Increased Blood Ammonia Levels Research Articles

Protective Effect of Carvacrol Against Acute Liver Damage and Encephalopathy Induced by Thioacetamide

Background: Cancer occurs in 83% of liver diseases. Other risk factors for liver cancer include viral hepatitis, alcohol consumption, industrial chemicals, and a number of toxins. Another major disease that occurs following liver damage is hepatic encephalopathy. This condition arises primarily due to increased blood ammonia levels. Carvacrol, with antioxidant properties, reduces oxidative stress on the liver. The aim of this study was to investigate the effect of carvacrol on the improvement of hepatic encephalopathy in rats. Methods: In this experimental study, 60 male Wistar rats were randomly divided into six groups of 10 each. Liver damage and induction of oxidative stress were caused in the rats by administering thioacetamide (100 mg/kg/day) intraperitoneally for three consecutive days. Carvacrol was administered by gavage at 25, 50, or 100 mg/kg/day after thioacetamide treatment. We investigated the biomarkers of liver damage in the blood, such as alanine transaminase, lactate dehydrogenase, total protein, and bilirubin. We also assessed the effect of oxidative stress, as the key inducer of hepatic encephalopathy, on the liver by measuring the lipid peroxidation, antioxidants, reactive oxygen species, glutathione reserves, and ammonium levels in the serum and brain. Results: Thioacetamide significantly increased the biochemical markers in the rat sera, reflecting ammonium release and the development of oxidative stress (P<0.05). Conversely, the various doses of carvacrol significantly reduced the levels of biomarkers that are indicative of liver damage (P<0.05). Conclusion: The study findings provided experimental evidence in favor of the therapeutic effects of carvacrol and against liver injury induced by thioacetamide, leading to encephalopathy.

Humanized liver mouse model with transplanted human hepatocytes from patients with ornithine transcarbamylase deficiency.

Ornithine transcarbamylase deficiency (OTCD) is a metabolic and genetic disease caused by dysfunction of the hepatocytic urea cycle. To develop new drugs or therapies for OTCD, it is ideal to use models that are more closely related to human metabolism and pathology. Primary human hepatocytes (HHs) isolated from two patients (a 6‐month‐old boy and a 5‐year‐old girl) and a healthy donor were transplanted into host mice (hemi‐, hetero‐OTCD mice, and control mice, respectively). HHs were isolated from these mice and used for serial transplantation into the next host mouse or for in vitro experiments. Histological, biochemical, and enzyme activity analyses were performed. Cultured HHs were treated with ammonium chloride or therapeutic drugs. Replacement rates exceeded 80% after serial transplantation in both OTCD mice. These highly humanized OTCD mice showed characteristics similar to OTCD patients that included increased blood ammonia levels and urine orotic acid levels enhanced by allopurinol. Hemi‐OTCD mice showed defects in OTC expression and significantly low enzymatic activities, while hetero‐OTCD mice showed residual OTC expression and activities. A reduction in ammonium metabolism was observed in cultured HHs from OTCD mice, and treatment with the therapeutic drug reduced the ammonia levels in the culture medium. In conclusion, we established in vivo OTC mouse models with hemi‐ and hetero‐patient HHs. HHs isolated from the mice were useful as an in vitro model of OTCD. These OTC models could be a source of valuable patient‐derived hepatocytes that would enable large scale and reproducible experiments using the same donor.

Effects of a high protein diet and liver disease in an in silico model of human ammonia metabolism

BackgroundAfter proteolysis, the majority of released amino acids from dietary protein are transported to the liver for gluconeogenesis or to peripheral tissues where they are used for protein synthesis and eventually catabolized, producing ammonia as a byproduct. High ammonia levels in the brain are a major contributor to the decreased neural function that occurs in several pathological conditions such as hepatic encephalopathy when liver urea cycle function is compromised. Therefore, it is important to gain a deeper understanding of human ammonia metabolism. The objective of this study was to predict changes in blood ammonia levels resulting from alterations in dietary protein intake, from liver disease, or from partial loss of urea cycle function.MethodsA simple mathematical model was created using MATLAB SimBiology and data from published studies. Simulations were performed and results analyzed to determine steady state changes in ammonia levels resulting from varying dietary protein intake and varying liver enzyme activity levels to simulate liver disease. As a toxicity reference, viability was measured in SH-SY5Y neuroblastoma cells following differentiation and ammonium chloride treatment.ResultsResults from control simulations yielded steady state blood ammonia levels within normal physiological limits. Increasing dietary protein intake by 72% resulted in a 59% increase in blood ammonia levels. Simulations of liver cirrhosis increased blood ammonia levels by 41 to 130% depending upon the level of dietary protein intake. Simulations of heterozygous individuals carrying a loss of function allele of the urea cycle carbamoyl phosphate synthetase I (CPS1) gene resulted in more than a tripling of blood ammonia levels (from roughly 18 to 60 μM depending on dietary protein intake). The viability of differentiated SH-SY5Y cells was decreased by 14% by the addition of a slightly higher amount of ammonium chloride (90 μM).ConclusionsData from the model suggest decreasing protein consumption may be one simple strategy to decrease blood ammonia levels and minimize the risk of developing hepatic encephalopathy for many liver disease patients. In addition, the model suggests subjects who are known carriers of disease-causing CPS1 alleles may benefit from monitoring blood ammonia levels and limiting the level of protein intake if ammonia levels are high.

