Abstract
Patients with congenital adrenal hyperplasia (CAH) appear to have adverse cardiovascular risk profile and other long-term health problems in adult life, but there are limited data in young CAH patients. We aim to evaluate the cardio-metabolic risk factors in adolescents and young adults with classical 21-hydroxylase deficiency (21-OHD). We performed a cross-sectional study of 21 patients (17 females) with classic CAH detected clinically and not through newborn screening, aged 15.2 ± 5.8 years, and 21 healthy matched controls. Anthropometric, biochemical, inflammatory markers, and body composition using dual-energy X-ray absorptiometry were measured. Obesity was observed in 33% of the CAH patients. The waist/hip ratio and waist/height ratio were significantly higher in CAH patients. Five out of 21 patients (24%) had elevated blood pressure. Silent diabetes was diagnosed in one patient (4.8%), but none in the control group. Serum leptin and interleukin-6 levels were not different between groups, but hs-CRP levels tended to be higher in CAH patients. Other metabolic profiles and body composition were similar in CAH and controls.
Conclusion: Adolescents and young adults with CAH appear to have an increased risk of obesity and cardio-metabolic risk factors. Close monitoring, early identification, and secondary prevention should be implemented during pediatric care to improve the long-term health outcomes in CAH patients.
What is Known: • Lifelong glucocorticoid (GC) replacement is the main treatment modality in patients with congenital adrenal hyperplasia which predispose to an adverse metabolic profile. • Adult CAH patients have adverse cardiovascular risk profile and other long-term health problems. |
What is New: • Adolescents and young adults with CAH appear to have an increased risk of obesity and cardio-metabolic risk factors. |
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Abbreviations
- 17-OHP:
-
17-Hydroxyprogesterone
- 21-OHD:
-
21-Hydroxylase deficiency
- ALT:
-
Alanine aminotransferase
- AST:
-
Aspartate aminotransferase
- BMC:
-
Bone mineral content
- BMD:
-
Bone mineral density
- CAH:
-
Congenital adrenal hyperplasia
- DXA:
-
Dual-energy X-ray absorptiometry
- FBG:
-
Fasting blood glucose
- GC:
-
Glucocorticoid
- HbA1c:
-
Hemoglobin A1c or glycosylated hemoglobin A protein
- HDL:
-
High-density lipoprotein
- HOMA-IR:
-
Homeostasis model assessment of insulin resistance
- hs-CRP:
-
High-sensitivity C-reactive protein
- IL-6:
-
Interleukin-6
- IQR:
-
Interquartile range
- LDL:
-
Low-density lipoprotein
- OGTT:
-
Oral glucose tolerance test
- SDS:
-
Standard deviation scores
- SV:
-
Simple virilizing
- SW:
-
Salt-wasting
References
Angulo P (2002) Nonalcoholic fatty liver disease. N Engl J Med 346:1221–1231
Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ (2010) Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab 95:5110–5121
Bachelot A, Plu-Bureau G, Thibaud E, Laborde K, Pinto G, Samara D, Nihoul-Fekete C, Kuttenn F, Polak M, Touraine P (2007) Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 67:268–276
Bamba V (2014) Update on screening, etiology, and treatment of dyslipidemia in children. J Clin Endocrinol Metab 99:3093–3102
Berardis S, Sokal E (2014) Pediatric non-alcoholic fatty liver disease: an increasing public health issue. Eur J Pediatr 173:131–139
Bouvattier C, Esterle L, Renoult-Pierre P, de la Perriere AB, Illouz F, Kerlan V, Pascal-Vigneron V, Drui D, Christin-Maitre S, Galland F, Brue T, Reznik Y, Schillo F, Pinsard D, Piguel X, Chabrier G, Decoudier B, Emy P, Tauveron I, Raffin-Sanson ML, Bertherat J, Kuhn JM, Caron P, Cartigny M, Chabre O, Dewailly D, Morel Y, Touraine P, Tardy-Guidollet V, Young J (2015) Clinical outcome, hormonal status, gonadotrope axis and testicular function in 219 adult men born with classic 21-hydroxylase deficiency. A French national survey J Clin Endocrinol Metab 100:2303–2313
Bunraungsak S, Klomchan T, Sahakitrungruang T (2013) Growth pattern and pubertal development in patients with classic 21-hydroxylase deficiency. Asian Biomed 7:787–794
Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP (2002) Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab 87:2114–2120
