Increase In Ammonia Levels Research Articles

A novel, simplified, and reproducible porcine model of acute ischemic liver failure with portal vein preservation.

The current ischemic models of liver failure are difficult and usually time-consuming to produce. The aim of this study was to develop a simplified and reproducible porcine model of acute liver failure for use in preclinical research. Eighteen Bama miniature pigs were randomly divided into Groups A, B, and C. The hepatic artery and common bile duct were ligated in all groups. While the portal vein was completely preserved in Group A, it was narrowed by 1/3 and 1/2 in Groups B and C, respectively. Results of biochemical analyses, encephalopathy scores, and survival times were compared among the groups. Results of hematoxylin-eosin staining, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, Masson staining, and Ki-67 analyses were recorded. Survival times in Groups B and C were 11.67 ± 1.86 and 2.16 ± 0.75 days, respectively, shorter than that in Group A (>15 days). Following surgery, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and direct bilirubin levels significantly increased relative to baseline values in all groups (P<0.05). Groups B and C exhibited a significant decrease in encephalopathy scores and a significant increase in ammonia levels, which were negatively correlated with one another. Pathological analysis revealed obvious necrosis of liver cells, which correlated closely with the degree of portal vein constriction. Our simple, highly reproducible model effectively mimics the clinical characteristics of acute liver failure in humans and provides a foundation for further research on artificial liver support system development.

Time-course analysis of metabolomic and microbial responses in anaerobic digesters exposed to ammonia

Omics longitudinal studies are effective experimental designs to inform on the stability and dynamics of microbial communities in response to perturbations, but time-course analytical frameworks are required to fully exploit the temporal information acquired in this context. In this study we investigate the influence of ammonia on the stability of anaerobic digestion (AD) microbiome with a new statistical framework. Ammonia can severely reduce AD performance. Understanding how it affects microbial communities development and the degradation progress is a key operational issue to propose more stable processes. Thirty batch digesters were set-up with different levels of ammonia. Microbial community structure and metabolomic profiles were monitored with 16 S-metabarcoding and GCMS (gas-chromatography-mass-spectrometry). Digesters were first grouped according to similar degradation performances. Within each group, time profiles of OTUs and metabolites were modelled, then clustered into similar time trajectories, evidencing for example a syntrophic interaction between Syntrophomonas and Methanoculleus that was maintained up to 387 mg FAN/L. Metabolites resulting from organic matter fermentation, such as dehydroabietic or phytanic acid, decreased with increasing ammonia levels. Our analytical framework enabled to fully account for time variability and integrate this parameter in data analysis.

Evaluation of gingival tissue samples for predicting the time of death using histological and biochemical tests

Thanatochemistry also known as chemistry of death and is used to determine post mortem interval (PMI). It is arguably one of the critical steps in forensic investigation. Recent addition of analyzing biochemical changes along with the traditional methods have gained importance, as they help us to record very early changes in the tissue specimens. In this view, our study aimed to correlate both histological changes and enzymatic changes in gingival tissue samples at intervals of immediate, 1 h, 5 h, 24 h and 48 h after death. Histologic changes noted were loss of epithelial architecture, chromatin clumping, nuclear vacuolation, karryopyknosis, eosinophilia and wide intercellular junctions. Two enzymes which differentiate between the autolytic phase (acid phosphatase) and putrefactive phase (ammonia) of decomposition were evaluated using UV spectrometer. Results in our study demonstrated there were variations as in gradual increase in ammonia levels (1.13±0.24–26.6±2.09) and gradual decrease in acid phosphatase levels (5.61±0.67–1.25±0.53) at different time intervals till 48 h. The cellular changes in gingival tissue could also be related to time. The result of our study helps us to identify potential of enzymatic changes which when correlated with histological reports helps us to predict the time of death accurately. Replicating this experiment in various known taphonomic conditions and other enzymes could highlight the usefulness of gingival tissue samples in determining time of death.

