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Hepatic encephalopathy (HE) is one of the major complications of liver disease and significantly affects the quality of life (QOL) of patients. HE is common and frequently relapses in cirrhotic patients. The management of HE is supportive, and precipitating conditions should be eliminated. Most drugs used to treat HE are conventional and include nonabsorbable disaccharides such as lactulose, and antibiotics such as rifaximin. However, their therapeutic efficacy is still suboptimal, and novel therapeutic agents are urgently needed. In addition, the optimal management and diagnosis of minimal HE/covert HE are under debate. In this review, we focus on novel pathogenetic mechanisms such as central nervous system clearance, and emerging therapeutic targets of HE, such as fecal material transplantation. We also discuss different classifications and etiologies of HE., Competing Interests: Conflicts of interest: Dr. Hui-Chun Huang, Dr. Ching-Chih Chang, Dr. Yi-Hsiang Huang, Dr. Ming-Chih Hou, and Dr. Fa-Yauh Lee, editorial board members at Journal of the Chinese Medical Association , have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Purpose: To develop and assess machine learning (ML) models' ability to predict post-procedural hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement., Materials and Methods: In this retrospective study, 327 patients who underwent TIPS for hepatic cirrhosis between 2005 and 2019 were analyzed. Thirty features (8 clinical, 10 laboratory, 12 procedural) were collected, and HE development regardless of severity was recorded one month follow-up. Univariate statistical analysis was performed with numeric and categoric data, as appropriate. Feature selection is used with a sequential feature selection model with fivefold cross-validation (CV). Three ML models were developed using support vector machine (SVM), logistic regression (LR) and CatBoost, algorithms. Performances were evaluated with nested fivefold-CV technique., Results: Post-procedural HE was observed in 105 (32%) patients. Patients with variceal bleeding (p = 0.008) and high post-porto-systemic pressure gradient (p = 0.004) had a significantly increased likelihood of developing HE. Also, patients having only one indication of bleeding or ascites were significantly unlikely to develop HE as well as Budd-Chiari disease (p = 0.03). The feature selection algorithm selected 7 features. Accuracy ratios for the SVM, LR and CatBoost, models were 74%, 75%, and 73%, with area under the curve (AUC) values of 0.82, 0.83, and 0.83, respectively., Conclusion: ML models can aid identifying patients at risk of developing HE after TIPS placement, providing an additional tool for patient selection and management., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Hepatic encephalopathy (HE) constitutes a neuropsychiatric syndrome which remains a major clinical problem in patients with cirrhosis. In the severest form of HE, cirrhotic patients may develop varying degrees of confusion and coma. Ammonia has been regarded as the key precipitating factor in HE, and astrocytes have been the most commonly affected cells neuropathologically. Although the evidence base supporting a pivotal role of ammonia is robust, in everyday clinical practice a consistent correlation between the concentration of ammonia in the blood and the manifest symptoms of HE is not observed. More recently the synergistic role of inflammation and infection in modulating the cerebral effects of ammonia has been shown to be important. Furthermore, it has been recognized that infection impairs brain function both in the presence and absence of liver disease. Thus it could be postulated that in the presence of ammonia, the brain is sensitized to a systemic inflammatory stimulus and is able to elicit an inflammatory response involving both proinflammatory and neurotransmitter pathways. Ammonia is not only directly toxic to astrocytes but induces neutrophil dysfunction with the release of reactive oxygen species, which contribute to oxidative stress and systemic inflammation. This may further exacerbate the cerebral effects of ammonia and potentially reduce the capacity of the neutrophil to fight microbial attack, thus inducing a vicious circle. This evidence supports the neutrophil in addition to ammonia as being culpable in the pathogenesis of HE, making the neutrophil a target for future anti-inflammatory therapeutic strategies in addition to ammonia lowering therapies.