Christiansen P, Molgaard C, Muller J (2004) Normal bone mineral content in young adults with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res 61:133–136
de Onis M (2007) Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ 85:660–667
de Silva KS, Kanumakala S, Brown JJ, Jones CL, Warne GL (2004) 24-hour ambulatory blood pressure profile in patients with congenital adrenal hyperplasia—a preliminary report. J Pediatr Endocrinol Metab 17:1089–1095
Falhammar H, Filipsson H, Holmdahl G, Janson PO, Nordenskjold A, Hagenfeldt K, Thoren M (2007) Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 92:110–116
Falhammar H, Filipsson H, Holmdahl G, Janson PO, Nordenskjold A, Hagenfeldt K, Thoren M (2009) Increased liver enzymes in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr J 56:601–608
Falhammar H, Filipsson Nystrom H, Wedell A, Thoren M (2011) Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur J Endocrinol 164:285–293
National high blood pressure education program working group on high blood pressure in children and adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576
Freedman DS, Kahn HS, Mei Z, Grummer-Strawn LM, Dietz WH, Srinivasan SR, Berenson GS (2007) Relation of body mass index and waist-to-height ratio to cardiovascular disease risk factors in children and adolescents: the Bogalusa Heart Study. Am J Clin Nutr 86:33–40
Gussinye M, Carrascosa A, Potau N, Enrubia M, Vicens-Calvet E, Ibanez L, Yeste D (1997) Bone mineral density in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia. Pediatrics 100:671–674
Hagenfeldt K, Martin Ritzen E, Ringertz H, Helleday J, Carlstrom K (2000) Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deficiency after glucocorticoid treatment since infancy. Eur J Endocrinol 143:667–671
Khoury M, Manlhiot C, McCrindle BW (2013) Role of the waist/height ratio in the cardiometabolic risk assessment of children classified by body mass index. J Am Coll Cardiol 62:742–751
King JA, Wisniewski AB, Bankowski BJ, Carson KA, Zacur HA, Migeon CJ (2006) Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia. J Clin Endocrinol Metab 91:865–869
Luukkaa V, Pesonen U, Huhtaniemi I, Lehtonen A, Tilvis R, Tuomilehto J, Koulu M, Huupponen R (1998) Inverse correlation between serum testosterone and leptin in men. J Clin Endocrinol Metab 83:3243–3246
Mancini MC (2009) Metabolic syndrome in children and adolescents—criteria for diagnosis. Diabetol Metab Syndr 1:20
Marra AM, Improda N, Capalbo D, Salzano A, Arcopinto M, De Paulis A, Alessio M, Lenzi A, Isidori AM, Cittadini A, Salerno M (2015) Cardiovascular abnormalities and impaired exercise performance in adolescents with congenital adrenal hyperplasia. J Clin Endocrinol Metab 100:644–652
Marshall WA, Tanner JM (1969) Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303
Marshall WA, Tanner JM (1970) Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419
Merke DP, Chrousos GP, Eisenhofer G, Weise M, Keil MF, Rogol AD, Van Wyk JJ, Bornstein SR (2000) Adrenomedullary dysplasia and hypofunction in patients with classic 21-hydroxylase deficiency. N Engl J Med 343:1362–1368
Mooij CF, Kroese JM, Sweep FC, Hermus AR, Tack CJ (2011) Adult patients with congenital adrenal hyperplasia have elevated blood pressure but otherwise a normal cardiovascular risk profile. PLoS One 6:e24204
Mora S, Saggion F, Russo G, Weber G, Bellini A, Prinster C, Chiumello G (1996) Bone density in young patients with congenital adrenal hyperplasia. Bone 18:337–340
Moreira RP, Villares SM, Madureira G, Mendonca BB, Bachega TA (2013) Obesity and familial predisposition are significant determining factors of an adverse metabolic profile in young patients with congenital adrenal hyperplasia. Horm Res Paediatr 80:111–118
Reisch N, Arlt W, Krone N (2011) Health problems in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res Paediatr 76:73–85
Sahakitrungruang T, Wacharasindhu S, Supornsilchai V, Srivuthana S, Kingpetch K (2008) Bone mineral density and body composition in prepubertal and adolescent patients with the classical form of 21-hydroxylase deficiency. J Med Assoc Thail 91:705–710
Sartorato P, Zulian E, Benedini S, Mariniello B, Schiavi F, Bilora F, Pozzan G, Greggio N, Pagnan A, Mantero F, Scaroni C (2007) Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 92:1015–1018
