title: Increased Cardiovascular and Metabolic Morbidity in Patients With 21-Hydroxylase Deficiency: A Swedish Population-Based National Cohort Study.
abstract: BACKGROUND
  Congenital adrenal hyperplasia (CAH) is lethal in its most severe forms if not treated with glucocorticoids. However, glucocorticoids may increase the risk of cardiovascular and metabolic morbidity.
  
  
  OBJECTIVE
  This study aimed to study cardiovascular and metabolic morbidity in CAH.
  
  
  METHODS
  Patients with CAH due to 21-hydroxylase deficiency (n = 588; >80% with known CYP21A2 mutations) were compared with controls matched for sex, year, and place of birth (n = 58 800). Data were obtained by linking national population-based registers. Subgroup analyses were performed regarding sex, clinical severity (salt wasting, simple virilizing, nonclassic), CYP21A2 genotype (null, I2 splice, I172N, P30L), and stratified by the introduction of neonatal screening, age groups, and nonobesity.
  
  
  METHODS
  To study cardiovascular and metabolic morbidity in CAH.
  
  
  RESULTS
  In CAH, both any cardiovascular and metabolic disorders (OR [odds ratio], 3.9; 95% CI [confidence interval], 3.1-5.0), and cardiovascular disease (OR, 2.7; 95% CI, 1.9-3.9) were increased. Separate analyses of the individual diseases showed higher frequencies in CAH of hypertension, hyperlipidemia, atrial fibrillation, venous thromboembolism, obesity, diabetes (mainly type 2), obstructive sleep disorder, thyrotoxicosis, and hypothyroidism. Similar results were seen in the stratified groups. On the subgroup level, females were generally more affected (especially I172N and the nonclassic group), as were males with the null genotype.
  
  
  CONCLUSIONS
  CAH was associated with excess cardiovascular and metabolic morbidity but the mechanism is not certain as the glucocorticoids were not assessed. Hypothyroidism and obesity may be an effect of close observation. However, more severe conditions were presumably detected equally in patients and controls. Screening for diabetes and other metabolic disorders that increase cardiovascular risk is important.
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Falhammar
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Frisén
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Angelica Linden
authors.initials: AL
authors.lastname: Hirschberg
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Norrby
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Catarina
authors.initials: C
authors.lastname: Almqvist
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordenskjöld
authors.affiliation: Department of Endocrinology, Metabolism and Diabetes (H.F.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Molecular Medicine and Surgery, SE-171 76 Karolinska Institutet (H.F.), Stockholm, Sweden; Department of Clinical Neuroscience (L.F.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Child and Adolescent Psychiatry Research Center (L.F.), SE-113 30 Stockholm, Sweden; Department of Obstetrics and Gynaecology (A.L.H.), Karolinska University Hospital, SE-171 76 Stockholm, Sweden; Department of Women's and Children's Health (A.L.H., Ag.N., An.N.), SE-171 76 Karolinska Institutet, Stockholm, Sweden; Department of Medical Epidemiology and Biostatistics (C.N., C.A.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Lung and Allergy Unit (C.A.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden; Center for Molecular Medicine (Ag.N.), Karolinska Institutet, SE-171 76 Stockholm, Sweden; and Paediatric Surgery (Ag.N.) and Department of Paediatric Endocrinology (An.N.), Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 64 Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Nordenström
mesh_terms: D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital / Q000453:epidemiology* / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases / Q000453:epidemiology* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008659:Metabolic Diseases / Q000453:epidemiology* / Q000235:genetics; D008875:Middle Aged; D015997:Neonatal Screening; D015995:Prevalence; D012306:Risk; D013255:Steroid 21-Hydroxylase / Q000235:genetics; D055815:Young Adult
chemical_list: C531510:CYP21A2 protein, human; D013255:Steroid 21-Hydroxylase