune dysfunction, has now become the focus of therapies that treat hepatic encephalopathy in cirrhosis, and may explain why the prebiotic lactulose and rifaximin are efficacious. This review summarises the current clinical perspective on the roles of inflammation and infection in hepatic encephalopathy and presents the evidence base for existing therapies and those in development in the setting of acute and chronic liver failure.

Update points for the 2022 edition of the European Association for the Study of Liver Diseases Clinical Practice Guidelines for the Management of Hepatic Encephalopathy and comparison with China's 2018 edition guidelines

The European Association for the Study of Liver Diseases issued the "Clinical Practice Guidelines for the Management of Hepatic Encephalopathy" in 2022, which included recommendations for clinical diagnosis, assessment, treatment, management, and prevention. The Society's "Hepatic Encephalopathy Clinical Practice Guidelines in Chronic Liver Disease," which was last published in 2014, and the "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy in Cirrhosis," which the Chinese Society of Hepatology, Chinese Medical Association, released in 2018, have certain differences and updates in terms of comparison to terminology, grading and classification, diagnosis, clinical evaluation and treatment, management, and prevention. Herein, the updated points of this guideline and the differences between it and our nation's guidelines are summarized in order to refine and understand the guiding role of the new version of the guideline for the clinical treatment of hepatic encephalopathy and provide aid for standardizing clinical diagnosis and treatment.

P7 Plasma Neurofilament Light Chain as a Novel Potential Biomarker for the Stratification and Risk Profiling of Hepatic Encephalopathy in Cirrhosis

P7 Plasma Neurofilament Light Chain as a Novel Potential Biomarker for the Stratification and Risk Profiling of Hepatic Encephalopathy in Cirrhosis

TOP-044 - Nutritional therapy improves minimal hepatic encephalopathy in cirrhosis by improvement in sarcopenia, proinflammatory cytokines and myostatin: a double blind randomized controlled trial

TOP-044 - Nutritional therapy improves minimal hepatic encephalopathy in cirrhosis by improvement in sarcopenia, proinflammatory cytokines and myostatin: a double blind randomized controlled trial

Intestinal dysbiosis and probiotic use: its place in hepatic encephalopathy in cirrhosis.

The gut microbiota, which plays an important role in health and disease processes, is affected by many disease processes, such as cirrhosis, and dysbiosis can lead to the development of numerous liver diseases, including complications of cirrhosis. In this disease group, the intestinal microbiota shifts towards dysbiosis for reasons such as endotoxemia, increased intestinal permeability, and decreased bile acid production. Although weak absorbable antibiotics and lactulose are among the treatment strategies in cirrhosis and its most common complication, hepatic encephalopathy (HE), this may not be the most appropriate treatment option for all patients, in view of its side-effects and high costs. Accordingly, it seems possible that probiotics could be used as an alternative treatment. The use of probiotics in these patient groups has a direct effect on the gut microbiota. Probiotics can also provide treatment with multiple effects through various mechanisms, such as lowering serum ammonia levels, reducing oxidative stress and reducing the intake of other toxins. This review was written to explain the intestinal dysbiosis associated with HE in cirrhotic patients, and the role of probiotics in treatment.

A STUDY OF SPECTRUM OF THE PRECIPITATING FACTORS OF HEPATIC ENCEPHALOPATHY IN CIRRHOSIS PATIENTS

Hepatic Encephalopathy (HE) is a complex, potentially reversible neuropsychiatric condition that occurs due to acute or chronic liver disease1. In managing patients with HE in cirrhosis of the liver it is very important to stage the encephalopathy into four clinical stages and then try to identify and treat the precipitating factors. In the presence of the precipitating factors, the neurological decits are usually completely reversible on their correction and the prognosis is good if the precipitant can be treated2. Results: A total of 54 patients with cirrhosis of the liver suffering from hepatic encephalopathy were studied for different precipitating factors over a period of 15 months. Spontaneous bacterial peritonitis (SBP) (48.14%) is the most common precipitating factor in our study, followed by gastrointestinal bleeding(31.48%), constipation(27.77%), sepsis(24.04%), hyponatremia(20.37%) and hypokalemia(11.11%). Conclusion: Early detection and diagnosis of the precipitating factors of HE help in the focused treatment of this highly fatal condition thereby reducing the mortality in such patients

The Link between Gut Microbiota and Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy.

