Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Association of leucine and other branched chain amino acids with clinical outcomes in malnourished inpatients: a secondary analysis of the randomized clinical trial EFFORT

European Journal of Clinical Nutrition (2024)Cite this article

Subjects

Abstract

Background

The essential branched-chain amino acids leucine, isoleucine and valine are considered anabolic and stimulate protein synthesis in the muscles as well in the liver. They also promote muscle recovery and contribute to glucose homeostasis. Recent studies in critically ill patients have demonstrated that depletion of plasma leucine is associated with increased mortality, but data in the non-critical care setting is lacking.

Methods

This secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), investigated the impact of leucine, isoleucine, and valine metabolism on clinical outcomes. The primary endpoint was 180-day all-cause mortality.

Results

Among 238 polymorbid patients with available metabolite measurements, low serum leucin levels were associated with a doubled risk of 180-day all-cause mortality in a fully adjusted regression model (adjusted HR 2.20 [95% CI 1.46–3.30], p < 0.001). There was also an association with mortality for isoleucine (1.56 [95% CI 1.03–2.35], p = 0.035) and valine (1.69 [95% CI 1.13–2.53], p = 0.011). When comparing effects of nutritional support on mortality in patients with high and low levels of leucine, there was no evidence of significant differences in effectiveness of the intervention. The same was true for isoleucine and valine.

Conclusion

Our data suggest that depletion of leucine, isoleucine, and valine among malnourished polymorbid patients is associated with increases in long-term mortality. However, patients with low metabolite levels did not show a pronounced benefit from nutritional support. Further research should focus on the clinical effects of nutritional support in patients with depleted stores of essential branched-chain amino acids.

Clinical trial registration

clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2: Kaplan–Meier survival estimates within 180-days comparing high vs. low leucine, isoleucine, and valine levels.
Fig. 3: Association between low leucine and mortality at 180 days in predefined subgroups.

Similar content being viewed by others

Data availability

Our data will be made available to others with the publication of this manuscript, as already outlined in the primary EFFORT publication, on receipt of a letter of intention detailing the study hypothesis and statistical analysis plan. A signed data access agreement is required from all applicants. Please send requests to the principal investigator of this trial.

References

  1. Tsou YL, Wang CH, Chen WS, Wu HP, Liu MH, Lin HC, et al. Combining phenylalanine and leucine levels predicts 30-day mortality in critically Ill patients better than traditional risk factors with multicenter validation. Nutrients 2023;15:649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Holeček M. Branched-chain amino acids in health and disease: metabolism, alterations in blood plasma, and as supplements. Nutr Metab. 2018;15:33.

    Article  Google Scholar 

  3. Wang MY, Wang CH, Chen WS, Chu CM, Wu HP, Liu MH, et al. U-shape relationship between plasma leucine level and mortality in the intensive care unit. Dis Mark. 2022;2022:7389258.

    Google Scholar 

  4. Mann G, Mora S, Madu G, Adegoke OAJ. Branched-chain amino acids: catabolism in skeletal muscle and implications for muscle and whole-body metabolism. Front Physiol. 2021;2021:12

  5. Nie C, He T, Zhang W, Zhang G, Ma X. Branched chain amino acids: beyond nutrition metabolism. Int J Mol Sci. 2018;19:954.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Atherton PJ, Smith K, Etheridge T, Rankin D, Rennie MJ. Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells. Amino Acids. 2010;38:1533–9.

    Article  CAS  PubMed  Google Scholar 

  7. Deutz NE, Matheson EM, Matarese LE, Luo M, Baggs GE, Nelson JL, et al. Readmission and mortality in malnourished, older, hospitalized adults treated with a specialized oral nutritional supplement: a randomized clinical trial. Clin Nutr. 2016;35:18–26.

    Article  PubMed  Google Scholar 

  8. Komar B, Schwingshackl L, Hoffmann G. Effects of leucine-rich protein supplements on anthropometric parameter and muscle strength in the elderly: a systematic review and meta-analysis. J Nutr Health Aging. 2015;19:437–46.

    Article  CAS  PubMed  Google Scholar 

  9. Schuetz P, Seres D, Lobo DN, Gomes F, Kaegi-Braun N, Stanga Z. Management of disease-related malnutrition for patients being treated in hospital. Lancet 2021;398:1927–38.

    Article  PubMed  Google Scholar 

  10. Imoberdorf R, Meier R, Krebs P, Hangartner PJ, Hess B, Staubli M, et al. Prevalence of undernutrition on admission to Swiss hospitals. Clin Nutr. 2010;29:38–41.

    Article  PubMed  Google Scholar 

  11. Reisinger AC, Posch F, Hackl G, Marsche G, Sourij H, Bourgeois B, et al. Branched-chain amino acids can predict mortality in ICU sepsis patients. Nutrients 2021;13:3106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schuetz P, Fehr R, Baechli V, Geiser M, Deiss M, Gomes F, et al. Individualised nutritional support in medical inpatients at nutritional risk: a randomised clinical trial. Lancet 2019;393:2312–21.

