Encephalopathy In Cirrhosis Research Articles

Chinese guidelines on the management of hepatic encephalopathy in cirrhosis (2024)

With the progress of basic and clinical research on hepatic encephalopathy in cirrhosis over the world, Chinese Society of Hepatology of the Chinese Medical Association has invited experts in relevant fields to revise the 2018 "Chinese Guidelines on the Management of Hepatic Encephalopathy in Cirrhosis". New guideline provides the recommendations for clinical diagnosis, treatment, primary and secondary prevention of hepatic encephalopathy in cirrhosis.

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.

Clinical and Biochemical Factors of Portosystemic Encephalopathy in Cirrhosis

Aim: Responsible factors in patients with portosystemic encephalopathy and their relation with the severity of encephalopathy using “west haven scoring”. Methods: This cross-sectional study was done in the Gastroenterology Department, Hayatabad Medical Complex Peshawar. After ethical approval, a sample of 500 patients was calculated by universally accepted sample calculators. 95% confidence intervals and 5%margin of error. The sample was taken by a non-probability consecutive sampling technique. Results: Out of 500 patients, 307 were male and 193 females. The mean age was 57.36(±17.65 SD). Electrolyte imbalance (79.2%) was the most prevalent responsible factor, followed by infection (47.4%) and dehydration (24.4%). The number of patients with Grade 1, 2, 3 and 4 encephalopathy were 48, 187, 223, 42 respectively. In the majority of patients with encephalopathy, more than one responsible factor was present. Conclusion: Portosystemic encephalopathy is one of the most serious and life-threatening complications of liver failure and cirrhosis. Keywords: Portosystemic encephalopathy, responsible factors, gastrointestinal bleeding.

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

ATP-binding cassette transporters expression in rats with cirrhosis and hepatic encephalopathy

Pathophysiology of acute encephalopathy in cirrhotic patients is not completely understood. Factors implicated include ammonia, inflammation, various metabolic disorders and drug toxicity. Recent studies have evidenced an increased permeability of the blood-brain barrier (BBB) in models of chronic liver disease and encephalopathy, either to solutes, or to leukocytes. A modification of the expression of BBB ATP-Binding Cassette (ABC) transporters, actively transporting endogenous and exogenous components through the BBB, has been described in models of acute liver failure. We hypothesized that a modification of ABC transporters expression may contribute to drug-induced acute encephalopathy in cirrhosis. A rat model of cirrhosis induced by Bile Duct Ligation (BDL) was studied, and compared to a SHAM rat model. Rats were sacrificed and brains studied after decapitation. Genic expression of ABC transporters, including P-gp, BCRP, MRP1, MRP2, MRP4 and MRP5 was evaluated by RT-qPCR on isolated brain microvessels. Encephalopathy was assessed 6 weeks after surgery by a trail suspension test and an Open Field Test. BDL rats developed a histologically proven cirrhosis and displayed a higher ammonemia than SHAM rats (183 µmol/L vs 53 µmol/L, p=0.0003). BDL rats presented with encephalopathy shown by neurobehavioral tests. MRP2 was not detected neither in BDL nor in SHAM rats. There was a decrease in the genic expression of MRP5 6 weeks after surgery. Expressions of P-gp, BCRP, MRP1 and MRP4 were not different between the 2 groups. We suggest that acute encephalopathy in cirrhotic BDL rats may be associated to a modification of ABC transporter MRP5 on the BBB, that could be responsible for a decrease clearance of neurotoxic agents.

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.

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

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: 44 Non-canonical Inflammasome as a Driver of Hepatic Encephalopathy in a Mouse Model of Acute-on-Chronic Liver Failure

BACKGROUND: Hepatic encephalopathy (EH) is a key feature of Acute-on-chronic liver failure, a common cause of mortality in cirrhosis. ACLF is characterized by multi-organ failure and disease progression is associated with elevated levels of circulating bacterial endotoxin (LPS), and increased non-apoptotic hepatocyte cell death. The non-canonical inflammasome is a LPS-sensing pathway, mediated by caspase-11 which, when activated, leads to cleavage of the cytoplasmic protein Gasdermin D (GSDMD) and subsequent pyroptosis - a form of non-apoptotic cell death. The aim of this study was to determine the role of the non-canonical inflammasome in the onset of EH in cirrhosis and ACLF. METHODS: Cirrhosis was induced in male C57BL mice by CCl4 gavage, twice weekly for 10 weeks. Subsequently, mice underwent i.p injection of LPS to induce ACLF. Brain tissue water content, plasma ALT and creatinine were measured by standard techniques. GSDMD cleavage was assessed by Western blot for full length and N-terminus protein. Caspase-11 activation was measured by colorimetric assay in liver protein extract. Mice deficient in Caspase11 showed protection against EH upon induction of ACLF, in the form of reduced brain swelling, and levels of circulating ALT and creatinine. RESULTS: All CCl4 + LPS mice showed features of ACLF following LPS injection, with increases in brain water (79.9 ± 0.2 vs 78.9 ± 0.1%, P &lt; 0.01), plasma ALT (102.0 ± 8.9 vs 79.2 ± 6.2 IU/ml, P = 0.05) and creatinine (48.9 ± 5.6 vs 34.8 ± 1.3 umol/L, P &lt; 0.05) at 4 hours compared to control (Figure 1a). Cleavage of hepatic GSDMD (ratio N-terminus: full length GSDMD 7.7 vs 2.1, P &lt; 0.001) and activation of caspase-11 (2 fold induction, P &lt; 0.05) (Figure 1b) was seen in the ACLF group at 4 hours compared to control. Caspase11-/- mice were protected against ACLF, with reduced brain water (78.9 ± 0.2% vs 78.3 ± 0.2%, P &lt; 0.05), plasma ALT (530 ± 144 vs 172 ± 18 IU/ml, P = 0.05) and creatinine (17.9 ± 1.4 vs 13.7 ± 1.0 µmol/L, P &lt; 0.05) at 4 hours after LPS injection compared to wild-type controls (Figure 1c). CONCLUSIONS: This study demonstrates non-canonical inflammasome activation and as a feature of ACLF concomitant to HE, resulting in activation of the target protein GSDMD in the liver. The non-canonical inflammasome activity is enhanced in cirrhosis, and deletion of Caspase-11 is shown to be protective against the onset of HE in ACLF.

