Long-Term Carbohydrate-Containing Late-Evening Snack Significantly Improves the Ratio of Branched Chain Amino Acids to Aromatic Amino Acids in Adults with Liver Cirrhosis due to Hepatitis B.

BACKGROUND: The liver is the primary organ for amino acid metabolism, and metabolic disorder of amino acids is common in liver disease. However, the characteristics of plasma amino acid profiles in patients with HBV-related cirrhosis and the impacts of late-evening snack (LES) on cirrhosis are unclear. OBJECTIVES: To investigate the characteristics of plasma amino acid profiles in patients with HBV-related chronic hepatitis, cirrhosis, and the effects of late-evening snacks on plasma amino acid profiles. METHODS: 86 patients with HBV-related cirrhosis and eighty patients with chronic hepatitis B were included in this study. The plasma amino acid profiles were measured by the amino acid analyzer. Patients were randomly divided into two groups, of which the liver cirrhosis group was to receive daily LES (n = 43) or non-LES (n = 43) for 6 months. Plasma amino acid profiles and biochemical parameters were measured in both groups at baseline and after 1, 3, and 6 months. RESULTS: Compared to healthy controls, the plasma concentration in the liver cirrhosis group of threonine, serine, glycine, glutamine, cysteine, tyrosine, phenylalanine, arginine, and methionine increased significantly (P < 0.05), while the ratio of branched chain amino acids (BCAA) to aromatic amino acids (AAA) decreased significantly (P < 0.05). A carbohydrate-predominant LES treatment resulted in a significant increase in BCAA/AAA and decrease in the level of ammonia and glutamine compared with baseline after 6 months of supplementation (P < 0.05). Patients with Child-Pugh B and C are more responsive to changes in amino acid profiles than those with Child-Pugh A. CONCLUSIONS: The application of an LES carbohydrate module for six months in liver cirrhosis patients was associated with increased BCAA/AAA and decreased level of ammonia. Patients with Child-Pugh B and C grades were the most beneficial population.

The effect of multi-ingredient intra- versus extra-cellular buffering supplementation combined with branched-chain amino acids and creatine on exercise-induced ammonia blood concentration and aerobic capacity in taekwondo athletes.

BACKGROUND: This study aimed to investigate the effect of multi-ingredient intra- (BA) versus extra- (ALK) cellular buffering factor supplementation, combined with the customary intake of branched-chain amino acids (BCAA) and creatine malate (TCM), on body composition, exercise variables, and biochemical and hematological parameters in 9 elite taekwondo athletes. METHODS: Eight-week randomized double-blind crossover BA (5.0 g·day-1 of ß-alanine) versus ALK (0.07 g·kgFFM-1·day-1 of sodium bicarbonate) supplementation combined with BCAA (0.2 g·kgFFM-1·day-1) and TCM (0.05 g·kgFFM-1·day-1) during a standard 8-week taekwondo training period was implemented. In the course of the experiment, body composition (dual X-ray absorptiometry), aerobic capacity (ergospirometric measurements during an incremental treadmill test until exhaustion), and exercise blood biomarkers concentrations were measured. Data were analyzed using repeated measures within-between interaction analysis of variance with the inclusion of experimental supplementation order. RESULTS: The maximum post-exercise blood ammonia concentration decreased in both groups after supplementation (from 80.3 ± 10.6 to 72.4 ± 10.2 µmol∙L-1, p = 0.013 in BA; from 81.4 ± 8.7 to 74.2 ± 8.9 µmol∙L-1, p = 0.027 in ALK), indicating reduced exercise-related adenosine triphosphate degradation. However, no differences were found in body composition, aerobic capacity, blood lactate concentration, and hematological parameters after neither BA (combined with BCAA and TCM) nor ALK (combined with BCAA and TCM) supplementation. CONCLUSIONS: In highly trained taekwondo athletes, neither extra- nor intracellular buffering enhancement resulting from BA and ALK supplementation, combined with BCAA and TCM treatment, affects body mass and composition, maximum oxygen uptake, and hematological indices, even though certain advantageous metabolic adaptations can be observed.

