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

Recurrent nocturnal hypoglycaemia as a cause of morning fatigue in treated Addison’s disease – Favourable response to dietary management: A case report

Background: Addison’s disease, or primary adrenal insufficiency, is often associated with reduced well-being and fatigue despite use of currently recommended adrenal hormone replacement. Hypoglycaemia is a known manifestation of glucocorticoid deficiency, but is generally considered rare in adults and not relevant to troubling ongoing symptoms in patients with Addison’s disease. Case presentation: A 43 year old woman with a three year history of Addison’s disease complained of severe morning fatigue and headaches, despite standard glucocorticoid replacement therapy in the form of thrice daily hydrocortisone and mineralocorticoid replacement with fludrocortisone. Alternative glucocorticoid replacement regimens and the addition of dehydroepiandrosterone replacement therapy had no effect. Nocturnal hypoglycaemia was suspected and a 4-day continuous glucose monitor system (CGMS) revealed hypoglycaemia (interstitial glucose \u3c 2.2mmol/L) between 0200–0400 h on 3 of 4 days. The patient was counselled to take an evening snack designed to ensure slow absorption of ingested carbohydrates. Nocturnal hypoglycaemia was then absent on follow up CGMS assessment. The patient noted a marked symptomatic improvement in morning symptoms, but with persistent fatigue during the day. Conclusion: Currently, the best strategy for control of non-specific symptoms in treated Addison’s disease is unknown, but it may be that investigation for hypoglycaemia and treatment, where necessary, could assist some sufferers to achieve improved wellbeing. A systematic study of this phenomenon in Addison’s disease is required

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

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

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

Pharmacological Fingerprints of Contextual Uncertainty

Successful interaction with the environment requires flexible updating of our beliefs about the world. By estimating the likelihood of future events, it is possible to prepare appropriate actions in advance and execute fast, accurate motor responses. According to theoretical proposals, agents track the variability arising from changing environments by computing various forms of uncertainty. Several neuromodulators have been linked to uncertainty signalling, but comprehensive empirical characterisation of their relative contributions to perceptual belief updating, and to the selection of motor responses, is lacking. Here we assess the roles of noradrenaline, acetylcholine, and dopamine within a single, unified computational framework of uncertainty. Using pharmacological interventions in a sample of 128 healthy human volunteers and a hierarchical Bayesian learning model, we characterise the influences of noradrenergic, cholinergic, and dopaminergic receptor antagonism on individual computations of uncertainty during a probabilistic serial reaction time task. We propose that noradrenaline influences learning of uncertain events arising from unexpected changes in the environment. In contrast, acetylcholine balances attribution of uncertainty to chance fluctuations within an environmental context, defined by a stable set of probabilistic associations, or to gross environmental violations following a contextual switch. Dopamine supports the use of uncertainty representations to engender fast, adaptive responses. \ua9 2016 Marshall et al