CAFOs and Surface Water Quality: Evidence from Wisconsin

Concentrated animal feeding operations (CAFOs)—animal feeding operations with over 1,000 animal units in confined spaces—have proliferated over the past thirty years in the United States. CAFOs provide operational cost savings, but higher animal concentrations in confined spaces can generate external costs, for example, non‐point source water pollution. In this study, we improve on previous research designs to estimate the relationship between the growth in CAFOs and surface water quality using longitudinal data on a large spatial scale. We use a panel dataset from 1995–2017 that links CAFO intensity with nearby surface water quality readings in Wisconsin to perform our analysis. Leveraging variation in CAFO intensity within hydrological regions over time, we find that increasing CAFO intensity increases the levels of nutrients, specifically total phosphorus and ammonia, in surface water; adding one CAFO to a Hydrologic Unit Code‐8 (HUC8) region leads to a 1.7% increase in total phosphorus levels and a 2.7% increase in ammonia levels, relative to sample mean levels. As an important contribution of our work, we use these results to calculate the external costs of surface water quality damages from CAFOs in Wisconsin. Our results imply that the marginal CAFO in Wisconsin produces non‐market surface water quality damages of at least $203,541 per year.

The alterations of tracheal microbiota and inflammation caused by different levels of ammonia exposure in broiler chickens

Ammonia (NH3) is a known harmful gas and exists in haze, forming secondary organic aerosols. Exposure to ambient ammonia correlates with the respiratory tract infection, and microbiota in the upper respiratory tract is an emerging crucial player in the homeostatic regulation of respiratory tract infection, and microbiota perturbation is usually accompanied by the inflammatory reactions; however, the effects of different levels of ammonia exposure on tracheal microbiota and inflammation are unclear. A total of 288 22-day-old male Arbor Acres broilers were chosen and divided into 4 groups with 6 replicates of 12 chickens, and respectively exposed to ammonia at 0, 15, 25, and 35 ppm for 21-d trial period. Cytokines (interleukin (IL)-1β, IL-6, and IL-10) in the trachea were measured at the 21 d of exposure to NH3. Tracheal microbiota at the 21 d was analyzed by the 16S rRNA gene analysis. The results showed that an increase in ammonia levels, even in 15 ppm, significantly decreased the alpha diversity and changed the bacterial community structure. Six genera (Faecalibacterium, Ruminococcus]_torques_group, unclassified_f__Lachnospiraceae, Ruminococcaceae_UCG-014, Streptococcus, Blautia) significantly increased, whereas Lactobacillus significantly decreased under different levels of ammonia exposure. We also observed positive associations of Faecalibacterium, Blautia, g__Ruminococcaceae_UCG-014, unclassified_f__Lachnospiraceae and Ruminococcus]_torques_group abundances with tracheal IL-1β concentration. Moreover, an increase in ammonia levels, even in 15 ppm, caused respiratory tract inflammatory injury. The results indicated that 15 ppm ammonia exposure changed the composition of tracheal microbiota that caused the tracheal injury possibly through increasing the IL-1β, which might make the broiler more sensitive to the changes of environment and pathogenic micro-organisms in the poultry house, and may be also a critical value that needs high alertness. Herein, the present experiment also suggested that the standard limit of ammonia concentration in adult poultry house is 15 ppm. This research provides an insight into the relationship between the upper respiratory tract microbiota and inflammation under ammonia exposure.