Primary hyperammonaemia: Current diagnostic and therapeutic strategies.

Primary hyperammonaemia is a term to describe an elevation of ammonia in blood or plasma due to a defect within the urea cycle, which is the pathway responsible for ammonia detoxification and arginine biosynthesis. Urea cycle disorders (UCDs) are rare diseases caused by genetic defects affecting any of the six enzymes or two transporters that are directly involved in the urea cycle function.The clinical situation is variable and largely depends on the time of onset. Newborns who are often affected by hyper-ammonaemic encephalopathy carry a potential risk of severe brain damage, which may lead to death. Outside the neonatal period, symptoms are very unspecific but most often neurological (with wide variability), psychiatric and/or gastrointestinal. Early identification of patients is extremely important to start effective treatment modalities immediately. The acute management includes detoxification of ammonia, which often requires extracorporeal means such as haemodialysis, and the use of intravenous drugs that work as nitrogen scavengers. Long-term management of patients with UCDs consists of a low-protein diet, which needs to be balanced and supplemented to avoid deficiencies of essential amino acids, trace elements or vitamins and the use of nitrogen scavengers.The reader will find here a brief overview describing the most relevant aspects of the clinical management of UCDs in an attempt to raise awareness for this important group of rare diseases.

Starting stiripentol in adults with Dravet syndrome? Watch for ammonia and carnitine.

OBJECTIVE: Dravet syndrome (DS) is a rare cause of severe and pharmacoresistant epileptic encephalopathy. Stiripentol (STP) has a significant therapeutic benefit in the pediatric DS population. However, STP effects on adult patients have not been well studied. In our adult STP-naive DS patient population, STP initiation was associated with encephalopathy, despite decreases in valproate and clobazam dosage. Here we explored the cause and treatment of encephalopathic manifestations associated with STP in adults. METHODS: Twenty-eight patients with a confirmed clinical and genetic diagnosis of DS who attended the Adult Epilepsy Genetics Clinic were identified retrospectively. Patients who declined or discontinued STP after fewer than 3 months of use, patients who were deceased before starting STP or seizure-free when the genetic diagnosis was confirmed, and those who started STP before leaving the pediatric system (<18 years) were excluded. Levels of ammonia, carnitine, and other anti-epileptic drugs (AEDs) were observed for patients receiving STP. Patients with high ammonia levels who received carnitine supplementation were reevaluated. They were also offered an increased dosage of stiripentol if treatment with carnitine improved the encephalopathy. RESULTS: We observed hyperammonemic encephalopathy in 77% of patients treated with STP. In seven of nine patients, we observed a rate of improvement in ammonia levels of 35% (95% confidence interval [CI] 21%-49%) at a mean carnitine dose of 991 ± 286 mg/d (range 660-1320 mg/d). Five patients whose ammonia levels normalized were also offered an increase in STP dose and they were able to tolerate higher doses with improvement in side effects. Despite such adjustments, the mean maximum stiripentol dose reached was 14.89 ± 8.72 mg/kg/d, which is lower than what is typically recommended in children (50 mg/kg/d). SIGNIFICANCE: We report hyperammonemia in adult STP-naive patients who were on valproate and clobazam, despite dose reduction of the latter drugs. We also report that treatment with carnitine improved hyperammonemia, allowing the continuation of STP.

Changes in the Body Composition and Nutritional Status after Long-term Rifaximin Therapy for Hyperammonemia in Japanese Patients with Hepatic Encephalopathy.

