Pathogenesis Of Hepatic Encephalopathy Research Articles

Navigating the Gut-Brain Axis: Insights into the Pathogenesis of Hepatic Encephalopathy

Abstract: Hepatic encephalopathy is a neurological condition that affects people who have an insufficient liver function. However, its pathophysiology is yet unclear. For hepatic encephalopathy, pharmacotherapy is the primary treatment choice. Lowering ammonia levels, enhancing neurotransmitter signal transduction, and modifying gut microbiota, tackles the pathophysiology of hepatic encephalopathy. The intestinal microbiota of liver disease patients differs greatly from that of healthy people, and this difference is linked to the development of hepatic encephalopathy. Additionally, gut microbiota is intimately linked to several theories in the pathophysiology of hepatic encephalopathy, such as the GABA-ergic tone hypothesis, bile acid circulation, ammonia poisoning theory, and neuroinflammation, all of which exacerbate patients' cognitive and motor impairments. Providing some probiotics or reestablishing the intestinal bacteria's balance has a substantial impact on neurological illnesses in hepatic encephalopathy. The goal of this review is to determine the possible metabolic impacts and microbiological pathways in the gut-brain axis mediated progression of hepatic encephalopathy, as well as its potential function as a therapeutic target.

Possible pathogenetic role of ammonia in liver cirrhosis without hyperammonemia of venous blood: The so-called latency period of abnormal ammonia metabolism.

Ammonia plays a crucial role in the pathogenesis of hepatic encephalopathy. Ammonia is also involved in many other pathological conditions seen in cirrhosis, such as sarcopenia, liver fibrosis, hepatocellular injury, immune dysfunction, and hyperammonemia. Furthermore, the ammonia level of the veins is a useful prognostic factor for cirrhosis. In cirrhosis without hyperammonemia of the vein, however, covert hepatic encephalopathy has been reported. This discrepancy is because of the anatomical features of ammonia metabolism. There are two systems in the body for detoxifying ammonia: one is the urea cycle in the liver, and the other is the glutamine synthesis pathway in skeletal muscle and other tissues. The blood processed in the liver's urea cycle is then transported via arteries to various organs. Further processing occurs in the brain and skeletal muscle's glutamine synthesis pathway before entering the veins. When the urea cycle function decreases in cirrhosis, the ammonia levels in the artery increase. In response, the glutamine synthesis pathway compensates by increasing the capacity to process ammonia. Therefore, the ammonia concentration in the veins downstream of skeletal muscles does not increase immediately. However, the brain and skeletal muscles, which receive arterial blood, might be exposed to high ammonia concentrations. In addition, branched-chain amino acids in venous blood decrease. This period is the transition phase from early- to late-phase cirrhosis, and understanding the pathophysiology during this stage is extremely important for preventing the progression of cirrhosis.

Direct contribution of Purkinje neurons death and morpho-functional astroglial changes involving oxidative stress and neuroinflammation in the pathogenesis of hepatic encephalopathy

Direct contribution of Purkinje neurons death and morpho-functional astroglial changes involving oxidative stress and neuroinflammation in the pathogenesis of hepatic encephalopathy

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice.

Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

#3739 SHUNT PORTOSYSTEMIC COMPLICATED BY HYPERAMMONEMIA AND HEPATIC ENCEPHALOPATHY SUPPORTED BY DAILY DIALYSIS IN A CHRONIC HEMODIALYSIS PATIENT

