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Challenges in Diagnosing Central Adrenal Insufficiency in Children: Cortisol-Stimulating Tests are Safe and Often
Mariana Peduti Halah1, Ana Carolina Maia Teodózio1, Davi Casale Aragon2
1Division of Pediatric Endocrinology-Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Brazil.
Insights
Cortisol-stimulating tests (CSTs) show variable accuracy in diagnosing central adrenal insufficiency (CAI) in children. While generally safe, basal cortisol levels alone are insufficient, necessitating further testing for accurate CAI diagnosis.
Area of Science:
- Pediatric Endocrinology
- Endocrine Diagnostics
- Hypothalamic-Pituitary-Adrenal Axis
Background:
- Uncertainty exists regarding the accuracy and safety of cortisol-stimulating tests (CSTs) for evaluating hypothalamic-pituitary-adrenal (HPA) axis integrity in children.
- Accurate diagnosis of central adrenal insufficiency (CAI) in pediatric populations is crucial for appropriate management.
- This study focuses specifically on cortisol measurements during CSTs, excluding growth hormone assessment.
Purpose of the Study:
- To evaluate the diagnostic accuracy and safety of CSTs, specifically the insulin tolerance test (ITT) and glucagon-stimulation test (GST), in pediatric patients.
- To assess the utility of basal (Fbasal) and peak (Fpeak) plasma cortisol levels in diagnosing CAI.
- To identify clinicopathological variables associated with cortisol responses during CSTs.
Main Methods:
- Retrospective cohort study of 904 pediatric patients undergoing ITT or GST over 15 years at a tertiary center.
- Classification of patients into CAI, indeterminate, and normal categories based on predefined Fbasal and Fpeak cortisol cutoffs (nmol/L).
- Plasma cortisol measured via radioimmunoassay (RIA); sensitivity, specificity, and likelihood ratios (LR) calculated.
Main Results:
- Central adrenal insufficiency (CAI) was confirmed in 8.7% of patients; 58% had indeterminate results based on Fbasal.
- A Fbasal cutoff of 96.6 nmol/L demonstrated high specificity (99%) but low sensitivity (5.3%) for CAI.
- ITT and GST were associated with mild hypoglycemia and gastrointestinal symptoms, respectively; no serious adverse events were reported.
Conclusions:
- Basal cortisol levels alone lack sufficient diagnostic accuracy for CAI in children.
- A Fbasal < 96.6 nmol/L may predict lower Fpeak cortisol levels, suggesting a need for further CST.
- ITT and GST are safe diagnostic tools for pediatric patients when conducted in experienced centers.
Introduction:
The accuracy and safety of cortisol-stimulating tests (CSTs) for assessing hypothalamic-pituitary-adrenal (HPA) axis integrity, including the diagnosis of central adrenal insufficiency (CAI), in children remain uncertain. Although these tests can simultaneously evaluate cortisol and growth hormone secretion, the present study focuses exclusively on cortisol measurements.
Methods:
We evaluated the diagnostic accuracy and safety profile of CST in pediatric patients submitted to insulin tolerance test (ITT) or glucagon-stimulation test (GST) in a tertiary center for 15 years in this retrospective cohort study. According to cortisol (F; nmol/L), we classified patients as having CAI (Fbasal < 138 or Fpeak < 414), indeterminate (Fbasal = 138-358.7 or Fpeak = 414-496.6), and normal (Fbasal > 358.7 or Fpeak > 496.6). Cutoffs were selected based on the literature and on our University Hospital protocol. Plasma cortisol was measured using a consistent radioimmunoassay (RIA) following extraction, with duplicate analyses. The assay had a detection limit of 33.11 nmol/L, with intra- and inter-assay coefficients of variation of 5% and 10.5%, respectively. We evaluated the sensitivity, specificity, likelihood ratios (LR), and clinicopathological variables associated with Fbasal and Fpeak.
Results:
Among 904 patients (60.1% males; median age 10.1 years [0.1-17.1]), CAI was confirmed in 79 (8.7%). Mild hypoglycemia (ITT), and nausea and vomiting (GST) occurred in 46% and 17.5%, respectively. No serious adverse events occurred. Fbasal classified 58% of patients as indeterminate. A Fbasal cutoff of 96.6 had a specificity of 99% and LR+ of 7.6, but low sensitivity (5.3%). In GST, a Fpeak of 303.5 had weak diagnostic accuracy (LR+ of 2.8) and low sensitivity (17%). Concomitant central hypothyroidism and a Fbasal < 154.5 were associated with lower Fpeak, and pituitary stalk interruption was associated with lower Fbasal and Fpeak.
Conclusions:
Fbasal did not present good diagnostic accuracy. However, Fbasal < 96.6 nmol/L predicted lower Fpeak. Therefore, many patients require CST to confirm or exclude CAI. ITT and GST are safe for young patients when performed in experienced centers in a controlled environment.
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