Should we routinely assess hypothalamic-pituitary-adrenal axis in pediatric patients with Prader-Willi syndrome?

Background: It has been reported that central adrenal insufficiency (CAI) in pediatric patients (pts) with Prader-Willi syndrome (PWS) may be a potential cause of their sudden death. In addition, the risk of CAI may increase during treatment with recombinant human growth hormone (rhGH). Objective: To prevent both over- and undertreatment with hydrocortisone, we evaluated the prevalence of CAI in a large multicenter cohort of pediatric pts with PWS analyzing adrenal response in the low-dose ACTH test (LDAT) and/or the glucagon stimulation test (GST) and reviewing the literature. Methods: A total of 46 pts with PWS were enrolled to the study, including 34 treated with rhGH with a median dose of 0.21 mg/kg/week. LDAT was performed in 46 pts, and GST was carried out in 13 pts. Both tests were conducted in 11 pts. The tests began at 8:00 a.m. Hormones were measured by radioimmunoassays. Serum cortisol response >181.2 ng/mL (500 nmol/L) in LDAT and >199.3 ng/mL (550 nmol/L) in GST was considered a normal response. Additionally, cortisol response delta (the difference between baseline and baseline) >90 ng/mL and doubling/tripling of baseline cortisol were considered indicators of normal adrenal reserve. Results: Three GSTs were not diagnostic (no hypoglycemia obtained). LDAT results suggested CAI in four pts, but in two out of four pts, and CAI was excluded in GST. GST results suggested CAI in only one patient, but it was excluded in LDAT. Therefore, CAI was diagnosed in 2/46 pts (4.3%), 1 treated and 1 untreated with rhGH, with the highest cortisol values of 162 and 175 ng/dL, but only in one test. However, in one of them, the cortisol delta response was >90 ng/mL and peak cortisol was more than tripled from baseline. Finally, CAI was diagnosed in one patient treated with rhGH (2.2%). Conclusion: We present low prevalence of CAI in pediatric pts with PWS according to the latest literature. Therefore, we do not recommend to routinely screen the function of the hypothalamic-pituitary-adrenal axis (HPAA) in all pts with PWS, both treated and untreated with rhGH. According to a review of the literature, signs and symptoms or low morning ACTH levels suggestive of CAI require urgent and appropriate diagnosis of HPAA by stimulation test. Our data indicate that the diagnosis of CAI should be confirmed by at least two tests to prevent overtreatment with hydrocortisone.

Stokes-Adams Syndrome as a Presenting Feature of Hypoadrenalism: A Rare Presentation.

Addison's disease is known to cause hyperkalemia. However, heart block as a result of such hyperkalemia is very rare. We report one such case where Addison's disease presented with hyperkalemia and resultant heart block and Stokes-Adam's syndrome along with other features of hypoadrenalism.

RésuméLa maladie d'Addison est connue pour provoquer une hyperkaliémie. Cependant, un bloc cardiaque résultant d'une telle hyperkaliémie est très rare. Nous rapportons un cas dans lequel la maladie d'Addison s'est accompagnée d'une hyperkaliémie et d'un bloc cardiaque et du syndrome de Stokes-Adam ainsi que d'autres caractéristiques d'hyposurrénalisme.

Urine metabolomics signature reveals novel determinants of adrenal suppression in children taking inhaled corticosteroids to control asthma symptoms.

BACKGROUND: Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long-term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS. METHODS: A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant-based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS. RESULTS: Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression. CONCLUSIONS: Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism.

Herbal remedies as a potential cause of hypoadrenalism.

A 37-year-old woman presented with nausea, vomiting and headache. She was found to be profoundly hyponatraemic with a sodium of 121 mmol/L, which deteriorated following a fluid challenge. An initial hyponatraemia screen identified adrenal insufficiency, with cortisol of 48 nmol/L. History confirmed she had been taking the herbal plant, ashwagandha. After 3 days of fluid restriction and steroid replacement, her sodium returned to normal (139 mmol/L). This article reviews the possible harmful effects of over-the-counter herbal remedies and highlights the importance of considering a wide differential diagnosis in patients presenting with non-specific symptoms.