Dipeptiven® is safe in a rat model of moderate liver dysfunction

Summary Background & aims Administration of glutamine in patients with liver failure is thought to possibly increase blood ammonia levels, thereby contributing to hepatic encephalopathy. In a rat model of moderate liver dysfunction with elevated plasma glutamine concentrations dose-dependent effects of intravenous alanyl-glutamine infusion on possible biochemical and histological signs of toxicity were investigated. Methods Rats with moderate liver dysfunction resulting from alpha-naphthylisothiocyanate (ANIT) induced cholestasis received a 9 days continuous intravenous infusion of 0.5 g/kg/day or 3.0 g/kg/day alanyl-glutamine (Dipeptiven®). Dose-dependent effects on liver injury were assessed by analyzing blood levels of ammonia, urea, ALT, AST, and ALP, glutamine, and histopathology. Results Continuous intravenous infusion of 3.0 g/kg/day alanyl-glutamine increased plasma glutamine concentrations up to 30% without increasing blood ammonia levels or inducing astrocyte swelling. Alanyl-glutamine did not aggravate underlying liver injury shown by absent increase in plasma levels of ALT, AST, ALP and no signs of histopathologic alterations. Conclusions Continuous intravenous infusion of alanyl-glutamine at 0.5 and 3.0 g/kg/day up to 9 consecutive days is safe in a rat model of moderate liver dysfunction based on ANIT-induced cholestasis.

Blood Ammonia level : Is it a Clue for the Presence of Oesophageal Varices in Cirrhotic Patients ?

Background and study aim: Endoscopic screening of all patients with liver cirrhosis add major burden to endoscopic units. Non-invasive detection of Oesophageal varices (OV) help to reduce the necessity of endoscopic screening.The aim of this work is to assess the diagnostic utility of blood ammonia level (BAL) as noninvasive predictor for presence of OV and evaluate its correlation with variceal size in cirrhotic patients. Patients and Methods: This prospective cross sectional study was conducted upon 100 cirrhotic patients who attended Hepatology, Gastroenterology and Infectious diseases department, Benha University Hospital. Fasting blood ammonia was measured and upper gastrointestinal endoscopy was done for all patients. Patients were divided according to presence of OV into two groups: Group I : included 30 patients with liver cirrhosis without OV. Group II: included 70 patients with liver cirrhosis with OV who were subdivided into four subgroups: Group IIa:included 11 patients with grade I O.V. Group IIb: included 21 patients with grade II O.V. Group IIc: included 15 patients with grade III O.V. Group IId: included 23 patients with grade IV O.V. Results: The study showed that there was a highly significant increase in the mean values of BAL in cirrhotic patients with varices in comparison to those without varices. Also the study showed highly significant increase in the mean values of BAL in patients with large OV (grade III,IV) in comparison to patients with small and medium sized varices (grade I,II). By multivariate analysis, the presence of O.V. was independently associated with increased blood ammonia levels. Conclusion: Blood ammonia level could be a non invasive predictor for the presence of OV and could be clinically useful, as it correlated with the size of OV.

Arterial ammonia levels: Prognostic marker in traumatic hemorrhage.

Background:In blunt trauma, extent of hemorrhage cannot be determined by physical examination, and vital signs may also not give clear picture in all the patients, especially young healthy ones. Hemorrhagic shock has been reported to increase blood ammonia levels. Arterial ammonia was analyzed in blunt trauma abdomen patients and correlated with shock index (SI). Its predictive value was determined for timely decision of intervention.Materials and Methods:Hundred blunt trauma abdomen patients presented in the emergency ward of tertiary care hospital were included in the study. Group I comprised 62 patients requiring either blood transfusion ≥2 units and/or intervention to control bleeding within 24 h following admission. Group II had 38 patients: Not requiring transfusion/intervention during hospital stay. Arterial blood sample was taken immediately after admission; ammonia was analyzed within 20 min of sampling on Cobas 6000 (Roche). SI was calculated. Predictive value of ammonia was determined using receiver operating characteristic curve.Results:Ammonia levels and SI were significantly (P < 0.001) higher in Group I compared to Group II patients (68.55 ± 14.36 umol/L vs. 37.55 ± 7.41 umol/L and 1.28 ± 0.5 vs. 0.74 ± 0.12, respectively). Significantly higher number of patients in Group I (88.7% vs. 13%) had SI > 0.9. Ammonia levels were significantly higher in patients with complications and in those expired.Conclusions:Ammonia levels were significantly higher in patients requiring blood transfusion/intervention in 24 h of admission. The best cutoff value to maximize sensitivity and specificity was ammonia >58.85 μmol/L. Ammonia estimation at admission can be clinically significant indicator of traumatic hemorrhage needing intervention.

