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.

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.

Secondary adrenocortical insufficiency after treatment with retifanlimab: a case report.

With advancements in medical oncology, immune checkpoint inhibitors (ICIs) have become the first-line treatment for many malignancies. ICIs play a significant role in improving cancer prognosis, but a series of immune-related adverse events (irAEs), including immune-related endocrine events (irEEs), caused by ICIs have also aroused concerns. Rapid clinical identification of irAEs caused by ICIs is particularly important. We describe a case of secondary adrenocortical insufficiency (AI) after PD-1 treatment in a postoperative patient with endometrial cancer. A 73-year-old female patient developed anorexia, nausea, vomiting, malaise, electrolyte disturbances, ineffective symptomatic treatment, and decreased serum adrenocorticotropin and cortisol levels six months after retifanlimab treatment. The vomiting resolved, and the electrolyte levels were corrected after 3 days of treatment with glucocorticoids (hydrocortisone, intravenous, 200 mg/day). When patients present with gastrointestinal symptoms, such as poor appetite and nausea, not only symptomatic treatment but also a search for the etiology behind the symptoms is needed, especially in immunotherapy patients who should undergo a thorough evaluation of the endocrine system and be alert for adrenocortical insufficiency.

Clinical characteristics of systemic lupus erythematosus patients with adrenal hemorrhage.

INTRODUCTION: Adrenal hemorrhage (AH) is a rare condition and severe cases can lead to acute adrenal insufficiency with potentially life-threatening consequences. AH can be caused by a variety of etiologic factors, including systemic lupus erythematosus and antiphospholipid syndrome (APS). The early identification and treatment of these patients improves their prognosis. OBJECTIVE: The aims of this study were to analyze and summarize the clinical characteristics of systemic lupus erythematosus patients with AH. METHODS: The clinical characteristics of 6 systemic lupus erythematosus patients complicated with AH admitted to Peking Union Medical College Hospital and Beijing Shijitan Hospital from May 2004 to April 2022 were retrospectively analyzed. RESULTS: The diagnosis of AH was based on computed tomography (CT) findings. Two patients had bilateral lesions, and the other 4 patients had unilateral lesions. The symptoms of adrenal insufficiency were observed in 2 patients. The frequent presenting symptoms were abdominal pain, lower abdominal distension, vomiting, weakness, fever, arthrodynia, and skin rash. Four patients had APS. Five patients (4 patients with APS and 1 patient without APS) had thromboembolic events. All patients received glucocorticoid and immunosuppressant therapy. Five patients were treated with anticoagulant therapy. Follow-up imaging examinations showed a partial or total regression of the lesions after treatment. CONCLUSIONS: In the proper clinical setting, having high clinical suspicion for AH, early diagnosis and timely management is crucial to avoid life-threatening adrenal insufficiency. Key Points • AH is a rare condition and severe cases may lead to death. It can be caused by a variety of etiologic factors, including SLE. • In patients with SLE, especially combined with APS, if they complain of abdominal pain, particularly when common gastrointestinal involvement is difficult to explain, a high index of clinical suspicion is needed for the diagnosis of AH. • Early identification of AH in SLE patients can improve their prognosis.

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.

Relationships between adrenal insufficiency and cardiovascular outcomes in patients with atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia.

BACKGROUND: Patients with Adrenal Insufficiency (AI) face elevated cardiovascular risks, but little remains known about arrhythmia outcomes in this context. METHOD: Analyzing the 2016-2019 Nationwide Inpatient Sample, we identified cases of Atrial Fibrillation, Atrial Flutter, and paroxysmal supraventricular tachycardia (PSVT) with a secondary diagnosis of AI. Mortality was the primary outcome while vasopressors and/or mechanical ventilation use, length of stay (LOS), and total hospitalization charges (THC) constituted secondary outcomes. Multivariate linear and logistic regression models were used to adjust for confounders. RESULTS: Among patients with Atrial Fibrillation, Atrial Flutter, and PSVT (N=1,556,769), 0.2% had AI. AI was associated with higher mortality (adjusted OR [aOR] 2.29, p=0.001), vasopressor and/or mechanical ventilation use (aOR 2.54, p<0.001), THC ($62,347 vs. $41,627, p<0.001) and longer LOS (4.4 vs. 3.2 days, p<0.001) compared to no AI. CONCLUSION: AI was associated with higher adverse outcomes in cases of Atrial Fibrillation, Atrial Flutter, and PSVT.

Severe adrenal insufficiency in six neonates with normal newborn screening for CAH.

