Factors Of Hepatic Encephalopathy Research Articles

Assessment of Clinical, Laboratory and Endoscopic Risk Factors for Hepatic Encephalopathy Development in Egyptian Cirrhotic Patients with Upper GIT Bleeding

Aim: to assess risk factors for hepatic encephalopathy development in Egyptianpatients with gastrointestinal bleeding.Material and methods: 120 cirrhotic patients with upper gastrointestinal bleedingwere randomly assigned into: (group I) patients who complicated with hepaticencephalopathy (n=60) versus (group II) patients not complicated with hepaticencephalopathy (n=60). Clinical, laboratory and endoscopic features of all patientswere explored and compared between the 2 groups.Results: Patients with Child's class C, more ascites and spontaneous bacterialperitonitis were significantly more in group I (p<0.001), also diabetic patients(p=0.02). Total leucocytic count, total, direct bilirubin, INR, creatinine and blood ureanitrogen were significantly higher in group I (p<0.001), also AST (p=0.04), albuminwas significantly lower (p<0.001). Higher degrees of esophageal varices and portalhypertensive gastropathy were the significant cause of bleeding in group I (p= 0.001& 0.02 respectively). Degree of ascites, Child's score points, diabetes, andspontaneous bacterial peritonitis were significantly related to encephalopathy grade(p<0.001, <0.001, <0.001, 0.016 respectively), also total, direct bilirubin, INR, bloodurea nitrogen and Total leucocytic count (p 0.005, 0.002, 0.001, 0.02, 0.018respectively). Patients with advanced encephalopathy grades had significantly highervariceal and gastropathy grades (p=0.002&0.038).Conclusion: Upper gastrointestinal bleeding is not alone the main precipitating factorfor hepatic encephalopathy but other cofactors as advanced Child's classes andscore, presence of ascites, renal impairment, leucocytosis, diabetes , spontaneousbacterial peritonitis and higher vaiceal and gastropathy grades are needed. Specialmonitoring and early prophylactic interventions are advised in these patients.

Current diagnosis and management of post-transjugular intrahepatic portosystemic shunt refractory hepatic encephalopathy.

Transjugular intrahepatic portosystemic shunt has evolved into an important option for management of complications of portal hypertension. The use of polytetrafluoroethylene covered stents enhances shunt patency. Hepatic encephalopathy (HE) remains a significant problem after TIPS placement. The approach to management of patients with refractory hepatic encephalopathy typically requires collaboration between different specialties. Patient selection for TIPS requires careful evaluation of risk factors for HE. TIPS procedure-related technical factors like stent size, attention to portosystemic pressure gradient reduction and use of adjunctive variceal embolization maybe important. Conservative medical therapy in combination with endovascular therapies often results in resolution or substantial reduction of symptoms. Liver transplantation is, however, the ultimate treatment.

Risk Factors for Hepatic Encephalopathy after Transjugular Intrahepatic Portosystemic Shunt in Patients with Hepatocellular Carcinoma and Portal Hypertension.

This study aimed at assessing the risk factors for hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) in patients with hepatocellular carcinoma (HCC) and portal hypertension. Consecutive patients (n=279) with primary HCC who underwent TIPS between January 1997 and March 2012 at a single institution were retrospectively reviewed. Patients were followed up for 2 years. Pre-TIPS, peri-TIPS and post-TIPS clinical variables were reviewed using univariate and multivariate analyses to identify risk factors for HE after TIPS. The overall incidence of HE was 41% (114/279). Multivariate analysis showed an increased odds for HE in patients with: &gt;3 treatments with transcatheter arterial chemoembolization (TACE) and/or trans-arterial embolization (TAE) (odds ratio [OR], 4.078; 95% confidence interval [95%CI], 1.748-9.515); hepatopetal portal flow (OR, 2.362; 95%CI, 1.032-5.404); high portosystemic pressure gradient (OR, 1.198; 95%CI, 1.073-1.336) and high pre-TIPS MELD score (OR, 1.693; 95%CI, 1.390-2.062). Odds for HE were increased 1.693 fold for each 1-point increase in the MELD score, and 1.198 fold for each 1-mmHg decrease in the post-TIPS portosystemic pressure gradient. The identification of clinical variables associated with increased odds of HE may be useful for the selection of appropriate candidates for TIPS. Results suggest that an inappropriate decrease in the portosystemic pressure gradient might be associated with HE after TIPS. In addition, >3 treatments with TACE/TAE, hepatopetal portal flow, and high MELD score were also associated with increased odds of HE after TIPS.