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

Association of serum albumin level with incidence and mortality of overt hepatic encephalopathy in cirrhosis during hospitalization.

Background:Hepatic encephalopathy (HE) is a serious complication of cirrhosis. Decreased serum albumin (ALB) level may facilitate the development of HE and accelerate the death of cirrhotic patients with HE. Recent evidence also suggests that human albumin infusion may reduce the incidence of HE and improve the outcomes of cirrhotic patients. This study aimed to explore the association of serum ALB level with the development of overt HE and HE-associated mortality during hospitalization.Methods:Cirrhotic patients admitted to our hospital between January 2010 and February 2019 were screened. Independent predictors for HE were identified by logistic regression analyses. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated. Area under curve (AUC) was calculated by receiver operator characteristic curve analyses.Results:Of the 2376 included patients with cirrhosis but without HE at admission, 113 (4.8%) developed overt HE during hospitalizations. ALB level (OR = 0.878, 95% CI = 0.834–0.924) was an independent risk factor for development of overt HE. AUC of ALB level for predicting the development of overt HE was 0.770 (95% CI = 0.752–0.787, p < 0.0001), and the best cut-off value was ⩽31.6 g/l. Of the 183 included patients with cirrhosis and overt HE at admission, 20 (10.9%) died during hospitalizations. ALB level (OR = 0.864, 95% CI = 0.771–0.967) was an independent risk factor for death from overt HE. The AUC of ALB level for predicting death from overt HE was 0.737 (95% CI = 0.667–0.799, p = 0.0001), and the best cut-off value was ⩽22.8 g/l.Conclusions:Decreased serum ALB level may be associated with higher risk of overt HE and HE-associated mortality during hospitalizations in cirrhosis.

Clinical Profile of Patients with Hepatic Encephalopathy in Cirrhosis of Liver

Backgroud: Hepatic encephalopathy (HE) is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction, after exclusion of other known causes of brain disease. In India hepatic encephalopathy is considered as indicator of poor prognosis in patients of cirrhosis of liver with 1 year survival in just 42% patients and 3 year survival in 23% of patients. Aim and Objective: Study clinical profile for adverse outcome in patients of hepatic encephalopathy due to cirrhosis of liver. Methods and Methodology: This was a cohort type of study done for a period of 2 years from September 2016 to September 2018 on a study population of 130 patients. Cirrhosis of liver was confirmed by ultrasound of liver. Results: Study included 130 patients of HE secondary to cirrhosis of liver, 82% were males, 44% and 45 % of patients were in grade 2 and grade 3 of West Haven criteria respectively. Icterus, ascites and asterexis were present in almost 65% patients. Cirrhosis was associated with alcohol dependence among 75% of patients followed by NAFLD in 6.15% of patients. Other unknown causes were among 19(14.62%) patients. In our study lactulose was found as the leading treatment modality in 73.84% of patients. Conclusion: Most of the patients were in grade III of HE, alcohol was the most common etiology of cirrhosis, icterus was the most common sign of liver cell failure, most common drug used was lactulose.

Guidelines for the diagnosis and management of hepatic encephalopathy in cirrhosis

Current guideline developed by the Chinese Society of Hepatology on the management of hepatic encephalopathy in cirrhosis is grounded on the published evidences and panelists' consensus. This guideline presents recommendations for diagnosis and management of covert and overt hepatic encephalopathy, and underline the importance of screening minimal hepatic encephalopathy in patients with end-stage liver diseases. In addition, it also stresses that early identification and timely treatments are the means to know the prognosis. The principles of treatment are primary and secondary prevention, prompt removal of the cause, and recovery of acute neuropsychiatric abnormalities to baseline status.

Guidelines on the management of hepatic encephalopathy in cirrhosis

The Chinese Society of Hepatology developed the current guidelines on the management of hepatic encephalopathy (HE) in cirrhosis based on the published evidences and panelists' consensus. The guidelines provided recommendations for the diagnosis and management of hepatic encephalopathy including minimal hepatic encephalopathy (MHE) and overt hepatic encephalopathy (OHE) emphasizing the importance on screening MHE in patients with end-stage liver diseases. The guidelines emphasized that early identification and prompt treatment are essential to improve the prognosis of HE. The principles of treatment mainly consist of eliminating precipitating factors, treating hyperammonemia to improve acute neuropsychiatric abnormalities rapidly, primary and secondary prophylaxis.