Variations in the management of acute illness in children with congenital adrenal hyperplasia: An audit of three paediatric hospitals

Objective: Episodes of acute adrenal insufficiency (AI)/adrenal crises (AC) are a serious consequence of congenital adrenal hyperplasia (CAH). This study aimed to assess morbidity from acute illness in CAH and identify factors associated with use of IV hydrocortisone, admission and diagnosis of an AC. Method: An audit of acute illness presentations among children with CAH to paediatric hospitals in New South Wales, Australia, between 2000 and 2015. Results: There were 321 acute presentations among 74 children with CAH. Two thirds (66.7%, n=214) of these resulted in admission and 49.2% (n=158) of the patients received intravenous (IV) hydrocortisone. An AC was diagnosed in (9.0%). Prior to presentation, 64.2% (n=206) had used oral stress dosing and 22.1% (n=71) had been given intramuscular (IM) hydrocortisone. Vomiting was recorded in 61.1% (n=196), 32.7% (n=64) of whom had used IM hydrocortisone. Admission, AC diagnosis, and use of stress dosing varied significantly between hospitals. IM use varied from 7.0% in one metropolitan hospital to 45.8% in the regional hospital. Children aged up to 12 months had the lowest levels of stress dosing and IV hydrocortisone administration. A higher number of prior hospital attendances for acute illness was associated with increased use of IM hydrocortisone. Conclusion: Pre-hospital and in-hospital management of children with CAH can vary between health services. Children under 12 months have lower levels of stress dosing prior to hospital than other age groups. Experience with acute episodes improves self-management of CAH in the context of acute illness in educated patient populations

Congenital Adrenal Hyperplasia in Adults

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder affecting adrenal steroid synthesis. More than 95% of CAH cases are caused by reduced 21-hydroxylase function leading to variable extent of cortisol and aldosterone deficiency in addition to androgen excess. The foundation of CAH treatment is the use of glucocorticoids. However, overtreatment leads to Cushing s syndrome and undertreatment to hyperandrogenism and Addisonian crisis. The aims of this thesis has been to evaluate the impact of CAH and its treatment on some factors that could lead to a reduced quality of life and increased morbidity or mortality during adult life. In total 93 patients (32 males) with CAH and 93 (32 males) age- and sex-matched controls were studied. Subgroups of different ages (<30 years or older), phenotypes and the three most common genotype groups (null, I2 splice and I172N) were studied. Focus was on cardiovascular and metabolic risk, bone health in females and fertility in males. Cardiovascular and metabolic risk: Younger female and male patients and controls had similar waist/hip ratio, lean and fat mass and insulin values. Older females had higher waist/hip ratio, lean mass and insulin values than controls. Fat mass was similar to controls but higher than in younger patients. Lipid profiles were slightly more favourable in older patients than in controls. Gestational diabetes was more common in patients. Few older female patients had hypertension, cardiovascular disease or diabetes. Despite moderate glucocorticoid doses, most patients had suppressed androgens. Serum liver enzymes were elevated in patients compared to controls. In patients, liver enzymes were correlated with waist circumference and with total body and trunk fat. Liver enzymes were increased even in non-obese patients mainly attributed to the patients ≥30 years who also demonstrated elevated insulin levels and HOMA-indices. In older males, waist/hip ratio, fat mass, and gamma-glutamyl transpeptidase were higher and heart rate faster than in controls. Insulin levels were increased during oral glucose tolerance test in all and older patients. Homocysteine was lower in all and in younger male patients which may be cardioprotective. Adverse cardiovascular profiles were mainly found in the mild genotype I172N. This group had normal urinary epinephrine concentrations whereas the more severe genotypes null and I2 splice had low levels. Few old male patients had cardiovascular disease and no patient had diabetes. Bone health in females: Patients had lower bone mineral density (BMD) than controls at all measured sites. In patients ≥30 years old 73% were osteopenic or osteoporotic vs 21% in controls. BMD was similar in the two classic forms and had no obvious relationship to genotypes. More fractures were reported in patients than controls. Fertility in males: Compared to national data the fertility was impaired in CAH males. The lifetime number of partners was smaller in all patients, in older patients and in the null group. Testicular tumours (TARTs) were found in 86% and 47% had pathological semen. Those with pathological semen had increased total and truncal fat mass, fat/lean mass ratio and heart rate. FSH was elevated and correlated negatively with sperm count and concentration. Conclusions: Adult CAH females and males have a number of issues due to the disease and to corticoid supplementation. However, the findings in this thesis are more positive than many of the previous reports on CAH. Many parameters studied in our CAH individuals <30 years were not different from age- and sex-matched controls. This is likely to reflect improvements in management