Hepatic encephalopathy (HE) is a challenging complication after transjugular intrahepatic portosystemic shunt (TIPS) placement. Despite recent advances, much is still uncertain regarding risk factors, preventative measures, and the management of HE after TIPS placement. Appropriate patient selection and pre-procedural risk stratification remain areas of focus. In this manuscript, we discuss the current state of research related to HE after TIPS placement, including information regarding risk stratification, complication prevention, and treatment options., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Hepatic encephalopathy (HE) is a debilitating and life-threatening disease. Results from acute or chronic liver failure and is characterized by abnormal cerebral and neurological alterations. This study aimed at investigating the effect of allicin, the major functional component in freshly crushed garlic extract, on thioacetamide (TAA)-induced HE in rats. Induction of HE by a single dose of TAA (300 mg/kg; I.P.) was associated with a marked elevation in the serum levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, total protein, blood urea nitrogen and serum ammonia besides reduction in the serum level of albumin. Moreover, it was accompanied with an increase in the hepatic and brain levels of inflammatory mediators; TNF-α and IL-1β as well as elevation of the hepatic and brain levels of oxidative stress biomarkers; reduced glutathione and lipid peroxidation evidenced by malondialdeyde. Oral administration of allicin (50, 100 and 200 mg/kg; P.O.) for 6 days prior to TAA injection restored the serum liver function, hepatic and brain levels of inflammatory mediators as well as oxidative stress biomarkers in a dose-dependent manner. From our results, it can be concluded that allicin has a protective effect on TAA-induced HE in rats in a dose-dependent manner due to its powerful antioxidant and anti-inflammatory properties., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin., Methods: We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons., Results: Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively)., Conclusion: Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE., (© 2020 American Society of Neuroimaging.)

Background: The aim of the present study was to investigate whether portal level of high-mobility group protein B1 (HMGB1) is associated with hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS)., Methods: We enrolled 127 consecutive patients who underwent TIPS and collected portal and peripheral blood samples in our department from December 2017 to May 2019. HMGB1 levels were determined using enzyme-linked immunosorbent assay kits. HMGB1 and other HE related parameters were estimated by competing risk analysis, receiver operating characteristic (ROC) analysis and Kaplan-Meier analysis., Results: Patients with HE after TIPS were older (P = .019) and had higher portal HMGB1 level (P = .038) than those without. Univariate competing risk analysis: age (sHR 1.025, P = .026), hepatorenal syndrome (sHR 3.149, P = .010), model for end-of-stage liver disease (MELD) score (sHR 1.055, P = .024), prior HE (sHR 4.029, P = .0005), portal HMGB1 before TIPS (sHR 1.177, P = .001) reached statistical significance. Multivariate analysis: age (sHR 1.025, P = .037), MELD score (sHR 1.062, P = .011), prior HE (sHR 2.492, P = .030) and portal HMGB1 level before TIPS (sHR 1.217, P = .0002) were significantly different. ROC analyses and Kaplan-Meier curve showed portal HMGB1 level changes before and after TIPS (ΔHMGB1) had good predictive value in the cut-off 0.012 ng/mL (AUC = 0.748, P < .001, Sensitivity = 0.743, Specificity = 0.655)., Conclusions: Portal HMGB1 may be a therapeutic target for post-TIPS HE., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: The occurrence of overt hepatic encephalopathy (OHE) is associated with increased mortality. HE is commonly precipitated by infection, but whether HE predisposes to new infection is unclear. This study aimed to test if OHE predisposes to de novo infection during hospitalisation and its association with short‐term mortality. Aims and Methods: Seven hundred and fifty‐nine consecutive patients were identified at two institutions from prospectively maintained clinical databases of cirrhotic patients admitted with acute decompensation (AD). Infection and HE data were collected on the day of admission, and the occurrence of de novo infections was assessed for 28 days after admission. EASL‐CLIF organ failure criteria were used to determine the presence of organ failures. Multivariable analysis using the logistic regression model was used to assess predictors of 28‐day mortality and de novo infection. Results: Patients were divided into four groups; no baseline OHE or infection (n = 352); OHE with no baseline Infection (n = 221); no OHE but baseline infection (n = 100) and OHE with baseline infection (n = 86). On multivariate analyses, OHE (OR, 1.532 [95% CI, 1.061–2.300, P = 0.024]), and admission to ITU (OR, 2.303 [95% CI, 1.508–3.517, P < 0.001]) were independent risk factors for de novo infection. 28‐day mortality was 25.3%, 60.2%, 55.0% and 72.1% in the 4‐groups respectively. Age, INR and creatinine were independently predictive of mortality. The presence of overt HE, infection, coagulation, kidney, circulatory, respiratory and liver failures were significantly associated with higher mortality. Conclusion: OHE is an independent risk factor for de novo infection in cirrhotic patients with AD. [ABSTRACT FROM AUTHOR]