Savva SC, Tornaritis M, Savva ME, Kourides Y, Panagi A, Silikiotou N, Georgiou C, Kafatos A (2000) Waist circumference and waist-to-height ratio are better predictors of cardiovascular disease risk factors in children than body mass index. Int J Obes Relat Metab Disord 24:1453–1458
Schwimmer JB, Dunn W, Norman GJ, Pardee PE, Middleton MS, Kerkar N, Sirlin CB (2010) SAFETY study: alanine aminotransferase cutoff values are set too high for reliable detection of pediatric chronic liver disease. Gastroenterology 138:1357–1364
Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE, Ritzen M, White PC (2010) Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95:4133–4160
Speiser PW, White PC (2003) Congenital adrenal hyperplasia. N Engl J Med 349:776–788
Stikkelbroeck NMML (2003) Normal bone mineral density and lean body mass, but increased fat mass, in young adult patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 88:1036–1042
Subbarayan A, Dattani MT, Peters CJ, Hindmarsh PC (2014) Cardiovascular risk factors in children and adolescents with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol 80:471–477
Volkl TM, Simm D, Beier C, Dorr HG (2006) Obesity among children and adolescents with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics 117:e98–105
Volkl TM, Simm D, Dotsch J, Rascher W, Dorr HG (2006) Altered 24-hour blood pressure profiles in children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:4888–4895
Volkl TM, Simm D, Korner A, Rascher W, Kiess W, Kratzsch J, Dorr HG (2009) Does an altered leptin axis play a role in obesity among children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency? Eur J Endocrinol 160:239–247
Wabitsch M, Blum WF, Muche R, Braun M, Hube F, Rascher W, Heinze E, Teller W, Hauner H (1997) Contribution of androgens to the gender difference in leptin production in obese children and adolescents. J Clin Invest 100:808–813
Walker BR (2007) Glucocorticoids and cardiovascular disease. Eur J Endocrinol 157:545–559
Weiss R, Dziura J, Burgert TS, Tamborlane WV, Taksali SE, Yeckel CW, Allen K, Lopes M, Savoye M, Morrison J, Sherwin RS, Caprio S (2004) Obesity and the metabolic syndrome in children and adolescents. N Engl J Med 350:2362–2374
World Health Organization (2011) Waist circumference and waist-hip ratio. Report of a WHO Expert Consultation, Geneva, 8–11 December 2008. WHO Document Production Services, Geneva
Zhang HJ, Yang J, Zhang MN, Liu CQ, Xu M, Li XJ, Yang SY, Li XY (2010) Metabolic disorders in newly diagnosed young adult female patients with simple virilizing 21-hydroxylase deficiency. Endocrine 38:260–265
Zimmermann A, Grigorescu-Sido P, AlKhzouz C, Patberg K, Bucerzan S, Schulze E, Zimmermann T, Rossmann H, Geiss HC, Lackner KJ, Weber MM (2010) Alterations in lipid and carbohydrate metabolism in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm Res Paediatr 74:41–49
Acknowledgments
We would like to thank the patients and their families for their participation in this study. This study was supported by the Ratchadapiseksompotch Fund (RA57/048), Faculty of Medicine, Chulalongkorn University and the Thailand Research Fund (IRG5780015).
Authors’ contributions
KA and TS had the core idea for this study. All authors either analyzed the data or interpreted the results. KA wrote the draft of the article. All other authors participated in the review of the literature, text editing, and finalization of the manuscript. All authors read and approved the final manuscript.
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All procedures were performed according to the Declaration of Helsinki and approved by the Ethics Committee, Faculty of Medicine, Chulalongkorn University. Written informed consent was obtained from the patient and/or the patient’s parent for their participation in this study.
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Ariyawatkul, K., Tepmongkol, S., Aroonparkmongkol, S. et al. Cardio-metabolic risk factors in youth with classical 21-hydroxylase deficiency. Eur J Pediatr 176, 537–545 (2017). https://doi.org/10.1007/s00431-017-2875-2
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DOI: https://doi.org/10.1007/s00431-017-2875-2