The high expressed serum soluble neural cell adhesion molecule, a high risk factor indicating hepatic encephalopathy in hepatocelular carcinoma patients.

To investigate whether the expression of serum soluble neural cell adhesion molecule (sNCAM) is associated with hepatic encephalopathy (HE) in hepatocelular carcinoma (HCC) patients. The Oncomine Cancer Microarray database was used to determine the clinical relevance of NCAM expression in different kinds of human cancers. Sera from 75 HCC cases enrolled in this study were assessed for expression of sNCAM by enzyme linked immunosorbent assay (ELISA). Dependent on the Oncomine Cancer Microarray database analysis, NCAM was down regulated in 10 different kinds of cancer, like bladder cancer, brain and central nervous system cancer, while up-regulated in lung cancer, uterine corpus leiomyoma and sarcoma, compared to normal groups. Puzzlingly, NCAM expression demonstrated no significant difference between normal and HCC groups. However, we found by quantitative ELISA that the level of sNCAM in sera from HCC patients with HE (347.4±151.9 ng/ml) was significantly more up-regulated than that in HCC patients without HE (260.3±104.2 ng/ml), the p-value being 0.008. sNCAM may be an important risk factor of HE in HCC patients, the correlation coefficients was 0.278 (P< 0.05) on rank correlation analysis. This study highlights that up-regulated level of serum sNCAM is associated with HE in HCC patients and suggests that the high expression can be used as an indicator.

Fecal Calprotectin Level in Decompensated Liver Cirrhosis Patients With Hepatic Encephalopathy

Introduction: Decompensated cirrhosis is associated with bacterial translocation from the gut lumen. It is one of the key mechanisms in the pathogenesis of hepatic encephalopathy (HE). Fecal calprotectin (FC) is an established biological marker of colonic inflammation. We aimed to compare the calprotectin concentration based on the severity of HE. Methods: A cross-sectional study of 38 cirrhosis patients was held in general hospital in Aceh between January 2014 and May 2014. Patients with diarrhea and gastrointestinal bleeding who were given antiplatelet, antibiotic, and proton pump inhibitor were excluded. Demographics, endoscopy, and abdominal sonogram findings were collected. HE grading was measured by West Heaven criteria and NCT test, and classified as severe, mild, and no HE. Stool sample were collected for measuring FC. The result was analyzed with Kruskall-Wallis followed by post hoc analysis using Mann-Whitney. Results: Mean age of patients was 52, 39±9, 18 years, and 78,9 % were male. The most common etiology of cirrhosis was HBV (68 %), while constipation was the most common precipitating factor of HE (52%). FC concentration were significantly increased in severe HE when compared with mild and no HE. The median (range) were 1659,0 (947,7-2836), 477,7 (12,5-992), and 138 (8,5-343) mg/mL), respectively (p<0,001 for all comparisons). Conclusion: Fecal calprotectin concentration were elevated along with the increasing of grading HE. FC is a promising test in diagnosing the onset and severity of HE, especially in limited resources.

Ammonium increases Ca(2+) signalling and up-regulates expression of TRPC1 gene in astrocytes in primary cultures and in the in vivo brain.