BYPASSING THE UREA CYCLE IN THE ICU

SESSION TITLE: Medical Student/Resident Critical Care Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Hyperammonemic encephalopathy is a rare, yet devastating complication of Rou-en-Y gastric bypass surgery. Though the mechanisms which underlie this complication are not completely understood, a partial underlying inborn error of metabolism has been proposed. In this case we describe a patient who presented with worsening altered mental status and ultimately improved after empiric treatment for a partial urea cycle disorder. CASE PRESENTATION: A 45 year-old female with a history of Roux-en-Y gastric bypass and recently diagnosed bilateral pulmonary emboli presented with altered mental status. One day prior to admission, she became lethargic and ultimately unresponsive, prompting her family to bring her to the hospital. She had 60 lbs of weight loss in the last 2 months, which her family attributed to poor oral intake. In the last 6 months, she had multiple episodes of dizziness, falls, and syncope as well as multiple admissions for nausea, intractable vomiting, and abdominal pain. On presentation, the patient was hemodynamically stable.Abdominal ultrasound revealed changes consistent with steatosis without evidence of cirrhosis. Laboratory results were significant for elevated ammonia (169 µmol/L) and INR (1.7). The patient was started on lactulose and rifaximin for suspected hepatic encephalopathy. After three days of therapy, the patient’s mental status declined and ammonia levels had increased to 192 µmol/L. She was intubated and started on continuous renal replacement therapy (CRRT) for ammonia clearance. Mental status improved. However, cessation of CRRT resulted in increased ammonia levels and worsening mental status. Further laboratory studies revealed deficiencies in zinc, selenium, and copper. Given the refractory hyperammonemia, encephalopathy, and history of gastric bypass surgery, the patient was started on treatment for a suspected partial urea cycle disorder, including arginine and sodium benzoate, as well as supplementation of zinc and copper, resulting in improvement of ammonia levels and mental status. Ultimately, the patient was discharged to an outside facility. DISCUSSION: Encephalopathy in the ICU patient is a frequent occurrence, and may be due to a myriad of metabolic derangements. Inborn errors of metabolism are not common in adult ICU patients, but should be considered in those with a history of gastric bypass surgery presenting with refractory hyperammonemia. As seen in our case, this deadly complication may be reversible with prompt initiation of empiric treatment. CONCLUSIONS: A rare complication of Rou-en Y gastric bypass surgery, hyperammonemic encephalopathy should be considered in patients with refractory hyperammonemia and a history of gastric bypass surgery. Reference #1: Fenves, A.Z., Shchelochkov, O.A. and Mehta, A. (2015), Hyperammonemic syndrome after Roux-en-Y gastric bypass. Obesity, 23: 746-749. doi:10.1002/oby.21037 Reference #2: Nagarur, A., & Fenves, A. Z. (2017). Late Presentation of Fatal Hyperammonemic Encephalopathy After Roux-En-Y Gastric Bypass. Baylor University Medical Center Proceedings, 30(1), 41–43. doi: 10.1080/08998280.2017.11929521 DISCLOSURES: No relevant relationships by Abigail Go, source=Web Response No relevant relationships by John Mwangi, source=Web Response No relevant relationships by Ara Vartanyan, source=Web Response

Ammonia predicts poor outcomes in patients with hepatitis B virus-related acute-on-chronic liver failure.

BackgroundHepatic encephalopathy (HE) is a common feature of acute liver failure and has been reported to be associated with poor outcomes. Ammonia is thought to be central to the pathogenesis of HE, but its role in hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) is unclear. The present study aimed to assess the prognostic role of ammonia level for patients with HBV‐ACLF.MethodsWe retrospectively recruited 127 patients diagnosed with HBV‐ACLF for the present study.ResultsAmmonia levels at the time of admission were higher among non‐surviving participants than in survivors. Increased ammonia level was found to be associated with severe liver disease and was identified as an independent predictor for mortality in patients with HBV‐ACLF.ConclusionsOur results suggest that high ammonia level at admission is an independent factor for predicting short‐term mortality in patients with HBV‐ACLF. Therefore, ammonia levels may represent a therapeutic target for this condition.