Objective Rifaximin has become available for treating hyperammonemia in patients with hepatic encephalopathy. This study analyzed the changes in the body composition and nutritional status after long-term rifaximin therapy. Methods Twenty-one patients who underwent rifaximin therapy at 1,200 mg/day for more than 24 weeks were evaluated for the changes in the controlling nutritional status (CONUT) scores for the nutritional assessment, albumin-bilirubin (ALBI) scores for the liver function assessment, and skeletal muscle index (SMI) for the body composition assessment. Results There were 17 men and 4 women, with a mean age of 67.14±8.32 years. Eleven cases had a portosystemic shunt (52.3%), and 10 had hepatocellular carcinoma (47.6%). The Child-Pugh class was A in 9 cases (42.9%), B in 9 cases (42.9%), and C in 3 cases (14.2%). The blood ammonia levels in the rifaximin group improved significantly upon rifaximin therapy, from 124.76±28.68 µg/dL at baseline to 47.00±14.43 µg/dL after 2 weeks (p<0.001) and 49.81±15.02 µg/dL after 24 weeks (p<0.001). The CONUT scores improved significantly during rifaximin therapy, from 6.47±3.25 at baseline to 3.33±2.65 after 24 weeks (p=0.0007). The ALBI scores also improved significantly from -0.39±1.89 at baseline to -2.20±0.55 after 24 weeks (p=0.0002). The SMI scores showed that the body composition had been maintained in response to rifaximin therapy (50.20±7.67 at baseline and 51.29±7.62 after 24 weeks). Conclusion Rifaximin administration for hepatic encephalopathy improved the CONUT and ALBI scores. It may have a secondary effect on the improvement in the nutritional status and hepatic reserve.

Safety, Tolerability, and Physiological Effects of AXA1665, a Novel Composition of Amino Acids, in Subjects With Child-Pugh A and B Cirrhosis.

INTRODUCTION: AXA1665 is a novel investigational amino acid (AA) composition specifically designed to impact AA imbalance, ammoniagenesis, and dysregulated anabolic activity associated with cirrhosis. METHODS: This 2-part study examined AXA1665 effects on safety, tolerability, and hepatic/muscle physiology in subjects with Child-Pugh A and B cirrhosis. Part 1 established plasma ammonia and AA concentration baselines with a standardized protein supplement. Part 2 included two 15-day domiciled periods separated by a 14-day washout. In period 1, subjects were randomly distributed to 2 groups: AXA1665 14.7 g t.i.d. (group 1) or control t.i.d. (group 2). In period 2, subjects from group 1 crossed over to control and those in group 2 crossed over to AXA1665 4.9 g t.i.d. All subjects were maintained on standard of care (standardized meals; 30-minute daily, supervised, mandatory physical activity; and daily late-evening snack). RESULTS: In parts 1 and 2, 23 and 17 participants were enrolled, respectively. Dose-dependent increases were observed in plasma concentrations of AXA1665-constituent AAs. Fasted branched-chain AA-to-aromatic AA and valine-to-phenylalanine ratios were both increased (AXA1665 14.7 g t.i.d. control-adjusted change: 44.3% ± 2.7% and 47.2% ± 3.9%, respectively; P < 0.0001). Despite provision of additional nitrogen, mean fasted plasma ammonia concentration at day 15 numerically decreased (-21.1% in AXA1665 14.7 g t.i.d. vs -3.8% in control; P > 0.05). AXA1665 14.7 g t.i.d. produced a leaner body composition and significantly decreased Liver Frailty Index at day 15 vs control (-0.70 ± 0.15 vs -0.14 ± 0.17; P < 0.05). AXA1665 was safe and well tolerated. DISCUSSION: AXA1665 has potential to mitigate core metabolic derangements associated with cirrhosis.

Effect of replacement of antibiotics with thyme and celery seed mixture on the feed intake and digestion, ruminal fermentation, blood chemistry, and milk lactation of lactating Barki ewes.

