Pathogenesis Of Hepatic Encephalopathy Research Articles

Mo1842 CCR2 and CCR4 Activation via CCL2/MCP-1 Contributes to Neurological Decline and Microglia Activation Associated With Hepatic Encephalopathy Pathogenesis

Mo1842 CCR2 and CCR4 Activation via CCL2/MCP-1 Contributes to Neurological Decline and Microglia Activation Associated With Hepatic Encephalopathy Pathogenesis

Gut microbiota and hepatic encephalopathy

There is a strong relationship between liver and gut; while the portal venous system receives blood from the gut, and its contents may affect liver functions, liver in turn, affects intestinal functions through bile secretion. There is robust evidence that the pathogenesis of hepatic encephalopathy (HE) is linked to alterations in gut microbiota and their by-products such as ammonia, indoles, oxindoles, endotoxins, etc. In the setting of intestinal barrier and immune dysfunction, these by-products are involved in the pathogenesis of complications of liver cirrhosis including HE and systemic inflammation plays an important role. Prebiotics, probiotics and synbiotics may exhibit efficacy in the treatment of HE by modulating the gut flora. They improve derangement in flora by decreasing the counts of pathogenic bacteria and thus improving the endotoxemia, HE and the liver disease. Current evidence suggest that the trials evaluating the role of probiotics in the treatment of HE are of not high quality and all trials had high risk of bias and high risk of random errors. Therefore, the use of probiotics for patients with HE cannot be currently recommended. Further RCTs are required. This review summarizes the main literature findings about the relationships between gut flora and HE, both in terms of the pathogenesis and the treatment of HE.

Acetyl-L-carnitine in hepatic encephalopathy

Hepatic encephalopathy is a common complication of hepatic cirrhosis. The clinical diagnosis is based on two concurrent types of symptoms: impaired mental status and impaired neuromotor function. Impaired mental status is characterized by deterioration in mental status with psychomotor dysfunction, impaired memory, and increased reaction time, sensory abnormalities, poor concentration, disorientation and coma. Impaired neuromotor function include hyperreflexia, rigidity, myoclonus and asterixis. The pathogenesis of hepatic encephalopathy has not been clearly defined. The general consensus is that elevated levels of ammonia and an inflammatory response work in synergy to cause astrocyte to swell and fluid to accumulate in the brain which is thought to explain the symptoms of hepatic encephalopathy. Acetyl-L-carnitine, the short-chain ester of carnitine is endogenously produced within mitochondria and peroxisomes and is involved in the transport of acetyl-moieties across the membranes of these organelles. Acetyl-L-carnitine administration has shown the recovery of neuropsychological activities related to attention/concentration, visual scanning and tracking, psychomotor speed and mental flexibility, language short-term memory, attention, and computing ability. In fact, Acetyl-L-carnitine induces ureagenesis leading to decreased blood and brain ammonia levels. Acetyl-L-carnitine treatment decreases the severity of mental and physical fatigue, depression cognitive impairment and improves health-related quality of life. The aim of this review was to provide an explanation on the possible toxic effects of ammonia in HE and evaluate the potential clinical benefits of ALC.

Glutamine in the Pathogenesis of Hepatic Encephalopathy: The Trojan Horse Hypothesis Revisited

Hepatic encephalopathy (HE) is major neuropsychiatric disorder occurring in patients with severe liver disease and ammonia is generally considered to represent the major toxin responsible for this condition. Ammonia in brain is chiefly metabolized ("detoxified") to glutamine in astrocytes due to predominant localization of glutamine synthetase in these cells. While glutamine has long been considered innocuous, a deleterious role more recently has been attributed to this amino acid. This article reviews the mechanisms by which glutamine contributes to the pathogenesis of HE, how glutamine is transported into mitochondria and subsequently hydrolyzed leading to high levels of ammonia, the latter triggering oxidative and nitrative stress, the mitochondrial permeability transition and mitochondrial injury, a sequence of events we have collectively termed as the Trojan horse hypothesis of hepatic encephalopathy.

Systemic inflammation and ammonia in hepatic encephalopathy

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.

