ESPE2021 Free Communications Adrenal (6 abstracts)
Variation of glucocorticoid dose and biomarkers in children with congenital adrenal hyperplasia – longitudinal analysis of real world data from the I-CAH registry
Neil Lawrence 1,2 , Irina Bacila 1 , Jeremy Dawson 3 , Jillian Bryce 4 , Erica LT van den Akker 5 , Tânia Aparecida Sartori , Sanchez Bachega 6 , Federico Baronio 7 , Niels Holtum Birkebæk 8 , Walter Bonfig 9,10 , Hedi Claahsen 11 , Eduardo Correa Costa 12 , Liat Devries 13 , Heba Elsedfy 14 , Ayla Guvan 15 , Sabine Hannema 16 , Violeta Iotova 17 , Hetty J van der Kamp 18 , Maria Clemente Leon 19 , Corina Raducanu Lichiardopol 20 , Tatjana Milenkovic 21 , Uta Neumann 22 , Anna Nordenström 23,24 , Sukran Poyrazoglu 25 , Ursina Probst-Scheidegger; 26 , Luisa De Sanctis 27 , Ajay Thankamony 28,29 , Ana Vieites 30 , Zehra Yavas 31 , Faisal Ahmed 4 & Nils Krone 1,2
1Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.;2Sheffield Children’s Hospital NHS Foundation Trust, Sheffield, United Kingdom.;3Sheffield University Management School, University of Sheffield, Sheffield, United Kingdom.;4Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom.;5Department of Pediatric Endocrinology, Sophia Children’s Hospital, Erasmus Medical Centre, Rotterdam, Netherlands.;6Department of Internal Medicine, University of Sao Paulo, Sao Paulo, Brazil.;7Department of Medical and Surgical Sciences, Pediatric Unit, Endo-ERN Center for Rare Endocrine Diseases, S.Orsola-Malpighi University Hospital, Bologna, Italy.;8Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark.;9Department of Pediatrics, Klinikum Wels-Grieskirchen, Wels, Austria.;10Department of Pediatrics, Technical University Munich, Munich, Germany.;11Department of Pediatric Endocrinology, Radboud University Medical Centre, Nijmegen, Netherlands.;12Pediatric Surgery Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.;13Institute for Diabetes and Endocrinology, Schneider’s Children Medical Center of Israel, Petah-Tikvah, Israel.;14Pediatrics Department, Ain Shams University, Cairo, Egypt.;15Pediatric Endocrinology, Baskent University İstanbul Hospital, Istanbul, Turkey.;16Department of Paediatrics, Leiden University Medical Centre, Leiden, Netherlands.;17Department of Paediatrics, Medical University of Varna, Varna, Bulgaria.;18Pediatric Endocrinology Wilhelmina Children’s Hospital, University Medical Centre Utrecht, Utrecht, Netherlands.;19Servicio de Endocrinología pediátrica. Hospital Universitario Vall d’Hebron. CIBER de Enfermedades Raras (CIBERER) ISCIII, Barcelona, Spain.;20Department of Endocrinology, University of Medicine and Pharmacy Craiova, Craiova, Romania.;21Department of Endocrinology, Institute for Mother and Child Healthcare of Serbia “Dr Vukan Čupić”, Belgrade, Serbia.;22Institute for Experimental Pediatric Endocrinology and Center for Chronically Sick Children, Charite - Universitätsmedizin Berlin, Berlin, Germany.;23Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden.;24Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, Stockholm, Sweden.;25Paediatric Endocrinology Unit, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey.;26Pediatric Department, Kantonsspital Winterthur, Winterthur, Switzerland.;27Department of Paediatric Endocrinology, Regina Margherita Children’s Hospital, University of Torino, Torino, Italy.;28Biomedical Campus, Cambridge, United Kingdom.;29Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom.;30Centro de Investigaciones Endocrinológicas (CEDIE-CONICET), Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina.;31Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey
Aim: Recommendations for replacement glucocorticoids in CAH suggest a dose per body surface area (BSA) of glucocorticoids of 10-15mg/m2/day to maintain a 17-OH Progesterone (17OHP) level of 12-36 nmol/l across all ages. We used longitudinal analysis to assess whether biomarkers and dose of hydrocortisone varied with age in children within the I-CAH registry .
Method: This retrospective multi-centre study, including 21 centres (14 countries), analysed data from the International-CAH Registry. We analysed repeated measures using linear mixed-effects modelling (LMEM) (lme4, Rstudio) to obtain insight into the within patients and between centres variability of dose and biomarkers.
Results: A total of 308 patients (50% female) from 21 centres on hydrocortisone replacement with 2707 visits between 2000-2020 were available for modelling, with 1813 visits with biomarker data available. Median age at visit was 3.2 years (Interquartile Range (IQR) 1.7, 6.1), maximum age at visit was 18.7 years, and median number of visits available per patient was 7 (IQR 5,10.5). Androstenedione increased with age in a univariate LMEM (0.86+0.56*age, P < 0.001) whereas 17OHP did not correlate with age within patients (P > 0.05). Weight z-scores increased with age within patients (fixed effects: -2.1+0.35*age). A random intercept multivariate LMEM showed that weight z-score had a significant impact upon dose, increasing weight correlating with a decrease in dose (mg/m2/day) (12.4-1.02*weight+0.085*age, P < 0.001). This equates to a child having a dose decrease of 1.02mg/m2/day with each 1 point increase in their weight z-score. Random effects of this model showed that the patient’s treating centre had a larger effect on dose than the individual patient effect (Centre Intraclass Correlation Coefficient=0.68).
Conclusions: Repeated measures analysis of real world data shows relative dose of glucocorticoid replacement per body surface area decreases as they experience an increase in weight z-score. The main contributor to dose variability is a difference in practice between centres, with notable interindividual variability in dose between patients within centres, an average increase in Androstenedione with age, but no change in 17OHP with age. Further use of appropriate multivariate and longitudinal analysis, accounting for puberty, will improve our understanding of how the dosing of glucocorticoids should be informed by patient biometrics and biomarkers, and help standardise the management of CAH across centres.
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