Adjunctive topiramate enhances the risk of hypothermia associated with valproic acid therapy

Topiramate was approved for the treatment of epilepsy in 1999 and has since been approved for the prevention of migraine headache. It is structurally different from the majority of antiepileptic medications and is pharmacodynamically unique in its ability to inhibit the enzyme carbonic anhydrase. Postmarketing reports of topiramate-associated hypothermia have occurred but this adverse event has not been well characterized. Data mining of an adverse event database was used to assist in the identification of hypothermia. We sought to explore a possible association between the concomitant use of topiramate and valproic acid and the induction of hypothermia. This was a pharmacovigilance case series survey of spontaneous hypothermia, a reported adverse event in patients treated with topiramate and valproic acid, alone and in combination. The U.S. Food and Drug Administration's Adverse Events Reporting System (AERS) database was searched for reports of hypothermia in association with the use of topiramate. A data mining algorithm was used on the AERS to identify scores for hypothermia associated with antiepileptic drugs. We identified 22 unduplicated reports of hypothermia in patients exposed to topiramate. Three of the 22 were confounded by patient overdoses with multiple drugs and not considered. Use of more than one antiepileptic drug was reported in most of the remaining 19 reports. Of these 19 reports, valproic acid was mentioned in 7. Two of the 19 reports mentioned topiramate only. Eleven of the 19 patients were men. The median age of the 19 patients was 40 years (range, 3(1/2)-82 years). Body temperatures ranged from 29.5 degrees C (moderate hypothermia) to 35 degrees C (mild hypothermia) with a median of 34 degrees C. Eleven of 18 reports of hypothermia occurred during the cooler months (one report did not indicate the time of year in which hypothermia occurred). Comorbid conditions included hypothyroidism in six reports, five in patients who received valproic acid concomitantly with topiramate and five reports of hyperammonemia in similarly treated patients. Data mining scores (empirical Bayes geometric mean) for antiepileptic drugs ranged from a high of 5.845 for phenobarbital to 2.956 for gabapentin. Hypothermia was reported 4.7 times more frequently when topiramate was used than was statistically expected. We have found hypothermia, defined as an unintentional drop in body core temperature to <35 degrees C, to be associated with concomitant administration of topiramate (a carbonic anhydrase inhibitor) and valproic acid in patients who have tolerated either drug alone. Data mining analysis for topiramate showed a signal of hypothermia. Topiramate was reported 4.72 times more frequently in the database than would be statistically expected when considering all other drugs. Topiramate may act pharmacodynamically to potentiate the effects of valproic acid as a result of its ability to decrease blood HCO(3) (-) and increase blood ammonia levels.

Helicobacter pylori infection in patients with liver cirrhosis: facts and fictions.

Helicobacter pylori infection could play a role in different clinical alterations observed in cirrhosis, from gastroduodenal lesions to hepatic encephalopathy. Although its prevalence in cirrhotics is similar to that in controls, H. pylori infection is responsible for the increased prevalence of peptic ulcer observed in these patients. The ammonia production by H. pylori urease does not seem to increase blood ammonia levels during cirrhosis, indicating that its role in hepatic encephalopathy could be marginalized in clinical practice. Dual and triple therapies have been shown to be equally effective for H. pylori eradication in these patients.

Carbohydrate availability affects ammonemia during exercise after beta 2-adrenergic blockade.

Beta-adrenergic blockade increases blood ammonia concentration during exercise. The purpose of this study was to assess the role of decreased carbohydrate availability in this process. Wistar rats (N = 47) were injected intravenously with a selective beta 2-adrenoceptor blocker (ICI 118,551), placebo, or beta 2-blocker + glucose 1 h before a treadmill exercise test. Blood samples were taken to measure the concentration of ammonia, glucose, lactic acid, free fatty acids (FFA), glycerol, branched-chain amino acids (BCAA), and muscle samples for determination of glycogen content. Beta 2-adrenergic blockade shortened running time to exhaustion (23 +/- 4.3 min compared to 44 +/- 5.2 min with placebo), increased blood ammonia levels (146.7 +/- 16.21 micromol x L(-1) compared to 47.5 +/- 0.92 micromol x L(-1) with placebo) and prevented exercise-induced glycogen breakdown in soleus and gastrocnemius muscles. Pre-exercise supplementation of glucose during beta 2-blockade restored exercise-induced glycogen breakdown and reduced blood ammonia concentration during exercise (66.5 +/- 5.65 mmol x L(-1)) but did not improve exercise capacity (26 +/- 3.2 min) when compared with beta2-blockade alone. The results suggest that the enhanced rise in blood ammonia concentration during exercise after beta-blockade is caused by impaired carbohydrate availability.