Liver-brain proinflammatory signalling in acute liver failure: Role in the pathogenesis of hepatic encephalopathy and brain edema

A robust neuroinflammatory response characterized by microglial activation and increased brain production of pro-inflammatory cytokines is common in acute liver failure (ALF). Mechanisms proposed to explain the neuroinflammatory response in ALF include direct effects of systemically-derived proinflammatory cytokines and the effects of brain lactate accumulation on pro-inflammatory cytokine release from activated microglia. Cell culture studies reveal a positive synergistic effect of ammonia and pro-inflammatory cytokines on the expression of proteins involved in glutamate homeostasis and in oxidative/nitrosative stress. Proinflammatory cytokines have the capacity to alter blood-brain barrier (BBB) integrity and preliminary studies suggest that the presence of infection in ALF results in rupture of the BBB and vasogenic brain edema. Treatments currently under investigation that are effective in prevention of encephalopathy and brain edema in ALF which are aimed at reduction of neuroinflammation in ALF include mild hypothermia, albumin dialysis systems, N-acetyl cysteine and the antibiotic minocycline with potent anti-inflammatory actions that are distinct from its anti-microbial properties.

Pathogenesis of hepatic encephalopathy: lessons from nitrogen challenges in man

Induction of hyperammonaemia with nitrogen challenge in man can be used to study the pathogenesis and treatment of hepatic encephalopathy complicating cirrhosis. Initially 20 g of glutamine was given orally as a flavored solution which resulted in doubling of blood ammonia concentration and this was associated with a deterioration in performance of the choice reaction time. The effect could have been due to a direct effect of glutamine rather than the ammonia generated so in subsequent experiments a glutamine free mixture of amino acids resembling the composition of haemoglobin was used (gastrointestinal bleeding is a known precipitant of hepatic encephalopathy). In Child grade B and C patients, 2-3 h after 54 g, slowing of the EEG was observed. The cerebral effects of induced hyperammonaemia were studied with diffusion weighted imaging and MR spectroscopy after giving 54 g of a mixture of threonine, serine and glycine when apparent diffusion coefficient increased. Also the change in ammonia levels correlated with the change in cerebral glutamine levels (r = 0.78, p = 0.002) suggesting intra cerebral formation of glutamine from ammonia and this may have accounted for the fall in cerebral myoinositol concentrations observed. Finally a colonic source for ammonia was confirmed by administering urea using colon coated capsules when ammonia concentrations slowly increased from 5 h after administration and rapidly after 10 h. In two patients the hyperammonaemia was ameliorated by pre treatment with Rifaximin 1200 mg per day for 1 week. Nitrogen challenge studies are thus a valuable model for studying new treatments for hepatic encephalopathy without the need to simultaneously treat precipitating factors.

Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy

Although ammonia is considered the main factor involved in the pathogenesis of hepatic encephalopathy (HE), it correlates well with the severity of HE in acute liver failure, but not in chronic liver disease. Oxidative stress is another factor believed to play a role in the pathogenesis of this syndrome; it represents an imbalance between the production and neutralization of reactive oxygen species, which leads to cellular dysfunction. In the setting of liver disease, oxidative stress represents a systemic phenomenon induced by several mechanisms: decreased antioxidant synthesis, increased systemic release of oxidant enzymes, generation of reactive oxygen species, and impaired neutrophil function. High ammonia concentrations induce cerebral oxidative stress, thus contributing to severe hepatic encephalopathy, as observed in acute liver failure. In chronic liver disease, significantly lower degrees of hyperammonemia (<500 μM) do not induce cerebral nor systemic oxidative stress. Data from both animal and human studies sustain that there is a synergistic effect between systemic oxidative stress, and ammonia that is implicated in the pathogenesis of hepatic encephalopathy.