    Article  PubMed  Google Scholar 

  13. Schuetz P, Fehr R, Baechli V, Geiser M, Gomes F, Kutz A, et al. Design and rationale of the effect of early nutritional therapy on frailty, functional outcomes and recovery of malnourished medical inpatients trial (EFFORT): a pragmatic, multicenter, randomized-controlled trial. Int J Clin Trials. 2018;5:142–50.

    Article  Google Scholar 

  14. Wunderle C, von Arx D, Mueller SC, Bernasconi L, Neyer P, Tribolet P, et al. Association of glutamine and glutamate metabolism with mortality among patients at nutritional risk-a secondary analysis of the randomized clinical trial EFFORT. Nutrients 2024;16:222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wunderle C, Siegenthaler J, Seres D, Owen-Michaane M, Tribolet P, Stanga Z, et al. Adaptation of nutritional risk screening tools may better predict response to nutritional treatment: a secondary analysis of the randomized controlled trial Effect of early nutritional therapy on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT). Am J Clin Nutr. 2024;119:800–8.

    Article  CAS  PubMed  Google Scholar 

  16. Stumpf F, Wunderle C, Ritz J, Bernasconi L, Neyer P, Tribolet P, et al. Prognostic implications of the arginine metabolism in patients at nutritional risk: A secondary analysis of the randomized EFFORT trial. Clin Nutr. 2024;43:660–73.

    Article  CAS  PubMed  Google Scholar 

  17. Ritz J, Wunderle C, Stumpf F, Laager R, Tribolet P, Neyer P, et al. Association of tryptophan pathway metabolites with mortality and effectiveness of nutritional support among patients at nutritional risk: secondary analysis of a randomized clinical trial. Front Nutr. 2024;11:1335242.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Haenggi E, Kaegi-Braun N, Wunderle C, Tribolet P, Mueller B, Stanga Z, et al. Red blood cell distribution width (RDW) - A new nutritional biomarker to assess nutritional risk and response to nutritional therapy? Clin Nutr. 2024;43:575–85.

    Article  CAS  PubMed  Google Scholar 

  19. Kaegi-Braun N, Tribolet P, Baumgartner A, Fehr R, Baechli V, Geiser M, et al. Value of handgrip strength to predict clinical outcomes and therapeutic response in malnourished medical inpatients: secondary analysis of a randomized controlled trial. Am J Clin Nutr. 2021;114:731–40.

    Article  CAS  PubMed  Google Scholar 

  20. Bounoure L, Gomes F, Stanga Z, Keller U, Meier R, Ballmer P, et al. Detection and treatment of medical inpatients with or at-risk of malnutrition: suggested procedures based on validated guidelines. Nutrition 2016;32:790–8.

    Article  PubMed  Google Scholar 

  21. Kondrup J, Rasmussen HH, Hamberg O, Stanga Z, Ad Hoc EWG. Nutritional risk screening (NRS 2002): a new method based on an analysis of controlled clinical trials. Clin Nutr. 2003;22:321–36.

    Article  PubMed  Google Scholar 

  22. Weinberger KM. Einsatz von Metabolomics zur Diagnose von Stoffwechselkrankheiten. Ther Umsch. 2008;65:487–91.

    Article  PubMed  Google Scholar 

  23. Yet I, Menni C, Shin SY, Mangino M, Soranzo N, Adamski J, et al. Genetic influences on metabolite levels: a comparison across metabolomic platforms. PLoS ONE. 2016;11:e0153672.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Illig T, Gieger C, Zhai G, Romisch-Margl W, Wang-Sattler R, Prehn C, et al. A genome-wide perspective of genetic variation in human metabolism. Nat Genet. 2010;42:137–41.

    Article  CAS  PubMed  Google Scholar 

  25. Trabado S, Al-Salameh A, Croixmarie V, Masson P, Corruble E, Feve B, et al. The human plasma-metabolome: Reference values in 800 French healthy volunteers; impact of cholesterol, gender and age. PLoS ONE. 2017;12:e0173615.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Lau C-HE, Siskos AP, Maitre L, Robinson O, Athersuch TJ, Want EJ, et al. Determinants of the urinary and serum metabolome in children from six European populations. BMC Med. 2018;16:202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Jacob M, Lopata AL, Dasouki M, Abdel Rahman AM. Metabolomics toward personalized medicine. Mass Spectrom Rev. 2019;38:221–38.

    Article  CAS  PubMed  Google Scholar 

  28. Mahoney FI, Barthel DW. Functional evaluation: the Barthel index. Md State Med J. 1965;14:61–5.

    CAS  PubMed  Google Scholar 

  29. Liu X. Classification accuracy and cut point selection. Stat Med. 2012;31:2676–86.

    Article  PubMed  Google Scholar 

  30. Petrie A, Sabin C. Medical statistics at a glance. 4th ed. Hoboken, NJ: Wiley-Blackwell; 2020.

  31. Holecek M. Why are branched-chain amino acids increased in starvation and diabetes? Nutrients 2020;12:3087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Huang SS, Lin JY, Chen WS, Liu MH, Cheng CW, Cheng ML, et al. Phenylalanine- and leucine-defined metabolic types identify high mortality risk in patients with severe infection. Int J Infect Dis. 2019;85:143–9.