Influence of valproate-induced hyperammonemia on treatment decision in an adult status epilepticus cohort

IntroductionStatus epilepticus (SE) is a neurological emergency in which immediate intervention is required to prevent permanent brain damage and death. Intravenous (IV) valproic acid (VPA) is often used for the treatment of SE. However, IV VPA frequently increases the blood ammonia level. In this study, we explore the impact of IV VPA-induced hyperammonemia (HA) on treatment management of SE and discuss the challenges related to this particular condition. MethodsWe used data from medical records of 31 adult patients (≥18 years) treated with IV VPA for SE at Oslo University Hospital between January 2006 and October 2019. Clinical and blood sample data and information about the influence of HA on treatment were collected. Correlations between ammonia levels and other continuous or categorical variables were tested using the Pearson's correlation coefficient. The Kruskal–Wallis H-test was used to analyze associations between different variables and treatment decisions. ResultsThirty of 31 patients had increased ammonia level during IV VPA treatment. In 16/30 patients, VPA was discontinued, and in 6/30 patients, the dose was reduced. We found a difference in the median peak ammonia level among the groups where VPA was discontinued (99 μmol/l), reduced (71 μmol/l), and continued (55.5 μmol/l) (P = 0.008). Also clinical status, measured by West Haven Criteria, varied among the groups where VPA was discontinued (3.5), reduced (2.5), and continued (2.0) (P = 0.01). Treatment decisions at peak ammonia were not associated with the level of liver enzymes and bilirubin. ConclusionHyperammonemia had a substantial impact on further management. To date, no recommendations exist on how to manage VPA-induced HA in SE. We call for systematic prospective studies and evidence-based guidelines.

Lupinus angustifolius seed meal supplemented to dairy cow diet improves fatty acid composition in milk and mitigates methane production

Recently, the narrow-leafed, blue lupine (Lupinus angustifolius) seeds, including the Tango variety, have been used as a potential feed of livestock animals. However, there is still a limited knowledge of possible action of the Tango lupine seed meal (LSM) on ruminal fermentation, enteric methane production, milk yield and composition in dairy cattle. Thus, the present study aimed to investigate the effect of LSM supplementation to dairy cows on ruminal enteric methane production, microbial population, ruminal biohydrogenation and fatty acid (FA) proportion in the ruminal fluid and milk. An in vitro trial comprising of control and five experimental groups (supplementation of LSM at 20, 40, 60, 80, and 100 g/kg diet) was conducted to determine an effective dose level for an in vivo experiment. The in vitro trial was followed by an in vivo experiment conducted on 60 high-yielding Polish Holstein Friesian dairy cows assigned into two groups: the control (n = 30) and the experimental LSM group (n = 30; 2 kg LSM/day/cow). Supplementation of LSM decreased methane emission and archaeal abundances in vitro and in vivo and increased ammonia level in vivo. Ruminal total volatile fatty acid concentration and acetate proportion were reduced by LSM supplementation both in vitro and in vivo. Milk yield and its basic composition were not influenced by the LSM. However, the LSM increased the unsaturated FA content and decreased n6 to n3 FA ratio in milk. Supplementation of LSM upregulated the mRNA expressions of FASN and ELOVL5 genes and downregulated the LPL gene expression in milk somatic cells. The daily cost of LSM diet and the cost of 1 kg of milk production were lower compared with the control. It is concluded that LSM supplementation may improve milk quality without affecting milk yield and has the potential to decrease methane production in dairy cows.

Increased ammonia levels and its association with visceral obesity and insulin resistance

Hyperammonemia is considered as a significant trigger factor in the progression of liver diseases, starting from the stage of steatosis. There is also a link between high levels of ammonia and metabolic syndrome. The article discusses the relationship of hyperammonemia with a violation of carbohydrate metabolism. It is likely that an increase in ammonia is associated with an increase in visceral fat and may be a predictor of the development of insulin resistance as a key factor in carbohydrate metabolism disorders.

Effects of histidine load on ammonia, amino acid, and adenine nucleotide concentrations in rats.

