Branched-chain amino acid supplementation does not improve measures of sarcopenia in cirrhosis: results of a randomised controlled trial.

BACKGROUND: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. AIMS: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. METHODS: We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. RESULTS: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). CONCLUSION: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

Effects of branched-chain amino acids supplementation on patients undergoing hepatic intervention: a meta-analysis of randomised controlled trials.

The benefits of branched-chain amino acid (BCAA) administration after hepatic intervention in patients with liver diseases remain unclear. We conducted a systematic review and meta-analysis to evaluate the effects of BCAA on patients undergoing hepatectomy, trans-arterial embolisation and radiofrequency ablation. Relevant randomised controlled trials (RCT) were obtained from PubMed, EMBASE and Cochrane Library databases. A meta-analysis was performed to calculate the pooled effect size by using random-effects models. The primary outcomes were survival and tumour recurrence. The secondary outcomes were hospital stay, nutrition status, biochemistry profile, complication rate of liver treatment and adverse effect of BCAA supplementation. In total, eleven RCT involving 750 patients were included. Our meta-analysis showed no significant difference in the rates of tumour recurrence and overall survival between the BCAA and control groups. However, the pooled estimate showed that BCAA supplementation in patients undergoing hepatic intervention significantly increased serum albumin (mean difference (MD): 0·11 g/dl, 95 % CI: 0·02, 0·20; 5 RCT) at 6 months and cholinesterase level (MD: 50·00 U/L, 95 % CI: 21·08, 78·92; 1 RCT) at 12 months and reduced ascites incidence (risk ratio: 0·39, 95 % CI: 0·21, 0·71; 4 RCT) at 12 months compared with the control group. Additionally, BCAA administration significantly increased body weight at 6 months and 12 months and increased arm circumference at 12 months. In conclusion, BCAA supplementation significantly improved the liver function, reduced the incidence of ascites and increased body weight and arm circumference. Thus, BCAA supplementation may beneficial for selected patients undergoing liver intervention.

Walking exercise through smartphone application plus branched-chain amino acid supplementation benefits skeletal muscle mass and strength in liver cirrhosis: A prospective control trial.

INTRODUCTION AND OBJECTIVES: Whether a combination of exercise and branched-chain amino acid (BCAA) supplementation was more beneficial than those given alone in sarcopenia related to liver cirrhosis (LC) is unknown. Widely used smartphone applications provide continuous and easily expandable management of chronic liver disease (CLD). This study is to investigate the effects of unsupervised walking exercise using WeChat combined with BCAA supplementation on skeletal muscle mass and strength in LC. MATERIALS AND METHODS: The 127 LC patients of Child-Pugh A/B were assigned to group A (BCAA supplements, n=42), group B (walking exercise, n=43) and group C (walking exercise plus BCAA supplements, n=42). Laboratory data, average daily steps, serum BCAA, skeletal muscle mass index (SMI) and grip strength were analyzed pre- and 3 months after interventions. RESULTS: Of the 124 patients who completed interventions, albumin and daily steps were significantly increased in all groups (p=0.0001). Post-intervention BCAA were significantly elevated in group A (A vs B, p=0.001) and C (C vs B, p=0.012;). While post-intervention daily steps in group B (B vs A, p=0.0001) and C (C vs A, p=0.0001) were higher. Grip strength (C vs A, p=0.020; C vs B, p=0.036) and SMI (C vs A, p=0.035; C vs B, p=0.012) were increased in group C. Prevalence of sarcopenia was significantly decreased in group C (p=0.015). CONCLUSIONS: A combination of unsupervised walking exercise using smartphone applications and BCAA supplementation might be an effective and safe treatment for cirrhosis patients with Child-Pugh A/B to improve skeletal muscle mass and strength or to prevent progress of sarcopenia.

Amino acids and cancer: potential for therapies?