Disseminated tuberculosis in PLWHIV presenting as primary adrenal insufficiency.

A woman in her 40s presented with a history of fatigue, symptoms of light-headedness on getting up from a sitting position and hyperpigmentation of the skin and mucous membranes. During the evaluation, she was diagnosed with primary adrenal insufficiency. Radiological imaging and microbiological evidence revealed features of disseminated tuberculosis involving the lungs and the adrenals. She was found to have an HIV infection. This patient was prescribed glucocorticoid and mineralocorticoid replacement therapy and was administered antituberculous and antiretroviral treatment.

Immune checkpoint inhibitor-induced hypophysitis with transient ACTH-dependent hypercortisolism.

A woman in her 70s with metastatic melanoma presenting with refractory hypokalaemia on combined immune checkpoint inhibitors, nivolumab-ipilimumab, was diagnosed with adrenocorticotropic hormone (ACTH)-dependent hypercortisolism 11 weeks following the initiation of her immunotherapy. Investigations also demonstrated central hypothyroidism and hypogonadotropic hypogonadism. She underwent imaging studies of her abdomen and brain which revealed normal adrenal glands and pituitary, respectively. She was started on levothyroxine replacement and had close pituitary function monitoring. Two weeks later, her cortisol and ACTH levels started to trend down. She finally developed secondary adrenal insufficiency and was started on hydrocortisone replacement 4 weeks thereafter.This report highlights a case of immunotherapy-related hypophysitis with well-documented transient central hypercortisolism followed, within weeks, by profound secondary adrenal insufficiency. Healthcare professionals should remain vigilant in monitoring laboratory progression in these patients. Early recognition of the phase of hypercortisolism and its likely rapid transformation into secondary adrenal insufficiency can facilitate timely hormonal replacement and prevent complications.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and therapy of glucocorticoid-induced adrenal insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

European Society of Endocrinology and Endocrine Society Joint Clinical Guideline: Diagnosis and Therapy of Glucocorticoid-induced Adrenal Insufficiency.

Glucocorticoids are widely prescribed as anti-inflammatory and immunosuppressive agents. This results in at least 1% of the population using chronic glucocorticoid therapy, being at risk for glucocorticoid-induced adrenal insufficiency. This risk is dependent on the dose, duration and potency of the glucocorticoid, route of administration, and individual susceptibility. Once glucocorticoid-induced adrenal insufficiency develops or is suspected, it necessitates careful education and management of affected patients. Tapering glucocorticoids can be challenging when symptoms of glucocorticoid withdrawal develop, which overlap with those of adrenal insufficiency. In general, tapering of glucocorticoids can be more rapidly within a supraphysiological range, followed by a slower taper when on physiological glucocorticoid dosing. The degree and persistence of HPA axis suppression after cessation of glucocorticoid therapy are dependent on overall exposure and recovery of adrenal function varies greatly amongst individuals. This first European Society of Endocrinology/Endocrine Society joint clinical practice guideline provides guidance on this clinically relevant condition to aid clinicians involved in the care of patients on chronic glucocorticoid therapy.

Impact of systemic treatments for advanced thyroid cancer on the adrenal cortex.

Background: Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI). Aim: The objective was to assess the entire adrenal function in patients on systemic treatments. Methods: ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases. Results: After a median treatment period of 7 months, we observed an increase in ACTH values in 80-100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI. Conclusion: Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Glucocorticoid prescribing in neurology.

Glucocorticoids are commonly used for neurological disorders, but they can have significant adverse effects, including adrenal insufficiency, hyperglycaemia, osteoporosis and increased infection risk. Long-term use of corticosteroids requires the prescriber to plan risk mitigation, including monitoring and often coprescribing. This article highlights the potential risks of corticosteroid prescribing and draws together up-to-date guidance with multispecialty input to clarify ways of reducing those risks. We discuss home blood glucose monitoring and consider a steroid safety checklist to promote safer steroid prescribing.