Abstract Background and Aims Hepatic encephalopathy is a neuropsychiatric syndrome that may develop as a consequence of liver insufficiency. In acute liver failure, hepatic encephalopathy suggests the severity of the disease. In end-stage chronic liver diseases, episodes of hepatic encephalopathy are frequently fully and spontaneously reversible. Clinical manifestations vary from mild neuropsychiatric disorders to coma. The pathogenesis of hepatic encephalopathy is complex and not clearly understood. Ammonia plays a key role. In the healthy individual, ammonia is, during its first hepatic passage, directly degraded into urea, itself excreted by the kidney and the stools, and to a lesser degree in glutamine. Ammonia is also metabolized by the muscle striped. In case of liver failure and/or shunts portosystemic, there is a defect in hepatic clearance ammonia which is then found in excess in systemic circulation. Decreased muscle mass, linked to malnutrition, frequent in the patient cirrhotic and chronic hemodialysis, also helps to decrease metabolism ammonia. Due to the increase in permeability of the blood-brain barrier, the brain is exposed to excessive concentrations ammonia causing functional brain abnormalities and structural, which can partly explain the signs neurology of hepatic encephalopathy. In end stage chronic renal failure, clearance of ammonia via extracorporeal treatment has not been systematically evaluated. Several studies with small samples have demonstrated the effectiveness of hemodialysis, compared to peritoneal dialysis, in terms of ammonium purification in chronic renal failure, on dialysis or not on dialysis. The aim of this study was to evaluate the effectiveness of daily dialysis for the purification of ammoniumin a chronic hemodialysis patient with hepatic encephalopathy. Case Report A 40-year-old man undergoing chronic hemodialysis was referred to gastroenterology department of Mohammed VI University center of Marrakesh for inoperable shunt portosystemic complicated by hyperammonemia causing hepatic encephalopathy consisting of headaches and seizures. His medical history was significant for liver cirrhosis caused by infection with hepatitis B, end stage kidney disease due to membranoproliferative glomerulonephritis, for which the patient is on hemodialysis at the rate of 3 sessions per week. The patient went on to develop portal hypertension and ascites requiring frequent hospital admissions and treatment with diuretics. He was on a low-protein and low-sodium diet. While on oral furosemide 250 mg daily and spironolactone 100 mg daily, his diuresis was adequate. Before referral, this patient had already suffered 4 episodes of tonic clonic seizures. His 1st hemodialysis session in our training was on January 10, 2023, he was given daily hemodialysis sessions with daily blood tests, including immediate pre and post dialysis ammonia. Pre-dialytic ammonia levels varied between 103 and 161 µmol/l, as well as post-dialytic ammonia levels varied between 24 and 37 µmol/l, knowing that the normal value of laboratory ammonia varied between 10 and 51 µmol/l. The evolution was marked by a clear clinical improvement, with a disappearance of the seizures without a significant drop in ammonia after 14 daily hemodialysis sessions. Serum creatinine and urea declined, and sodium increased. Accumulation of ascites slowed and the patient could eat and sleep normally and was again independent with self care. The patient returned home on January 24. Conclusion This study shows the interest of daily hemodialysis sessions as a potential treatment for hyperammonemia in a patient on chronic intermittent hemodialysis, with a portosystemic shunt. The interest lies in the fact that the improvement is mainly clinical than biological (persistent hyperammonemia).

Hyperammonemia induces microglial NLRP3 inflammasome activation via mitochondrial oxidative stress in hepatic encephalopathy

BackgroundThe role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in the pathogenesis of hepatic encephalopathy (HE) is unclear. Mitochondrial reactive oxygen species (mtROS) is a signal for NLRP3 inflammasome activation. Therefore, we aimed to determine whether mtROS-dependent NLRP3 inflammasome activation is involved in HE, using in vivo and in vitro models. MethodsBile duct ligation (BDL) in C57/BL6 mice was used as an in vivo HE model. NLRP3 activation was assessed in the hippocampus. Immunofluorescence staining was performed to determine the cellular source of NLRP3 in the hippocampal tissue. For the in vitro experiment, BV-2 microglial cells were primed with lipopolysaccharide (LPS), followed by ammonia treatment. NLRP3 activation and mitochondrial dysfunction were measured. Mito-TEMPO was used to suppress mtROS production. ResultsBDL mice showed cognitive impairment with hyperammonemia. Both the priming and activation steps of NLRP3 inflammasome activation were processed in the hippocampus of BDL mice. Moreover, intracellular ROS levels increased in the hippocampus, and NLRP3 was mainly expressed in the microglia of the hippocampus. In LPS-primed BV-2 cells, ammonia treatment induced NLRP3 inflammasome activation and pyroptosis, with elevation of mtROS and altered mitochondrial membrane potential. Pretreatment with Mito-TEMPO suppressed mtROS production and the subsequent NLRP3 inflammasome activation and pyroptosis under LPS and ammonia treatment in BV-2 cells. ConclusionsHyperammonemia in HE may be involved in mtROS overproduction and subsequent NLRP3 inflammasome activation. Further studies using NLRP3-specific inhibitor or NLRP3 knockout mice are needed to elucidate the important role of NLRP3 inflammasome in HE development.