Rapid rise in ammonium concentration in the brain is the major pathogenic factor in hepatic encephalopathy that is manifested by state of confusion, forgetfulness and irritability, psychotic symptoms, delusions, lethargy, somnolence and, in the terminal stages, coma. Primary cultures of mouse astrocytes were used to investigate effects of chronic treatment (3 days) with ammonium chloride (ammonium) at 3 mM, this being a relevant concentration for hepatic encephalopathy condition, on metabotropic receptor agonist-induced increases in free cytosolic Ca(2+) concentration [(Ca(2+))i], measured with fura-2 based microfluorimetry and on store-operated Ca(2+) entry (SOCE) activated following treatment with the SERCA inhibitor thapsigargin. The agonists used were the β-adrenergic agonist isoproterenol, the α2-adrenergic agonist dexmedetomidine, the InsP3 receptor (InsP3R) agonist adenophostin A and ryanodine receptor agonist 4-Chloro-m-cresol (4-CMC). Agonist-induced [Ca(2+)]i responses were significantly increased in astrocytes chronically exposed to ammonium. Similarly, the SOCE, meditated by the transient receptor potential channel 1 (TRPC1), was significantly augmented. The ammonium-induced increase in SOCE was a result of an up-regulation of mRNA and protein expression of TRPC1 in astrocytes. Increase in TRPC1 expression and in SOCE were both prevented by ouabain antagonist canrenone. Similar up-regulation of TRPC1 gene expression was found in the brain of adult mice subjected to intraperitoneal injection of urease for 3 days. In transgenic mice tagged with an astrocyte-specific or a neurone-specific markers and treated with intraperitoneal injections of urease for 3 days, the fluorescence-activated cell sorting of neurones and astrocytes demonstrated that TRPC1 mRNA expression was up-regulated in astrocytes, but not in neurones.

Risk factors for hepatic encephalopathy in patients with hepatitis B liver failure

Risk factors for hepatic encephalopathy in patients with hepatitis B liver failure

A study on the position and etiology of infection in cirrhotic patients: A potential precipitating factor contributing to hepatic encephalopathy

Hepatic encephalopathy (HE) is a severe and high-mortality complication in cirrhotic patients. In this study, we analyzed infection, one of the common precipitating factors of HE in patients with cirrhosis, in order to identify common infection sites and the etiology. In addition, we aimed to identify information useful in the early prevention and effective treatment of HE. Ninety-two patients presenting with hepatitis B virus-related cirrhosis with HE (HBC-HE) and 45 patients presenting with alcoholic cirrhosis with HE (ALD-HE) were enrolled in this study. We collected and analyzed data concerning the precipitating factors of HE using blood tests, biochemical detection and bacterial culture to identify which precipitating factor was the most common. Fifty-three patients with HE (37 with HBC-HE and 16 with HBC-HE) had infection as the precipitating factor. These infections included respiratory tract infection (56.6%), intestinal tract infection (20.7%), peritoneal infection (17.0%) and urinary tract infection (5.7%). The white blood cell (WBC) counts increased in 17 cases (32.1%) and neutrophil (NEUT) numbers increased in 39 cases (73.6%), while WBC counts were lower in the patients with respiratory tract infection compared with those in the patients with infections at other sites (P<0.05). The levels of plasma ammonia were significantly higher in patients with intestinal tract infection than in those with other sites of infection (P<0.05). The proportions of patients with hyperammonemia, increased NEUT numbers, hyponatremia and low albumin were higher in the infection group compared with those in the non-infection group (P<0.05). Pneumococci and E. coli were common bacteria that induced infection in the respiratory tract and at other infection sites, respectively. Respiratory tract infection was identified to be the most common precipitating factor for HE.

Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients?

Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy (HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients.

Precipitating factors of Hepatic Coma

Objective: The objective of this study was to: Find the age and gender distribution and frequency of preci-pitating factors of hepatic coma in chronic liver dise-ase. Study Design: Comparative cross - sectional study. Material and Methods: In the Gastroenterology Unit and East Medical Ward KEMU. The study duration was one year and started in May 2005. Fifty cases of hepatic encephalopathy due to chronic liver disease were selected. It was probability sampl-ing and random table was used. The complete record of the patients was maintained on the structured pro-forma. After informed consent all record was kept con-fidential. Results: Constipation, upper gastrointestinal bleed-ing, and infection were the common precipitating fac-tors. It was found that constipation was more in old age group (75%) and the difference was found signifi-cant (p< 0.05). The upper gastrointestinal bleeding was found more in young group (44%) and this was found significant (p < 0.05). Conclusions: The precipitating factors of hepatic encephalopathy should be early recogonized and awa-reness should be created. Lifestyle modifications like exercise, low fat diet, high fibre diet and active work should be encouraged to prevent constipation. Emer-gency endoscopic facilities should be made available. Keywords: Cirrhosis, encephalopathy, hepatic.