Copyright of Summa, Animali da Compagnia is the property of Point Veterinaire Italie s.r.l. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Purpose: Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE. Materials and Methods: Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue. Results: The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal's locomotor activity and improved brain tissue markers of oxidative stress. Conclusion: These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate whether portal level of high‐mobility group protein B1 (HMGB1) is associated with hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS). Methods: We enrolled 127 consecutive patients who underwent TIPS and collected portal and peripheral blood samples in our department from December 2017 to May 2019. HMGB1 levels were determined using enzyme‐linked immunosorbent assay kits. HMGB1 and other HE related parameters were estimated by competing risk analysis, receiver operating characteristic (ROC) analysis and Kaplan–Meier analysis. Results: Patients with HE after TIPS were older (P =.019) and had higher portal HMGB1 level (P =.038) than those without. Univariate competing risk analysis: age (sHR 1.025, P =.026), hepatorenal syndrome (sHR 3.149, P =.010), model for end‐of‐stage liver disease (MELD) score (sHR 1.055, P =.024), prior HE (sHR 4.029, P =.0005), portal HMGB1 before TIPS (sHR 1.177, P =.001) reached statistical significance. Multivariate analysis: age (sHR 1.025, P =.037), MELD score (sHR 1.062, P =.011), prior HE (sHR 2.492, P =.030) and portal HMGB1 level before TIPS (sHR 1.217, P =.0002) were significantly different. ROC analyses and Kaplan–Meier curve showed portal HMGB1 level changes before and after TIPS (ΔHMGB1) had good predictive value in the cut‐off 0.012 ng/mL (AUC = 0.748, P <.001, Sensitivity = 0.743, Specificity = 0.655). Conclusions: Portal HMGB1 may be a therapeutic target for post‐TIPS HE. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE. [ABSTRACT FROM AUTHOR]

Hyperammonaemia is a common complication of liver disease in dogs. High concentrations of ammonia can be detrimental to dogs with liver disease for several reasons, notably by causing hepatic encephalopathy (HE) which describes the wide range of neurological abnormalities ranging from altered behaviour to seizures that are well recognised complications in dogs with hepatic disorders. In human patients with liver disease, hyperammonaemia has also been linked to the development of other systemic complications such as dysregulation of the innate immune system. In contrast, the effects of hyperammonaemia on the canine innate immune system is currently unknown. The aim of this study was to investigate the effects of ammonia on the oxidative burst activity of canine polymorphonuclear cells in vitro. Blood obtained from healthy dogs (n = 8) was incubated with escalating concentrations of ammonia ranging from 0 to 250 μM, and the percentage of cells experiencing an oxidative burst was evaluated using a commercial kit (Phagoburst™) and flow cytometry. The spontaneous oxidative burst was evaluated without stimulation and also following stimulation with E coli. The pH of the blood was also measured at the differing ammonia concentrations. There was an increase in the percentage of cells experiencing a spontaneous oxidative burst from ammonia concentrations of 125 μM (p = <0.05) and above (p = <0.01), with a 4.9 fold increase at 200 μM (p = < 0.001). In those cells stimulated with E coli, incubation with increasing ammonia concentrations did not result in a significant difference in oxidative burst from baseline (p = 0.953). There was no statistically significant difference between the pH of the blood at the various ammonia concentrations (p = 0.2) suggesting that the difference in spontaneous oxidative burst was due to the ammonia rather than simply a change in pH conditions. In summary, the spontaneous oxidative burst of neutrophils was significantly increased from baseline. This supports a potential role of ammonia in contributing to innate immune system dysfunction in dogs with liver disease, and may present a future therapeutic target. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. 99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins. [ABSTRACT FROM AUTHOR]