PURPOSE OF REVIEW: Cancer patients may have a variety of disorders associated with systemic inflammation caused by disease progression. Consequently, we have protein hypercatabolism. In view of this, protein and amino acid adequacy should be considered in relation to nutritional behavior. Therefore, this review aims to evaluate the influence of protein and amino acids in the nutritional therapy of cancer. RECENT FINDINGS: Diets with adequate protein levels appear to be beneficial in the treatment of cancer; guidelines suggest consumption of greater than 1.0-1.5 g/kg body weight/day. In patients diagnosed with malnutrition, sarcopenia, or cachexia, it is recommended to use the maximum amount of protein (1.5 g/kg of weight/day) to adapt the diet. In addition, based on the evidence found, there is no consensus on the dose and effects in cancer patients of amino acids such as branched-chain amino acids, glutamine, arginine, and creatine. SUMMARY: When evaluating the components of the diet of cancer patients, the protein recommendation should be greater than 1.0-1.5 g/kg of weight/day, with a distribution between animal and vegetable proteins. We found little evidence demonstrating clinical benefits regarding individual or combined amino acid supplementation. Still, it is unclear how the use, dose, and specificity for different types of cancer should be prescribed or at what stage of treatment amino acids should be prescribed.

Use of Branched-Chain Amino Acids as a Potential Treatment for Improving Nutrition-Related Outcomes in Advanced Chronic Liver Disease.

Advanced chronic liver disease (ACLD) represents a complex and multifactorial clinical entity characterized by liver dysfunction and associated complications. In recent years, the significance of nutritional status in ACLD prognosis has gained considerable attention. This review article delves into the multifactorial pathogenesis of malnutrition in ACLD and its profound consequences for health outcomes. We explore the clinical implications of secondary sarcopenia in ACLD and highlight the critical relevance of frailty in both decompensated and compensated ACLD. A specific focus of this review revolves around branched-chain amino acids (BCAAs) and their pivotal role in managing liver disease. We dissect the intricate relationship between low Fischer's ratio and BCAA metabolism in ACLD, shedding light on the molecular mechanisms involved. Furthermore, we critically evaluate the existing evidence regarding the effects of BCAA supplementation on outcomes in ACLD patients, examining their potential to ameliorate the nutritional deficiencies and associated complications in this population.

The Role of Nutrition in the Treatment of Sarcopenia in Old Patients: From Restoration of Mitochondrial Activity to Improvement of Muscle Performance, a Systematic Review.

Sarcopenia is an age-related disease characterized by loss of muscle strength, mass and performance. Malnutrition contributes to sarcopenia pathogenesis. The aim of this systematic review is to analyze existing evidence on the efficacy of nutritional supplementation on muscle and mitochondrial health among sarcopenic or malnourished older adults. We included randomized controlled trials (RCTs) assessing the effect of branched-chain amino acid (BCAA), vitamin D and/or omega-3 polyunsaturated fatty acid (PUFA) on muscle mass, strength and performance and/or on mitochondrial activity and redox state in older sarcopenic and/or malnourished adults. The literature search was on MEDLINE, Embase and Cochrane Central, restricted to articles published in the last 10 years (2012-2022). Twelve RCTs with a total of 1337 subjects were included. BCAA with vitamin D significantly ameliorates appendicular muscle mass (4 RCTs), hand grip strength (4 RCTs), gait speed (3 RCTs), short physical performance battery (3 RCTs) or chair stand test (3 RCTs) among six out of nine RCTs. BCAA alone (2 RCTs) or PUFA (1 RCT) were not effective in improving muscle health. Mitochondrial function was significantly improved by the administration of BCAA alone (1 RCT) or in association with vitamin D (1 RCT). In conclusion, BCAA in association with vitamin D may be useful in the treatment of sarcopenia and boost mitochondrial bioenergetic and redox activity. PROSPERO CRD42022332288.

GPRC5C drives branched-chain amino acid metabolism in leukemogenesis.

Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through the activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong antileukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow cells. This antileukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.

Management of minimal and overt hepatic encephalopathy with branched-chain amino acids: a review of the evidence.