    Article  CAS  PubMed  Google Scholar 

  33. Chen L, Chen Y, Wang X, Li H, Zhang H, Gong J, et al. Efficacy and safety of oral branched-chain amino acid supplementation in patients undergoing interventions for hepatocellular carcinoma: a meta-analysis. Nutr J. 2015;14:67.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Teymoori F, Ahmadirad H, Jahromi MK, Mokhtari E, Farhadnejad H, Mohammadzadeh M, et al. Serum branched amino acids and the risk of all-cause mortality: a meta-analysis and systematic review. Amino Acids. 2023;55:1475–86.

    Article  CAS  PubMed  Google Scholar 

  35. Lee SY, Lee HJ, Lim JY. Effects of leucine-rich protein supplements in older adults with sarcopenia: a systematic review and meta-analysis of randomized controlled trials. Arch Gerontol Geriatr. 2022;102:104758.

    Article  CAS  PubMed  Google Scholar 

  36. Wunderle C, Gomes F, Schuetz P, Stumpf F, Austin P, Ballesteros-Pomar MD, et al. ESPEN practical guideline: Nutritional support for polymorbid medical inpatients. Clin Nutr. 2024;43:674–91.

    Article  PubMed  Google Scholar 

  37. Marik PE. Feeding critically ill patients the right ‘whey’: thinking outside of the box. A personal view. Ann Intens Care. 2015;5:51.

    Article  Google Scholar 

  38. Marik PE. Nutritional support among medical inpatients-feed the cold (and malnourished) and starve the febrile. JAMA Netw Open. 2019;2:e1915707.

    Article  PubMed  Google Scholar 

  39. Cardenas D, Ochoa JB. A paradigm shift in clinical nutrition. Clin Nutr. 2023;42:380–3.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the contributors to the EFFORT trial for their valuable support.

Funding

This trial was supported by grants from the Swiss National Science Foundation (PP00P3_150531), and from the Research Council of the Kantonsspital Aarau (1410.000.058 and 1410.000.044). The funders had no influence over the design and conduct of this study, the collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or the decision to submit the manuscript for publication.

Author information

Author notes

  1. These authors contributed equally: Carla Wunderle, Claudia Ciobanu, Jacqueline Ritz.

Authors and Affiliations

  1. Medical University Department, Division of General Internal and Emergency Medicine, Division of Endocrinology, Diabetes and Metabolism, Kantonsspital Aarau, Aarau, Switzerland

    Carla Wunderle, Claudia Ciobanu, Jacqueline Ritz, Pascal Tribolet, Beat Mueller & Philipp Schuetz

  2. Medical Faculty of the University of Basel, Basel, Switzerland

    Claudia Ciobanu, Jacqueline Ritz, Beat Mueller & Philipp Schuetz

  3. Department of Health Professions, Bern University of Applied Sciences, Bern, Switzerland

    Pascal Tribolet

  4. Department of Nutritional Sciences and Research Platform Active Ageing, University of Vienna, Vienna, Austria

    Pascal Tribolet

  5. Institute of Laboratory Medicine, Kantonsspital Aarau, Aarau, Switzerland

    Peter Neyer & Luca Bernasconi

  6. Division of Diabetes, Endocrinology, Nutritional Medicine, and Metabolism, Bern University Hospital and University of Bern, Bern, Switzerland

    Zeno Stanga

Authors
  1. Carla Wunderle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudia Ciobanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jacqueline Ritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pascal Tribolet
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter Neyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Luca Bernasconi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zeno Stanga
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Beat Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philipp Schuetz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Claudia Ciobanu, Jacqueline Ritz, Carla Wunderle, and Philipp Schuetz: conceptualization, methodology, software, validation, formal analysis, investigation, data curation, writing - original draft, writing - review & editing. Beat Mueller, Zeno Stanga, and Pascal Tribolet: conceptualization. Philipp Schuetz and the EFFORT Team: investigation. Philipp Schuetz, Zeno Stanga, and Beat Mueller: resources, supervision, project administration, funding acquisition. All authors read and approved the final version of the manuscript. All authors confirm they had full access to all data in this secondary analysis. All authors accept responsibility for the decision to submit for publication.

Corresponding author

Correspondence to Philipp Schuetz.

Ethics declarations

Competing interests

Philipp Schuetz and Beat Mueller reports grants from Nestlé Health Science, Thermo Fisher, bioMérieux, Abbott Nutrition and Roche Diagnostics, not related to this project. No other disclosures are reported.

Ethics approval and consent to participate

The Ethics Committee of Northwestern/Central Switzerland (EKNZ; 2014_001) approved the study protocol. All participants or their authorized representatives provided written informed consent. The trial was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/ NCT02517476).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wunderle, C., Ciobanu, C., Ritz, J. et al. Association of leucine and other branched chain amino acids with clinical outcomes in malnourished inpatients: a secondary analysis of the randomized clinical trial EFFORT. Eur J Clin Nutr (2024). https://doi.org/10.1038/s41430-024-01507-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41430-024-01507-8

Search

Advanced search

Quick links