Growth Hormone-Insulin-like Growth Factor Axis and GDF-15 in Critical Illness: Implications for Survival Stratification.

Overview

1. Department of Endocrinology, Hippokration Hospital, 11527 Athens, Greece
2. 1st Department of Critical Care Medicine, Evangelismos Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece; (C.K.); (G.P.); (V.I.); (N.S.L.); (S.K.); (C.S.V.); (A.G.V.); (I.D.)
3. Department of Endocrinology, Diabetes and Metabolism, National Expertise Center for Rare Endocrine Diseases, Evangelismos Hospital, 10676 Athens, Greece; (E.B.); (M.T.); (D.A.V.)

Abstract

Background: The growth hormone (GH)–insulin-like growth factor (IGF) axis is profoundly dysregulated in critical illness. GDF-15 and individual IGF-binding proteins (IGFBPs) have separately been proposed as prognostic biomarkers, but to our knowledge, no prior study has simultaneously characterized all major GH–IGF axis components and GDF-15 in the same critically ill cohort, precluding assessment of their joint intercorrelation structure. Aim: To provide the first simultaneous characterization of the intercorrelation structure among ten GH–IGF axis components and GDF-15 in a single ICU cohort, testing whether this structure is robust to adjustment for illness severity; and, secondarily, to describe admission discriminatory performance relative to APACHE II and SOFA. Methods: This was a prospective observational pilot study of 43 critically ill adults with admission (T01) measurement of ten GH–IGF axis biomarkers and longitudinal follow-up to day 15. Spearman correlations and hierarchical clustering characterized the admission intercorrelation structure; partial correlations adjusting for APACHE II and SOFA, and bootstrap confidence intervals, assessed robustness. Secondary analyses included the examination of admission discrimination (ROC/AUC), a leave-one-out cross-validated combined model, and longitudinal trajectories. All analyses were exploratory, hypothesis-generating, and unadjusted for multiple comparisons unless stated. Results: Hierarchical clustering identified a coherent cluster comprising GDF-15, IGFBP-1, IGFBP-2, and growth hormone-binding protein (GHBP), distinct from classical GH-resistance markers (GHR vs. healthy controls, GHR vs. admission) and from GH, IGF-1, acid-labile subunit (ALS), and IGFBP-3. Within this cluster, GDF-15 correlated with IGFBP-1 (ρ = 0.65, 95% bootstrap CI 0.44–0.78), IGFBP-2 (ρ = 0.50, CI 0.19–0.71), and GHBP (ρ = 0.47, CI 0.20–0.68); GDF-15 showed no correlation with classical GH-resistance markers. These correlations were essentially unchanged after adjusting for APACHE II or SOFA (partial ρ within 0.03–0.16 of unadjusted values), indicating the structure is not attributable to shared confounding by illness severity. This robustness extended to further adjustment for IL-6, age, BMI, and mechanical-ventilation duration, and results from all 45 pairwise T01 correlations were re-examined with Benjamini–Hochberg false-discovery-rate correction (9 of 11 nominally significant pairs retained q < 0.05). However, the GDF-15–GHBP correlation, unlike the GDF-15–IGFBP-1/IGFBP-2 correlations, attenuated substantially after adjustment for IL-6 and was not consistent across a brain-injury/non-brain-injury subgroup sensitivity analysis, indicating this specific link is less specific than the others. In secondary exploratory analyses, GDF-15 had the highest individual admission AUC (0.74) among biomarkers but was substantially outperformed by APACHE II (AUC 0.90) and SOFA (AUC 0.81); a combined GDF-15 + IGFBP-2 model did not improve on GDF-15 alone. Conclusions: This study identifies a severity-independent intercorrelation structure linking GDF-15 to inhibitory IGFBPs, distinct from classical GH-resistance signaling, in critically ill patients. Although the findings do not support any clinical application at this stage, further study in adequately powered, multicenter cohorts can be contemplated.

Reproduced under the paper's license (CC BY), from the paper cited above.

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• zenodo:20844938, at Zenodo; found in “Data Availability Statement”

Data Availability Statement

Anonymized data used in this study are available at Zenodo: https://doi.org/10.5281/zenodo.20844938. During the preparation of this manuscript, the authors used Claude Sonnet 4.6 (Anthropic, https://claude.ai/, accessed on 1 May 2026) and Gemini 2.5 Flash (Google, https://gemini.google.com/, accessed on 1 May 2026) for statistical code assistance, artwork, and language/syntax corrections. The authors have reviewed and edited the output and take full responsibility for the content of this publication.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Funding: added Stavros Niarchos Foundation

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 10 keywords, 26 references.

Cite

This paper

Ilias, I., Keskinidou, C., Poupouzas, G., Issaris, V., Lotsios, N. S., Botoula, E., Tzanela, M., Vassiliadi, D. A., Kokkoris, S., Vrettou, C. S., Vassiliou, A. G., & Dimopoulou, I. (2026). Growth Hormone-Insulin-like Growth Factor Axis and GDF-15 in Critical Illness: Implications for Survival Stratification. Life (Basel, Switzerland), 16(8), 1245. https://doi.org/10.3390/life16081245

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