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

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

Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy

BackgroundRecent observations suggest that inflammatory response may be important in the pathogenesis of hepatic encephalopathy. The aim of the study was to measure arterial ammonia, tumour necrosis factor-alpha, Interleukin-6, Interleukin-18, and serum endotoxin levels and their correlation with different grades of hepatic encephalopathy. Methods120 patients with cirrhosis were enrolled: 20 patients each of cirrhosis with grades I, II, III and IV hepatic encephalopathy, cirrhosis with and without minimal hepatic encephalopathy and healthy controls were tested for arterial ammonia, tumour necrosis factor-alpha, Interleukin-6, Interleukin-18 and serum endotoxin levels. ResultsMedian arterial ammonia, tumour necrosis factor-alpha, Interleukin-6, Interleukin-18 and serum endotoxin levels were significantly higher in patient with hepatic encephalopathy and minimal hepatic encephalopathy as compared to patients without minimal hepatic encephalopathy and healthy controls. Arterial ammonia (r=0.72, p=0.03), tumour necrosis factor alpha (r=0.87, p=0.02), Interleukin-6 (r=0.50, p=0.05), Interleukin-18 (r=0.76, p=0.02) and serum endotoxin (r=0.91, p=0.01) correlated with higher grades of hepatic encephalopathy. ConclusionIn hepatic encephalopathy arterial ammonia, inflammatory mediators, and serum endotoxin are elevated and correlate with encephalopathy grade.

Ammonia-Lowering Strategies for the Treatment of Hepatic Encephalopathy

Hyperammonemia leads to neurotoxic levels of brain ammonia and is a major factor involved in the pathogenesis of hepatic encephalopathy (HE). Ammonia-lowering treatments primarily involve two strategies: inhibiting ammonia production and/or increasing ammonia removal. Targeting the gut has been the primary focus for many years, with the goal of inhibiting the generation of ammonia. However, in the context of liver failure, extrahepatic organs containing ammonia metabolic pathways have become new potential ammonia-lowering targets. Skeletal muscle has the capacity to remove ammonia by producing glutamine through the enzyme glutamine synthetase (amidation of glutamate) and, given its large mass, has the potential to be an important ammonia-removing organ. On the other hand, glutamine can be deaminated to glutamate by phosphate-activated glutaminase, thus releasing ammonia (ammonia rebound). Therefore, new treatment strategies are being focused on stimulating the removal of both ammonia and glutamine.

A longitudinal systems biology analysis of lactulose withdrawal in hepatic encephalopathy

The pathogenesis of hepatic encephalopathy(HE) is unclear. However gut flora changes, inflammation and neuro-glial injury have been implicated. The aim was to evaluate factors that were associated with HE recurrence after lactulose withdrawal by analyzing the clinical phenotype, stool microbiome and systemic metabolome longitudinally. HE patients on a standard diet who were adherent on lactulose underwent characterization of their phenotype [cognition, inflammatory cytokines, in-vivo brain MR spectroscopy(MRS)], gut microbiome (stool Multitag Pyrosequencing) and metabolome (urine/serum ex-vivo MRS) analysis while on lactulose and on days 2, 14 and 30 post-withdrawal. Patients whose HE recurred post-withdrawal were compared to those without recurrence. We included seven men (53 ± 8 years) who were adherent on lactulose after a precipitated HE episode were included. HE recurred in three men 32 ± 6 days post-withdrawal. In-vivo brain MRS showed increased glutamine+glutamate (Glx) and decreased myoinositol with a reduction in stool Faecalibacterium spp., post-withdrawal. HE recurrence was predicted by poor baseline inhibitory control and block design performance and was associated with a shift of choline metabolism from tri-methylamine oxide formation towards the development of di-methylglycine, glycine and creatinine. This was accompanied by a mixed effect on the immune response (suppressed IL-10 and Th1/Th2/Th17 response). The correlation network showed Prevotella to be linked to improved cognition and decreased inflammation in patients without HE recurrence. We conclude that lactulose withdrawal results in worsening cognition, mixed inflammatory response effect, lowered stool Faecalibacterium and increase in MR-measurable brain Glx. HE recurrence post-lactulose withdrawal can be predicted by baseline cognitive performance and is accompanied by disrupted choline metabolism.

Importance of nutritional support in patients with hepatic encephalopathy

Protein calorie malnutrition is frequently a complication in the chronic liver disease patient and is considered to be a negative prognostic factor. Anorexia and several other endocrine metabolic complications produce an hypermetabolic state that needs more caloric intake. Hepatic encephalopathy is one of the developments possible in patients with descompensated cirrhosis. The wellknown role of ammonia in the pathogenesis of hepatic encephalopathy has determined a restriction in dietary protein along many decades. Nevertheless, there is no evidence about a low protein diet being better in the outcome of hepatic encephalopathy, it worsens, moreover, the nutritional status and helps in the development of many nutritional related complications. This article reviews the use of oral branched-chain amino acids and proteins of different sources, probiotics, synbiotics, antioxidants, oral L-Ornithine L-Aspartate and acetyl-L-carnitine in patients with hepatic encephalopathy.