Hepatic encephalopathy (HE) is a challenging complication of liver disease that is associated with substantial morbidity and mortality. Branched-chain amino acid (BCAA) supplementation in the management of HE is a debated topic. This narrative review aims to provide an up-to-date review of the topic and includes studies featuring patients with hepatocellular carcinoma. A review of the literature was performed using the online databases MEDLINE and EMBASE for studies between 2002 and December 2022. Keywords 'branched-chain amino acids', 'liver cirrhosis' and 'hepatic encephalopathy' were used. Studies were assessed for inclusion and exclusion criteria. Of 1045 citations, 8 studies met the inclusion criteria. The main outcomes reported for HE was changed in minimal HE (MHE) (n = 4) and/or incidence of overt HE (OHE) (n = 7). Two of the 4 studies reporting on MHE had improvement in psychometric testing in the BCAA group, but there was no change in the incidence of OHE in any of the 7 papers in the BCAA group. There were few adverse effects of BCAA supplementation. This review found weak evidence for BCAA supplementation for MHE, and no evidence for BCAAs for OHE. However, given the relative paucity and methodological heterogeneity of the current research, there is scope for future studies to examine the effects of varying timing, dosage, and frequency of BCAAs on outcomes such as HE. Importantly, research is also needed to examine BCAAs in conjunction with standard therapies for HE such as rifaximin and/or lactulose.

Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: Evidence and uncertainties.

Liver cirrhosis is commonly associated with nutritional alterations, reported in 20% of patients with compensated disease and over 60% of patients with decompensated cirrhosis. Nutritional disturbances are associated with a worse prognosis and increased risk of complication. Serum levels of branched-chain amino acids (BCAAs) are decreased in patients with liver cirrhosis. The imbalance of amino acids levels has been suggested to be associated with the development of complications, such as hepatic encephalopathy and sarcopenia, and to affect the clinical presentation and prognosis of these patients. Several studies investigated the efficacy of BCAAs supplementation as a therapeutic option in liver cirrhosis, but uncertainties remain about the real efficacy, the best route of administration, and dosage.

Branched-chain amino acids supplementation improves liver frailty index in frail compensated cirrhotic patients: a randomized controlled trial.

BACKGROUND: Physical frailty is related with morbidity and mortality in patients with cirrhosis. Currently, there is no approved treatment of frailty in these patients. Here, we evaluated the efficacy of 16 weeks branched-chain amino acids (BCAA) supplementation on frailty in frail compensated cirrhotic patients. METHODS: After a 4-week run-in period consisted of dietary and exercise counseling, compensated cirrhotic patients with frailty, defined by liver frailty index (LFI)≥4.5, were randomly assigned (1:1) to BCAA or control group. The BCAA group received twice daily BCAAs supplementation (210 kcal, protein 13.5 g, BCAA 2.03 g) for 16 weeks. The primary outcome was frailty reversion. The secondary outcomes were changes in biochemistries, body composition evaluated by bioelectrical impedance analysis, and quality of life (QoL). RESULTS: 54 patients were prospectively enrolled (age 65.5 ± 9.9 years, 51.9% female, Child-Pugh A/B 68.5%/31.5%, MELD 10.3 ± 3.1). Baseline characteristics were similar between both groups. At week 16, BCAA group had a significant improvement in LFI (-0.36 ± 0.3 vs. -0.15 ± 0.28, P = 0.01), BMI (+ 0.51 ± 1.19 vs. -0.49 ± 1.89 kg/m2, P = 0.03), and serum albumin (+ 0.26 ± 0.27 vs. +0.06 ± 0.3 g/dl, P = 0.01). The proportion of frailty reversion at week 16 was significantly higher in BCAA group (36% vs. 0%, P < 0.001). Compared with baseline, BCAA group had a significant increase in skeletal muscle index (7.5 ± 1.6 to 7.8 ± 1.5 kg/m2, P = 0.03). Regarding the QoL, only the BCAA group had a significant improvement in all 4 domains of physical component score of the SF-36 questionnaire. CONCLUSIONS: A 16-week BCAA supplementation improved frailty in frail compensated cirrhotic patients. In addition, this intervention resulted in an improvement of muscle mass and physical domain of QoL in these patients. TRIAL REGISTRATION: This study was registered with Thai Clinical Trial Registry (TCTR20210928001; https://www.thaiclinicaltrials.org/# ).