Precipitating factors of hepatic encephalopathy: An experience at Mansoura Specialized Medical Hospital, Egypt

Background/Aim: Hepatic encephalopathy (HE) is a frequent complication of liver cirrhosis, and its development heralds a poor prognosis as it is associated with shortened patients' survival. Reversibility of the precipitating factors of HE is of prognostic significance. This work was designed to study the precipitating factors of HE in patients with liver cirrhosis at Mansoura Specialized Medical Hospital, Egypt. Materials and Methods: A total of 237 consecutive known chronic liver disease patients, presented with signs and symptoms of hepatic encephalopathy, were admitted in the hepatology unit of Mansoura Specialized Medical Hospital from September 2009 to September 2010. The precipitating factors of hepatic encephalopathy were identified with the aid of clinical examination and appropriate investigations. Grades of HE and Child-Pugh scores were determined. Results: The precipitating factors of HE in our studied cases were upper GI bleeding in 87 patients (36.7%), advanced HCC in 43 patients (18.14%), infections in 37 patients (15.61%), excess protein intake in 27 patients (11.39%), electrolyte imbalance in 7 patients (2.95%), and altered bowel habits in 33 patients (13.92%). Males were commonly affected by HCC (P < 0.05) and upper GI bleeding more than female patients (P < 0.05). Male patients were commonly presented with HE (63.29%), and this gender difference reached a statistical significance among those presented with upper GI bleeding (P < 0.05) and HCC (P < 0.05). Upper GI bleeding, advanced HCC, and infections were the leading causes of death with a higher prevalence in grade IV comatose (P < 0.05), child C (P < 0.05), male patients (P < 0.05). Conclusions: Our data revealed that upper GI bleeding, advanced HCC, and infections are the main precipitating factors of HE as well as the major leading causes of death in patients with liver cirrhosis. Priority should be given to control these factors by allocation of the hospital funds, medications, and human efforts. Implementation of an effective screening program for early HCC detection all over the country should be on the top of the official health concerns.

P11 Induction of hyperammonaemia from the small and large intestine in patients with cirrhosis with magnetic resonance quantification of brain water and metabolites

IntroductionInduction of hyperammonaemia from glutaminase action in the small intestine1 or systemic catabolism of oral amino acids2 3 is well recognised but, although suggested in 1959 by Walser and Bodenlos,4...

Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes

Hepatic encephalopathy (HE) is the major neurological complication occurring in patients with acute and chronic liver failure. Elevated levels of blood and brain ammonia are characteristic of HE, and astrocytes are the primary target of ammonia toxicity. In addition to ammonia, recent studies suggest that inflammation and associated cytokines (CKs) also contribute to the pathogenesis of HE. It was previously established that ammonia induces the mitochondrial permeability transition (mPT) in cultured astrocytes. As CKs have been shown to cause mitochondrial dysfunction in other conditions, we examined whether CKs induce the mPT in cultured astrocytes. Cultures treated with tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ, individually or in a mixture, resulted in the induction of the mPT in a time-dependent manner. Simultaneous treatment of cultures with a mixture of CKs and ammonia showed a marked additive effect on the mPT. As oxidative stress (OS) is known to induce the mPT, so we examined the effect of CKs and ammonia on hemeoxygenase-1 (HO-1) protein expression, a marker of OS. Such treatment displayed a synergistic effect in the upregulation of HO-1. Antioxidants significantly blocked the additive effects on the mPT by CKs and ammonia, suggesting that OS represents a major mechanism in the induction of the mPT. Treatment of cultures with minocycline, an antiinflammatory agent, which is known to inhibit OS, also diminished the additive effects on the mPT caused by CKs and ammonia. Induction of the mPT in astrocytes appears to represent a major pathogenetic factor in HE, in which CKs and ammonia are critically involved.

