Frequency of stress dosing and adrenal crisis in paediatric and adult patients with congenital adrenal hyperplasia: a prospective study.

OBJECTIVE: Patients with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement, including stress dosing (SD). This study prospectively assessed adrenal crisis (AC) incidence, frequency, and details of SD and disease knowledge in adult and paediatric patients and their parents. DESIGN: Prospective, observational study. METHODS: Data on AC and SD were collected via a patient diary. In case of AC, medical records were reviewed and patient interviews conducted. Adherence to sick day rules of the German Society of Endocrinology (DGE) and disease knowledge using the German version of the CAH knowledge assessment questionnaire (CAHKAQ) were assessed. RESULTS: In 187 adult patients, the AC incidence was 8.4 per 100 patient years (py) and 5.1 in 100 py in 38 children. In adults, 195.4 SD episodes per 100 py were recorded, in children 169.7 per 100 py. In children 72.3% and in adults 34.8%, SD was performed according to the recommendations. Children scored higher on the CAHKAQ than adults (18.0 [1.0] vs 16.0 [4.0]; P = .001). In adults, there was a positive correlation of the frequency of SD and the incidence of AC (r = .235, P = .011) and CAHKAQ score (r = .233, P = .014), and between the incidence of AC and CAHKAQ (r = .193, P = .026). CONCLUSION: The AC incidence and frequency of SD in children and adults with CAH are high. In contrast to the paediatric cohort, the majority of SD in adults was not in accordance with the DGE recommendations, underlining the need for structured and repeated education of patients with particular focus on transition.

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.

Iatrogenic adrenal insufficiency in adults.

Iatrogenic adrenal insufficiency (IAI) is the most common form of adrenal insufficiency in adult patients, although its overall exact prevalence remains unclear. IAI is associated with adverse clinical outcomes, including adrenal crisis, impaired quality of life and increased mortality; therefore, it is imperative that clinicians maintain a high index of suspicion in patients at risk of IAI to facilitate timely diagnosis and appropriate management. Herein, we review the major causes, clinical consequences, diagnosis and care of patients with IAI. The management of IAI, particularly glucocorticoid-induced (or tertiary) adrenal insufficiency, can be particularly challenging, and the provision of adequate glucocorticoid replacement must be balanced against minimizing the cardiometabolic effects of excess glucocorticoid exposure and optimizing recovery of the hypothalamic-pituitary-adrenal axis. We review current treatment strategies and their limitations and discuss developments in optimizing treatment of IAI. This comprehensive Review aims to aid clinicians in identifying who is at risk of IAI, how to approach screening of at-risk populations and how to treat patients with IAI, with a focus on emergency management and prevention of an adrenal crisis.

Effects and mechanisms of perioperative medications on the hypothalamic pituitary adrenal response to surgical injury: A narrative review.

The adrenal gland is a vital endocrine organ, and adrenal steroid synthesis and secretion are closely regulated by the hypothalamic-pituitary-adrenal (HPA) axis in response to various stimuli. Surgery or trauma can activate the HPA axis and induce the secretion of cortisol. Different cortisol responses vary with the grade of surgery. Perioperative medications have the potential to decrease the cortisol level in the body, and both excessive and insufficient cortisol levels after surgery are disadvantageous. The effect of perioperative medications on the HPA response to surgery can be divided into three levels: "adrenal insufficiency (AI)", "stress response inhibition", and "uncertainty". The clinical presentation of AI includes fatigue, nausea, vomiting, abdominal pain, muscle cramps, hypotension, hypovolemic shock and prerenal failure, which may result in fatal consequences. Stress response inhibition can reduce postoperative complications, such as pain and cognitive dysfunction. This is protective to patients during perioperative and postoperative periods. The aim of the present review is to shed light on current evidence regarding the exact effects and mechanisms of perioperative medications on the HPA response to surgical injury and provide the applicable guidance on clinical anesthesia.

SNARE-ing the Reason for Post-Cardiac Surgery Critical Illness-Related Corticosteroid Insufficiency.

