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


Journal

Alimentary pharmacology & therapeutics
ISSN: 1365-2036
Titre abrégé: Aliment Pharmacol Ther
Pays: England
ID NLM: 8707234

Informations de publication

Date de publication:
26 Feb 2024
Historique:
revised: 08 11 2023
received: 14 09 2023
accepted: 11 02 2024
medline: 26 2 2024
pubmed: 26 2 2024
entrez: 26 2 2024
Statut: aheadofprint

Résumé

Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. 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. 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). 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.

Sections du résumé

BACKGROUND 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 OBJECTIVE
We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis.
METHODS 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 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 CONCLUSIONS
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.

Identifiants

pubmed: 38404263
doi: 10.1111/apt.17917
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : National Health and Medical Research Council
ID : APP11511317
Organisme : Austin Medical Research Foundation
ID : 2-1340

Informations de copyright

© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.

Références

Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019;48:16-31.
Montano-Loza AJ, Meza-Junco J, Prado CM, Lieffers JR, Baracos VE, Bain VG, et al. Muscle wasting is associated with mortality in patients with cirrhosis. Clin Gastroenterol Hepatol. 2012;10:166-173.e1.
Sinclair M, Gow PJ, Grossmann M, Angus PW. Review article: sarcopenia in cirrhosis - aetiology, implications and potential therapeutic interventions. Aliment Pharm Ther. 2016;43:765-777.
Holeček M. The role of skeletal muscle in the pathogenesis of altered concentrations of branched-chain amino acids (valine, leucine, and isoleucine) in liver cirrhosis, diabetes, and other diseases. Physiol Res. 2021;70:293-305.
Saeki C, Kanai T, Nakano M, Oikawa T, Torisu Y, Saruta M, et al. Low serum branched-chain amino acid and insulin-like growth Factor-1 levels are associated with sarcopenia and slow gait speed in patients with liver cirrhosis. J Clin Med. 2020;9:3239.
Gluud LL, Dam G, Les I, Marchesini G, Borre M, Aagaard NK, et al. Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;5:CD001939.
Kitajima Y, Takahashi H, Akiyama T, Murayama K, Iwane S, Kuwashiro T, et al. Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis. J Gastroenterol. 2018;53:427-437.
Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway. J Nutr. 2000;130:2413-2419.
Matsumura T, Morinaga Y, Fujitani S, Takehana K, Nishitani S, Sonaka I. Oral administration of branched-chain amino acids activates the mTOR signal in cirrhotic rat liver. Hepatol Res. 2005;33:27-32.
Uojima H, Sakurai S, Hidaka H, Kinbara T, Sung JH, Ichita C, et al. Effect of branched-chain amino acid supplements on muscle strength and muscle mass in patients with liver cirrhosis. Eur J Gastroenterol Hepatol. 2017;29:1402-1407.
Hernández-Conde M, Llop E, Gómez-Pimpollo L, Fernández Carrillo C, Rodríguez L, Van Den Brule E, et al. Adding branched-chain amino acids to an enhanced standard-of-care treatment improves muscle mass of cirrhotic patients with sarcopenia: a placebo-controlled trial. Am J Gastroenterol. 2021;116:2241-2249.
Mohta S, Anand A, Sharma S, Qamar S, Agarwal S, Gunjan D, et al. Randomised clinical trial: effect of adding branched chain amino acids to exercise and standard-of-care on muscle mass in cirrhotic patients with sarcopenia. Hepatol Int. 2022;16:680-690.
Singh Tejavath A, Mathur A, Nathiya D, Singh P, Raj P, Suman S, et al. Impact of branched chain amino acid on muscle mass, muscle strength, physical performance, combined survival, and maintenance of liver function changes in laboratory and prognostic markers on Sarcopenic patients with liver cirrhosis (BCAAS study): a randomized clinical trial. Front Nutr. 2021;8:715795.
Muscular weakness assessment: use of normal isometric strength data. The National Isometric Muscle Strength (NIMS) Database Consortium. Arch Phys Med Rehabil. 1996;77:1251-1255.
Ney M, Abraldes JG, Ma M, Belland D, Harvey A, Robbins S, et al. Insufficient protein intake is associated with increased mortality in 630 patients with cirrhosis awaiting liver transplantation. Nutr Clin Pract. 2015;30:530-536.
Marrone G, Serra A, Miele L, Biolato M, Liguori A, Grieco A, et al. Branched chain amino acids in hepatic encephalopathy and sarcopenia in liver cirrhosis: evidence and uncertainties. World J Gastroenterol. 2023;29:2905-2915.