Early hepatic encephalopathy after transjugular intrahepatic portosystemic shunt: the risk factors and long-time survival

To identify the risk factors of early post-TIPS hepatic encephalopathy (HE) and the long-time survival of patients with or without early post-TIPS HE. Consecutive cirrhotic patients who underwent TIPS for variceal rebleeding or refractory ascites in our center from January 2003 to December 2008 were included in this study. More than 60 clinical characteristics were enrolled in univariate analysis and logistic regression analysis to define the risk factors of HE in 3 months after TIPS procedure (early post-TIPS HE). The long-time survival of patients with or without early post-TIPS HE was compared by Cox regression with several covariates. According to our inclusion criteria, 190 patients were included. The median follow-up was 30.5 months. Lower serum concentration of fibrinogen and higher Child-Pugh score were the independent risk factors for suffering early post-TIPS HE. Patients without early post-TIPS HE after TIPS showed better prognosis than those with early post-TIPS HE after TIPS (P = 0.044). Patients with lower serum fibrinogen and higher Child-Pugh score before TIPS might be more probably attacked by early post-TIPS HE which indicated worse long-term survival.

Down‐regulation of Kir4.1 in the cerebral cortex of rats with liver failure and in cultured astrocytes treated with glutamine: Implications for astrocytic dysfunction in hepatic encephalopathy

Brain edema in acute hepatic encephalopathy (HE) is due mainly to swelling of astrocytes. Efflux of potassium is implicated in the prevention of glial swelling under hypoosmotic conditions. We investigated whether pathogenic factors of HE, glutamine (Gln) and/or ammonia, induce alterations in the expression of glial potassium channels (Kir4.1, Kir2.1) and Na(+) -K(+) -2Cl(-) cotransporter-1 (NKCC1) in rat cerebral cortex and cultured rat cortical astrocytes and whether these alterations have consequences for potassium efflux and astrocytic swelling. Thioacetamide-induced acute liver failure in rats resulted in significant decreases in the Kir4.1 mRNA and protein contents of cerebral cortex, whereas expression of Kir2.1 and NKCC1 remained unaltered. Incubation of primary cortical astrocytes for 72 hr in the presence of Gln (5 mM), but not of ammonia (5 mM or 10 mM), induced a decrease in the levels of Kir4.1 mRNA and protein. Similarly to incubation with Gln, reduction of Kir4.1 mRNA expression by RNA interference caused swelling of astrocytes as shown by confocal imaging followed by 3D computational analysis. Gln reduced the astrocytic uptake of D-[(3) H]aspartate, but, in contrast to the earlier reported effect of ammonia, this reduction was not accompanied by decreased expression of the astrocytic glutamate transporter GLT-1 mRNA. Both Gln and ammonia decreased hypoosmolarity-induced (86) Rb efflux from the cells, but the effect was more pronounced with Gln. The results indicate that down-regulation of Kir4.1 may mediate distinct aspects of Gln-induced astrocytic dysfunction in HE.

Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis

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.

Hyponatremia Is a Risk Factor of Hepatic Encephalopathy in Patients With Cirrhosis: A Prospective Study With Time-Dependent Analysis

The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis. A total of 61 patients with cirrhosis were evaluated prospectively for 1 year and all episodes of overt HE were recorded. Predictive factors of HE were analyzed using a conditional model (Prentice, Williams, and Peterson) for recurrent events to assess the relationship between HE and time-dependent covariates. The effects of hyponatremia on the brain concentration of organic osmolytes were analyzed in 25 patients using 1 H-magnetic resonance spectroscopy. Twenty-eight of the 61 patients developed 57 episodes of overt HE during follow-up. Among a number of clinical and laboratory variables analyzed, the only independent predictive factors of overt HE were hyponatremia (serum sodium < 130 mEq / l), history of overt HE, serum bilirubin,and serum creatinine. Hyponatremia was associated with low brain concentration of organic osmolytes, particularly myo-inositol (MI). Furthermore, patients with low brain MI levels had a higher probability of development of overt HE compared with that of patients with high brain MI levels. In patients with cirrhosis, the existence of hyponatremia is a major risk factor of the development of overt HE. Treatment of hyponatremia may be a novel therapeutic approach to preventing HE in cirrhosis.