Effect of dietary branched chain amino acids on liver related mortality: Results from a large cohort of North American patients with advanced HCV infection.

Branched chain amino acids (BCAA) supplementation may reduce the incidence of liver failure and hepatocellular carcinoma in patients with cirrhosis. We aimed to determine whether long-term dietary intake of BCAA is associated with liver-related mortality in a well-characterized cohort of North American patients with advanced fibrosis or compensated cirrhosis. We performed a retrospective cohort study using extended follow-up data from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. The analysis included 656 patients who completed two Food Frequency Questionnaires. The primary exposure was BCAA intake measured in grams (g) per 1000 kilocalories (kcal) of energy intake (range 3.0-34.8 g/1000 kcal). During a median follow-up of 5.0 years, the incidence of liver-related death or transplantation was not significantly different among the four quartiles of BCAA intake before and after adjustment of confounders (AHR 1.02, 95% CI 0.81-1.27, P-value for trend = 0.89). There remains no association when BCAA was modeled as a ratio of BCAA to total protein intake or as absolute BCAA intake. Finally, BCAA intake was not associated with the risk of hepatocellular carcinoma, encephalopathy or clinical hepatic decompensation. We concluded that dietary BCAA intake was not associated with liver-related outcomes in HCV-infected patients with advanced fibrosis or compensated cirrhosis. The precise effect of BCAA in patients with liver disease warrants further study.

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice.

Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

The effect of branched-chain amino acid supplementation on cancer treatment.

Background: Anticancer therapies are associated with significant adverse side effects and few treatments that alleviate symptoms exist. Branched-chain amino acids (BCAAs) have been investigated as an intervention for reducing anticancer therapy side effects, although a review of the literature results has yet to be published. Aim: The current review summarizes evidence surrounding this topic and suggests both support and caution in using BCAAs as a treatment for patients receiving anticancer therapies. Methods: In this review, two literature searches were completed. Google Scholar, PubMed, EBSCOhost, and Cochrane databases were searched using the terms "branched-chain amino acids and cancer" and "BCAA and cancer." Results: Two bodies of evidence emerged: One supporting beneficial effects and the other showing adverse outcomes of BCAA supplementation in patients with cancer. Evidence of benefit was a decrease in malnourishment and unintentional weight loss during and after chemotherapy. Potential harms included the idea cancer cells may utilize BCAAs as a source of energy for growth. Conclusions: Supplementation of BCAAs in individuals with cancer should be implemented cautiously. Those who are severely malnourished due to anticancer therapy may benefit the most. BCAA supplementation may also be provided once cancer has been destroyed from the individual's body to aid with recovery.

The impact of branched-chain amino acid supplementation on measures of glucose homeostasis in individuals with hepatic disorders: A systematic review of clinical studies.

BACKGROUND: Branched chain amino acid (BCAA) supplementation may influence glucose metabolism in individuals with an impaired glyceamic profile. This systematic review investigated the effects of isolated BCAA supplementation on measures of glucose homeostasis in individuals with hepatic disorders. METHODS: We searched PubMed, Web of Science, Cochrane Library and Scopus for published clinical trials that investigated the effects of isolated BCAA supplementation on measures of glucose homeostasis, including serum glucose and insulin, glycated haemoglobin (HbA1c) levels and homeostatic model assessment for insulin resistance (HOMA-IR) scores. RESULTS: Eleven trials met the inclusion criteria. Only one study revealed a decrease in serum glucose from BCAA supplementation compared to three studies that showed increases. Five studies demonstrated no significant changes in serum glucose, and two studies displayed no changes in HbA1c following BCAA supplementation. Serum levels of insulin were decreased in three studies, remained unchanged in one, and increased in the remaining three studies. BCAA supplementation reduced HOMA-IR scores in two studies, increased HOMA-IR scores in another two, or resulted in no changes in two other studies. CONCLUSIONS: BCAA supplementation in isolation had no effect on overall glucose homeostasis in individuals with hepatic disorders, although some improvements on serum insulin levels and HOMA-IR scores were observed. Overall, there is little evidence to support the utilisation of BCAA supplementation as a potential nutritional strategy for improving measures of glucose homeostasis in individuals with hepatic disorders.