The unique capability of proton buffering is the rationale for using histidine (HIS) as a component of solutions for induction of cardiac arrest and myocardial protection in cardiac surgery. In humans, infusion of cardioplegic solution may increase blood plasma HIS from ~ 70 to ~ 21,000µM. We examined the effects of a large intravenous dose of HIS on ammonia and amino acid concentrations and energy status of the body. Rats received 198mM HIS intravenously (20ml/kg) or vehicle. Samples of blood plasma, urine, liver, and soleus (SOL) and extensor digitorum longus (EDL) muscles were analysed at 2 or 24h after treatment. At 2h after HIS load, we found higher HIS concentration in all examined tissues, higher urea and ammonia concentrations in blood and urine, lower ATP content and higher AMP/ATP ratio in the liver and muscles, higher concentrations of almost all examined amino acids in urine, and lower glycine concentration in blood plasma, liver, and muscles when compared with controls. Changes in other amino acids were tissue dependent, markedly increased alanine and glutamate in the blood and the liver. At 24h, the main findings were lower ATP concentrations in muscles, lower concentrations of branched-chain amino acids (BCAA; valine, leucine, and isoleucine) in blood plasma and muscles, and higher carnosine content in SOL when compared with controls. It is concluded that a load of large HIS dose results in increased ammonia levels and marked alterations in amino acid and energy metabolism. Pathogenesis is discussed in the article.

The Pivotal Role of the Glutamate - glutamine Cycle in Minimal Hepatic Encephalopathy. An experimental magnetic resonance spectroscopy study

The glutamate-glutamine cycle is essential for sustaining the neuronal secretion of the excitatory neurotransmitter glutamate. Hepatic encephalopathy, even in its most discreet form, minimal hepatic encephalopathy (MHE), interferes with the glutamate and glutamine balance due to the increase in ammonia levels in the central nervous system (CNS), induced by a combination of liver dysfunction, increased blood-brain barrier permeability and many other factors. An experimental study on 21 patients with chronic liver disease and 11 healthy volunteers was performed. Magnetic resonance spectroscopy demonstrated an increase of the glutamate-glutamine complex peak, with high predictive value for MHE, especially when the metabolites are referenced to creatine, a stabile metabolite in the CNS. This paper also explores the pathophysiology of MHE with emphasis on the involvement of the glutamate-glutamine cycle in the development of this complication.

The Variation of Nasal Microbiota Caused by Low Levels of Gaseous Ammonia Exposure in Growing Pigs.

Exposure to gaseous ammonia, even at low levels, can be harmful to pigs and human health. However, less is known about the effects of sustained exposure to gaseous ammonia on nasal microbiota colonization in growing pigs. A total of 120 Duroc×Landrace×Yorkshire pigs were housed in 24 separate chambers and continuously exposed to gaseous ammonia at 0,5, 10, 15, 20, and 25 ppm (four groups per exposure level) for 4 weeks. Then, we used high-throughput sequencing to perform 16S rRNA gene analysis in nasal swabs samples from 72 pigs (n = 12). The results of the nasal microbiota analysis showed that an increase in ammonia concentration, especially at 20 and 25 ppm, decreased the alpha diversity and relative abundance of nasal microbiota. Proteobacteria, Firmicutes, Bacteroidetes, Actinobacteria, and Chloroflexi were the most abundant phyla. In addition, the relative abundances of 24 microbial genera significantly changed as the ammonia level increased. Four microbial genera (Pseudomonas, Lactobacillus, Prevotella, and Bacteroides) were significantly decreased at 25 ppm, while only two genera (Moraxella and Streptococcus) were increased at 25 ppm. PICRUSt analyses showed that the relative abundances of the nasal microbiota involved in cell motility, signal transduction, the nervous system, environmental adaptation, and energy and carbohydrate metabolism were significantly decreased, while genes involved in the immune system, endocrine system, circulatory system, immune system diseases and metabolism of vitamins, lipid, and amino acids were increased with increased ammonia levels. The results of in vivo tests showed that an increase in ammonia levels, especially an ammonia level of 25 ppm, caused respiratory tract injury and increase the number of Moraxella and Streptococcus species, while simultaneously decreasing respiratory immunity and growth performance, consistent with the increased presence of harmful bacteria identified by nasal microbiota analysis. Herein, this study also indicted that the threshold concentration of ammonia in pig farming is 20 ppm.