Natural endogenous ligands for benzodiazepine receptors in hepatic encephalopathy

Benzodiazepines of natural origin (NBZDs) have been found in human blood and brains as well as in medicinal plants and foods. In plasma and brain tissue there are i.e. diazepam and nordiazepam equal to commercial drugs but there are also other benzodiazepine-like compounds termed "endozepines", which act as agonists at the benzodiazepine receptors of central type (CBR). A synthetic pathway for the production of NBZDs has not yet been found, but it has been suggested that micro-organisms may synthesize molecules with benzodiazepine-like structures. Hence NBZDs could be of both endogenous and exogenous source and be considered as natural anxyolitic and sedative. Interestingly there are also natural compounds, such as the polypeptide Diazepam Binding Inhibitor (DBI) acting as an "inversive agonist" implicated in fair and panic disorders. It has been suggested that NBZDs may play a role in the pathogenesis of hepatic encephalopathy (HE). Multidirectional studies evaluated NBZDs levels (1) in the blood of normal subjects, of cirrhotic with or without HE and in commercial benzodiazepine consumers; (2) in the blood of cirrhotic treated or not with a non-absorbable antibiotic; (3) in several constituents of our diet. In conclusion, NBZDs increase sometime in cirrhotics with or without HE but they reach concentrations not higher than those found in commercial benzodiazepines consumers. Hence NBZDs must be considered as occasional precipitating factor of HE and benzodiazepine antagonists only symptomatic drugs. The finding that NBZDs may be in part synthesized by intestinal bacterial flora and in part constituent of our diet underlines the importance to feed cirrhotic patients with selected food.

The anaplerotic flux and ammonia detoxification in hepatic encephalopathy

Metabolic alterations in the brain underly many of the mechanisms leading to acute and chronic Hepatic Encephalopathy (HE). Controversy exists about the role of glutamine accumulation as a causal factor in HE. Glutamine formation contributes to detoxify ammonia, whereby anaplerotic mechanisms in the astrocytes have to be sufficient to replenish Krebs cycle intermediates. The application of ex vivo high-resolution nuclear magnetic resonance (NMR) spectroscopy permits direct measurements of metabolites and different metabolic pathways. Ex vivo (13)C-NMR studies in experimental animal models of acute and chronic HE have provided new insights. In an experimental rat model of ALF, (13)C isotopomer analysis of glucose metabolism showed that alterations of glucose flux through astrocytic pyruvate carboxylase might be linked to the pathogenesis of ALF as a limited anaplerotic flux in the brain, but not in the muscle, correlates with the development of brain edema. Moreover, (13)C-NMR data from a rat model of mild HE demonstrated relative differences in the pathway of glucose through pyruvate carboxylase in thalamus compared to frontal cortex, which might explain the vulnerability of this brain region compared to thalamus. These findings further support that glutamine accumulation might be not the primary cause of neurological symptoms in HE, and show that anaplerotic mechanisms could be essential for ammonia detoxification in HE.

Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment

Hyperammonemia, a major pathophysiological factor in hepatic encephalopathy, impairs long-term potentiation (LTP) of synaptic transmission, a cellular model of learning and memory, in the hippocampus. We have now studied the protective action of taurine on this paradigm by analyzing LTP characteristics in mouse hippocampal slices treated with ammonium chloride (1 mM) in the presence of taurine (1 mM), an ubiquitous osmolyte, antioxidant, and neuromodulator, as well as other substances with such properties. Ammonia-treated slices displayed a significant impairment of LTP maintenance. Taurine and the mitochondrial enhancer l-carnitine, but not the antioxidants (ascorbate, carnosine, and the novel compound GVS-111) or the osmolyte betaine prevented this impairment. The protective effect of taurine was preserved under the blockade of inhibitory GABA(A) and glycine receptors. It is suggested that taurine may rescue the mechanisms of hippocampal synaptic plasticity by improving mitochondrial function under hyperammonemic conditions.