Trends in hospital admissions for adrenal insufficiency in adolescents and young adults in the 21st century.

Background: Very little is known about the epidemiology of adrenal crises (AC) and adrenal insufficiency (AI) in adolescents and young adults. Methods: Data on all admissions to Australian hospitals between 2000/1 to 2019/20 for a principal diagnosis of AI (including AC) in 10-24 year olds were extracted from a national repository. Age and sex-specific rates and age-adjusted rates were compared. Findings: Over the study, there were 3386 admissions for a principal diagnosis of AI; 24.0% (n=812) were for an AC and 50·7% (n=1718) were for secondary AI. Age-adjusted AI admissions increased from 31·70/million in 2000/1 to 54·68/million in 2019/20 (p<0·0001). Age-adjusted AC admissions also increased, most notably in the second decade (from 5·80/million in 2010/11 to 15·75/million in 2019/20) (p<0·00001). Average AI and AC admission rates were comparable between the sexes, but rates increased significantly in females, especially in those aged 20 to 24 years, whose AC rate in 2019/20 (39·65/million) was significantly higher than the corresponding rate in 2000/1 (3·15/million) (p<0·00001). Average age-adjusted SAI admission rates were higher in males (23·92/million) than females (15·47/million) (p<0·00001). However, SAI admission rates increased only among females (from 11·81/million to 22·12/million in 2019/20), with an increase in 20-24 year old females in the second decade from 5·07/million in 2010 to 20·42/million (p<0·00001). Age adjusted admissions for congenital adrenal hyperplasia, primary AI (PAI) and drug-induced AI did not change significantly over the study. Interpretation: AC/AI admissions increased over the first two decades of this century in the emerging adult population, particularly among females who also experienced a marked increase in AC admission rates, most evident in the second decade. Although uncertain, possible explanations include: dose of glucocorticoid replacement; non-adherence to therapy; psychosocial factors; and difficulty in transition to adult services. Admissions for SAI also increased, while rates of PAI and CAH remained constant.

Adrenal crises in adolescents and young adults.

PURPOSE: Review the literature concerning adrenal insufficiency (AI) and adrenal crisis (AC) in adolescents and young adults. METHODS: Searches of PubMed identifying relevant reports up to March 2022. RESULTS: AI is rare disorder that requires lifelong glucocorticoid replacement therapy and is associated with substantial morbidity and occasional mortality among adolescents and young adults. Aetiologies in this age group are more commonly congenital, with acquired causes, resulting from tumours in the hypothalamic-pituitary area and autoimmune adrenalitis among others, increasing with age. All patients with AI are at risk of AC, which have an estimated incidence of 6 to 8 ACs/100 patient years. Prevention of ACs includes use of educational interventions to achieve competency in dose escalation and parenteral glucocorticoid administration during times of physiological stress, such as an intercurrent infection. While the incidence of AI/AC in young children and adults has been documented, there are few studies focussed on the AC occurrence in adolescents and young adults with AI. This is despite the range of developmental, psychosocial, and structural changes that can interfere with chronic disease management during this important period of growth and development. CONCLUSION: In this review, we examine the current state of knowledge of AC epidemiology in emerging adults; examine the causes of ACs in this age group; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in these patients.

Use of medical identification jewellery in children and young adults with adrenal insufficiency in Australia.

PURPOSE: Patients with adrenal insufficiency (AI) are at risk of life-threatening illness. Medical jewellery is recommended for emergencies, but its uptake is unknown. This study assessed the use of medical jewellery among Australian AI patients aged 25 years and under. METHODS: Data on the age, sex, region, and diagnosis of subscribers to the largest medical jewellery provider in Australia were analysed. Subscription rates were calculated using 2017 Australian population data. RESULTS: There were 666 patients aged 25 years and under in the database but only 358 (53.8%) had an active (up to date) subscription, corresponding to a subscription rate of 43.67/million or approximately 14.6% of the estimated patient population. The majority (n = 238, 66.5%) had primary AI; followed by secondary AI (n = 82, 22.9%); and the remaining patients (n = 38, 10.6%) could not be classified. Congenital adrenal hyperplasia (CAH) was the most frequent diagnosis (n = 153, 42.7%), corresponding to a subscription rate of 18.67/ million or 28.9% of the estimated number of patients with CAH. The mean age of subscribers was 15.9 (SD = 5.8) years. Only 18 (5%) patients were aged under 5 years. More females (n = 199, 55.9%) than males were active subscribers and subscription rates differed significantly by geographic area. Inactive (lapsed) subscriptions increased with age and were highest in the 20-25 year age group. CONCLUSION: Subscription rates were lower than recommended; increased with age; and were more common in females. Older age was associated with higher levels of lapsed subscriptions. Factors leading to low use and discontinuation in young adults should be addressed.