Importancia de la nutrición en enfermos con encefalopatía hepática

Protein calorie malnutrition is frequently a complication in the chronic liver disease patient and is considered to be a negative prognostic factor. Anorexia and several other endocrine metabolic complications produce an hypermetabolic state that needs more caloric intake. Hepatic encephalopathy is one of the developments possible in patients with descompensated cirrhosis. The well-known role of ammonia in the pathogenesis of hepatic encephalopathy has determined a restriction in dietary protein along many decades. Nevertheless, there is no evidence about a low protein diet being better in the outcome of hepatic encephalopathy, it worsens, moreover, the nutritional status and helps in the development of many nutritional related complications. This article reviews the use of oral branched-chain amino acids and proteins of different sources, probiotics, synbiotics, antioxidants, oral L-Ornithine L-Aspartate and acetyl-L-carnitine in patients with hepatic encephalopathy.

Systemic oxidative stress is implicated in the pathogenesis of brain edema in rats with chronic liver failure

Chronic liver failure leads to hyperammonemia, a central component in the pathogenesis of hepatic encephalopathy (HE); however, a correlation between blood ammonia levels and HE severity remains controversial. It is believed oxidative stress plays a role in modulating the effects of hyperammonemia. This study aimed to determine the relationship between chronic hyperammonemia, oxidative stress, and brain edema (BE) in two rat models of HE: portacaval anastomosis (PCA) and bile-duct ligation (BDL). Ammonia and reactive oxygen species (ROS) levels, BE, oxidant and antioxidant enzyme activities, as well as lipid peroxidation were assessed both systemically and centrally in these two different animal models. Then, the effects of allopurinol (xanthine oxidase inhibitor, 100mg/kg for 10days) on ROS and BE and the temporal resolution of ammonia, ROS, and BE were evaluated only in BDL rats. Similar arterial and cerebrospinal fluid ammonia levels were found in PCA and BDL rats, both significantly higher compared to their respective sham-operated controls (p<0.05). BE was detected in BDL rats (p<0.05) but not in PCA rats. Evidence of oxidative stress was found systemically but not centrally in BDL rats: increased levels of ROS, increased activity of xanthine oxidase (oxidant enzyme), enhanced oxidative modifications on lipids, as well as decreased antioxidant defense. In PCA rats, a preserved oxidant/antioxidant balance was demonstrated. Treatment with allopurinol in BDL rats attenuated both ROS and BE, suggesting systemic oxidative stress is implicated in the pathogenesis of BE. Analysis of ROS and ammonia temporal resolution in the plasma of BDL rats suggests systemic oxidative stress might be an important “first hit”, which, followed by increases in ammonia, leads to BE in chronic liver failure. In conclusion, chronic hyperammonemia and oxidative stress in combination lead to the onset of BE in rats with chronic liver failure.

HELICOBACTER PYLORI &amp; HEPATIC ENCEPHALOPATHY;

Introduction: Hepatic encephalopathy is a common and serious complication affecting patients with liver disease. Helicobacterpylori bacterium is postulated to be involved in worsening of this condition via its potential to create ammonia within the gastrointestinal tract.Objective: The objective of this study was to determine the frequency of H pylori infection in cirrhotic patients who were suffering from hepaticencephalopathy. Design: Case series study. Setting: Medical Unit-IV of Liaquat University Hospital, Hyderabad. Period: January to July 2010.Methodology: Methodology: Every confirmed case of cirrhosis of liver who presented with acute confusional state, and loss of consciousnessto the emergency department of hospital was considered for enrollment in the study. The presence of hepatic encephalopathy was confirmedand its severity grading was done clinically. Subsequently H pylori serological tests were done on every patient and a cut off value of 200:1antibody titer was considered as positive. Primary outcome variable was presence or absence of H pylori antibody titer. Results: A total of 115patients were selected, 69 (60%) were males and 46 (40%) were females. The mean age of patients was 49.36 years with a SD of 7.8. Antibodyto H pylori was present in 83 (72.17%) patients, whereas it was absent in 32 (27.83%). Two out of ten patients (20%) who were in Grade I hepaticencephalopathy showed a positive test for H pylori antibody. In Grade II hepatic encephalopathy 17 out of 19 patients (89.47%) were havingpositive H pylori antibody, in grade III 29 out of 34 (85.29%) and grade IV 35 out of 52 patients (67.3%) were having the antibody to H pylori.Conclusions: Further studies are warranted to evaluate the arguments for and against the role of H pylori in the pathogenesis of hepaticencephalopathy.