Systematic review with meta-analysis: Branched-chain amino acid supplementation in liver disease.

BACKGROUND: Dietary supplementation with branched-chain amino acids (BCAA) is often used in cirrhotic patients to improve nutritional status. We wanted to explore the evidence for BCAA supplementation in chronic liver disease. METHODS: We searched MEDLINE and EMBASE for studies with BCAA supplementation with the presence of a disease-control group (placebo or no intervention) using search terms 'liver cirrhosis', 'hepatocellular carcinoma', 'branched chain amino acids' and relevant synonyms. Risk of bias was assessed using ROBINS-I and RoB 2.0 tools. Meta-analyses were performed with a random-effects model. Results were reported following EQUATOR guidelines. RESULTS: Of 3378 studies screened by title and abstract, 54 were included (34 randomized controlled trials, 5 prospective case-control studies, 13 retrospective case-control studies: in total 2308 patients BCAA supplementation, 2876 disease-controls). Risk of bias was high/serious for almost all studies. According to meta-analyses, long-term (at least 6 months) BCAA supplementation in cirrhotic patients significantly improved event-free survival (p = .008; RR .61 95% CI .42-.88) and tended to improve overall survival (p = .05; RR .58 95% CI .34-1.00). Two retrospective studies suggested the beneficial effects during sorafenib for hepatocellular carcinoma. Available studies reported no beneficial effects or contradictory results of BCAA after other specific therapeutic interventions (resection or radiological interventions for hepatocellular carcinoma, liver transplantation, paracentesis or variceal ligation). No convincing beneficial effects of BCAA supplementation on liver function, nutritional status or quality of life were found. No study reported serious side effects of BCAA. CONCLUSIONS: Prophylactic BCAA supplementation appears safe and might improve survival in cirrhotic patients.

New Evidence of Oral Branched-Chain Amino Acid Supplementation on the Prognosis of Patients With Advanced Liver Disease.

INTRODUCTION: Oral branched-chain amino acids (BCAAs) might benefit patients with advanced liver disease. We assess its effects on prognosis compared with control from the meta-analysis. METHODS: Study end points were development of hepatic encephalopathy (HE), hepatocellular carcinoma (HCC), mortality, and overall liver-related events (LREs). Risk ratios (RRs) and hazard ratios (HRs) were calculated using random effects model and heterogeneity using I 2 statistic. RESULTS: Twenty-eight studies were included in this meta-analysis; 1,578 and 1,727 patients in oral BCAAs and control groups, respectively. From studies using RRs as outcome measures, oral BCAAs were better in preventing HE and LRE than controls, with RRs 0.684 (95% confidence interval [CI] 0.497-0.941; P = 0.019) and 0.788 (95% CI 0.585-0.810; P < 0.001), respectively. Oral BCAAs had marginal effect on preventing HCC compared with control, with RR 0.791 (95% CI 0.619-1.011; P = 0.061); no significant difference in mortality was detected. From studies using HRs as outcome measures, oral BCAAs were superior to control in preventing LRE with adjusted HR 0.497 (95% CI 0.321-0.770; P = 0.002). In subgroups undergoing HCC resection, oral BCAAs had beneficial effect in preventing HE (RR 0.716, 95% CI 0.514-0.996; P = 0.047) and LRE (RR 0.716, 95% CI 0.595-0.860; P < 0.001). DISCUSSION: Oral BCAAs could afford clinical benefits in reducing HE and LRE risks, especially among patients undergoing HCC resection.