Critical illness-related corticosteroid insufficiency (CIRCI) can cause hemodynamic instability in neonates after congenital heart surgery with manifestations that increase morbidity and potential mortality. We retrospectively reviewed neonates who underwent cardiac surgery between August 2018 and July 2020 at a freestanding children's hospital, had next-generation sequencing performed, and had their cortisol levels drawn as standard clinical care after cardiac surgery. The groups were defined as CIRCI (with a cortisol level ≤ 4.5 mcg/dL) and non-CIRCI (level > 4.5 mcg/dL). The CIRCI group (n = 8) had a 100% incidence of heterozygous gene mutation on STX1A with splicing or loss of function, and this mutation was not found in the non-CIRCI group (n = 8). Additional gene mutations were found in the CIRCI group on RAB6A, ABCA3, SIDT2, and LILRB3, with no incidence in the non-CIRCI group. Three additional mutations were found across the CIRCI group in INPPL1 and FAM189A2 (both splicing and missense), with 12-25% of patients in the non-CIRCI group also displaying these mutations. Novel genetic abnormalities were seen in neonates with symptoms of CIRCI with potential cardiac implications from a gene mutation for STX1A. Compounding effects of additional gene mutations need to be confirmed and explored for potential predisposition to hemodynamic instability during times of stress.

Spectrum of Adrenal Dysfunction in Hemoglobin E/Beta Thalassemia.

BACKGROUND: Adrenal insufficiency (AI) in hemoglobin E (HbE)/beta thalassemia, including evaluation of mineralocorticoid axis, had not been studied. AIMS AND OBJECTIVES: In this study, we attempted to evaluate the prevalence of AI in HbE/beta thalassemia and wanted to determine if the prevalence of AI varied according to severity of HbE/beta thalassemia and transfusion requirements. METHODS: In this observational, cross-sectional study, 104 patients with HbE/beta thalassemia were evaluated. Among them, 57 and 47 were transfusion dependent and non-transfusion dependent. According to Mahidol criteria, patients were classified into mild (n = 39), moderate (n = 39), and severe (n = 26) disease. Early morning (8 Am) serum cortisol, plasma ACTH, and plasma aldosterone, renin were measured. Patients with baseline cortisol of 5 to 18 µg/dL underwent both 1 µg and 250 µg short Synacthen test. According to these results, patients were classified as having either normal, subclinical, or overt (primary/secondary) adrenal dysfunction. RESULTS: Adrenal insufficiency was found in 41% (n = 43). Among them 83.7% (n = 34) had primary AI and 16.3% (n = 9) had secondary AI. Thirty-three patients (31%) with normal or elevated ACTH and with low or normal aldosterone with high renin were diagnosed as having subclinical AI. There was no difference in prevalence of AI between transfusion dependent and non-transfusion dependent (P = .56) nor was there was any difference in prevalence of AI according to disease severity (P = .52). CONCLUSION: Adrenal insufficiency is common in HbE/beta thalassemia and is independent of transfusion dependency and disease severity.

Perioperative growth hormone levels as an early predictor of new-onset secondary adrenal insufficiency following transsphenoidal pituitary tumor resection.

OBJECTIVE: This study aims to predict new-onset secondary adrenal insufficiency (NOSAI) after transsphenoidal pituitary tumor resection surgery using perioperative growth hormone (GH) and prolactin (PRL) levels, among other factors. METHODS: A cohort of 124 adult patients who underwent transsphenoidal resection for non-functioning pituitary adenoma, with routine perioperative glucocorticoid use, was used to develop the predictive regression model. An additional 46 patients served as the validation cohort. Generalized additive models were used to identify optimal cut-off points for the variables. RESULTS: The GH level on postoperative day one (POD1) can be a simple predictor by implementing a cut-off point of 0.41 ng/ml. A value ≤ 0.41 ng/mL predicted NOSAI with 0.6316 sensitivity and 0.7810 specificity for the original cohort and 1.0000 sensitivity and 0.7143 specificity for the validation cohort. The multiple logistic regression model included perioperative PRL level difference, perioperative GH level difference, intraoperative cerebrospinal fluid (CSF) leakage, tumor size, and the combined effect of diabetes insipidus (DI) and relative perioperative GH level difference. The areas under the receiver operating characteristic curves were 0.9410 (original cohort) and 0.9494 (validation cohort) for the regression model. CONCLUSION: Early morning GH level on POD1 can predict NOSAI with fair accuracy when perioperative stress dose glucocorticoid is administered. Prediction accuracy can be improved by considering CSF leakage, DI, and perioperative changes in GH and PRL in the final regression model.

Basal cortisol levels do not predict adrenal responsiveness in acute decompensated cirrhosis.