Comparison of the effects of probiotics, rifaximin, and lactulose in the treatment of minimal hepatic encephalopathy and gut microbiota.

Minimal hepatic encephalopathy (MHE) is an early stage in the pathogenesis of hepatic encephalopathy. Intestinal microbiota is involved in the pathogenesis of hepatic encephalopathy and has become an important therapeutic target. Since there is no unified treatment principle for MHE, this study was conducted to determine the safety and efficacy of different intestinal microecological modulators in the treatment of MHE, and to explore the potential mechanism through intestinal microbiota analysis. Patients with liver cirrhosis were screened for MHE using psychometric hepatic encephalopathy score test. Patients diagnosed with MHE were enrolled and received probiotics, rifaximin, or lactulose for 4 weeks. Adverse events were recorded. The psychometric hepatic encephalopathy score test was performed after treatment. Samples of blood and stool were collected at entry and 4 weeks. Blood samples were analyzed to assess blood ammonia, liver, kidney, and hemostatic functions. Stool microbiota were sequenced to confirm changes in microbial composition. Of 323 patients with liver cirrhosis, 74 patients were diagnosed with MHE. In all, 54 patients were enrolled and 52 who agree to follow-up were included in analysis. The recovery rates of MHE patients received probiotics, rifaximin, and lactulose were 58.8% (20/34), 45.5% (5/11), and 57.1% (4/7), respectively. Probiotics and rifaximin improved liver function in MHE patients to a certain extent. Taxonomic compositions of gut microbiota in MHE patients were distinct from healthy people before treatment; the differences were significantly reduced after treatment, and the gut microbiota gradually resembled the structure of healthy individuals. We found that the relative abundance of specific taxa associated with anti-inflammatory and good cognitive functions was increased in MHE patients after treatment. Accordingly, metabolic pathways in MHE patients were altered before and after treatment. Downregulated pathways after probiotics treatment included glycometabolism and degradation of aromatic compounds. After lactulose treatment, degradation pathways of arginine and ornithine showed a downward trend. Probiotics, rifaximin, and lactulose are safe and effective in the treatment of MHE, and improve the composition of gut microbiota to some extent.

The Glymphatic System May Play a Vital Role in the Pathogenesis of Hepatic Encephalopathy: A Narrative Review

Hepatic encephalopathy (HE) is a neurological complication of liver disease resulting in cognitive, psychiatric, and motor symptoms. Although hyperammonemia is a key factor in the pathogenesis of HE, several other factors have recently been discovered. Among these, the impairment of a highly organized perivascular network known as the glymphatic pathway seems to be involved in the progression of some neurological complications due to the accumulation of misfolded proteins and waste substances in the brain interstitial fluids (ISF). The glymphatic system plays an important role in the clearance of brain metabolic derivatives and prevents aggregation of neurotoxic agents in the brain ISF. Impairment of it will result in aggravated accumulation of neurotoxic agents in the brain ISF. This could also be the case in patients with liver failure complicated by HE. Indeed, accumulation of some metabolic by-products and agents such as ammonia, glutamine, glutamate, and aromatic amino acids has been reported in the human brain ISF using microdialysis technique is attributed to worsening of HE and correlates with brain edema. Furthermore, it has been reported that the glymphatic system is impaired in the olfactory bulb, prefrontal cortex, and hippocampus in an experimental model of HE. In this review, we discuss different factors that may affect the function of the glymphatic pathways and how these changes may be involved in HE.