Aim of the study: Hepatic encephalopathy and hyperammonemia is a clinical complication associated with liver cirrhosis. The brain is the target organ for ammonia toxicity. Ammonia-induced brain injury is related to oxidative stress, locomotor activity dysfunction, and cognitive deficit, which could lead to permanent brain injury, coma and death if not appropriately managed. There is no promising pharmacological intervention against cirrhosisassociated brain injury. Taurine (TAU) is one of the most abundant amino acids in the human body. Several physiological and pharmacological roles have been attributed to TAU. TAU may act as an antioxidant and is an excellent neuroprotective agent. This study aimed to evaluate the effect of TAU supplementation on cirrhosisassociated locomotor activity disturbances and oxidative stress in the brain. Material and methods: Rats underwent bile duct ligation (BDL) surgery, and plasma and brain ammonia level, plasma biochemical parameters, and rats' locomotor function were monitored. Furthermore, brain tissue markers of oxidative stress were assessed. Results: It was found that plasma and brain ammonia was increased, and markers of liver injury were significantly elevated in the cirrhotic group. Impaired locomotor activity was also evident in BDL rats. Moreover, an increase in brain tissue markers of oxidative stress was detected in the brain of cirrhotic animals. It was found that TAU supplementation (50, 100, and 200 mg/kg, gavage) alleviated brain tissue markers of oxidative stress and improved animals' locomotor activity. Conclusions: These data suggest that TAU is a potential protective agent against cirrhosis-associated brain injury. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness. [ABSTRACT FROM AUTHOR]

Background & Aims Minimal hepatic encephalopathy is associated with poor prognosis and mortality in patients with cirrhosis. We aimed at investigating whether bacterial- DNA translocation affects hyperammonaemia and neurocognitive scores in patients with mHE according to the use of lactulose. Methods Observational study including 72 mHE cirrhotic patients, as defined by a psychometric hepatic encephalopathy score ( PHES)<−4 and/or a critical flicker frequency ( CFF)<39 Hz. Bacterial- DNA, serum ammonia, pro-inflammatory cytokines and nitric oxide levels were evaluated. A second cohort of 40 lactulose-untreated patients were evaluated before and 6-month after lactulose administration (30-60 mL/d). Results In the first cohort, bacterial- DNA rate was significantly higher in patients without lactulose (39% vs 23%, P=.03). Serum ammonia and inflammatory markers were significantly increased in patients with bacterial- DNA, regardless the use of lactulose, and correlated with the amount of amplified bacterial- DNA. Neurocognitive scores were significantly worse in bacterial- DNA positive vs negative patients ( PHES −7.6±1.1 vs −5.5±1.0; CFF 32.5±2.6 vs 36.2±2.8, P=.01). Lactulose was associated with improved neurocognitive scores in patients without bacterial- DNA. Serum ammonia levels inversely correlated with neurocognitive scores in patients with bacterial- DNA ( PHES r=−.84; CFF r=−.72, P=.001). In the second cohort, lactulose reduced bacterial- DNA translocation (36%-16%, P=.02). Neurocognitive scores were significantly improved in bacterial- DNA positive patients who cleared bacterial- DNA during the period on lactulose. Serum ammonia levels correlated with both neurocognitive scores in patients with bacterial- DNA, either before or after lactulose. Conclusion Bacterial- DNA translocation worsens neurocognitive scores in mHE patients and it is reduced by lactulose, enhancing the relevance of controlling bacterial antigen translocation in these patients. [ABSTRACT FROM AUTHOR]