OBJECTIVE: Morning total cortisol (TC) levels have been shown to predict adrenal dysfunction (AD) in the general population, but their utility in cirrhosis is unknown. METHODS: A retrospective cohort study was performed including all noncritically ill patients at our institution between 2011 and 2022 admitted with acute decompensated cirrhosis who underwent standard-dose adrenocorticotropic hormone (ACTH) stimulation testing. Adrenal dysfunction was defined as an increase in TC (delta TC) level <9 µg/dl 60 minutes after ACTH dosing. Spearman correlation was utilized to assess the relationship between binding globulins and cortisol levels. Multivariate regression analysis was performed to determine if basal TC level or common clinical parameters were predictive of AD. RESULTS: One hundred and nineteen patients were included, with a median model for end-stage liver disease score of 18. Albumin levels did not correlate with basal TC levels (ρ = 0.127; P = 0.169); basal TC did not correlate with delta TC (ρ = 0.050; P = 0.591). The degree of hypoalbuminemia did not alter these relationships. On multivariate regression, only albumin level [odds ratio (OR) = 0.418; 95% confidence interval (CI), 0.196-0.890; P = 0.024] and MELD score (OR, 1.094; 95% CI, 1.019-1.174; P = 0.014) were predictive of AD. Basal TC levels were not predictive of AD (OR = 0.991; 95% CI, 0.903-1.088; P = 0.855) or delta TC (ß = 0.000; 95% CI -0.147 to 0.147; P = 0.999). CONCLUSION: Baseline TC levels do not predict ACTH stimulation testing response in patients with acute decompensated cirrhosis. Clinicians should avoid utilizing an isolated morning cortisol result as a screening method for AD in this population.

Prolonged adrenal insufficiency following discontinuation of osilodrostat treatment for intense hypercortisolism.

The cases of 3 patients with Cushing's disease who developed long-term adrenal insufficiency after discontinuation of prolonged osilodrostat therapy were recently described for the first time. We report 2 additional cases of persistent prolonged adrenal insufficiency after discontinuation of osilodrostat treatment for intense hypercortisolism due to Cushing's disease and ectopic ACTH syndrome. In addition, we show for that adrenal insufficiency in these patients was associated with low/normal 11-deoxycortisol concentrations despite high plasma ACTH concentrations. These results suggest that CYP11B1 is not the only target of osilodrostat and that, in vivo, osilodrostat has other prolonged and strong inhibitory effect on adrenal steroidogenesis upstream of CYP11B1. Knowledge of this remnant effect is important for the care of patients with Cushing's syndrome treated with osilodrostat. Further studies are needed to clarify the frequency and the mechanisms of this remnant effect.

Idiopathic isolated adrenocorticotropic hormone deficiency: a systematic review of a heterogeneous and underreported disease.

Isolated adrenocorticotropic hormone deficiency (IAD) is considered to be a rare disease. Due to the nonspecific clinical presentation, precise data on the prevalence and incidence are lacking. In this systematic review, we aimed to analyse the clinical characteristics, association with autoimmune diseases, and management of acquired idiopathic IAD cases. A structured search was conducted after developing a search strategy combining terms for acquired (idiopathic) IAD. Articles describing an adult case with a diagnosis of ACTH deficiency using dynamic testing, no deficiency of other pituitary axes, and MRI of the brain/pituitary protocolled as normal, were included. Exclusion criteria were cases describing congenital IAD, cases with another aetiology for IAD, and articles where full text was not available. In total 42 articles were included, consisting of 85 cases of acquired idiopathic IAD. Distribution by sex was approximately equal (F:M; 47:38). Lethargy was the most common presenting symptom (38%), followed by weight loss (25%), anorexia (22%), and myalgia/arthralgia (12%). Eight cases (9.5%) presented with an Addison crisis. 31% of cases had an autoimmune disease at diagnosis of which Hashimoto hypothyroidism was the most frequent. Data about follow-up was scarce; dynamic testing was repeated in 4 cases of which 2 showed recovery of the adrenal axis. We report the largest case series of acquired idiopathic IAD to date. Our systematic review highlights the lack of a clear definition and diagnostic work-up. Based on the findings in this review a proposition is made for a flowchart to diagnose acquired idiopathic IAD.

Asymptomatic trigger of adrenal crisis in a patient with Sheehan syndrome: importance of timely recognition and intervention.

Our patient is a female in her 70s who initially presented following an episode of bowel and bladder incontinence, as well as unresponsiveness. Her family denied any preceding illness or sick symptoms. During her workup, it was noted that she was wearing a medical bracelet, which listed prednisone as one of her daily medications, raising concern for an acute adrenal crisis (AC). Ultimately, our patient's condition improved with high-dose intravenous steroids before being tapered to her home regimen. Current literature highlights the pathophysiological complexity of an AC but fails to identify clear risk factors that trigger such events, especially in asymptomatic patients. Accordingly, our case highlights this gap, arguing the importance of appropriate patient education and timely intervention for such clinically ambiguous yet life-threatening presentations.

The 1 µg Synacthen stimulation test in the diagnosis of secondary adrenal insufficiency in patients with Rathke's cleft cyst and empty sella syndrome.