Adrenal Crisis

Glucocorticoid replacement therapy, available since the 1950s, has prolonged the survival of patients with adrenal insufficiency. However, adrenal crises, which are life-threatening medical emergencies, still develop in many affected patients. Adrenal crisis appears to be increasing in frequency, despite the availability of effective preventive strategies. This review examines the definitions, pathophysiology, epidemiology, and treatment of adrenal crises

Adrenal crises: perspectives and research directions

Adrenal crises (AC) are life-threatening complications of adrenal insufficiency (AI). These events have an estimated incidence of between 5 and 10 ACs/100 patient years (PY) and are responsible for some of the increased morbidity and excess mortality experienced by patients with AI. Treatment involves urgent administration of IV/IM hydrocortisone and IV fluids. Patient education regarding preventive measures, such as increasing the dose of replacement therapy (“stress dosing”) when sick, using parenteral hydrocortisone as necessary and accessing medical assistance promptly, is still considered the best approach to averting the onset of an AC at times of physiological stress, most commonly an infection. However, recent evidence has demonstrated that patient education does not prevent many AC events and the reasons for this are not fully understood. Furthermore, there is no widely accepted definition of AC. Without a validated AC definition it is difficult to interpret variations in the incidence of AC and determine the effectiveness of preventive measures. This article aims to review the clinical aspects of AC events; to explore the epidemiology; and to offer a definition for an AC and to offer a perspective on future directions for research into AC prevention

Adrenal insufficiency due to bilateral adrenal metastases - A systematic review and meta-analysis

Objective: Bilateral adrenal metastases may cause adrenal insufficiency (AI) but it is unclear if screening for AI in patients with bilateral adrenal metastases is justified, despite the potential for adrenal crises. Method: A search using PubMed/Medline, ScienceDirect and Cochrane Reviews was performed to collect all original research articles and all case reports from the past 50 years that describe AI in bilateral adrenal metastases. Results: Twenty studies were included with 6 original research articles, 13 case reports and one case series. The quality was generally poor. The prevalence of AI was 3–8%. Of all cases of AI (n ¼ 25) the mean pooled baseline cortisol was 318 237 nmol/L and stimulated 423 238 nmol/L. Hypotension was present in 69%, hyponatremia in 9% and hyperkalemia in 100%. Lung cancer was the cause in 35%, colorectal 20%, breast cancer 15% and lymphoma 10%. The size of the adrenal metastases was 5.5 2.8 cm (left) and 5.5 3.1 cm (right), respectively. There was no correlation between basal cortisol, stimulated cortisol concentration or ACTH with the size of adrenal metastases. The median time to death was 5.0 months (IQR 0.6–6.5). However, two cases were alive after 12–24 months. Conclusion: The prevalence of AI in patients with bilateral adrenal metastases was low. Prognosis was very poor. Due to the low prevalence of AI, screening is likely only indicated in patients with symptoms and signs suggestive of hypocortisolism

Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency : a Swedish population-based national cohort study

CONTEXT: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. MAIN OUTCOME MEASURES: 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.Magn. Bergvalls FoundationKarolinska InstitutetStockholm County CouncilSwedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences, SIMSAM 340-2013-5867Manuscrip

Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Context: Reports on mortality in patients with congenital adrenal hyperplasia (CAH) are lacking. Objective: To study mortality and causes of death in CAH. Design, Setting and Participants: We studied patients with CAH (21-hydroxylase deficiency, n=588; CYP21A2 mutations known, >80%), and compared them with controls (n=58800). Data were derived through linkage of national population-based registers. Main Outcome Measures: Mortality and causes of death. Results: The mean age of death was 41.2±26.9 years in CAH patients and 47.7±27.7 years in controls (P<0.001). Among CAH patients 23 (3.9%) had deceased compared to 942 (1.6%) of controls. The hazard ratio (and 95% confidence interval) of death was 2.3(1.2-4.3) in CAH males and 3.5(2.0-6.0) in CAH females. Including only patients born 1952-2009, gave similar total results but only patients with salt-wasting or with unclear phenotype had an increased mortality. The causes of death in CAH patients were adrenal crisis (42%), cardiovascular (32%), cancer (16%), and suicide (10%). There were seven additional deaths in CAH individuals with incomplete or reused personal identification number that could not be analyzed using linkage of registers. Of the latter all except one were deceased before the introduction of neonatal screening in 1986 and most of them in the first weeks of life, probably in an adrenal crisis. Conclusions: CAH is a potentially lethal condition and was associated with excess mortality due to adrenal crisis. The salt-wasting phenotype seemed to have worse outcome also in children and adults due to adrenal crisis and not only before the introduction of neonatal screening.NonePublishe

Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia : epidemiological studies in a nonbiased national cohort in Sweden

Context: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. Objective: To study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. Design: An epidemiological study with a matched cohort control design. Setting: All known CAH patients in Sweden. Participants: 588 patients, >95% with known severity of CAH; 100 controls per patient matched for sex, year and place of birth. Main outcome and measures: Proxies for quality of life were selected: level of education, employment, income, sick-leave, disability pension, marriage and children. Results: Women with salt-wasting (SW) CAH had completed primary education less often (OR 0.3), not explained by neonatal salt-crisis or hypoglycemia since the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8) SW women were more likely to have an income in the top 20 percentile (OR 2.0 ). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long lasting employment (OR 3.1). Men were more often (OR 1.6) while women were less often married (OR 0.7). Patients had children less often (OR 0.3). Conclusions: This study shows important outcome differences regarding education, employment, marriage and fertility depending on sex and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care.The Swedish Research CouncilAccepte

Hospital admission patterns in children with CAH: admission rates and adrenal crises decline with age

Objective: To examine patterns of hospitalisation for acute medical conditions in children with congenital adrenal hyperplasia (CAH). Design: A retrospective study of hospitalisation using administrative data. Setting. All hospitals in NSW, Australia. Patients: All patients admitted with CAH and a random sample of admissions in patients aged 0 to 18 years without adrenal insufficiency (AI). Main Outcome Measures: Admissions and comorbidities by age and sex. Results: Of 573 admissions for medical problems in CAH children, 286 (49.9%) were in males, and 236 (41.2%) had a principal diagnosis of CAH or had an adrenal crisis (AC). 37 (6.5%) ACs were recorded. An infection was found in 43.5% ( = 249) of the CAH patient admissions and 51.7% ( = 1613) of the non-AI group, \u3c 0.001. Children aged up to one year had the highest number of admissions ( = 149) and six ACs (four in males).There were 21 ACs recorded for children aged 1–5 years. Older CAH children had fewer admissions and fewer ACs. No in-hospital deaths were recorded. Conclusions. Admission for medical problems in CAH children declines with age. An AC was recorded in 6.5% of the admissions, with the majority of ACs occurring in the 1 to 5 years age group and there were no deaths

Pubertal presentation in seven patients with congenital adrenal hyperplasia due to P450 Oxidoreductase deficiency

Context: P450 oxidoreductase (POR) is a crucial electron donor to all microsomal P450 cytochrome (CYP) enzymes including 17α-hydroxylase (CYP17A1), 21-hydroxylase (CYP21A2) and P450 aromatase. Mutant POR causes congenital adrenal hyperplasia with combined glucocorticoid and sex steroid deficiency. P450 oxidoreductase deficiency (ORD) commonly presents neonatally, with disordered sex development in both sexes, skeletal malformations, and glucocorticoid deficiency. \ud \ud Objective: The aim of the study was to describe the clinical and biochemical characteristics of ORD during puberty. \ud \ud Design: Clinical, biochemical, and genetic assessment of seven ORD patients (five females, two males) presenting during puberty was conducted. \ud \ud Results: Predominant findings in females were incomplete pubertal development (four of five) and large ovarian cysts (five of five) prone to spontaneous rupture, in some only resolving after combined treatment with estrogen/progestin, GnRH superagonists, and glucocorticoids. Pubertal development in the two boys was more mildly affected, with some spontaneous progression. Urinary steroid profiling revealed combined CYP17A1 and CYP21A2 deficiencies indicative of ORD in all patients; all but one failed to mount an appropriate cortisol response to ACTH stimulation indicative of adrenal insufficiency. Diagnosis of ORD was confirmed by direct sequencing, demonstrating disease-causing POR mutations. \ud \ud Conclusion: Delayed and disordered puberty can be the first sign leading to a diagnosis of ORD. Appropriate testosterone production during puberty in affected boys but manifest primary hypogonadism in girls with ORD may indicate that testicular steroidogenesis is less dependent on POR than adrenal and ovarian steroidogenesis. Ovarian cysts in pubertal girls may be driven not only by high gonadotropins but possibly also by impaired CYP51A1-mediated production of meiosis-activating sterols due to mutant POR