The study investigated the effect of in-feed administration of dried thyme leaf and celery seed mixture (at 1 : 1 DM basis) compared with salinomycin ionophore on milk production and milk nutritive value of Barki ewes. Thirty ewes (37.5 ± 1.8 kg), divided into 3 treatment groups, were fed: (1) a complete control diet comprising concentrates and fodder maize (Zea mays L.) at 60 : 40 dry matter basis, (2) the control diet plus 20 g of thyme and celery mixture supplementation and (3) the control diet supplemented with 1 g of salinomycin per ewe daily for 90 days. Inclusion of thyme-celery treatment increased (P < 0.05) weight gain, average daily gain, milk yield, milk component yields, and feed efficiency, without affecting milk composition. In addition, the thyme-celery treatment enhanced (P < 0.05) nutrient intake and digestibility, total ruminal volatile fatty acids, branched chain fatty acids, and acetate proportions and decreased ammonia-N concentration. Thyme-celery treatment increased (P < 0.05) serum glucose, thyroxine, and glutamate-pyruvate transaminase concentrations. It is concluded that the thyme and celery mixture (1 : 1 DM basis) at 20 g per lactating ewe daily can replace the salinomycin ionophore. Enhanced feed utilization and lactational performance as well as milk nutritive value for human consumption were observed with the natural additive mixture supplementation.

Involvement of ammonia metabolism in the improvement of endurance performance by tea catechins in mice.

Blood ammonia increases during exercise, and it has been suggested that this increase is both a central and peripheral fatigue factor. Although green tea catechins (GTCs) are known to improve exercise endurance by enhancing lipid metabolism in skeletal muscle, little is known about the relationship between ammonia metabolism and the endurance-improving effect of GTCs. Here, we examined how ammonia affects endurance capacity and how GTCs affect ammonia metabolism in vivo in mice and how GTCs affect mouse skeletal muscle and liver in vitro. In mice, blood ammonia concentration was significantly negatively correlated with exercise endurance capacity, and hyperammonaemia was found to decrease whole-body fat expenditure and fatty acid oxidation-related gene expression in skeletal muscle. Repeated ingestion of GTCs combined with regular exercise training improved endurance capacity and the expression of urea cycle-related genes in liver. In C2C12 myotubes, hyperammonaemia suppressed mitochondrial respiration; however, pre-incubation with GTCs rescued this suppression. Together, our results demonstrate that hyperammonaemia decreases both mitochondrial respiration in myotubes and whole-body aerobic metabolism. Thus, GTC-mediated increases in ammonia metabolism in liver and resistance to ammonia-induced suppression of mitochondrial respiration in skeletal muscle may underlie the endurance-improving effect of GTCs.

High ambient temperature increases the toxicity and lethality of 3,4-methylenedioxymethamphetamine and methcathinone.

RATIONALE: Methylenedioxymethamphetamine (MDMA) and methcathinone (MCAT) are abused psychostimulant drugs that produce adverse effects in human users that include hepatotoxicity and death. Recent work has suggested a connection between hepatotoxicity, elevations in plasma ammonia, and brain glutamate function for methamphetamine (METH)-induced neurotoxicity. OBJECTIVES: These experiments investigated the effect of ambient temperature on the toxicity and lethality produced by MDMA and MCAT in mice, and whether these effects might involve similar mechanisms to those described for METH neurotoxicity. RESULTS: Under low (room temperature) ambient temperature conditions, MDMA induced hepatotoxicity, elevated plasma ammonia levels, and induced lethality. Under the same conditions, even a very high dose of MCAT produced limited toxic or lethal effects. High ambient temperature conditions potentiated the toxic and lethal effects of both MDMA and MCAT. CONCLUSION: These studies suggest that hepatotoxicity, plasma ammonia, and brain glutamate function are involved in MDMA-induced lethality, as has been shown for METH neurotoxicity. The toxicity and lethality of both MDMA and MCAT were potentiated by high ambient temperatures. Although an initial mouse study reported that several cathinones were much less toxic than METH or MDMA, the present results suggest that it will be essential to assess the potential dangers posed by these drugs under high ambient temperatures.

