Analysis of Therapy Monitoring in the International Congenital Adrenal Hyperplasia Registry

Neil Lawrence; Irina Bacila; Jeremy Dawson; Jillian Bryce; Salma R. Ali; Erica L. T. van den Akker; Tânia A. S. S. Bachega; Federico Baronio; Niels H. Birkebæk; Walter Bonfig; Hedi C. van der Grinten; Eduardo C. Costa; Liat de Vries; Heba Elsedfy; Ayla Güven; Sabine Hannema; Violeta Iotova; Hetty J. van der Kamp; María Clemente; Corina R. Lichiardopol; Tatjana Milenkovic; Uta Neumann; Ana Nordenström; Şukran Poyrazoğlu; Ursina Probst-Scheidegger; Luisa De Sanctis; Rieko Tadokoro-Cuccaro; Ajay Thankamony; Ana Vieites; Zehra Yavaş; Syed Faisal Ahmed; Nils Krone

Disclosures

Clin Endocrinol. 2022;97(5):551-561. 

In This Article

Abstract and Introduction

Abstract

Objective: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4).

Design: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries.

Patients: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry.

Measurements: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM).

Results: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1–9.2) were taking a median 11.3 mg/m2/day (8.6–14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0–104.0). Median D4 under 12 years was 0 nmol/L (0–2.0) and above 12 years was 10.5 nmol/L (3.9–21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R 2 = 0.29).

In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R 2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2/day for every 1 point increase in weight standard deviation score.

Discussion: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Introduction

Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition leading to glucocorticoid deficiency, androgen excess, variable degrees of mineralocorticoid deficiency, salt wasting and a risk of life-threatening adrenal crisis. Poorly controlled CAH causes abnormal growth resulting in reduced adult height, reduced quality of life, increased comorbidities and shorter life expectancy.[1,2] Significant variation in treatment strategies has been noted in the United Kingdom and internationally, including using different formulations and dosing regimens.[3] An international consensus statement in 2002[4] was followed by a 2010 Endocrine Society guideline,[5] updated in 2018, that improved guidance for clinicians,[6] but there remain points of contention. The optimal balance of glucocorticoid, mineralocorticoid replacement, and need for salt replacement in infants is debated. It is acknowledged that treatment should be individualised, but precisely how to use the results from biochemical markers in the context of biometric measurements in children is unknown.[2,7]

The recommended daily dose range of hydrocortisone (HC) is 10–15 mg/m2/day, with a recent review advocating doses up to 18 mg/m2/day.[7] However, others suggest doses over 17 mg/m2/day should only be used with care during puberty as adult height has been shown to correlate negatively with glucocorticoid dose.[1,2,8] Maintaining 17-OH progesterone (17OHP) concentrations in the upper end of the normal range is suggested,[6] with alternative targets including 17OHP of 10–20,[9] 12–36[10] or 3–36 nmol/l across all ages and sexes.[2] Interpreting 17OHP and Androstenedione (D4) is challenging due to interindividual variability of their concentration profile in relation to glucocorticoid replacement, and variable practice in measurement in relation to timing of medication administration.[11,12] While alternative serum steroids[13] and urinary steroids[14] have been advocated for monitoring CAH, 17OHP and D4 are likely to be most frequently used in the medium term.

We analysed real-world data from the International Congenital Adrenal Hyperplasia Registry (I-CAH) (www.i-cah.org) to compare reported measurements of serum hormones in relation to prescribed doses of HC. We designed a longitudinal analysis, with repeated measures from patients managed in centres throughout different countries of the world, to gain insight into variations within patients as they age, between patients and to quantify the differences in results between different centres.

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