Plasma ammonia levels predict hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis.

Hyperammonaemia is central in the pathogenesis of hepatic encephalopathy. It also has pleiotropic deleterious effects on several organ systems, such as immune function, sarcopenia, energy metabolism and portal hypertension. This study was performed to test the hypothesis that severity of hyperammonaemia is a risk factor for liver-related complications in clinically stable outpatients with cirrhosis. We studied 754 clinically stable outpatients with cirrhosis from 3 independent liver units. Baseline ammonia levels were corrected to the upper limit of normal (AMM-ULN) for the reference laboratory. The primary endpoint was hospitalisation with liver-related complications (a composite endpoint of bacterial infection, variceal bleeding, overt hepatic encephalopathy, or new onset or worsening of ascites). Multivariable competing risk frailty analyses using fast unified random forests were performed to predict complications and mortality. External validation was carried out using prospective data from 130 patients with cirrhosis in an independent tertiary liver centre. Overall, 260 (35%) patients were hospitalised with liver-related complications. On multivariable analysis, AMM-ULN was an independent predictor of both liver-related complications (hazard ratio 2.13; 95% CI 1.89-2.40; p <0.001) and mortality (hazard ratio 1.45; 95% CI 1.20-1.76; p <0.001). The AUROC of AMM-ULN was 77.9% for 1-year liver-related complications, which is higher than traditional severity scores. Statistical differences in survival were found between high and low levels of AMM-ULN both for complications and mortality (p <0.001) using 1.4 as the optimal cut-off from the training set. AMM-ULN remained a key variable for the prediction of complications within the random forests model in the derivation cohort and upon external validation. Ammonia is an independent predictor of hospitalisation with liver-related complications and mortality in clinically stable outpatients with cirrhosis and performs better than traditional prognostic scores in predicting complications. We conducted a prospective cohort study evaluating the association of blood ammonia levels with the risk of adverse outcomes in 754 patients with stable cirrhosis across 3 independent liver units. We found that ammonia is a key determinant that helps to predict which patients will be hospitalised, develop liver-related complications and die; this was confirmed in an independent cohort of patients.

Inhibition of Autotaxin Ameliorates LPA-Mediated Neuroinflammation and Alleviates Neurological Dysfunction in Acute Hepatic Encephalopathy.

Growing evidence suggests an essential role of neuroinflammation in behavioral abnormalities associated with hepatic encephalopathy (HE). Here, we report the involvement of autotaxin-lysophosphatidic acid (LPA) signaling in HE's pathogenesis. We demonstrate that the autotaxin (ATX) inhibitor PF-8380 attenuates neuroinflammation and improves neurological dysfunction in the mouse model of HE. In the thioacetamide (TAA)-induced model of HE, we found a twofold increase in the levels of ammonia in the brain and in plasma along with a significant change in HE-related behavioral parameters. Mice with HE show an increased brain weight, increased levels of tumor necrosis factor-α (TNF-α), IL-1β (interleukin-1β), interleukin-6 (IL-6), and LPA 18:0 in the cerebral cortex and hippocampus, and increased levels of LPA 18:0 in plasma. Treatment with the autotaxin inhibitor (ATXi) did not affect liver injury, as we observed no change in liver function markers including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) and no change in ammonia levels in the brain and plasma. However, ATXi treatment significantly ameliorated the neuroinflammation, reduced the levels of LPA 18:0 in the cerebral cortex and hippocampus in the brain and plasma, and reduced brain edema and the levels of IL1β, IL-6, and TNF-α. The neurobehavioral symptoms for HE such as the cognitive and motor function deficit and overall clinical grading score were significantly improved in ATXi-treated mice. Mouse astrocytes and microglia stimulated with NH4CL with or without ATXi showed significant attenuation of oxidative stress and the neuroinflammatory effect of NH4CL in ATXi-treated cells.