The Effect of Aspartate and Sodium Bicarbonate Supplementation on Muscle Contractile Properties Among Trained Men.

Farney, TM, MacLellan, MJ, Hearon, CM, Johannsen, NM, and Nelson, AG. The effect of aspartate and sodium bicarbonate supplementation on muscle contractile properties among trained men. J Strength Cond Res 34(3): 763-770, 2020-The focus of this investigation was to examine the effects of aspartate and NaHCO3 supplementation on muscle contractile properties within trained men. Eleven men (21.9 ± 1.5 years) ingested supplementation as 4 conditions all separated by 1 week and included the following: placebo (PLA), L-aspartate (12.5 mg) (ASP), NaHCO3 (0.3 g·kg) (SBC), or combination of ASP and SBC (CBO). For each day of testing, participants performed 1 high-intensity exercise session along with a pre- and postexercise (pre- or postex) isometric mid thigh pull test to measure peak force (PF) production and rate of force development (RFD). Blood was collected for all testing sessions before and after the high-intensity exercise to determine ammonia accumulation (AMM). Exercise sessions consisted of 4 exercises: barbell thrusters, squat jumps, lunge jumps, and forward jumps, with the total amount of work being equated for all 4 exercises across all 4 testing sessions. Participants performed the exercises in the aforementioned order, which was designated as 1 round. Each participant performed 3 rounds, with the work-to-rest ratio being 20-second work, 30-second rest. A 1-minute rest was given between the rounds. There were no treatment effects (p > 0.05) for PF, RFD, or AMM. However, there was a significant main effect for supplement consumption for the total time of work with the ASP, SBC, and CBO treatments having a lower time to completion compared with the PLA treatment. Ammonia was significantly elevated postexercise (p = 0.004), whereas there were no differences from preexercise to postexercise for PF or RFD (p > 0.05). The only significant treatment × time interaction was for RFD (p = 0.03) with CBO increasing postexercise, with the other 3 treatments all decreasing postexercise. The combination of ASP and SBC together may have the potential to reduce fatigue by mitigating the effects of metabolic by-product accumulation.

Effect of L-carnitine on liver enzymes and biochemical factors in hepatic encephalopathy: A systematic review and meta-analysis.

BACKGROUND AND AIMS: We aimed to investigate the effect of L-carnitine on biochemical factors including ammonia, bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) in patients with hepatic encephalopathy (HE). METHODS: A systematic search was carried out in Web of Science, PubMed, Scopus, and Cochrane Library databases to find articles related to the effect of L-carnitine supplementation in patients with HE, up to 7 February 2019. There was no language and time limitation. Meta-analyses were carried out using both the random and fixed effects models where appropriate, and I2 index was used to evaluate the heterogeneity. RESULTS: Search yielded 3462 publications. Nine randomized clinical trials with 779 patients were eligible. L-carnitine supplementation significantly reduced blood levels of ammonia. Furthermore, our results indicated that L-carnitine supplementation significantly reduced blood levels of bilirubin, AST, BUN, and Cr in patients with HE. Subgroup analysis demonstrated that L-carnitine significantly reduced ammonia in patients with all the ages, long and short duration of the supplementation, doses less or higher than 4000 mg/day, any route of treatment (intravenous or oral), and in patients with any grade of the symptoms of HE. Moreover, we found that L-carnitine significantly increased circulating levels of albumin in HE patients. CONCLUSIONS: Present systematic review and meta-analysis revealed that L-carnitine supplementation significantly reduced blood levels of ammonia, bilirubin, AST, BUN, and Cr in HE patients. Moreover, we found that L-carnitine significantly increased circulating levels of albumin. However, further large-scale randomized clinical trials are needed.

The Effects of Ergosta-7,9(11),22-trien-3ß-ol from Antrodia camphorata on the Biochemical Profile and Exercise Performance of Mice.