The effect of patient-managed stress dosing on electrolytes and blood pressure in acute illness in children with adrenal insufficiency.

BACKGROUND: Adrenal crises (AC) are acute episodes of adrenal insufficiency (AI). Manifestations include hypotension and electrolyte disturbances. Glucocorticoid stress dosing (SD) can prevent AC progression, but its effect on physiological parameters has not been assessed in a 'real world setting'. AIMS: To assess the effect of prior self-managed glucocorticoid dose escalation on physiological markers in children with congenital adrenal hyperplasia (CAH) presenting to hospital for an acute illness. METHODS: An audit of records of all children with CAH presenting to paediatric referral hospital between 2000 and 2015. Potassium, sodium and glucose levels, and hypotension were compared between children who had and had not used SD. RESULTS: There were 321 attendances by patients with CAH and an acute illness during the study period. Any form of SD was used by 64.2% (n = 206); intramuscular (IM) hydrocortisone was used by 22.1% (n = 71) and oral only by 41.7% (n = 134). Use of SD (oral and/or IM) was associated with a significantly lower mean potassium level (4.02 ± 0.71 vs. 4.27 ± 0.79 mmol/l, P < .05). Linear regression analysis showed that age (beta: -0.04 years (95% CI -0.06, -0.02)), diarrhoea (beta: -0.41 (95% CI -0.06, -0.02)) and any form of stress dosing (oral, IM or both) (beta: -0.29 (95% CI -0.55, -0.04)) were each independently and significantly associated with potassium levels. SD was not significantly associated with sodium or glucose concentrations or with estimates of hypotension. CONCLUSION: Patient-initiated SD resulted in a significant reduction in hyperkalaemia and lowered mean potassium levels in paediatric patients with CAH but did not alter significantly sodium and glucose concentrations or incidences of hypotension.

P450 Oxidoreductase Deficiency: A Systematic Review and Meta-analysis of Genotypes, Phenotypes, and Their Relationships.

CONTEXT: P450 oxidoreductase deficiency (PORD) is a rare genetic disorder that is associated with significant morbidity. However there has been limited analysis of reported PORD cases. OBJECTIVE: To determine, based on the cohort of reported PORD cases, genotype-phenotype relationships for skeletal malformations, maternal virilisation in pregnancy, adrenal insufficiency, and disorders of sexual development (DSD). DATA SOURCES: PubMed and Web of Science from January 2004 to February 2018. STUDY SELECTION: Published case reports/series of patients with PORD. Eligible patients were unique, had biallelic mutations, and their clinical features were reported. DATA EXTRACTION: Patient data were manually extracted from the text of case reports/series. A malformation score, representing the severity of skeletal malformations, was calculated for each patient. DATA SYNTHESIS: Of the 211 patients published in the literature, 90 were eligible for inclusion. More than 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modeling, as having significantly different skeletal malformation scores. Maternal virilization in pregnancy, reported for 21% of patients, was most common for R457H mutations. Adrenal insufficiency occurred for the majority of patients (78%) and was typically mild, with homozygous R457H mutations being the least deficient. DSD affected most patients (72%), but were less common for males (46XY) with homozygous R457H mutations. CONCLUSIONS: PORD is a complex disorder with many possible mutations affecting a large number of enzymes. By analyzing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features.

The use of medical identification jewellery in adults with adrenal insufficiency in Australia.

OBJECTIVE: Hydrocortisone stress dosing during illness can prevent adrenal crises (AC) in patients with adrenal insufficiency (AI). When patients cannot communicate, medical identification jewellery may facilitate parenteral hydrocortisone provision but patient adoption rates are not known. DESIGN: A cross-sectional analysis of Australian medical identification jewellery subscription data. PATIENTS: Patients with AI aged 20 years and over with an active subscription to a large medical jewellery provider. MEASUREMENTS: Subscription rates by AI subtype, geographic area, age and gender. RESULTS: There were 1955 patients with AI and an active subscription in the database, corresponding to a subscription rate of 105.79/million or approximately one-third of the AI population. The subscription rate was substantially higher in primary AI (60.72/million) than secondary AI (23.16/million), corresponding to approximately 60.7% and 11.6% of the estimated population prevalence of each disorder, respectively. There was substantial variation in use by state/territory, with the highest subscribing state having a rate of over four times that of the lowest (P < 0.001). Women comprised 64.8% (n = 1266) of the group. Subscription also varied by age, being highest in the 60-69 year age group (165.15/million) and lowest in those aged 30-39 years (47.23/million) (P < 0.001). Few patients (4.8%, n = 94) mentioned, either in their record or on their jewellery, the need for urgent parenteral hydrocortisone in the event of severe illness. CONCLUSIONS: Medical jewellery is a component of AC risk reduction. However, subscription appears to be underutilised in the Australian AI population, especially among patients with secondary AI. Urgent treatment recommendations should be inscribed on the jewellery.