Pathogenesis of Hepatic Encephalopathy

Hepatic encephalopathy can be a serious complication of acute liver failure and chronic liver diseases, predominantly liver cirrhosis. Hyperammonemia plays the most important role in the pathogenesis of hepatic encephalopathy. The brain-blood barrier disturbances, changes in neurotransmission, neuroinflammation, oxidative stress, GABA-ergic or benzodiazepine pathway abnormalities, manganese neurotoxicity, brain energetic disturbances, and brain blood flow abnormalities are considered to be involved in the development of hepatic encephalopathy. The influence of small intestine bacterial overgrowth (SIBO) on the induction of minimal hepatic encephalopathy is recently emphasized. The aim of this paper is to present the current views on the pathogenesis of hepatic encephalopathy.

Emerging Role of NF-&amp;#954;B in the Pathogenesis of Hepatic Encephalopathy

Hepatic encephalopathy (HE) is a common clinical complication in patients with severe liver disease. While the pathogenesis of HE is incompletely understood, ammonia has been strongly implicated as an important etiological factor, and astrocytes appear to be the primary target of its neurotoxicity. In addition to ammonia, infection and inflammation have increasingly been implicated in the pathogenesis of HE. Nuclear factor-kappa B (NF-κB), a major signaling molecule involved in inflammation and immune responses, is activated in cultured astrocytes treated with ammonia, as well as in brains of experimental animals with HE. Such activation may be a consequence of systemic inflammatory events, or as a result of hyperammonemia-induced central nervous system inflammation. Once activated, NF-κB stimulates the transcription of genes involved in immune responses and inflammation, that produce factors which may contribute to cellular dysfunction such as astrocyte swelling and glutamate transport impairment as occurs in HE. This review summarizes the evidence for NF-κB activation in HE, the signaling pathways involved in its activation, and consequences of such activation.

Hepatitis C and Metabolic Disorders: Genetics, Mechanism, and Therapies (Clinical and Experimental)

Hepatitis C and Metabolic Disorders: Genetics, Mechanism, and Therapies (Clinical and Experimental)

Chronotherapeutic effect of morin in experimental chronic hyperammonemic rats

Aim: Ammonia is a neurotoxin that has been strongly implicated in the pathogenesis of hepatic encephalopathy and a major pathogenic factor associated with inborn errors of urea cycle. In this present work we aimed to evaluate the chronotherapeutic effect of morin (3,5,7,2',4'-pentahydroxyflavone), a plant component, on ammonium chloride (AC) (100 mg/kg; intraperitoneal)-induced hyperammonemia in Wistar rats (180-200 g). Materials, Methods and Results: Morin (30 mg/kg body weight) was administered to rats at 06:00, 12:00, 18:00, and 24:00 hours in hyperammonemia. The influence of morin on AC-induced hyperammonemia at different time points (06:00, 12:00, 18:00, and 24:00 hours) was evaluated by analyzing the circulatory levels of ammonia; urea; thiobarbituric acid reactive substances (TBARS); hydroperoxides (HP); liver markers [alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP)]; glutathione peroxidase (GPx); superoxide dismutase (SOD); catalase (CAT); reduced glutathione (GSH); and vitamins A, C, and E. The levels of these components were significantly elevated in AC-treated rats but were decreased significantly after treatment with morin. Administration of morin at 24:00 h caused significantly greater reduction in these parameters than administration at other time points (P<0.05; Duncan's multiple range test). Conclusion: The chronotherapeutic effect of morin in hyperammonemic rats may be due to various factors, including (i) temporal variations of metabolic enzymes involved in the degradation of morin; (ii) temporal variations of lipid peroxidation and of antioxidants, urea cycle enzymes etc.; and (iii) temporal variation in bioavailability of morin. However, the exact underlying mechanism(s) is/are still unclear and further investigations are needed.