Blood Ammonia Levels after Intravenous Infusion of Glycine Solution with and without Ethanol

Absorption of glycine 1.5% during transurethral resection of the prostate may increase blood ammonia levels, but hyperammonaemia has not been described when the fluid also contained ethanol 1%. The aim of this experimental study was to evaluate whether ethanol 1% reduces glycine-induced hyperammonaemia. Two intravenous infusions of glycine solution with and without ethanol 1% added were given on different occasions to 20 male volunteers (mean age 30 years). Half of them received 22 g of glycine over 50 min and the others approximately 18 g over 30 min. Blood ammonia was measured before and 30 min after the infusion. The serum levels of free amino acids were measured on 7 occasions during 10 of the experiments. The glycine infusions increased blood ammonia levels from 37 micromol/l (median, 10th and 90th percentile limits 34-53) to 57 micromol/l (27-110; p < 0.001). The change was greater after the larger glycine dose, regardless of whether the fluid contained ethanol (p < 0.05). The only amino acid concentration correlating with blood ammonia was glycine, which showed higher levels in those who had a rise in blood ammonia of 50% or more. Ethanol 1% did not reduce the increase in blood ammonia concentration after the administration of glycine solution.

Possible role of neuropeptide Y in experimental cancer anorexia.

The efficacy of NPY to elicit feeding in TB rats was reduced prior to the onset of overt anorexia, with the feeding response decreasing further as anorexia developed. Hypothalamic concentration of NPY was reduced in TB rats, with the magnitude of the decrease paralleling the degree of anorexia. Binding affinity of NPY to hypothalamic membranes taken from TB rats suggested decreased binding affinity with no change in receptor number. Infusing ammonium salts at a concentration and rate necessary to increase blood ammonia levels to the degree observed in TB rats, produced anorexia and decreased NPY feeding. These results suggest that NPY feeding systems are abnormal in TB rats and that hyperammonemia may be of primary importance in this dysfunction.

A possible mechanism for the increase in brain tyrosine levels induced by cyanide in mice

Subcutaneous administration of cyanide significantly increased blood tyrosine levels of mice in a dose dependent manner. Tyrosine aminotransferase activity in liver of mice was significantly decreased in the presence of cyanide (8, 10, 20, 40, 50, 65, 80 and 100 μ M), also in a concentration-dependent manner, with a positive correlation between the percentage increase of blood tyrosine levels and the percentage decrease of hepatic tyrosine aminotransferase activity. These results suggest that the increased tyrosine levels induced in blood by cyanide may be related to its inhibition of tyrosine aminotransferase activity in the liver. Cyanide decreased hepatic ATP content and increased blood ammonia levels and brain tyrosine in a dose-dependent manner. As it is known that hyperammonaemia increases the uptake of neutral amino acids such as tyrosine into the brain from blood, the mechanism by which tyrosine levels increase in the brain may be based on increases of both tyrosine and ammonia levels in blood.

Accelerated leucine decarboxylation in the rat brain in relation to increased blood ammonia levels during acute hepatic failure.

Leucine decarboxylation in rat brain was investigated during acute hepatic failure, induced by partial hepatectomy after carbon tetrachloride (CCl4) pretreatment of rats. These rats presented metabolic alkalosis, and had significantly higher levels of arterial blood and brain ammonia than control and CCl4-treated rats. Brain leucine decarboxylation was elevated in rats with hepatic failure. This alteration correlated with arterial blood ammonia concentrations, and probably with elevated brain ammonia levels, as brain ammonia levels were directly related to arterial blood ammonia.

Carbon Dioxide Retention: A Mechanism of Ammonia Tolerance in Mammals

When guano bats, Tadarida brasiliensis, inhale ammonia in air mixtures, carbon dioxide is passively retained in sufficient amounts to neutralize alkali excess resulting from increased blood ammonia levels. There is no change in blood carbon dioxide levels in house mice, Mus musculus. Little brown bats, Myotis lucifugus, are intermediate in this respect. Passive carbon dioxide retention is clearly related to ammonia tolerance in these mammals.