Antrodia camphorata (AC) is a rare and unique mushroom that is difficult to cultivate. Previous studies have demonstrated the bioactivity of the compound Ergosta-7,9(11),22-trien-3ß-ol (EK100) from AC in submerged culture. The purpose of this study is to evaluate the potential beneficial effects of EK100 on fatigue and ergogenic functions following physiological challenge. Male ICR (Institute of Cancer Research) mice were randomly divided into three groups (n = 8 per group) and orally administered EK100 for six weeks at 0 (Vehicle), 10 (EK100-1X), and 20 (EK100-2X) mg/kg/day. The six-week Ek100 supplementation significantly increased grip strength (P = 0.0051) in trend analysis. Anti-fatigue activity was evaluated using 15-min. acute exercise testing and measuring the levels of serum lactate, ammonia, glucose, blood urea nitrogen (BUN), and creatine kinase (CK) after a 15-min. swimming exercise. Our results indicate that AC supplementation leads to a dose-dependent decrease in serum lactate, ammonia, BUN, and CK activity after exercise and significantly increases serum glucose and glycogen content in liver tissues. Biochemical and histopathological data demonstrated that long term daily administration of EK100 for over six weeks (subacute toxicity) was safe. EK100's anti-fatigue properties appear to be through the preservation of energy storage, increasing blood glucose and liver glycogen content, and decreasing the serum levels of lactate, ammonia, BUN, and CK. EK100 could potentially be used to improve exercise physiological adaptation, promote health, and as a potential ergogenic aid in combination with different nutrient strategies.

Resveratrol Restores Neuronal Tight Junction Proteins Through Correction of Ammonia and Inflammation in CCl4-Induced Cirrhotic Mice.

Systemic inflammation and ammonia (hyperammonemia) act synergistically in the pathogenesis of hepatic encephalopathy (HE), the neurobehavioral sequelae of advanced liver disease. In cirrhotic patients, we have recently observed elevated levels of circulating neuronal tight junction (TJ) protein, zonula occludens 1 (ZO-1), reflective of a change to blood-brain barrier (BBB) integrity. Moreover, ZO-1 levels positively correlated with hyperammonemia, although any potential relationship remains unclear. Using a carbon tetrachloride (CCl4)-induced mouse model of cirrhosis, we primarily looked to explore the relationship between neuronal TJ protein expression and hyperammonemia. Secondarily, we assessed the potential role of a natural antioxidant, resveratrol, on neuronal TJ protein expression and hyperammonemia. Over 12 weeks, male Swiss mice were randomized (n = 8/group) to either naïve controls or induced cirrhosis, using two doses of intraperitoneal CCl4 (0.5 ml/kg/week). After 12 weeks, naïve and cirrhotic mice were randomized to receive either 2 weeks of par-oral resveratrol (10 mg/kg). Plasma samples were analyzed for ammonia, liver biochemistry (ALT, AST, albumin, and bilirubin), and pro-inflammatory cytokines (TNF-α and IL-1ß), and brain tissue for brain water content, TJ protein expression (e.g., ZO-1, claudin 5, and occludin), and tissue oxidative stress and inflammatory markers (NF-κB and iNOS) using western blotting. Compared to naïve mice, cirrhosis significantly increased circulating ammonia, brain water, ALT, AST, TNF-α, IL-1ß, 4HNE, NF-κB, and iNOS levels, with a concomitant reduction in all TJ proteins (P < 0.05, respectively). In cirrhotic mice, resveratrol treatment ameliorated these changes significantly (P < 0.05, respectively). Our findings provide evidence for a causal association between hyperammonemia and inflammation in cirrhosis linked to TJ protein alterations, BBB disruption, and HE predilection. Moreover, this is the first report of a potential role for resveratrol as a novel therapeutic approach to managing neurological sequelae complicating cirrhosis.

L-Carnitine for the Treatment of Overt Hepatic Encephalopathy in Patients with Advanced Liver Cirrhosis.