Sex is associated with differences in oxidative stress and susceptibility to severe hepatic encephalopathy in bile-duct ligated rats.

Hepatic encephalopathy (HE) is a debilitating neurological complication of chronic liver disease (CLD). Hyperammonemia plays an important role in HE's pathogenesis, acting synergistically with systemic oxidative stress. During CLD, muscle plays a compensatory role in detoxifying ammonia, and therefore muscle loss leads to an increase in the risk of developing HE. With most animal studies involving males, sex's impact on the development of CLD and associated complications such as HE and muscle loss remains unknown. Therefore, we aimed to identify the impact of sex on CLD, HE, and muscle mass loss in a rodent model of CLD. Liver injury markers, hyperammonemia, oxidative stress, muscle mass, and ammonia clearance were measured in female and male bile-duct ligated (BDL) rats. In addition, covert HE was assessed in females while ammonia-precipitated severe HE was assessed in female and male BDL rats, and male BDL rats treated with allopurinol (100 mg/kg), an antioxidant (xanthine oxidase inhibitor). Female BDL developed CLD and HE (impaired motor coordination and night activity) compared to respective SHAM. Hyperammonemia and muscle ammonia clearance were similar between female and male BDL. However, only female BDL rats did not develop muscle loss, brain edema, and short-term memory impairment (vs. female SHAM) and systemic oxidative stress and decreased albumin levels (vs. male BDL). Furthermore, both female BDL and allopurinol-treated male BDL rats were protected against ammonia-induced overt HE. In conclusion, female and male BDL rats develop distinct features of CLD and HE, with systemic oxidative stress playing a pivotal role in the susceptibility to ammonia-precipitated overt HE.

The Role of Gut Microbiota in Mice With Bile Duct Ligation-Evoked Cholestatic Liver Disease-Related Cognitive Dysfunction.

The pathogenesis of Hepatic Encephalopathy (HE) is complex and multifactorial. The development of metagenomics sequencing technology led to show the significant role of gut microbiota in the pathogenesis of cognitive dysfunction, which paved the way for further research in this field. However, it is unknown whether gut microbiota plays a role in bile duct ligation (BDL)-evoked cholestatic liver disease-related cognitive dysfunction. The aim of this investigation is to assess BDL mice induced cognitive dysfunction and meanwhile to delineate the alteration of gut microbiota in cognitive dysfunction mice, which may underline the role of gut microbiota in BDL mice induced cognitive dysfunction. Our study was carried out in male C57BL/6 J mice with bile duct ligation. The liver functions were assessed via different biochemical markers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), and total bile acid (TBA)] and a histopathological examination of the liver tissue. We used the novel object recognition test (NORT) to assess cognitive dysfunction. And BDL mice were divided into BDL with cognitive dysfunction (BDL-CD) or BDL without cognitive dysfunction (BDL-NCD groups) by the result of hierarchical cluster analysis of NORT. Then, 16S ribosomal RNA (rRNA) gene sequencing was used to compare the gut bacterial composition between BDL-CD and BDL-NCD groups. According to our results, we concluded that bile duct ligation can significantly change the gut microbiota composition, and Bacteroides fragilis, Bacteroides ovatus V975, and Bacteroides thetaiotaomicron play a vital role in BDL-evoked cholestatic liver disease-related cognitive dysfunction.

Is NMDA-Receptor-Mediated Oxidative Stress in Mitochondria of Peripheral Tissues the Essential Factor in the Pathogenesis of Hepatic Encephalopathy?