BACKGROUND: Newborn screening (NBS) reduces the risk of mortality in congenital adrenal hyperplasia (CAH), mainly due to the salt-wasting form of 21-hydroxylase deficiency. There is limited knowledge regarding the results of NBS in non-CAH primary adrenal insufficiency (non-CAH PAI). PATIENTS AND METHODS: Clinical and NBS for CAH data of neonates who were diagnosed with non-CAH PAI between January and December 2022 were examined. RESULTS: Patients (n = 6, 4 females) were presented with severe hyperpigmentation (n = 6), hypoglycemia (n = 4), hyponatremia (n = 3), hyperkalemia (n = 1), respiratory distress syndrome (n = 1) between 3rd hour to 2 months of life. All had normal NBS results. The median first-tier 17-hydroxyprogesterone (17OHP) concentration in NBS for CAH was 0.14 ng/mL (range; 0.05-0.85). Molecular studies revealed biallelic mutations in the MC2R (n = 4; 3 homozygous, 1 compound heterozygous), MRAP (n = 1) and STAR (n = 1) genes. Glucocorticoid with or without mineralocorticoid replacement was initiated once the diagnosis of non-CAH PAI was established. CONCLUSION: Neonates with non-CAH PAI have always normal NBS due to persistently low 17OHP, even when these newborn infants are severely symptomatic for adrenal insufficiency. Clinicians should be alert for signs of adrenal insufficiency in neonates, even if the patient has a 'normal' screening for CAH, so as not to delay diagnosis and treatment. This fact should be kept in mind particularly in countries where these conditions are more common than elsewhere.

A case series of adrenal insufficiency (likely due to hypophysitis) in cancer patients treated with immune checkpoint inhibitors.

The number of approved immune checkpoint inhibitors (ICIs) and their indications have significantly increased over the past decade. Immune-related adverse effects (irAEs) of ICIs vary widely in presentation and symptoms and can present diagnostic challenges to emergency department (ED) physicians. Moreover, when ICIs are combined with radiotherapy, cytotoxic chemotherapy, or targeted therapy, the attribution of signs and symptoms to an immune-related cause is even more difficult. Here, we report a series of 5 ED cases of adrenal insufficiency in ICI-treated cancer patients. All 5 patients presented with severe fatigue and nausea. Four patients definitely had and one patient possibly had central adrenal insufficiency, and 4 patients had undetectable serum cortisol levels. The majority of the patients had nonspecific symptoms that were not recognized at their first ED presentation. These cases illustrate the need for a heightened level of suspicion for adrenal insufficiency in ICI-treated cancer patients with hypotension, nausea and/or vomiting, abdominal pain, fatigue, or hypoglycemia. As ICI use increases, irAE-associated oncologic emergencies will become more prevalent. Thus, ED physicians must update their knowledge regarding the diagnosis and management of irAEs and routinely inquire about the specific antineoplastic therapies that their ED patients with cancer are receiving. A random cortisol level (results readily available in most EDs) with interpretation taking the circadian rhythm and the current level of physiological stress into consideration can inform the differential diagnosis and whether further investigation of this potential irAE is warranted.

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.

Adrenal insufficiency in pediatric kidney transplantation recipients.

BACKGROUND: Immunosuppression of pediatric kidney transplant (PKT) recipients often includes corticosteroids. Prolonged corticosteroid exposure has been associated with secondary adrenal insufficiency (AI); however, little is known about its impact on PKT recipients. METHODS: This was a retrospective cohort review of PKT recipients to evaluate AI prevalence, risk factors, and adverse effects. AI risk was assessed using morning cortisol (MC) and diagnosis confirmed by an ACTH stimulation test. Potential risk factors and adverse effects were tested for associations with MC levels and AI diagnosis. RESULTS: Fifty-one patients (60.8% male, age 7.4 (IQR 3.8, 13.1) years; 1 patient counted twice for repeat transplant) were included. Patients at risk for AI (MC < 240 nmol/L) underwent definitive ACTH stimulation testing, confirming AI in 13/51 (25.5%) patients. Identified risk factors for AI included current prednisone dosage (p = .001), 6-month prednisone exposure (p = .02), daily prednisone administration (p = .002), and rejection episodes since transplant (p = .001). MC level (2.5 years (IQR 1.1, 5.1) post-transplant) was associated with current prednisone dosage (p < .001), 6-month prednisone exposure (p = .001), daily prednisone administration (p = .006), rejection episodes since transplant (p = .003), greater number of medications (ß = -16.3, p < .001), 6-month hospitalization days (ß = -3.3, p = .013), creatinine variability (ß = -2.4, p = .025), and occurrence of acute kidney injury (ß = -70.6, p = .01). CONCLUSION: Greater corticosteroid exposure was associated with a lower MC level and confirmatory diagnosis of AI noted with an ACTH stimulation test. Adverse clinical findings with AI included greater medical complexity and kidney function lability. These data support systematic clinical surveillance for AI in PKT recipients treated with corticosteroids.

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.

Excessive pickle consumption: beware of adrenal crisis.