CAFOs and Surface Water Quality: Evidence from the Proliferation of Large Farms in Wisconsin

Concentrated Animal Feeding Operations (CAFOs) – animal feeding operations with over 1,000 animal units in confined spaces – have proliferated over the past 30 years in the United States. CAFOs provide operational cost savings, but higher animal concentrations in confined spaces can generate external costs, e.g., non-point source water pollution. In this study, we improve on previous research designs to estimate the relationship between the growth in CAFOs and surface water quality using longitudinal data on a large spatial scale. We use a panel dataset from 1995-2017 that links CAFO intensity with nearby surface water quality readings in Wisconsin to perform our analysis. Leveraging variation in CAFO intensity within hydrological regions over time, we find that increasing CAFO intensity increases the levels of nutrients, specifically total phosphorus and ammonia, in surface water; adding one CAFO to a Hydrologic Unit Code-8 (HUC8) region leads to a 1.7% increase in total phosphorus levels and a 2.7% increase in ammonia levels, relative to sample mean levels. As an important contribution of our work, we use these results to calculate the external costs of surface water quality damages from CAFOs in Wisconsin. Our results imply that the marginal CAFO in Wisconsin produces non-market surface water quality damages of at least $203,541 per year.

Sensitivity and Specificity of Alzheimer Type II Astrocytes in Hepatic Encephalopathy.

Hepatic encephalopathy (HE) is associated with presence of type II astrocytes in the brain on the basis of observations made in single uncontrolled cases. This finding was subsequently demonstrated by in vitro studies with replication of microenvironment of HE by increase in ammonia levels. However, no human studies have been done correlating HE with type II astrocytes. To determine the sensitivity and specificity of type II astrocytes in HE. This is a retrospective cohort study in which cases and controls were included. A database search was conducted to identify potential cases of hepatic encephalopathy during a 3-year period, as well as concomitant cases with altered mental status from other causes, liver disease, both, and neither. The presence of HE was determined according to standard clinical criteria, and a coronal section of basal ganglia was selected for examination from each case. Type II astrocytes were enumerated over 20 random high-power fields (HPFs). Twenty-one patients with HE were identified, with 35 patient controls (18 females, 38 males). Among the patients with HE there was a mean of 19.8 type II astrocytes in 20 HPFs. Patients with altered mental status without HE had an average of 7.2 type II astrocytes per 20 HPFs, and for those without altered mental status, the average was 2.8. For patients with hepatic insufficiency without HE, the average was 11, while for patients with normal hepatic function, the average was 4.1. Overall, for those without HE, the average was 5.4 type II astrocytes per 20 HPFs. At a cutoff of 5 or more type II astrocytes per 20 HPFs, sensitivity for HE was 85.7% and specificity was 68.6%. Alzheimer type II astrocytes were present in all cases of HE but were also present in a wide variety of patients without HE.

Approach to Hyponatremia in Cirrhosis.

The patient in the case presented with hypervolemic hyponatremia associated with ascites and edema. The sNa concentration of 120 mmol/L is bordering severe hyponatremia and is associated with renal insufficiency. The management of this patient includes free water restriction, holding diuretics, and consideration of albumin infusion (Fig. ​(Fig.1).1). Tolvaptan is not recommended in patients with liver disease. Furthermore, hyponatremia and renal dysfunction are associated with poor prognosis. If the hyponatremia is persistent, liver transplant evaluation should be considered. Open in a separate window Figure 1 Algorithm depicting suggested management of hyponatremia in the patient with cirrhosis.

Assessment and Management of Nutrition Status in the Hospitalized Patient With Cirrhosis.

Assessment and Management of Nutrition Status in the Hospitalized Patient With Cirrhosis.

Ammonia-weighted imaging by chemical exchange saturation transfer MRI at 3T.

Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

T118. Cerebellar inhibition in hepatic encephalopathy - A transcranial magnetic stimulation study

Introduction Hepatic Encephalopathy (HE) is a frequent complication in patients suffering from liver cirrhosis. HE comprises a variety of neuropsychiatric and motor symptoms. Increased ammonia levels have been suggested as a key factor in the disease pathology. Using animal models, Cauli and colleagues reported that hyperammonemia may lead to brain area depending alteration of GABAergic neurotransmission with an increase of GABAeric tone in the cerebellum and a decrease in the cerebral cortex. Consistent with this data, recent work from our group revealed a reduced GABAergic tone in the motor cortex of patients with manifest HE using transcranial magnetic stimulation (TMS). The aim of this study is to probe how GABAergic cerebellar tone is altered in patients at different stages of HE and how this alteration is related to clinical parameters such as the critical flicker frequency and ataxia scoring. Methods 30 participants [15 patients with HE (5 minimal HE, 6 HE grade I, and 4 HE grade II) and 15 age matched healthy controls] were subjected to the following: 1- Critical flicker frequency (CFF) which is a sensitive and reliable parameter for quantification of low-grade HE in cirrhotic patients. 2- Cerebellar brain inhibition TMS paradigm (CBI): in this paradigm, a conditioning TMS pulse is applied over one hemisphere of the cerebellum followed by a test pulse over the contralateral motor cortex resulting in a motor evoked potential (MEP). In healthy subjects, the MEP is inhibited when the test stimulus is preceded by the conditioning stimulus at an interval between 5 and 7 ms through inhibition of the fascilitatory disynaptic dentato-thalamo-cortical pathway. 3- Score for assessment and rating of ataxia (SARA) to detect symptoms of cerebellar affection. Results Cerebellar inhibition at ISI 5–7 ms was significantly reduced in patients with HE compared to healthy controls. However, the magnitude of cerebellar inhibition at 7 ms increased with disease severity and correlated with SARA score and with CFF by trend. Conclusion Overall cerebellar inhibition is significantly reduced in patients with HE, suggesting affection of the dentato-thalamo-cortical pathway in this disease. However, the magnitude of cerebellar inhibition at 7 ms increases with disease severity and correlates with SARA score and with CFF by trend, supporting the hypothesis of disease stage dependent increase of GABAergic tone in the Purkinje cells. Our results are consistent with pervious animal in vitro data suggesting increased GABA-ergic tone in the cerebellum and decreased GABA-ergic tone in the motor cortex.

Valproic Acid-Induced Hyperammonemia with Encephalopathy (VIHE): A Case Report

Valproic acid (VPA) is a wide spectrum antiepileptic medication indicated for seizure prophylaxis across the spectrum of epilepsy. Since coming into clinical use, VPA has also been recommended for the management of a variety of other pathologies, including, most notably, mood stabilization in the manic patient. VPA’s common adverse effects include gastrointestinal, influenza-like symptoms, headache, and difficulties with sleep; nonetheless, in rare instances, VPA has been noted to cause the severe and potentially lethal condition of hyperammonemia with encephalopathy (VIHE). VIHE is the result of a dose-independent increase in ammonia levels. Often the patient is asymptomatic; if symptoms reach clinical threshold, lethargy is most common, though seizures, focal neurologic deficits and even coma are possible. VIHE can occur in patients despite normal hepatic function, normal loading doses, chronic stable doses and normal free serum drug levels. Once the diagnosis is confirmed, the first approach for symptomatic patients is to discontinue VPA, start alternative mood stabilizer as indicated, and supplement hyperammonemia treatment with lactulose, carnitine or carglumic acid. Below is a case report of VIHE that developed in an adolescent girl with a history of Bipolar I Disorder who was hospitalized in our facility for stabilization of mania. As demonstrated below, early diagnosis of VIHE is pivotal in reducing morbidity and ultimately can be life-saving.&#x0D; Keywords: Valproic acid, Hyperammonemia, Encephalopathy