Critical illness-related corticosteroid insufficiency (CIRCI) in paediatric patients: a diagnostic and therapeutic challenge.

Critical illness-related corticosteroid insufficiency or CIRCI is characterized by acute and life-threatening disfunction of hypothalamic-pituitary-adrenal (HPA) axis observed among intensive care unit- staying patients.It is associated with increased circulating levels of biological markers of inflammation and coagulation, morbidity, length of ICU stay, and mortality.Several mechanisms are involved in CIRCI pathogenesis: reduced CRH-stimulated ACTH release, peripheral resistance to glucocorticoids, altered cortisol synthesis, impaired cortisol-free fraction and bioavailability.Diagnostic and therapeutic management of this condition in children is still debated, probably because of the lack of agreement among intensive care specialists and endocrinologists regarding diagnostic criteria and prevalence of CIRCI in paediatric age.In the present narrative review, we focused on definition of CIRCI in paediatric age and we advise on how to diagnose and treat this poorly understood condition, based on current literature data.

A case of Empty Sella syndrome with adrenal insufficiency masked by prednisolone after administration of immune checkpoint inhibitors.

INTRODUCTION: The use of immune checkpoint inhibitors (ICIs) is gradually increasing; ICIs produce a variety of immune-related adverse events (irAEs), especially ICI-induced hypoadrenocorticism, which can be a lethal complication if treatment is delayed. PATIENT CONCERNS: A 63-year-old man received chemotherapy with pembrolizumab for nonsmall cell lung cancer. He developed drug-induced interstitial pneumonia 366 days after receiving pembrolizumab and was treated with prednisolone. Five hundred thirty-seven days later, he developed drug-induced eosinophilic enteritis, and pembrolizumab was discontinued and prednisolone was continued. After discontinuation of prednisolone, general malaise and edema of the lower extremities appeared, and adrenal insufficiency was suspected. DIAGNOSIS: In blood tests on admission adrenocorticotropic hormone (ACTH) was 2.2 pg/mL and cortisol was 15 µg/dL, with no apparent cortisol deficiency. However, the cortisol circadian rhythm disappeared and remained low throughout the day; a corticotropin-releasing hormone stimulation test showed decreased reactive secretion of ACTH. Pituitary magnetic resonance imaging showed pituitary emptying, suggesting Empty Sella syndrome. INTERVENTIONS AND OUTCOMES: We started hydrocortisone and his symptoms were improved. CONCLUSIONS: The administration of high-dose steroids after ICI administration may mask the symptoms of hypoadrenocorticism as irAEs. Therefore, we should bear in mind the possibility of hypoadrenocorticism when we stop steroid therapy in patients who are treated with steroids after ICI administration.

Follow up of a rare case of adrenal insufficiency due to NNT mutation.

Hypoglycaemia is one of the most common causes of convulsions in neonatal period. Repeated hypoglycaemic convulsions have to be addressed with utmost urgency to prevent its morbid sequelae. Repeated ketotic hypoglycaemia in the infantile period needs detailed endocrine evaluation. Our patient is a boy in the third year of his life, had presented in infancy with hypoglycaemic convulsions and hyperpigmentation of skin and mucous membrane. Investigations revealed ketotic hypoglycaemia, hypocortisolaemia with high adrenocorticotropic hormone (ACTH) and normal aldosterone, 17-hydroxyprogesterone (17-OHP) and testosterone levels. This suggested isolated glucocorticoid deficiency without mineralocorticoid deficiency. He responded well to hydrocortisone therapy with resolution of symptoms and normalisation of lab parameters. Genetic study confirmed the diagnosis of familial glucocorticoid deficiency (FGD) with homozygous mutation in NNT (nicotinamide nucleotide transhydrogenase) gene with a novel p.Thr578lle variant. This is the first case of FGD with NNT mutation to be reported from the Indian subcontinent.

Adrenal insufficiency in hemodialysis patients-An under-recognized problem: A case series.