Background: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of increased ammonia-mediated brain dysfunction caused by impaired hepatic detoxification or when the blood bypasses the liver. Ammonia-activated signal transduction pathways of hyperactivated NMDA receptors (NMDAR) are shown to trigger a cascade of pathological reactions in the brain, leading to oxidative stress. NMDARs outside the brain are widely distributed in peripheral tissues, including the liver, heart, pancreas, and erythrocytes. To determine the contribution of these receptors to ammonia-induced oxidative stress in peripheral tissues, it is relevant to investigate if there are any ammonia-related changes in antioxidant enzymes and free radical formation and whether blockade of NMDARs prevents these changes. Methods: Hyperammonemia was induced in rats by ammonium acetate injection. Oxidative stress was measured as changes in antioxidant enzyme activities and O2•− and H2O2 production by mitochondria isolated from the tissues and cells mentioned above. The effects of the NMDAR antagonist MK-801 on oxidative stress markers and on tissue ammonia levels were evaluated. Results: Increased ammonia levels in erythrocytes and mitochondria isolated from the liver, pancreas, and heart of hyperammonemic rats are shown to cause tissue-specific oxidative stress, which is prevented completely (or partially in erythrocyte) by MK-801. Conclusions: These results support the view that the pathogenesis of HE is multifactorial and that ammonia-induced multiorgan oxidative stress-mediated by activation of NMDAR is an integral part of the disease and, therefore, the toxic effects of ammonia in HE may be more global than initially expected.

Rifaximin Modulates the Gut Microbiota to Prevent Hepatic Encephalopathy in Liver Cirrhosis Without Impacting the Resistome.

The gut microbiota has an important role in the pathogenesis of hepatic encephalopathy(HE). Rifaximin, an intestinal non-absorbable antibacterial agent, is effective in the treatment of HE. However, whether long-term prophylactic use induces antibacterial resistance and its mechanism for treating HE remains unclear. This prospective study assessed the impact of 12 weeks rifaximin administration on the gut microbiota and resistome in cirrhotic patients. Fecal sampling was conducted 1 day before the first rifaximin administration and at Weeks 1, 2, 4, 6, 8, 10, 12 of the study. Thirty cirrhotic patients who were in remission from recurrent HE was enrolled to receive rifaximin (400mg TID for 12 weeks). Rifaximin improved hyperammonemia and cognitive function in the 21 patients who completed rifaximin treatment. The dynamic observations showed the gut microbiota diversity, composition and the number of resistance genes, plasmids, insertion sequences did not change significantly during the period(P>0.05). Metabolic pathways such as aromatic amino acids, tryptophan synthesis, urea cycle, and LPS synthesis reduced. No new antimicrobial resistance genes was emergenced. However, the number of aminoglycosides, rifamycin and phenolic resistance genes increased, whereas tetracycline, fosfomycin and cephamycin decreased (P<0.05). Changes in the abundance of E. coli, K. pneumoniae, and B. longum strains correlated with changes of resistance genes. Prophylactic use of rifaximin for 12 weeks improved hyperammonemia and neurophysiological function, maintained gut microbiota diversity, composition and did not change the overall resistome. Rifaximin altered expression of HE-related metabolic pathways. All of these effects could play a key role in preventing HE. Clinical Trial Registration: ChiCTR1900022234 (registered at the Chinese Clinical Trial Registry).

Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study.

Introduction Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic effects on astrocytes. Objectives This follow-up study was designed to confirm the direct effects of BCAA on human astrocytes and clarify their underlying mechanisms using metabolome analysis and evaluation of associated signaling. Methods We performed cytotoxicity and cell proliferation tests on astrocytes following BCAA treatment with and without ammonium chloride (NH4Cl) and then compared the results with the effects of BCAA on hepatocytes and neurons. Subsequently, we used metabolomic analysis to investigate intracellular metabolite levels in astrocytes with and without BCAA treatment. Results The astrocytes showed increased leakage of intracellular lactate dehydrogenase and reduced proliferation rate upon BCAA treatment. Interestingly, our analysis showed a BCAA-induced impairment of intracellular glycolysis/glyconeogenesis as well as amino acid and butyric acid metabolism. Furthermore, BCAA treatment was found to cause decreased levels of Glut-1 and phosphorylated GSK-3β and mTOR in astrocytes. Conclusions Although further investigations of the effect of BCAA on human astrocytes with hyperammonemia are needed, our work demonstrates that BCAA supplementation has direct negative effects on astrocyte survival and intracellular metabolism.