Protective effect of probiotics and ascorbic acid on bile duct ligation-induced chronic hepatic encephalopathy in rats.

Background and purpose:Hepatic encephalopathy (HE) is a brain dysfunction caused by acute and chronic hepatic failure. The pathogenesis of HE is unknown, although small intestinal bacterial overgrowth associated with chronic liver damage, hyperammonemia, and oxidative stress are considered major factors for HE. Effective lowering of circulating ammonia and neuroinflammation is the main strategy for preventing and treating HE in cirrhosis. In the present study, the protective effect of probiotics (Lactobacillus plantarum and Bacillus clausii) and ascorbic acid in combination was assessed in bile duct ligation (BDL)-induced chronic HE in rats.Experimental approach:Sprague Dawley rats were divided into five groups (n = 6). All groups were subjected to double ligation of the bile duct and fed a hyperammonemia diet, except group I (normal control). Groups III and IV were treated with a low and high dose of combination therapy, respectively, while group V was given lactulose. Four weeks post ligation, behavioral, biochemical, and neurochemical parameters were measured. The liver and brain were dissected for histopathology and protein analyses.Findings / Results:Combination therapy reduced plasma AST, ALT, ALP, and ammonia levels and attenuated hepatic inflammation/fibrosis in cirrhotic rats. Furthermore, combination therapy significantly improved behavioral parameters and restored the antioxidant enzyme activity. Histological changes were observed in the brain and liver of BDL animals.Conclusion and implications:The additive impact of probiotics and ascorbic acid on BDL-induced chronic HE in rats was mediated by a reduction in ammonia and oxidative stress, implying the therapeutic potential of combination therapy in HE.

Современные подходы к диагностике и лечению минимальной печеночной энцефалопатии у пациентов с циррозом печени

Hepatic encephalopathy (HE) is one of the most common and dangerous complications of cirrhosis. HE is considered a predictor of death within the first year after onset in more than 60% of patients. Recently, studies have focused on minimal HE (MHE) which is characterized by medical, social, and clinical relevance. MHE patients are a risk group for cirrhosis complications and hospital admission. This demonstrates the need for early therapeutic and preventive measures for MHE. This paper provides information on current diagnostic and treatment tools for MHE in cirrhosis and illustrates the efficacy of various therapies on the outcomes and quality of life in these patients. The authors conclude that one should rely on studies establishing the efficacy of rifaximin-α to regress MHE, improve the quality of life and reduce the risks of complications and decompensation in cirrhosis compared to other medications. Meanwhile, further studies are needed to reveal favorable and unfavorable predictors of disease course and to optimize therapeutic and preventive measures in these patients. KEYWORDS: cirrhosis, hepatic encephalopathy, minimal hepatic encephalopathy, psychometric tests, lactulose, L-ornithine-L-aspartate, rifaximin-α FOR CITATION: Bakulin I.G., Ivanova K.N. Up-to-date diagnostic and treatment approaches to minimal hepatic encephalopathy in cirrhosis. Russian Medical Inquiry. 2022;6(5):272–277 (in Russ.). DOI: 10.32364/2587-6821-2022-6-5-272-277

Ammonia Removal by Metabolic Scavengers for the Prevention and Treatment of Hepatic Encephalopathy in Cirrhosis.