Adrenal insufficiency is an uncommon disorder and presents with non-specific symptoms. Identifying adrenal insufficiency in patients with chronic kidney disease requiring dialysis is increasingly difficult as there is a significant overlap of the signs and symptoms of adrenal insufficiency with those seen in chronic kidney failure. We highlight this diagnostic uncertainty in a case series of three patients with chronic kidney disease requiring hemodialysis as renal replacement therapy from a single center identified as hypoadrenal. Steroid replacement improved symptoms and hemodynamic parameters. Increased vigilance for adrenal insufficiency in dialysis patients is necessary. It is likely under recognized in hemodialysis patients given their multi-morbidity.

Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency: a systematic review.

Background: Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease. Methods: We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded. Results: We identified 123 cases diagnosed as immune checkpoint inhibitor-induced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD. Conclusion: IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs.

Dual-release hydrocortisone improves body composition and the glucometabolic profile in patients with secondary adrenal insufficiency.

PURPOSE: Studies have suggested improved metabolic profiles in patients with adrenal insufficiency treated with dual-release hydrocortisone (DR-HC) compared with conventional hydrocortisone (C-HC). This study investigates the effect of DR-HC compared with C-HC treatment on five health variables: diurnal salivary cortisol/cortisone, body composition, bone health, glucose metabolism, lipids, and blood pressure. METHODS: Prospective study of 27 participants (24 men) with secondary adrenal insufficiency with measurements during stable C-HC and 16 weeks after treatment switch to DR-HC. OUTCOMES: Diurnal salivary-cortisol/cortisone, body composition assessed by Dual-Energy X-ray absorptiometry scan, bone status indices (serum type I N-terminal procollagen [PINP], collagen type I cross-linked C-telopeptide [CTX], osteocalcin, receptor activator kappa-B [RANK] ligand, osteoprotegerin, and sclerostin), lipids, haemoglobin A1c (HbA1c), and 24-hour blood pressure. RESULTS: After the switch to DR-HC, the diurnal salivary-cortisol area under the curve (AUC) decreased non-significantly (mean difference: -55.9 nmol/L/day, P = 0.06). The salivary-cortisone-AUC was unchanged. Late-evening salivary-cortisol and cortisone were lower (-1.6 and -1.7 nmol/L, P = 0.002 and 0.004). Total and abdominal fat mass (-1.5 and -0.5 kg, P = 0.003 and 0.02), HbA1c (-1.2 mmol/mol, P = 0.02), and osteocalcin decreased (-7.0 µg/L, P = 0.03) whereas sclerostin increased (+41.1 pg/mL, P = 0.0001). The remaining bone status indices, lipids, and blood pressure were unchanged. CONCLUSION: This study suggests that switching to DR-HC leads to lower late-evening cortisol/cortisone exposure and a more favourable metabolic profile and body composition. In contrast, decreased osteocalcin with increasing sclerostin might indicate a negative impact on bones. CLINICAL TRIAL REGISTRATION: EudraCT201400203932.

A Contemporary Approach to the Diagnosis and Management of Adrenal Insufficiency.

Adrenal insufficiency (AI) can be classified into three distinct categories based on its underlying causes: primary adrenal disorders, secondary deficiencies in adrenocorticotropin, or hypothalamic suppression from external factors, most commonly glucocorticoid medications used for anti-inflammatory therapy. The hallmark clinical features of AI include fatigue, appetite loss, unintentional weight loss, low blood pressure, and hyponatremia. Individuals with primary AI additionally manifest skin hyperpigmentation, hyperkalemia, and salt craving. The diagnosis of AI is frequently delayed due to the non-specific symptoms and signs early in the disease course, which poses a significant challenge to its early detection prior to an adrenal crisis. Despite the widespread availability of lifesaving glucocorticoid medications for decades, notable challenges persist, particularly in the domains of timely diagnosis while simultaneously avoiding misdiagnosis, patient education for averting adrenal crises, and the determination of optimal replacement therapies. This article reviews recent advancements in the contemporary diagnostic strategy and approaches to optimal treatment for AI.