Objective To comparatively review the pathogenesis, clinical presentation, diagnosis, and management of hepatic encephalopathy (HE) in dogs and cats. Data Sources The Medline database was searched for articles related to HE in people, dogs, and cats. Articles published within the last 5 years were given special importance. Human Data Synthesis The pathogenesis of HE is complex and incompletely understood, but ammonia appears to play a central role. Hyperammonemia leads to accumulation of glutamine in astrocytes, with subsequent astrocyte swelling and neurological dysfunction. The development of HE in patients with hepatic cirrhosis is a poor prognostic indicator. The fermentable disaccharide lactulose and the antimicrobial rifaximin are US Food and Drug Administration approved treatments for human HE. Severe protein restriction is no longer recommended for patients with this condition. Veterinary Data Synthesis HE is often associated with portosystemic shunting in dogs and cats. Ammonia plays a central role in the pathogenesis of HE in dogs and cats, but other factors such as manganese and endogenous benzodiazepines may also contribute. Recently, a soy protein-based diet was found to be beneficial in treating canine HE. Severe dietary protein restriction is likely to be detrimental in affected animals. There have been no clinical trials of drugs routinely used in the management HE in veterinary medicine, but lactulose and antimicrobials such as metronidazole are well-established treatments. Conclusions HE is a potentially life-threatening condition that is probably underdiagnosed in companion animals. Although various treatment recommendations have been proposed, there is a lack of evidence in the veterinary literature regarding optimal strategies for the management of this condition. As our understanding of the pathogenesis of HE in dogs and cats evolves, novel diagnostic tests and therapeutic agents may become available. [ABSTRACT FROM AUTHOR]

Background: Acute-on-chronic liver failure (ACLF) is a form of liver disease with high short-term mortality. ACLF offers considerable potential to affect the cortical areas by significant tissue injury due to loss of neurons and other supporting cells. We measured changes in cortical thickness and metabolites profile in ACLF patients following treatment, and compared it with those of age matched healthy volunteers.Methods: For the cortical thickness analysis we performed whole brain high resolution T1-weighted magnetic resonance imaging (MRI) on 15 ACLF and 10 healthy volunteers at 3T clinical MR scanner. Proton MR Spectroscopy ((1)H MRS) was also performed to measure level of altered metabolites. Out of 15 ACLF patients 10 survived and underwent follow-up study after clinical recovery at 3 weeks. FreeSurfer program was used to quantify cortical thickness and LC- Model software was used to quantify absolute metabolites concentrations. Neuropsychological (NP) test was performed to assess the cognitive performance in follow-up ACLF patients compared to controls.Results: Significantly reduced cortical thicknesses in multiple brain sites, and significantly decreased N-acetyl aspartate (NAA), myo-inositol (mI) and significantly increased glutamate/glutamine (glx) metabolites were observed in ACLF compared to those of controls at baseline study. Follow-up patients showed significant recovery in cortical thickness and Glx level, while NAA and mI were partially recovered compared to baseline study. When compared to controls, follow-up patients still showed reduced cortical thickness and altered metabolites level. Follow-up patients had abnormal neuropsychological (NP) scores compared to controls.Conclusions: Neuronal loss as suggested by the reduced NAA, decreased cellular density due to increased cerebral hyperammonemia as supported by the increased glx level, and increased proinflammatory cytokines and free radicals may account for the reduced cortical thickness in ACLF patients. Presence of reduced cortical thickness, altered metabolites and abnormal NP test scores in post recovery subjects as compared to those of controls is associated with incomplete clinical recovery. The current imaging protocol can be easily implemented in clinical settings to evaluate and monitor brain tissue changes in patients with ACLF during the course of treatment. [ABSTRACT FROM AUTHOR]