Effective lowering of circulating ammonia is the mainstay strategy in the prevention and treatment of hepatic encephalopathy in cirrhosis and there is increasing interest in agents with the metabolic potential for the active removal of ammonia by the liver and skeletal muscle by agents including l-ornithine l-aspartate, branched-chain amino acids, as well as the re-purposing of benzoate and phenylacetate currently employed for the control of hyperammonaemia in congenital urea-cycle enzymopathies. Based upon results of multiple systematic reviews with meta-analyses, l-ornithine l-aspartate demonstrably lowers circulating ammonia in patients with cirrhosis with concomitantly improved mental status. Distinct mechanisms responsible include optimisation of hepatic metabolic pathways for ammonia removal as well as direct hepatoprotective effects involving the release of glutathione and of nitric oxide with beneficial effects on hepatic microcirculation. l-ornithine l-aspartate also prevents cirrhosis-related sarcopenia, leading to increased capacity for ammonia removal by skeletal muscle. Branched-chain amino acids continue to be prescribed as nutritional supplements with the potential to result in improvements in liver function. Sodium benzoate, glycerol phenylbutyrate and an analogous compound l-ornithine phenylacetate were also evaluated. Glycerol phenylbutyrate was the only agent with a beneficial effect on both hyperammonaemia and hepatic encephalopathy. None were superior to lactulose for the lowering of blood ammonia.

A Comprehensive Review Evaluating the Impact of Protein Source (Vegetarian vs. Meat Based) in Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is a common neurological consequence in patients with cirrhosis and has a healthcare burden of USD 5370 to 50,120 per patient annually. HE significantly hampers the quality of life and is a major cause of morbidity and mortality. Patients with cirrhosis are at a high risk for protein-calorie malnutrition due to altered metabolism. Current evidence has changed the old belief of protein restriction in patients with cirrhosis and now 1.2 to 1.5 g/kg/day protein intake is recommended. Case series and studies with small numbers of participants showed that a vegetarian protein diet decreases the symptoms of HE when compared to a meat-based diet, but the evidence is limited and requires further larger randomized controlled trials. However, vegetable or milk-based protein diets are good substitutes for patients averse to meat intake. Branch chain amino acids (BCAA) (leucine, isoleucine and valine) have also been shown to be effective in alleviating symptoms of HE and are recommended as an alternative therapy in patients with cirrhosis for the treatment of HE. In this review, we provide an overview of current literature evaluating the role of protein intake in the management of HE in cirrhosis.

Role of Brain Biomarkers S-100-Beta and Neuron-Specific Enolase for Detection and Follow-Up of Hepatic Encephalopathy in Cirrhosis before, during and after Treatment with L-Ornithine-L-Aspartate

Introduction: Hepatic encephalopathy (HE), in the context of liver cirrhosis, seems to result from low-grade cerebral edema of the astrocytes. Serum brain biomarkers S-100-beta und neuron-specific enolase (NSE) are often elevated in brain injury. We hypothesized that neuromarkers S-100-beta and NSE can be used in the diagnosis of HE, compared with standardized diagnostic tools. Material and Methods: A prospective non-randomized intervention study was performed using L-ornithine-L-aspartate (LOLA) for HE treatment. Primary endpoint was the evaluation of neuromarkers S-100-beta and NSE for detection and diagnosis of follow-up of HE. As secondary endpoints, the efficacy of LOLA on the course of HE and the diagnostic role of Portosystemic-Encephalopathy-Syndrome score (PHES) and critical flicker frequency (CFF) were analyzed. For diagnosis of covert (CHE) and overt (OHE) HE, West-Haven criteria (WHC), PHES and CFF were assessed at study entry. LOLA was applied (20 g i.v.) for 6 days. At the end of the study, HE evaluation was repeated. S-100-beta, NSE and ammonia were assessed in each patient before, during and after therapy with LOLA. Results: 30 patients were included. At study entry, CHE was diagnosed in 50% and OHE in 50% of all subjects. A total of 25 participants completed the study. After LOLA therapy, deterioration of HE occurred in <11%, while most patients showed improvement (e.g. improved CFF in 79%). No significant correlation with HE severity (as diagnosed by WHC, PHES and CFF) could be demonstrated for any biochemical parameter. In addition, there were no significant changes in brain biomarkers during the treatment period. Discussion: While CFF as well as PHES showed good correlation with treatment response, S-100-beta and NSE did not significantly correlate with HE severity compared to proven diagnostic methods, and do not seem reliable biochemical markers for the follow-up under therapy.