18F]PBR146 and [18F]DPA-714 in vivo Imaging of Neuroinflammation in Chronic Hepatic Encephalopathy Rats.

Neuroinflammation is an important pathogenesis of hepatic encephalopathy (HE). The upregulation of translocator protein (TSPO) during neuroinflammation provides an imaging molecular target to evaluate the severity of neuroinflammation in chronic HE rats. [18F]DPA-714 and [18F]PBR146 targeting TSPO are often used for neuroinflammation imaging. This study performed bile duct ligation (BDL) in rats to simulate chronic HE model, tested the behavioral experiments, and conducted [18F]PBR146 and [18F]DPA-714 micro-PET/CT scans followed analyzing the average %ID/g values of the whole brain, brain regions and main organs of subjects. After sacrifice the rats, the blood plasma samples were taken for blood biochemical indexes and plasma inflammatory factor levels examination, the liver and brain specimens were obtained for pathological analysis. The BDL rats showed chronic liver failure with defects in cognition, motor coordination ability and mental state. [18F]PBR146 and [18F]DPA-714 micro-PET/CT imaging results were similar in whole brain of BDL group and Sham group. Besides, some regional brain areas in BDL rats were found abnormal uptakes mainly located in basal ganglia area, auditory cortex, motor cortex, cingulate gyrus, somatosensory cortex, hippocampus, thalamus, midbrain, and medulla oblongata, and these regions also correlated with behavioral alterations. In conclusion, both [18F]PBR146 and [18F]DPA-714 had the similar imaging effects in hepatic encephalopathy models could quantitatively evaluate neuroinflammation load and distribution. The difference brain regions with higher uptake values of radiotracers in BDL rats were correlated with behavioral alterations.

The critical role of hippocampal dopamine in the pathogenesis of hepatic encephalopathy.

The pathogenesis of hepatic encephalopathy (HE) has been generally linked to blood ammonia, gamma-aminobutyric acid and serotonin. However, the exact mechanism remains unclear. In the present study, we aimed to explore the role of hippocampal dopamine (DA) and its receptors in the pathogenesis of HE through the use of behavioral testing, western blotting, and immunofluorescence staining in normal rats, HE model rats and rats treated with the DA precursor-levodopa (L-DOPA). HE model rats manifested fibrotic livers and showed serious behavioral disorders. They also had significantly lower hippocampal DA content and increased expression of both D1 and D2 receptors relative to normal rats. After treatment with L-DOPA, the HE model rats showed normal behavior and expression of D1 returned to normal levels. Furthermore, pretreatment with the D1 antagonist SCH23390 blocked the therapeutic effect of L-DOPA on behavior in HE model rats. Taken together, these results clarify that the decrease in hippocampal DA plays a role in the pathogenesis of HE and that this effect is mediated by D1. These findings provide new evidence for the pathogenesis of HE.

Cognitive Dysfunction in Non-Alcoholic Fatty Liver Disease-Current Knowledge, Mechanisms and Perspectives.

Non-alcoholic fatty liver disease (NAFLD) has emerged as the hepatic component of the metabolic syndrome and now seemingly affects one-fourth of the world population. Features associated with NAFLD and the metabolic syndrome have frequently been linked to cognitive dysfunction, i.e. systemic inflammation, vascular dysfunction, and sleep apnoea. However, emerging evidence suggests that NAFLD may be a cause of cognitive dysfunction independent of these factors. NAFLD in addition exhibits dysbiosis of the gut microbiota and impaired urea cycle function, favouring systemic ammonia accumulation and further promotes systemic inflammation. Such disruption of the gut–liver–brain axis is essential in the pathogenesis of hepatic encephalopathy, the neuropsychiatric syndrome associated with progressive liver disease. Considering the growing burden of NAFLD, the morbidity from cognitive impairment is expected to have huge societal and economic impact. The present paper provides a review of the available evidence for cognitive dysfunction in NAFLD and outlines its possible mechanisms. Moreover, the clinical challenges of characterizing and diagnosing cognitive dysfunction in NAFLD are discussed.