INTRODUCTION: Rathke's cleft cyst (RCC) and primary empty sella syndrome (PESS) are usually incidental findings on magnetic resonance imaging (MRI) scans. In most cases, these lesions do not cause mass effect symptoms and do not require surgical intervention. In patients with RCC or PESS, it is important to exclude secondary adrenal insufficiency (SAI), which may be a life-threatening condition. MATERIAL AND METHODS: The incidence of SAI was assessed in patients with RCC or PESS detected by MRI, using the 1 µg Synacthen stimulation test. A total of 38 patients were analysed. Test results were linked to clinical symptoms and the type of cystic lesion. RESULTS: Assuming that cortisol levels < 14.6 µg/dL in Synacthen test are the criterion of SAI diagnosis, SAI was diagnosed only in 2 patients (5%). Adopting the traditional criterion of cortisol levels < 18 µg/dL, SAI would be diagnosed in 7 patients (18.4 %). Dizziness (Chi2 = 3.89; p = 0.049) and apathy (Chi2 = 3.87; p = 0.049) were significantly more frequent in the PESS group than in the RCC group. CONCLUSIONS: The incidence of SAI in the general patient population with empty sella syndrome and Rathke's cleft cysts is low. The 1 µg Synacthen test seems to be a valuable tool in the diagnosis of SAI among patients with RCC and PESS. Further studies are necessary to determine the sensitivity and specificity of the 1 µg Synacthen test with the standardization of test protocol and considering the cortisol level at the 20-minute timepoint. PESS patients report dizziness and apathy more frequently than RCC patients, which does not result from the disturbance of the hypothalamic-pituitary-adrenal axis, but probably from the different pathogenesis of these cystic lesions.

Clinical insights of pregnancy management, adrenal insufficiency as a possible cause of elevated TSH: a pilot study of case series.

BACKGROUND: The upper limit for thyroid-stimulating hormone has been strictly defined for pregnancy management, at which point levothyroxine replacement therapy will been initiated. However, it is essential to exclude adrenal insufficiency, including subclinical adrenal insufficiency, when initiating levothyroxine replacement therapy. However, in pregnancy management, it has rarely reported the incidence, clinical course, and characteristics of adrenal insufficiency as a possible cause of elevated thyroid-stimulating hormone. METHODS: This case series study included pregnant patients undergoing thyroid-stimulating hormone management in a single-center diabetes endocrinology department between 2017 and 2020. The primary study outcome was the incidence of newly diagnosed adrenal insufficiency. We reported the clinical course and assessed the adrenal insufficiency characteristics at baseline and delivery and compared them with those of hypothyroidism. RESULT: Fifteen pregnant women were included for thyroid-stimulating hormone management; and nine were below the basal serum cortisol level, and four were newly diagnosed as having adrenal insufficiency (26.7%) with the endocrinological stimulation test. Among them, two cases exhibited nausea and hypoglycemic symptoms after the start of levothyroxine replacement therapy. In cases of adrenal insufficiency, the patients were successfully treated with appropriate steroid coverage. CONCLUSIONS: In the management of elevated thyroid-stimulating hormone levels during pregnancy, the frequency of adrenal insufficiency suspecting hypothyroidism may be higher than expected; therefore, we must be careful about starting levothyroxine replacement therapy for hypothyroidism. These clinical insights can have a significant impact on the pregnancy outcomes.

The impacts of adrenoleukodystrophy newborn screening on the evaluation of adrenal dysfunction in male children: An integrative literature review.

PROBLEM: Adrenoleukodystrophy (ALD) is an x-linked genetic condition with a high risk of adrenal dysfunction recommended for newborn screening. This review aims to critically appraise and synthesize existing literature identifying the impacts of ALD newborn screening in the United States on the evaluation and treatment of adrenal dysfunction in male children. ELIGIBILITYCRITERIA: An integrative literature review was conducted using the Embase, PubMed, and CINAHL databases. English-language primary source studies published in the past decade and seminal studies were included. SAMPLE: Twenty primary sources met the inclusion criteria, including five seminal studies. RESULTS: Three major themes emerged from the review: 1) prevention of adrenal crisis, 2) unexpected outcomes, and 3) ethical impacts. CONCLUSIONS: ALD screening increases disease identification. Serial adrenal evaluation prevents adrenal crisis and death; data is needed to establish predictive outcomes in ALD prognosis. Disease incidence and prognosis will become more apparent as states increasingly add ALD screening to their newborn panel. IMPLICATIONS FOR PRACTICE: Clinicians need awareness of ALD newborn screening and state screening protocols. Families first learning of ALD through newborn screening results will require education, support, and timely referrals for appropriate care.

