Plasma metabolomic profile varies with glucocorticoid dose in patients with congenital adrenal hyperplasia

Mohammad A Alwashih,Ruth Andrew,David G Watson,Manal Alossaimi,Brian R Walker,Roland H Stimson,Gavin Blackburn

doi:10.1038/s41598-017-17220-5

Abstract

Glucocorticoid replacement therapy is the mainstay of treatment for congenital adrenal hyperplasia (CAH) but has a narrow therapeutic index and dose optimisation is challenging. Metabolomic profiling was carried out on plasma samples from 117 adults with 21-hydroxylase deficiency receiving their usual glucocorticoid replacement therapy who were part of the CaHASE study. Samples were profiled by using hydrophilic interaction chromatography with high resolution mass spectrometry. The patients were also profiled using nine routine clinical measures. The data were modelled by using both multivariate and univariate statistics by using the clinical metadata to inform the choice of patient groupings. Comparison of 382 metabolites amongst groups receiving different glucocorticoid doses revealed a clear distinction between patients receiving ≤5 mg (n = 64) and >5 mg (n = 53) daily prednisolone-equivalent doses. The 24 metabolites which were statistically significantly different between groups included free fatty acids, bile acids, and amino acid metabolites. Using 7 metabolites improved the receiver operating characteristic with area under the curve for predicting glucocorticoid dose of >0.9 with FDR adjusted P values in the range 3.3 E-04 -1.9 E-10. A combination of seven plasma metabolite biomarkers readily discriminates supraphysiological glucocorticoid replacement doses in patients with CAH.

Highlights

Glucocorticoid replacement therapy is the mainstay of treatment for congenital adrenal hyperplasia (CAH)[1] and both primary and secondary adrenal insufficiency[2]
The aim of this study was to employ metabolomics in plasma samples which were available from patients with CAH1,6,10 firstly to establish whether the metabolomics profile varies across the range of glucocorticoid replacement regimes employed in these patients, and secondly to identify metabolites which might be useful for monitoring glucocorticoid toxicity
In order to examine relationships between glucocorticoid dose and metabolomic profiles, patients were grouped by their daily dose; (1) 1–2.5 mg, (2) >2.5–5 mg, (3) >5–7.5 mg and (4) >7.5–15 mg prednisolone equivalents

Summary

Introduction

Glucocorticoid replacement therapy is the mainstay of treatment for congenital adrenal hyperplasia (CAH)[1] and both primary and secondary adrenal insufficiency[2]. Treatment with glucocorticoids is generally associated with adverse effects such as obesity, hyperglycaemia, hypertension, cardiovascular disease[4] and osteoporosis[5], and in children, retarded linear growth. These dose-related adverse effects are observed even amongst CAH patients when the goal is physiological replacement rather than pharmacological anti-inflammatory therapy[6,7,8]. Given the narrow therapeutic index, objective monitoring of glucocorticoid toxicity would be valuable to assist with dose optimisation; the pharmacokinetics of oral glucocorticoids preclude maintenance of blood steroid concentrations within physiological reference ranges, and no sensitive pharmacodynamic biomarkers exist with which to assess glucocorticoid toxicity. The aim of this study was to employ metabolomics in plasma samples which were available from patients with CAH1,6,10 firstly to establish whether the metabolomics profile varies across the range of glucocorticoid replacement regimes employed in these patients, and secondly to identify metabolites which might be useful for monitoring glucocorticoid toxicity

Objectives

Methods

Conclusion