Efficacy of branched chain amino acids supplementation in liver cirrhosis: A systematic review and meta-analysis.

BACKGROUND: Branched chain amino acids' (BCAAs) beneficial role in the management of hepatic encephalopathy is already well established, whereas a number of randomized clinical trials (RCTs) have showed promising results examining BCAA supplementation in the management of other aspects of liver cirrhosis. Current results in the light of BCAAs' biochemical properties make them an attractive supplementation option, in addition to standard pharmaceutical treatment of cirrhosis. AIM: The aim of this systematic review is to summarize the current literature and assess the efficacy of BCAA supplementation in patients with liver cirrhosis. METHODS: Major electronic databases and grey literature sources were searched up to October 4th, 2021 for RCTs assessing the supplementation of BCAA against an active comparator, diet or placebo in patients with liver cirrhosis. RESULTS: Twenty RCTs fulfilled selection criteria. Relative to other interventions BCAAs showed beneficial effect regarding muscle mass (SMD 0.21, 95% CI 0.01 to 0.4, I2 0%), but no effect regarding fat mass. Furthermore, BCAAs were associated with significant increase in plasma albumin concentration (SMD 0.52, CI 95% 0.18 to 0.86, I2 84.99%), reduction in occurrence of serious cirrhotic complications (logOR -046, CI 95% -0.78 to -0.13, I2 0%) and increase in body mass index (WMD 0.24, CI 95% 0.08 to 0.40, I2 0%). On the other hand, no significant effect was noted concerning the incidence of mortality. CONCLUSION: Supplementation with BCAA seems to improve significant prognostic factors for patients with cirrhosis, with potential positive impact in mortality. Heterogeneity of study findings attributed to many factors limit overall conclusion and results require further assessment.

Neuroinflammatory responses following zinc or branched-chain amino acids supplementation in obese rats.

The excessive production of pro-inflammatory mediators, characteristic of obesity, leads to neuroinflammation. Zinc (Zn) and the branched-chain amino acids (BCAA) are supplements known for their immunomodulatory properties. Our goal was to evaluate if Zn or BCAA supplementation can affect long-term recognition memory and neuroinflammatory parameters of obese rats after a high-fat diet (HFD). Three-month-old Wistar rats were divided into six groups: Standard diet (SD) + vehicle; SD + Zn; SD + BCAA; High-fat diet (HFD) + vehicle; HFD + Zn; and HFD + BCAA. Diets were administrated for 19 weeks, Zn (1,2 mg/kg/day) or BCAA (750 mg/kg/day) supplementation was conducted in the last 4 weeks. Long-term recognition memory was evaluated by the novel object recognition test. IL-1ß immunoreactivity in the cortex and hippocampus, and IL-6 levels in the cortex tissue were assessed. Astrogliosis were evaluated through GFAP + cell count and morphological analysis (Sholl Method). Zn supplementation improved object recognition memory in HFD-fed rats, which was not observed following BCAA supplementation. The levels of IL-6 in the cerebral cortex were higher after HFD, which was not diminished after neither supplementation. Obesity also led to increased IL-1ß immunoreactivity in the cerebral cortex and hippocampus, which was reduced by Zn. BCAA supplementation also diminished IL-1ß immunoreactivity, but only in the hippocampus. We also showed that astrocyte reactivity caused by HFD is area-dependent, being the cerebral cortex more susceptible to the diet. Even though BCAA and Zn can affect IL-1ß immunoreactivity and astrocyte morphology, only Zn improved memory. Future studies are needed to clarify the pathways by which Zn improves cognition in obesity.

Intravenous administration of a branched-chain amino-acid-free solution in children and adults with acute decompensation of maple syrup urine disease: a prospective multicentre observational study.