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Hepatic encephalopathy (HE) is a common complication of chronic alcoholism and patients show neurological symptoms ranging from mild cognitive dysfunction to coma and death. The HE brain is characterized by glial changes, including microglial activation, but the exact pathogenesis of HE is poorly understood. During a study investigating cell proliferation in the subventricular zone of chronic alcoholics, a single case with widespread proliferation throughout their adjacent grey and white matter was noted. This case also had concomitant HE raising the possibility that glial proliferation might be a pathological feature of the disease. In order to explore this possibility fixed postmortem human brain tissue from chronic alcoholics with cirrhosis and HE ( n = 9), alcoholics without HE ( n = 4) and controls ( n = 4) were examined using immunohistochemistry and cytokine assays. In total, 4/9 HE cases had PCNA- and a second proliferative marker, Ki-67-positive cells throughout their brain and these cells co-stained with the microglial marker, Iba1. These cases were termed 'proliferative HE' (pHE). The microglia in pHEs displayed an activated morphology with hypertrophied cell bodies and short, thickened processes. In contrast, the microglia in white matter regions of the non-proliferative HE cases were less activated and appeared dystrophic. pHEs were also characterized by higher interleukin-6 levels and a slightly higher neuronal density . These findings suggest that microglial proliferation may form part of an early neuroprotective response in HE that ultimately fails to halt the course of the disease because underlying etiological factors such as high cerebral ammonia and systemic inflammation remain. [ABSTRACT FROM AUTHOR]

Background Alcohol abuse is the world's third leading cause of disease and disability, and one potential sequel of chronic abuse is alcohol-related brain damage ( ARBD). This clinically manifests as cognitive dysfunction and pathologically as atrophy of white matter (WM) in particular. The mechanism linking chronic alcohol intoxication with ARBD remains largely unknown but it is also complicated by common comorbidities such as liver damage and nutritional deficiencies. Liver cirrhosis, in particular, often leads to hepatic encephalopathy (HE), a primary glial disease. Methods In a novel transcriptomic study, we targeted the WM only of chronic alcoholics in an attempt to tease apart the pathogenesis of ARBD. Specifically, in alcoholics with and without HE, we explored both the prefrontal and primary motor cortices, 2 regions that experience differential levels of neuronal loss. Results Our results suggest that HE, along with 2 confounders, gray matter contamination, and low RNA quality are major drivers of gene expression in ARBD. All 3 exceeded the effects of alcohol itself. In particular, low-quality RNA samples were characterized by an up-regulation of translation machinery, while HE was associated with a down-regulation of mitochondrial energy metabolism pathways. Conclusions The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non- HE alcoholics had widespread but only subtle changes in gene expression in their WM. Notwithstanding the latter result, this study demonstrates that significant confounders in transcriptomic studies of human postmortem brain tissue can be identified, quantified, and 'removed' to reveal disease-specific signals. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric disorders related to liver failure. The development of HE can have a profound impact on mortality as well as quality of life for patients and carers. Ammonia is central in the disease process contributing to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure. Inflammation in the presence of ammonia coactively worsens HE. Inflammation can result from hyperammonemic responses, endotoxemia, innate immune dysfunction or concurrent infection. This review summarizes the current processes implicated in the pathogenesis of HE, as well as current and potential treatments. Treatments currently focus on reducing inflammation and/or blood ammonia levels and provide varying degrees of success. Optimization of current treatments and initial testing of novel therapies will provide the basis of improvement of care in the near future. [ABSTRACT FROM AUTHOR]