Adrenal insufficiency (AI) is one of the most life-threatening disorders resulting from adrenal cortex dysfunction. Symptoms and signs of AI are often nonspecific, and the diagnosis can be missed and lead to the development of AI with severe hypotension and hypovolemic shock. We report the case of a 13-year-old child admitted for cardiac arrest following severe hypovolemic shock. The patient initially presented with isolated mild abdominal pain and vomiting together with unexplained hyponatremia. He was discharged after an initial short hospitalization with rehydration but with persistent hyponatremia. After discharge, he had persistent refractory vomiting, finally leading to severe dehydration and extreme asthenia. He was admitted to pediatric intensive care after prolonged hypovolemic cardiac arrest with severe anoxic encephalopathy leading to brain death. After re-interviewing, the child's parents reported that he had experienced polydipsia, a pronounced taste for salt with excessive consumption of pickles lasting for months, and a darkened skin since their last vacation 6 months earlier. A diagnosis of autoimmune Addison's disease was made. Primary AI is a rare life-threatening disease that can lead to hypovolemic shock. The clinical symptoms and laboratory findings are nonspecific, and the diagnosis should be suspected in the presence of unexplained collapse, hypotension, vomiting, or diarrhea, especially in the case of hyponatremia.

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The male patient, one day old, was admitted to the hospital due to hypoglycemia accompanied by apnea appearing six hours after birth. The patient had transient hypoglycemia early after birth, and acute heart failure suddenly occurred on the eighth day after birth. Laboratory tests showed significantly reduced levels of adrenocorticotropic hormone and cortisol, and pituitary magnetic resonance imaging was normal. Genetic testing results showed that the patient had probably pathogenic compound heterozygous mutations of the TBX19 gene (c.917-2A>G+c.608C>T), inherited respectively from the parents. The patient was conclusively diagnosed with congenital isolated adrenocorticotropic hormone deficiency caused by mutation of the TBX19 gene. Upon initiating hydrocortisone replacement therapy, cardiac function rapidly returned to normal. After being discharged, the patient continued with the hydrocortisone replacement therapy. By the 18-month follow-up, the patient was growing and developing well. In neonates, unexplained acute heart failure requires caution for possible endocrine hereditary metabolic diseases, and timely cortisol testing and genetic testing should be conducted.

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.

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.

Diagnosis and management of secondary adrenal crisis.

Adrenal crisis (AC) is a life threatening acute adrenal insufficiency (AI) episode which can occur in patients with primary AI but also secondary AI (SAI), tertiary AI (TAI) and iatrogenic AI (IAI). In SAI, TAI and IAI, AC may develop when the HPA axis is unable to mount an adequate glucocorticoid response to severe stress due to pituitary or hypothalamic disruption. It manifests as an acute deterioration in multi-organ homeostasis that, if untreated, leads to shock and death. Despite the availability of effective preventive strategies, its prevalence is increasing in patients with SAI, TAI and IAI due to more frequent exogenous steroid administration, pituitary immune-related effects of immune checkpoint inhibitors and opioid use in pain management. The delayed diagnosis of acute AI which remains infrequently suspected increases the risk of AC. Its main precipitating factors are infections, emotional distress, surgery, cessation or reduction in GC doses, pituitary infarction or surgical cure of endogenous Cushing's syndrome. In patients not known previously to have SAI/TAI/IAI, recognition of its symptoms, signs, and biochemical abnormalities can be challenging and cause delay in proper diagnosis and therapy. Effective therapy of AC is rapid intravenous administration of hydrocortisone (initial bolus of 100 mg followed by 200 mg/24 h as continuous infusion or bolus of 50 mg every 6 h) and 0.9% saline. In diagnosed patients, preventive education in sick-day rules adjustment of glucocorticoid replacement and hydrocortisone parenteral self-administration must be performed repeatedly by trained health care providers. Strategies to improve the adequate preventive education in patients at risk for secondary AI should be promoted in collaboration with various medical specialist societies and patients support associations.

Critical Illness-Related Corticosteroid Insufficiency (CIRCI) After Pediatric Cardiac Surgery.

Although current studies do not support the routine use of corticosteroids after cardiopulmonary bypass in pediatric patients, there is incomplete understanding of the potential hemodynamic contribution of postoperative critical illness-related corticosteroid insufficiency in the intensive care unit. By reviewing the available studies and underlying pathophysiology of these phenomena in critically ill neonates, we can identify a subset of patients that may benefit from optimal diagnosis and treatment of receiving postoperative steroids. A suggested algorithm used at our institution is provided as a guideline for treatment of this high-risk population.

Bilateral adrenal cryptococcosis causing adrenal insufficiency in an immunocompetent patient.

ABSTRACT: Cryptococcosis usually occurs in immunocompromised patients and presents as meningitis and lung disease. Adrenal gland involvement may be observed, yet primary adrenal insufficiency by cryptococcal infection is infrequent. We present a case of a middle-aged immunocompetent man with primary adrenal insufficiency and bilateral adrenal lesions, splenomegaly, and miliary mottling in the lungs on imaging. No evidence of meningitis was witnessed. The clinico-radiological findings led toward the differential diagnosis of disseminated tuberculosis or fungal infection. Detection of cryptococcus organism was done on fine-needle aspiration cytology and biopsy on periodic acid-Schiff stain and Gomori`s methenamine silver stain. Thus, it is recommended to keep the possibility of cryptococcosis in mind while dealing with instances that have a tuberculosis-like clinico-radiological presentation. The detection of the causal organism on Fine needle aspiration (FNA)/biopsy examination may be useful in confirming the diagnosis and determining the appropriate medical treatment.