Hepatic encephalopathy is a major complication in patients with advanced cirrhosis and is associated with poor prognosis. To evaluate the effectiveness of L-carnitine supplementation in patients with overt hepatic encephalopathy (OHE), outcomes were retrospectively analyzed in patients with OHE who were treated with intravenous branched-chain amino acids (BCAA), with or without intravenous L-carnitine. Twenty-six patients were treated with intravenous BCAA in addition to conventional agents such as lactulose and non-absorbable antibiotics (Group A), and 19 patients were treated with these agents plus intravenous L-carnitine (Group L). Changes in blood ammonia concentrations, hepatic coma grade and the Glasgow Coma Scale (GCS) were compared in the two groups. Recurrence-free survival (RFS) was evaluated in the two groups and in patients who were and were not administered oral L-carnitine supplementation. At baseline, GCS scores were significantly lower and deterioration in liver function greater in Group L. After 3 d of intravenous L-carnitine, however, GCS showed a significantly greater improvement in Group L than in Group A. Blood ammonia levels improved stably over time in Group L. Overall survival and RFS were similar in Group L and Group A, but median RFS was significantly longer in patients who did than did not receive oral L-carnitine supplementation (735 versus 497 d, p=0.03). Although these findings are preliminary, L-carnitine supplementation may be a therapeutic option for patients with OHE and disturbed consciousness.

Effects of three probiotic Bacillus on growth performance, digestive enzyme activities, antioxidative capacity, serum immunity, and biochemical parameters in broilers.

This study was conducted to evaluate the effects of three Bacillus strains on growth performance, digestive enzyme activities, antioxidative capacity, serum immunity, and biochemical parameters in broilers. A total of 360 one-day-old Ross 308 chicks were randomly allocated into four groups with three replicates per group (n = 30). The control group was fed a basal diet, whereas the other groups fed basal diet supplemented with either Bacillus subtilis natto or Bacillus licheniformis or Bacillus cereus (108  cfu/kg) for 42 days, respectively. The results revealed that the probiotic-treated groups markedly improved final body weight, daily weight gain, and the activities of trypsin, amylase, lipase and total protease (p < 0.05). Moreover, chicks fed probiotics had higher serum glutathione peroxidase activity and O2 - level, as well as hepatic catalase and superoxide dismutase activities, whereas malondialdehyde levels in serum and liver were reduced (p < 0.05). The significant increased IgA (p < 0.05) was observed in the probiotics groups as compared to the control group. In addition, dietary administration of probiotic strain markedly reduced the levels of serum ammonia, uric acid, total cholesterol, and triglyceride. Taken together, these three probiotic Bacillus showed beneficial effects on chickens with minor strain specificity.

Keto analogues and amino acid supplementation and its effects on ammonaemia during extenuating endurance exercise in ketogenic diet-fed rats.

Keto analogues and amino acids (KAAA) supplementation can reduce blood ammonia concentrations in athletes undergoing high-intensity exercise under both ketogenic and thermoneutral conditions. This study evaluated the acute effects of KAAA supplementation on ammonia metabolism during extenuating endurance exercise in rats fed a ketogenic diet. In all, eighty male Fischer rats at 90 d of age were divided into eight groups, and some were trained using a swimming endurance protocol. A ketogenic diet supplemented with keto analogues was administered for 10 d. Administration of the ketogenic diet ended 3 d before the exhaustion test (extenuating endurance exercise). A ketogenic diet plus KAAA supplementation and extenuating endurance exercise (trained ketogenic diet supplemented with KAAA (TKKa)) increased blood ammonia concentrations by approximately 50 % compared with the control diet (trained control diet supplemented with KAAA (TCKa)) and similar training (effect size=1·33; statistical power=0·50). The KAAA supplementation reduced blood urea concentrations by 4 and 18 % in the control and ketogenic diet groups, respectively, compared with the groups fed the same diets without supplementation. The trained groups had 60 % lower blood urate concentrations after TCKa treatment than after TKKa treatment. Our results suggest that KAAA supplementation can reduce blood ammonia concentrations after extenuating endurance exercise in rats fed a balanced diet but not in rats fed a ketogenic diet.

