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

Pre-hospital management of acute Addison’s Disease – Audit of patients attending a referral hospital in a regional area

Context: Adrenal crises (AC) cause morbidity and mortality in patients with Addison’s disease [primary adrenal insufficiency (PAI)]. Patient-initiated oral stress dosing, with parenteral hydrocortisone, is recommended to avert ACs. While these should be effective, the continued incidence of ACs remains largely unexplained. Methods: Audit of all attendances between 2000 and 2017 by adult patients with treated PAI to one large regional referral centre in New South Wales, Australia. Measurements were those taken on arrival at hospital. Results: There were 252 attendances by 56 patients with treated PAI during the study period. Women comprised 60.7% (n=34) of the patients. The mean age of attendees was 53.7 (19.6) years. Nearly half (45.2%, n=114) the patients had an infection. There were 61 (24.2%) ACs diagnosed by the treating clinician. Only 17.9% (n=45) of the hospital presentations followed any form of stress dosing. IM hydrocortisone was used before 7 (2.8%) attendances only. Among patients with a clinician diagnosed AC, only 32.8% (n=20) had used stress dosing before presentation. Vomiting was reported by 47.6% (n=120) of the patients but only 33 (27.5%) of these attempted stress dosing and 5 patients with vomiting used IM hydrocortisone. The number of prior presentations was a significant independent predictor of use of stress doses [1.05 (1.01,1.09)]. Conclusion: Dose escalation strategies are not used universally or correctly by unwell patients with PAI, many patients do not use IM or SC hydrocortisone injections. Previous hospital treatment increases the likelihood of stress dosing and offers the opportunity for reinforcement of prevention strategies

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

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

Factors underlying a disproportionate increase in hospital admissions for adrenal insufficiency in women aged 20-29 years

Since the year 2000, admissions for adrenal insufficiency (AI) and adrenal crises (AC) have shown a particular increase in young adult females. We examined data on acute non-surgical hospitalisations for AI/AC from New South Wales, Australia, to determine relevant factors that may have contributed to this increase. Data were analysed to ascertain associations between various comorbid psychosocial issues, identified by relevant ICD-10-AM codes in each record, and ACs. From 2005 to 2021. There were 877 admissions for an acute non-surgical illness in this age group. The average admission rate for females [63.5/million/year] was almost twice that for males [34.0/million/year] (p<0.01), as was the average female AC admission rate [14.7/million/year] relative to that in males [6.75/million/year] (p=NS). Infection was present in 41.6% (n=365) of the admissions and Type 1 diabetes mellitus was present in 12.2% (n=107). Overall, psychosocial factors were considered by the senior clinician to have contributed to the illness episode in 22.1% of all admissions and 29.0% of AC admissions. Having one or more psychosocial problems was associated with an AC in females (37.4%, n=49, in those having an AC, p<0.001) but not males. Females with an AC also had a higher mean composite psychosocial, psychiatric and drug/alcohol score [0.47 (0.67)] than females without an AC [0.32 (0.62) p<0.05]. No comparable associations were found in male patients. An increase in the rates of hospitalisations that included a code for at least one psychosocial problem was highly correlated with increases in admission rates for both ACs (r=0.82, p<0.001) and all AI (r=0.98, p<0.001) in females but there was no such relationship in males. This new evidence suggests that psychosocial factors may play an important role in ongoing rates of ACs in treated AI (incidence approximately 6-8 ACs/100PY) particularly in young adult females. In order to minimize AC episodes, all barriers to self-management need exploration on an individual patient basis and with regard to the patient population as a whole

Cortisol, Stress, and Disease—Bidirectional Associations:Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent “primary stress system disorders” were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the “hypocortisolemic symptom triad” of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation–genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders

The epidemiology, healthcare and societal burden and costs of asthma in the UK and its member nations: analyses of standalone and linked national databases