BACKGROUND: Patients with maple syrup urine disease (MSUD) experiencing metabolic decompensations have traditionally been treated with branched-chain amino acid (BCAA)-free mixture via oral or nasogastric administration routes. In some patients, enteral administration is not possible, either because the patient presents with vomiting, coma, or refuses nasogastric administration, thus intravenous (IV) BCAA-free solution is an appropriate intervention for these challenging cases. AIMS: This study aimed to evaluate the effectiveness and safety of managing metabolic decompensations by administering an IV BCAA-free solution. METHODS: This is an observational prospective study of data from MSUD patients hospitalised for decompensation episodes between 2010 and 2016 at 6 centres for rare metabolic diseases in France. RESULTS: A total of 24 patients (16 males; 8 females) experiencing 126 MSUD metabolic decompensation episodes (39 in children; 87 in adults) were admitted to hospital. At presentation, mean leucine plasma concentration was ≥ 381 µmol/L in 113/126 (89.7%) episodes. Children were treated with continuous IV BCAA-free solution at doses of 0.8 to 2.0 g/kg/day, for 4.8 days and adults for 3.8 days at doses of 0.5 to 2.6 g/kg/day. In the efficacy set of 102 analysable episodes leucine concentrations were normalised (to below 381 µmol/L) in 82% (n = 18/22) of episodes in children and in 84% (n = 67/80) of episodes in adults. Mean time to leucine normalisation was 3.0 days. This was significantly (p < 0.001) shorter than the algorithmically predicted time to leucine normalisation with traditional BCAA-free mixture. Duration of hospitalisation was significantly longer for children than for adults (7.1 days in children vs 5.2 days in adults, p = 0.012). No treatment-related adverse events were reported in any patients on IV BCAA-free solution. CONCLUSION: The IV BCAA-free solution is safe and effective in normalising leucine concentrations during MSUD decompensation episodes in both children and adults, offering a practical treatment alternative for those patients who cannot receive BCAA-free mixture via oral or nasogastric routes.

Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia.

BACKGROUND: The role of branched-chain amino acids (BCAA) in improving muscle mass in cirrhosis is presently debatable. AIMS: To evaluate the role of BCAA in improving muscle mass in a double-blind randomized placebo-controlled trial in patients with cirrhosis having sarcopenia. METHODS: Consecutive patients with cirrhosis with Child-Pugh score < 10 and sarcopenia were randomized to receive either 12 g/day of BCAA orally or a placebo (1:1) for 6 months in addition to a home-based exercise program (30 min/day), dietary counselling and standard medical therapy. Sarcopenia was defined according to gender-specific axial skeletal muscle index (SMI) cut-offs. The primary endpoint was a change in muscle mass based on CT scan (SMI) after 6 months of supplementation. RESULTS: Sixty patients [mean age 41.6 ± 9.9 years; males (66.6%) of predominantly viral (40%) and alcohol-related (31.7%) cirrhosis] were randomized. Baseline clinical and demographic characters were similar except MELD score (10.2 ± 2.8 vs. 12.2 ± 3.5, p = 0.02) and calorie intake (1838.1 kcal ± 631.5 vs. 2217.5 kcal ± 707.3, p = 0.03), both being higher in the placebo arm. After adjusting for both baseline confounders, baseline SMI and protein intake, the change in SMI at 6 months was similar in both groups [mean adjusted difference (MAD) + 0.84, CI - 2.9; + 1.2, p = 0.42] by intention-to-treat analysis. The secondary outcomes including change in handgrip strength (p = 0.65), 6-m gait speed (p = 0.20), 6-min walk distance (p = 0.39) were similar in both arms. Four patients had minor adverse events in each arm. CONCLUSION: Addition of BCAA to exercise, dietary counselling and standard medical therapy did not improve muscle mass in patients with cirrhosis having sarcopenia. (CTRI/2019/05/019269). TRIAL REGISTRATION NUMBER: CTRI/2019/05/019269 (Clinical Trials Registry of India).