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 75 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. Higher numbers of prior hospital attendances for acute illness were associated with increased use of IM hydrocortisone. CONCLUSION: Prehospital 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.

GLUCOCORTICOID-INDUCED ADRENAL INSUFFICIENCY: A STUDY OF THE INCIDENCE IN HOSPITAL PATIENTS AND A REVIEW OF PERI-OPERATIVE MANAGEMENT.

OBJECTIVE: Glucocorticoid (GC) pharmacotherapy is an effective treatment for a range of diseases, but exposure can suppress the hypothalamic-pituitary-adrenal axis, leading to glucocorticoid-induced adrenal insufficiency (GC-AI) in some patients. However, the incidence of diagnosed GC-AI and the associated health burden, including the incidence of adrenal crises (ACs), are unknown. Although GC-AI treatment is based on well-established principles, there are no agreed protocols regarding the peri-operative management of exposed patients. The aims of this study were to assess the incidence of diagnosed GC-AI in hospital patients and review current approaches to peri-operative management of surgical patients with GC exposure. METHODS: An analysis of hospital admission data concerning adult patients diagnosed with GC-AI and a review of published recommendations for peri-operative GC cover. RESULTS: Between 2001 and 2013, admission with a diagnosis of GC-AI in New South Wales, Australia was rare (annual average of 22.5 admissions/year) and ACs were even more rare (n = 3). Almost two-thirds (64.4%, n = 188) of the patients with diagnosed GC-AI were aged between 50 and 79 years and 45.2% (n = 132) had a comorbid infection. The current approach to peri-operative management of patients with GC exposure appears to be influenced by both the absence of clear guidelines and historic practices. This results in the exposure of some patients to supraphysiologic doses of GCs during the peri-operative period. CONCLUSION: Hospital admission with a diagnosis of GC-AI (with or without an AC) is very rare. Clear guidelines on peri-operative GC cover are necessary to avoid overreplacement with supraphysiologic doses in susceptible patients. ABBREVIATIONS: AC = adrenal crisis; ACTH = adrenocorticotropic hormone; AI = adrenal insufficiency; CI = confidence interval; GC = glucocorticoid; GC-AI = glucocorticoid-induced adrenal insufficiency; HPA = hypothalamic-pituitary-adrenal; OR = odds ratio.

Hospitalisation in Children with Adrenal Insufficiency and Hypopituitarism: Is There a Differential Burden between Boys and Girls and between Age Groups?

BACKGROUND/AIMS: To determine the burden of hospitalisation in children with adrenal insufficiency (AI)/hypopituitarism in Australia. METHODS: A retrospective study of Australian hospitalisation data. All admissions between 2001 and 2014 for patients aged 0-19 years with a principal diagnosis of AI/hypopituitarism were included. Denominator populations were extracted from national statistics datasets. RESULTS: There were 3,779 admissions for treatment of AI/hypopituitarism in patients aged 0-19 years, corresponding to an average admission rate of 48.7 admissions/million/year. There were 470 (12.4%) admissions for an adrenal crisis (AC). Overall, admission for AI/hypopituitarism was comparable between the sexes. Admission rates for all AI, hypopituitarism, congenital adrenal hyperplasia (CAH), and "other and unspecified causes" of AI were highest among infants and decreased with age. Admissions for primary AI increased with age in both sexes. Males had significantly higher rates of admission for hypopituitarism. AC rates differed by both sex and age group. CONCLUSION: This nationwide study of the epidemiology of hospital admissions for a principal diagnosis of AI/hypopituitarism shows that admissions generally decreased with age; males had higher rates of admission for hypopituitarism; females had higher rates of admission for CAH and "other and unspecified causes" of AI; and AC incidence varied by age and sex. Increased awareness of AI and AC prevention strategies may reduce some of these admissions.