Efficacy of L-Ornithine L-Aspartate for the prevention and Treatment of Hepatic Encephalopathy in Cirrhosis: An Update of the Evidence Base

Efficacy of L-Ornithine L-Aspartate for the prevention and Treatment of Hepatic Encephalopathy in Cirrhosis: An Update of the Evidence Base

Albumin infusion may decrease the incidence and severity of overt hepatic encephalopathy in liver cirrhosis.

Background: The role of human albumin infusion for the prevention and treatment of overt hepatic encephalopathy (HE) in liver cirrhosis remains unclear. Results: Among the 708 patients without pre-existing overt HE, albumin infusion significantly decreased the incidence of overt HE (4.20% versus 12.70%, P<0.001) and in-hospital mortality (1.70% versus 5.40%, P=0.008). Among the 182 patients with overt HE at admission or during hospitalization, albumin infusion significantly improved overt HE (84.60% versus 68.10%, P=0.009) and decreased in-hospital mortality (7.70% versus 19.80%, P=0.018). Meta-analysis of 6 studies found that albumin infusion might decrease the risk of overt HE (OR=1.63, P=0.07), but the difference was not statistically significant. Meta-analysis of 3 studies found that albumin infusion significantly improved overt HE (OR=2.40, P=0.04). Conclusions: Based on the results of our retrospective study and meta-analysis, albumin infusion might prevent from the occurrence of overt HE and improve the severity of overt HE in cirrhosis. Our retrospective study also suggested that albumin infusion improved the outcomes of cirrhotic patients regardless of overt HE. Methods: Cirrhotic patients consecutively admitted between January 2010 and June 2014 were considered in a retrospective study. A 1:1 propensity score matching analysis was performed. Additionally, publications regarding albumin infusion for the management of overt HE were systematically searched. Meta-analyses were performed by random-effect model. Odds ratio (OR) was calculated.

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.

P: 39 Modulation of the Urea Cycle Function by Toll-like Receptor 4 Signaling: A Potential Novel Therapeutic Target for Hyperammonemia and Hepatic Encephalopathy

BACKGROUND: Lipopolysaccharide (LPS) and ammonia act synergistically in mediating the severity of hepatic encephalopathy (HE) in cirrhosis. Although LPS results in neuroinflammation, it is not clear whether it induces hyperammonemia (HA) contributing to HE. This study addressed the following questions: 1) Does LPS worsen HA in cirrhosis? 2) Does treatment with an antagonist (TAK242) of the LPS receptor, toll-like receptor 4 (TLR4), prevent HA? 3) Is a TLR4 knock-out (TLR4-/-) animal protected from HA? 4) If so, what is the underlying mechanism? Do they have a more effective urea cycle? METHODS: Study 1: Sprague Dawley rats were treated with LPS (0.025 mg/kg, ip.) 4 weeks after bile duct ligation (BDL). 4 groups of rats were studied: sham (n = 4), BDL (n = 4), BDL+LPS (n = 6) and BDL+TAK242 (10 mg/kg ip.) 3 hours before LPS injection (n = 7). Study 2: 4 groups of mice were studied: wild type control (WTC, n = 7), WT with HA (WTH, n = 10), TLR4-/- control (TLR4-/-C, n = 10) and TLR4-/- with HA (TLR4-/-H, n = 10). HA was induced by adding 0.28M ammonium chloride to drinking water for 3 days. For both studies, plasma ammonia and liver gene expression (qPCR, data shown as 2^-ΔΔCT compared to sham/WT) of the 5 urea cycle enzymes (UCEs) were assessed. For study 2, protein expression of the key, rate-limiting enzyme carbamoyl phosphate synthetase 1 (CPS1) was also assessed (Western Blot, immunohistochemistry). RESULTS: Study 1: There was a stepwise increase in plasma ammonia throughout sham, BDL and BDL+LPS groups (P &lt; 0.001). Pre-treatment with TAK242 prior to LPS injection in BDL rats was associated with a reduction in plasma ammonia (P &lt; 0.01, Figure 1a) and a higher coma-free survival rate (100% vs. 15%). Gene expression of all UCEs showed a stepwise decrease throughout sham, BDL and BDL+LPS (all P &lt; 0.05), which was prevented by TAK242 (all P &lt; 0.05). This was most pronounced for CPS1, for which expression levels in the TAK242-treated group were restored to that of the sham animals (Figure 1b). Study 2: In TLR4-/- mice, the increase in plasma ammonia was less compared to WT mice (P &lt; 0.001). Although no significant changes were found for gene expression of UCEs between groups, protein expression of CPS1 was significantly higher in TLR4-/- mice as compared to WT mice, as shown by both Western Blot and immunohistochemistry. CONCLUSIONS: These data suggest that TLR4 signaling contributes to the development of hyperammonemia by modulating the urea cycle function. Inhibition of TLR4 with TAK242 offers a potential novel therapy for HA and HE in cirrhosis.