Sinclair M, Hoermann R, Peterson A, Testro A, Angus PW, Hey P, et al. Use of dual X-ray absorptiometry in men with advanced cirrhosis to predict sarcopenia-associated mortality risk. Liver Int. 2019;39:1089-1097.
Hey P, Chew M, Wong D, Gow P, Testro A, Kutaiba N, et al. Moving CT-based quantification of muscle mass to the mainstream-validation of a web-based platform to calculate skeletal muscle index in cirrhosis. Liver Transpl. 2022;28:1944-1946.
Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156.
Lai JC, Covinsky KE, Dodge JL, Boscardin WJ, Segev DL, Roberts JP, et al. Development of a novel frailty index to predict mortality in patients with end-stage liver disease. Hepatology. 2017;66:564-574.
Bajaj JS, Heuman DM, Sterling RK, Sanyal AJ, Siddiqui M, Matherly S, et al. Validation of EncephalApp, smartphone-based Stroop test, for the diagnosis of covert hepatic encephalopathy. Clin Gastroenterol Hepatol. 2015;13:1828-1835.e1.
Zambon Azevedo V, Silaghi CA, Maurel T, Silaghi H, Ratziu V, Pais R. Impact of sarcopenia on the severity of the liver damage in patients with non-alcoholic fatty liver disease. Front Nutr. 2021;8:774030.
Calandra T, Cohen J. The international sepsis forum consensus conference on definitions of infection in the intensive care unit. Crit Care Med. 2005;33:1538-1548.
Sood S, Yu L, Visvanathan K, Angus PW, Gow PJ, Testro AG. Immune function biomarker QuantiFERON-monitor is associated with infection risk in cirrhotic patients. World J Hepatol. 2016;8:1569-1575.
Younossi ZM, Guyatt G, Kiwi M, Boparai N, King D. Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease. Gut. 1999;45:295-300.
R Core Team. R: a language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2021. https://www.R-project.org/
Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67:1-48.
Fox J, Weisberg S. Visualizing fit and lack of fit in complex regression models with predictor effect plots and partial residuals. J Stat Softw. 2018;87:1-27.
Grund S, Lüdtke O, Robitzsch A. Multiple imputation of multilevel missing data: an introduction to the R package pan. SAGE Open. 2016;6.
van Buuren S, Groothuis-Oudshoorn K. Mice: multivariate imputation by chained equations in R. J Stat Softw. 2011;45:1-67.
Tsien C, Davuluri G, Singh D, Allawy A, Ten Have GA, Thapaliya S, et al. Metabolic and molecular responses to leucine-enriched branched chain amino acid supplementation in the skeletal muscle of alcoholic cirrhosis. Hepatology. 2015;61:2018-2029.
Holecek M. Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions. J Cachexia Sarcopenia Muscle. 2017;8:529-541.
Dasarathy S. Myostatin and beyond in cirrhosis: all roads lead to sarcopenia. J Cachexia Sarcopenia Muscle. 2017;8:864-869.
Lai JC, Dodge JL, Sen S, Covinsky K, Feng S. Functional decline in patients with cirrhosis awaiting liver transplantation: results from the functional assessment in liver transplantation (FrAILT) study. Hepatology. 2016;63:574-580.
Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, et al. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology. 2003;124:1792-1801.
Bischoff SC, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, et al. ESPEN practical guideline: clinical nutrition in liver disease. Clin Nutr. 2020;39:3533-3562.
Lai JC, Tandon P, Bernal W, Tapper EB, Ekong U, Dasarathy S, et al. Malnutrition, frailty, and sarcopenia in patients with cirrhosis: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;74:1611-1644.
Palmese F, Bolondi I, Gionnone F, Xaccherini G, Tufoni M, Baldassarre M, et al. The analysis of food intake in patients with cirrhosis waiting for liver transplantation: a neglected step in the nutritional assessment. Nutrients. 2019;11:2462.
Lowe R, Hey P, Sinclair M. The sex-specific prognostic utility of sarcopenia in cirrhosis. J Cachexia Sarcopenia Muscle. 2022;13:2608-2615.

Auteurs

Penelope Hey (P)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Rudolf Hoermann (R)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.

Marie Sinclair (M)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Brooke Chapman (B)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Nutrition and Dietetics, Austin Health, Heidelberg, Victoria, Australia.

Adam Testro (A)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Ross Apostolov (R)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Peter Angus (P)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Paul Gow (P)

Department of Medicine, The University of Melbourne, Parkville, Victoria, Australia.
Department of Gastroenterology, Austin Health, Heidelberg, Victoria, Australia.

Classifications MeSH