OBJECTIVES:Elucidating the minimal hepatic encephalopathy (MHE)-associated gut microbiome may help in predicting and lowering the high risk for MHE in patients with cirrhosis.METHODS:Twenty-six MHE patients were recruited and screened from among those with liver cirrhosis without overt hepatic encephalopathy as defined by abnormality seen on two test modalities: number connection test part A and the digit symbol test. Using 26 MHE-matched normal relatives and 25 cirrhotic patients without MHE as controls, by means of 16S ribosomal RNA (rRNA)-based pyrosequencing, we examined and analyzed 241,622 bacterial 16S rDNA gene sequences from feces of 77 subjects.RESULTS:Using multiple comparative analyses, our results found the continuous overrepresentation of two bacterial families, Streptococcaceae and Veillonellaceae, in cirrhotic patients with and without MHE, compared with normal individuals. In addition, we also discovered an MHE-unique interplay pattern of gut microbiota largely influenced by the members of those two families. Following these findings, we further revealed that gut urease-containing bacteria Streptococcus salivarius was absent in the normal group but was present in cirrhotic patients with and without MHE. The abundance of S. salivarius was significantly higher in cirrhotic patients with MHE than in those without (P=0.030), and the change in the amount of this bacteria was positively correlated with ammonia accumulation (R=0.58, P=0.003) in cirrhotic patients with MHE but not in those without.CONCLUSIONS:Gut microbiota dysbiosis may be associated with the presence of MHE in cirrhotic patients, in particular with ammonia-increasing phenotype in MHE. Gut ammonia-increasing bacteria S. salivarius might be expected to be a potential biomarker of ammonia-lowering therapies in cirrhotic patients with MHE. [ABSTRACT FROM AUTHOR]

Infection and inflammation have been associated with the development of delirium for many centuries and there is a rapidly growing evidence base supporting the role of inflammation in exacerbating the neurological manifestations of both acute and chronic liver failure. Inflammation in the context of hepatic encephalopathy (HE) can arise directly within the brain itself resulting in astrocytic, microglial and neuronal dysfunction, impacting on the development of 'brain failure'. Inflammation may also develop systemically and indirectly influence brain function. Systemic inflammation develops following liver injury, resulting in hyperammonemia and a 'cytotoxic soup' of pro-inflammatory mediators which are released into the circulation and modulate the impact of ammonia on the brain. The aim of this review is to summarise the current evidence base supporting the synergistic role of systemic inflammation and hyperammonemia in the pathogenesis of hepatic encephalopathy. Systemic inflammation and ammonia induce neutrophil degranulation and release reactive oxygen species into the peripheral circulation that may ultimately cross the blood brain barrier. Circulating endotoxin arising from the gut (bacterial translocation), superimposed sepsis, and hyperammonemia upregulate the expression of microbial pattern recognition receptors such as Toll-like receptors. The early recognition and management of systemic inflammation may not only facilitate improved outcomes in HE but supports the development of novel therapeutic strategies that reduce circulating endotoxemia and immune cell dysfunction. [ABSTRACT FROM AUTHOR]

The aetiology of minimal hepatic encephalopathy (mHE) remains unclear. It is generally accepted that hyperammonaemia plays a major role, however there are a multitude of metabolic perturbations present. To determine the contribution of hyperammonaemia to mHE symptom development, ten healthy males (Age:25 ± 5 yrs, BM:76.3 ± 7.1 kg, Height:178.6 ± 4.5 cm, mean ± SD) received two 4 h intravenous infusions of either a 2% ammonium chloride solution (AMM) or a placebo (PLA;0.9% sodium chloride) using a double blind cross-over design. Sensations of fatigue were measured at baseline, 2 and 4 h using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) questionnaire. Learning & memory, motor control and cognition were assessed using Rey's Auditory Verbal Learning Test (AVL), Continuous Compensatory Tracking (COMPTRACK) Task and Inhibitory Control Test (ICT) respectively. Arterialised venous blood samples were collected every hour, and analysed for ammonia concentration. There was a significantly higher plasma ammonia concentration in the AMM trial than the PLA trial at every time point during the infusion, peaking at 2 h (57 ± 4 μmol/L PLA, 225 ± 14 μmol/L AMM; p < 0.05). At 2 h there were significantly higher sensations of general fatigue ( Z = −2.527, p = 0.008, 2 tailed) and physical fatigue ( Z = −2.156, p = 0.027, 2 tailed), and lower sensations of vigour ( Z = −2.456, p = 0.012, 2 tailed) for the AMM trial. There were no significant effects on the performance of the psychological tasks. These results demonstrate that hyperammonaemia in the absence of other complications induces significant sensations of fatigue but does not cause the typically observed performance impairment in individuals with mHE. Supporting the hypothesis for synergism between ammonia and other co-factors in mHE. [ABSTRACT FROM AUTHOR]