Dietary approach and gut microbiota modulation for chronic hepatic encephalopathy in cirrhosis.

Hepatic encephalopathy (HE) is a common and serious neuropsychiatric complication of cirrhosis, acute liver failure, and porto-systemic shunting. HE largely contributes to the morbidity of patients with liver disease, severely affecting the quality of life of both patients and their relatives and being associated with poor prognosis. Its presentation is largely variable, manifesting with a broad spectrum of cognitive abnormalities ranging from subtle cognitive impairment to coma. The pathogenesis of HE is complex and has historically been linked with hyperammonemia. However, in the last years, it has become evident that the interplay of multiple actors, such as intestinal dysbiosis, gut hyperpermeability, and neuroinflammation, is of crucial importance in its genesis. Therefore, HE can be considered a result of a dysregulated gut-liver-brain axis function, where cognitive impairment can be reversed or prevented by the beneficial effects induced by “gut-centric” therapies, such as non-absorbable disaccharides, non-absorbable antibiotics, probiotics, prebiotics, and fecal microbiota transplantation. In this context dietary modifications, by modulating the intestinal milieu, can also provide significant benefit to cirrhotic patients with HE. This review will provide a comprehensive insight into the mechanisms responsible for gut-liver-brain axis dysregulation leading to HE in cirrhosis. Furthermore, it will explore the currently available therapies and the most promising future treatments for the management of patients with HE, with a special focus on the dietary approach.

Clinical Spectrum of Precipitating Factors of Hepatic Encephalopathy in Cirrhosis of Liver and Its Relation to Prognosis in a Tertiary Care Hospital - A Retrospective Study

Clinical Spectrum of Precipitating Factors of Hepatic Encephalopathy in Cirrhosis of Liver and Its Relation to Prognosis in a Tertiary Care Hospital - A Retrospective Study

L-Ornithine L-Aspartate for the Treatment of Sarcopenia in Chronic Liver Disease: The Taming of a Vicious Cycle.

Sarcopenia is a common complication of cirrhosis with a negative impact on posttransplant outcome, health-related quality of life (HRQOL), and patient survival. Studies in experimental animals and in patients demonstrate that ammonia is directly implicated in the pathogenesis of sarcopenia in cirrhosis via mechanisms involving increased expression of myostatin and of autophagy markers such as LC3 lipidation and p62 leading to muscle dysmetabolism and sarcopenia. Paradoxically, skeletal muscle replaces liver as the primary ammonia-detoxifying site as a result of the modification of genes coding for key proteins implicated in ammonia-lowering pathways in cirrhosis. Thus, a vicious cycle occurs whereby hyperammonemia causes severe muscle damage and sarcopenia that, in turn, limits the capacity of muscle to remove excess blood-borne ammonia and the cycle continues. Randomized clinical trials and meta-analyses confirm that L-ornithine L-aspartate (LOLA) is an effective ammonia-lowering agent currently employed for the treatment of hepatic encephalopathy (HE) that stimulates both urea synthesis by residual hepatocytes and muscle glutamine synthesis together with putative hepatoprotective actions. Treatment of cirrhotic patients with LOLA limits ammonia-induced sarcopenia by improving muscle protein synthesis and function. It is conceivable that the antisarcopenic action of LOLA contributes to its efficacy for the treatment of HE in cirrhosis.

Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology.

Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, ‘Parkinsonism in cirrhosis’. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.