COVID-19 pandemic and adrenals: deep insights and implications in patients with glucocorticoid disorders.

PURPOSE: Coronavirus disease-19 (COVID-19) has spread throughout the world. It was initially defined as a potentially severe syndrome affecting the respiratory tract, but it has since been shown to be a systemic disease with relevant extrapulmonary manifestations that increase mortality. The endocrine system has been found to be vulnerable to COVID-19 infection. The current review aims to evaluate the available data on the impact of COVID-19 infection and treatment, as well as COVID-19 vaccines, on adrenal gland function, particularly in patients with GC disorders. METHODS: A thorough search of published peer-reviewed studies in PubMed was performed using proper keywords. RESULTS: Adrenal viral tropism and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in the adrenal glands have been demonstrated, and adrenal insufficiency (AI) is a rare, but potentially severe complication in COVID-19 disease, whose recognition can be difficult if only for the empirical treatments administered in the early stages. Glucocorticoid (GC) treatment have had a pivotal role in preventing clinical deterioration in patients with COVID-19, but long-term GC use may increase COVID-19-related mortality and the development of iatrogenic AI. Patients with GC disorders, especially AI and Cushing's syndrome, have been identified as being at high risk of COVID-19 infection and complications. Published evidence suggests that AI patient awareness and proper education may help adjust GC replacement therapy appropriately when necessary, thereby reducing COVID-19 severity. The COVID-19 pandemic has had an impact on AI management, particularly in terms of adherence to patients' care plans and self-perceived challenges. On the other hand, published evidence suggests that the clinical course of COVID-19 may be affected by the severity of hypercortisolism in patients with CS. Therefore, to ameliorate the risk profile in these patients, cortisol levels should be adequately controlled, along with careful monitoring of metabolic and cardiovascular comorbidities. To date, the COVID-19 vaccine remains the only available tool to face SARS-CoV-2, and it should not be treated differently in patients with AI and CS. CONCLUSION: SARS-CoV-2 infection has been linked to adrenal damage and AI is a rare complication in COVID-19 disease, requiring prompt recognition. Educational efforts and patient awareness may reduce COVID-19 severity in patients with AI. Control of cortisol levels and monitoring of complications may improve the clinical course of COVID-19 in patients with CS.

Sepsis and Adrenal Insufficiency.

In sepsis, dysregulation of the hypothalamic-pituitary-adrenal axis, alterations in cortisol metabolism, and tissue resistance to glucocorticoids can all result in relative adrenal insufficiency or critical illness-related corticosteroid insufficiency (CIRCI). The symptoms and signs of CIRCI during sepsis are nonspecific, generally including decreased mental status, unexplained fever, or hypotension refractory to fluids, and the requirement of vasopressor therapy to maintain adequate blood pressure. While we have been aware of this syndrome for over a decade, it remains a poorly understood condition, challenging to diagnose, and associated with significantly diverging practices among clinicians, particularly regarding the optimal dosing and duration of corticosteroid therapy. The existing literature on corticosteroid use in patients with sepsis and septic shock is vast with dozens of randomized controlled trials conducted across the past 4 decades. These studies have universally demonstrated reduced duration of shock, though the effects of corticosteroids on mortality have been inconsistent, and their use has been associated with adverse effects including hyperglycemia, neuromuscular weakness, and an increased risk of infection. In this article, we aim to provide a thorough, evidence-based, and practical review of the current recommendations for the diagnosis and management of patients with sepsis who develop CIRCI, explore the controversies surrounding this topic, and highlight what lies on the horizon as new evidence continues to shape our practice.

Acute Gastroenteritis Induced Adrenal Crisis in a patient with Congenital Adrenal Hyperplasia: A Case Report.

Congenital Adrenal Hyperplasia is a group of autosomal recessive diseases due to deficiencies of enzymes involved in steroidogenesis. If not diagnosed and treated adequately, Congenital Adrenal Hyperplasia can lead to an acute adrenal crisis with hemodynamic collapse. Acute stressors and steroid insufficiency precipitate an adrenal crisis. The major clinical features are hypotension and volume depletion. Nonspecific symptoms such as fatigue, lack of energy, anorexia, nausea, vomiting, and abdominal pain are common. We report a case of a 3-year male previously diagnosed with congenital adrenal hyperplasia in adrenal crisis secondary to medicine noncompliance and gastroenteritis. The diagnosis was based on the clinical history and biochemical investigations. After initial resuscitation was managed; lifelong oral prednisolone and fludrocortisone were prescribed. Keywords: adrenal insufficiency; gastroenteritis; glucocorticoids.