Background: Hepatic encephalopathy is a syndrome whose physiopathology is poorly understood; therefore, current diagnostic tests are imperfect and modern therapy is nonspecific. Particularly, it has been suggested that inflammation plays an important role in the pathogenesis of portal hypertensive encephalopathy in the rat.Aim: We have studied an experimental model of portal hypertension based on a triple partial portal vein ligation in the rat to verify this hypothesis.Methods: One month after portal hypertension we assayed in the splanchnic area (liver, small bowel and mesenteric lymph nodes) and in the central nervous system (hippocampus and cerebellum) fractalkine (CX3CL1) and stromal cell-derived factor alpha (SDF1-α) as well as their respective receptors (CX3CR1 and CXCR4) because of their key role in inflammatory processes.Results: The significant increase of fractalkine in mesenteric lymph nodes (P<0.05) and its receptor (CX3CR1) in the small bowel (P<0.05) and hippocampus (P<0.01), associated with the increased expression of SDF1-α in the hippocampus (P<0.01) and the cerebellum (P<0.01) suggest that prehepatic portal hypertension in the rat induces important alterations in the expression of chemokines in the gut-brain axis.Conclusion: The present study revealed that portal hypertension is associated with splanchnic-brain inflammatory alterations mediated by chemokines. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress induced by a high ammonia concentration has been suggested to be implicated in the pathophysiology of hepatic encephalopathy (HE). Therefore, oxidative damage of brain biomolecules could contribute towards explaining the neurological and motor alterations observed in HE. Methods: Portacaval-shunted (PCS) rats (n = 5) were used as an animal model of chronic HE. Plasma and brain ammonia were measured by the L-glutamate dehydrogenase method. Reactive oxygen species was measured by the dichlorodihydrofluorescein diacetate method.Lipid peroxidation was measured as thiobarbituric acid-reactive substances (TBARS) by a colorimetric method; malondialdehyde (MDA) and 4 hydroxy-2-noneal (HNE) were measured by HPLC and an immunological method respectively. Protein oxidation (carbonylation) was measured as total carbonyl after labelling with 2,4-dinitrophenyl hydrazine (DNPH) using a spectrophotometric ethod. Individual protein oxidation was studied, after labelling with DNPH and its separation by one-dimensional (1D) electrophoresis, by an immunological method. Results: Ammonia-induced oxidative stress in PCS rats was associated with increased MDA and HNE, together with increased protein oxidation, evidenced by total carbonyl quantification and by the analysis of individual protein bands separated by 1D electrophoresis. However, lipid peroxidation measured as TBARS did not show differences. Conclusion: Our data show an increased evidence of oxidative stress in PCS rat brain; moreover, PCS rat brain proteins are oxidized (carbonylated), some proteins being more sensitive to oxidation than others. These data also showthat at least six specific brain proteins in PCS rats are highly sensitive to carbonylation. Identification of these proteins may be crucial for a better understanding of HE pathophysiology. [ABSTRACT FROM AUTHOR]

The article presents information on hepatic encephalopathy in cirrhosis patients. It provides an overview of the mental and motor disorder that may arise in overt hepatic encephalopathy, including rigidity, movement-induced tremor and disturbed neurophysiological function. It discusses some of the techniques used for diagnosing hepatic encephalopathy, including the West Haven criteria and the Psychometric Hepatic Encephalopathy Score (PHES). The treatment options for the condition include non-absorbable antibiotics and liver transplantation.

See article in J. Gastroenterol. Hepatol. 2012; 27: 1329-1335. [ABSTRACT FROM AUTHOR]