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.

The Effect of Cisplatin on Blood Ammonia Elevation by Alanyl-Glutamine Supplementation.

BACKGROUND: Although there are many clinical studies in which the beneficial effect of glutamine formulation on mucositis induced by chemo/radiotherapy was evaluated, the results are sometimes conflicting with the report of clinical deterioration. Then, we hypothesized that chemotherapy may increase the incidence of hyperammonemia without comparable change of major parameters of hepatic/renal disorder. METHODS: To verify our hypothesis, we examined the increase in blood ammonia level with 1-h intravenous infusion of alanyl-glutamine on day 1-4 after cisplatin (CDDP) administration in rats and assessed the correlation with hepatic/renal parameters. RESULTS: Hepatic parameters (glutamate-oxaloacetic transaminase [GOT] and glutamic-pyruvic transaminase [GPT]) with CDDP did not change until day 3 and only GOT increased on day 4. Renal parameters (plasma creatinine, blood urea nitrogen) with CDDP continuously increased up to day 4. Alanyl-glutamine infusion significantly elevated blood ammonia level of CDDP rats with the peak on day 3, although the same dose did not change that of control rats. CONCLUSION: These results indicates that CDDP enhances the increase in blood ammonia level by glutamine supplementation without correlating with primary parameters for hepatic/renal dysfunction.

Safety, tolerability, and pharmacokinetics of l-ornithine phenylacetate in patients with acute liver injury/failure and hyperammonemia.

Cerebral edema remains a significant cause of morbidity and mortality in patients with acute liver failure (ALF) and has been linked to elevated blood ammonia levels. l-ornithine phenylacetate (OPA) may decrease ammonia by promoting its renal excretion as phenylacetylglutamine (PAGN), decreasing the risk of cerebral edema. We evaluated the safety, tolerability, and pharmacokinetics of OPA in patients with ALF and acute liver injury (ALI), including those with renal failure. Forty-seven patients with ALI/ALF and ammonia ≥60 µM were enrolled. Patients received OPA in a dose escalation scheme from 3.3 g every 24 hours to 10 g every 24 hours; 15 patients received 20 g every 24 hours throughout the infusion for up to 120 hours. Plasma phenylacetate (PA) concentrations were uniformly below target (<75 µg/mL) in those receiving 3.3 g every 24 hours (median [interquartile range] 5.0 [5.0] µg/mL), and increased to target levels in all but one who received 20 g every 24 hours (150 [100] µg/mL). Plasma [PAGN] increased, and conversion of PA to PAGN became saturated, with increasing OPA dose. Urinary PAGN clearance and creatinine clearance were linearly related (r = 0.831, P < 0.0001). Mean ammonia concentrations based on the area under the curve decreased to a greater extent in patients who received 20 g of OPA every 24 hours compared with those who received the maximal dose of 3.3 or 6.7 g every 24 hours (P = 0.046 and 0.022, respectively). Of the reported serious adverse events (AEs), which included 11 deaths, none was attributable to study medication. The only nonserious AEs possibly related to study drug were headache and nausea/vomiting. CONCLUSION: OPA was well-tolerated in patients with ALI/ALF, and no safety signals were identified. Target [PA] was achieved at infusion rates of 20 g every 24 hours, leading to ammonia excretion in urine as PAGN in proportion to renal function. Randomized, controlled studies of high-dose OPA are needed to determine its use as an ammonia-scavenging agent in patients with ALF. (Hepatology 2018;67:1003-1013).

Metabolically based liver damage pathophysiology in patients with urea cycle disorders - A new hypothesis.

The underlying pathophysiology of liver dysfunction in urea cycle disorders (UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle (UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. CONCLUSION: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liver damage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.