The Psychometric Hepatic Encephalopathy Syndrome score does not correlate with blood ammonia, endotoxins or markers of inflammation in patients with cirrhosis.

The pathogenesis of hepatic encephalopathy (HE) remains unclear but impaired clearance of gut-derived neurotoxins and increased systemic inflammation are thought to play key roles. The diagnosis is based on detection of neurophysiological and neuropsychometric abnormalities. The Psychometric Hepatic Encephalopathy Score (PHES) have been found to correlate with markers of systematic inflammation including interleukin 6, C-reactive protein (CRP) and tumor necrosis factor-α (TNF-α). This study explores the associations between the PHES score and systemic inflammation, endotoxins and disease severity using baseline data from a trial involving patients with cirrhosis and minimal or no HE (NCT01769040). Arterial blood was obtained during hepatic vein catheterization, from 54 patients [median age 55 (range, 33-70) years; 83% men] with decompensated but stable cirrhosis. None had clinical evidence of HE but 34 (55.6%) had an abnormal PHES score indicating the presence of minimal HE. Relationships were sought between the PHES score and markers of systemic inflammation, high sensitivity-CRP, cytokines (SDF-1α, TGF-b1, IP-10, IL-6, 10 and 18, and TNF-α; lipopolysaccharide (LPS), the lipopolysaccharide binding protein (LBP) and soluble CD14 (sCD14); and the blood ammonia. No significant relationships were found between the PHES score and any of the variables tested with the single exception of the correlation with serum IL-6 (r=-0.29, 95% confidence interval, -0.53 to -0.02, P=0.031). No independent predictors of the PHES score were identified in regression analyses. No predictive associations were identified between the PHES scores and circulating blood ammonia, endotoxins, or markers of systemic inflammation in this patient population.

Interaction of Manganese and Ammonia in the Brain of Hepatic Encephalopathy Rats

Background: Both ammonia and manganese (Mn) play a key role in the pathogenesis of hepatic encephalopathy (HE) and cause similar morphological and functional changes in astrocytes. Objectives: To investigate the interaction between brain Mn and ammonia in HE rats. Methods: Three rat models of minimal HE (MHE), chronic manganism (CHM), and chronic hyperammonemia (CHA) were constructed. A total of 48 Sprague-Dawley rats were divided into one control group (n = 6), MHE groups (n = 18, among which six rats were used to evaluate the MHE model), CHM groups (n = 12), and CHA groups (n = 12). The CHM, CHA, and the rest of MHE rats were randomly divided further into two subgroups, according to the MgSO4 treatment (oral administration of 496 mg/kg/day for seven weeks): MHE-7W and MHE + Mg-7W; CHM-7W and CHM + Mg-7W; and CHA-7W and CHA + Mg-7W, respectively. Rats’ blood ammonia, brain Mn, glutamine synthetase (GS), and glutamine (GLN) levels were measured and compared among groups. Results: Significantly higher brain Mn content in MHE-7W and CHM-7W rats, higher blood ammonia levels, brain GS activity, and GLN content were observed in MHE-7W, CHM-7W, and CHA-7W rats than in control rats. After MgSO4 treatment for seven weeks, significantly lower brain Mn content, blood ammonia levels, and GLN content were observed in MHE, CHM, and CHA rats. Conclusions: Our study showed that brain Mn accumulation could increase brain ammonia levels, while the accumulation of brain ammonia had no effect on the content of brain Mn.