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

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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.

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