Background There are a lack of reliable data on the epidemiology and associated burden and costs of asthma. We sought to provide the first UK-wide estimates of the epidemiology, healthcare utilisation and costs of asthma. Methods We obtained and analysed asthma-relevant data from 27 datasets: these comprised national health surveys for 2010–11, and routine administrative, health and social care datasets for 2011–12; 2011–12 costs were estimated in pounds sterling using economic modelling. Results The prevalence of asthma depended on the definition and data source used. The UK lifetime prevalence of patient-reported symptoms suggestive of asthma was 29.5 % (95 % CI, 27.7–31.3; n = 18.5 million (m) people) and 15.6 % (14.3–16.9, n = 9.8 m) for patient-reported clinician-diagnosed asthma. The annual prevalence of patient-reported clinician-diagnosed-and-treated asthma was 9.6 % (8.9–10.3, n = 6.0 m) and of clinician-reported, diagnosed-and-treated asthma 5.7 % (5.7–5.7; n = 3.6 m). Asthma resulted in at least 6.3 m primary care consultations, 93,000 hospital in-patient episodes, 1800 intensive-care unit episodes and 36,800 disability living allowance claims. The costs of asthma were estimated at least £1.1 billion: 74 % of these costs were for provision of primary care services (60 % prescribing, 14 % consultations), 13 % for disability claims, and 12 % for hospital care. There were 1160 asthma deaths. Conclusions Asthma is very common and is responsible for considerable morbidity, healthcare utilisation and financial costs to the UK public sector. Greater policy focus on primary care provision is needed to reduce the risk of asthma exacerbations, hospitalisations and deaths, and reduce costs

The impact of iodine supplementation and bread fortification on urinary iodine concentrations in a mildly iodine deficient population of pregnant women in South Australia

Mild iodine deficiency during pregnancy can have significant effects on fetal development and future cognitive function. The purpose of this study was to characterise the iodine status of South Australian women during pregnancy and relate it to the use of iodine-containing multivitamins. The impact of fortification of bread with iodized salt was also assessed. Women (n = 196) were recruited prospectively at the beginning of pregnancy and urine collected at 12, 18, 30, 36 weeks gestation and 6 months postpartum. The use of a multivitamin supplement was recorded at each visit. Spot urinary iodine concentrations (UIC) were assessed. Median UICs were within the mildly deficient range in women not taking supplements (<90 μg/L). Among the women taking iodine-containing multivitamins UICs were within WHO recommendations (150–249 μg/L) for sufficiency and showed an increasing trend through gestation. The fortification of bread with iodized salt increased the median UIC from 68 μg/L to 84 μg/L (p = .011) which was still in the deficient range. Pregnant women in this region of Australia were unlikely to reach recommended iodine levels without an iodine supplement, even after the mandatory iodine supplementation of bread was instituted in October 2009.Vicki L Clifton, Nicolette A Hodyl, Paul A Fogarty, David J Torpy, Rachel Roberts, Ted Nettelbeck, Gary Ma and Basil Hetze

Impulse control disorders in dopamine agonist-treated hyperprolactinemia: Prevalence and risk factors

Context: There are growing reports of dopamine agonist (DA)-induced impulse control disorders (ICDs) in hyperprolactinemic patients. However, the magnitude of this risk and predictive factors remain uncertain. Objective: To determine ICD prevalence and risk factors in DA-treated hyperprolactinemic patients compared to community controls. Design, Setting and Participants: Multicenter cross-sectional analysis of 113 patients and 99 healthy controls. Main Outcome Measures: Participants completed a neuropsychological questionnaire consisting of the Depression Anxiety Stress Scale (DASS21), Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s disease (QUIP-S), Hypersexual Behavior Inventory (HBI), Hypersexual Behavior Consequences Scale and Social Desirability Response Set Scale. Demographic and clinical data were collated to determine ICD risk factors. Patients testing positive for an ICD were offered a semi-structured psychological interview. Results: Patients were more likely than controls to test positive by QUIP-S for any ICD (61.1 vs 42.4%, P=0.01), hypersexuality (22.1 vs 8.1%, P=0.009), compulsive buying (15.9 vs 6.1%, P=0.041) and punding (18.6 vs 6.1%, P=0.012), and by HBI for hypersexuality (8.0 vs 0.0%, P=0.004). Independent risk factors were male sex (OR 13.85), eugonadism (OR 7.85), Hardy’s tumor score, and psychiatric comorbidity (OR 6.86) for hypersexuality; and age (OR 0.95) for compulsive buying. DASS21 subset scores were higher in patients vs controls, and in patients with vs without different ICDs. Only 19/51 (37.3%) interviewed patients were aware of the relationship between DAs and ICDs before the study. Conclusions: DA therapy poses a high, previously underestimated risk of ICDs, especially in the form of hypersexuality in eugonadal men

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 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 patients were eligible for inclusion. Over 60 unique mutations were identified in this cohort. Four groups of mutations were identified, through regression modelling, as having significantly different skeletal malformation scores. Maternal virilisation 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 analysing the cohort of reported PORD cases, this study identified clear relationships between genotype and several important phenotypic features