Screening For Adrenal Insufficiency Research Articles

P970 Iatrogenic adrenal insufficiency on discontinuation of glucocorticoid treatment in children and adolescent patients with inflammatory bowel disease: to screen or not to screen?

Abstract Background Glucocorticoids are a mainstay of inflammatory bowel disease (IBD) treatment, with oral tapering courses frequently used to induce remission or limit flares. Iatrogenic adrenal insufficiency (AI), due to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is an established side effect of exogenous glucocorticoids. The rate of AI in this population is unknown. There is no standard guidance to suggest routine screening in paediatric IBD (pIBD). This study aimed to better understand the rates of AI with a screening and management protocol developed for pIBD patients given glucocorticoid therapy (GT) Methods All patients with IBD under 18 years treated with GT (prednisolone) for 3 weeks or longer from March 2022 to August 2023 were identified. Patients on other GT were excluded. Patients were screened for AI by serum early morning cortisol (Vitros Ortho Clinical Diagnostics immunoassay) and ACTH, and if indicated underwent standard short synacthen(SST) testing. Adrenal axis function was divided into normal allowing cessation of GT, or impaired response requiring hydrocortisone maintenance therapy (see figure1). A serum morning cortisol >250nmol/l indicated a normal adrenal axis; whereas dynamic adrenal axis testing was recommended for cortisol of 175-249 nmol/l. Those with cortisol <175nmol were diagnosed with AI and started on maintenance hydrocortisone. Repeat testing with SST was performed 3 monthly to reassess the adrenal-axis. Patients with an abnormal SST at the 6-month mark were referred to endocrinology Results 14 subjects were identified (8 male),7 with Ulcerative colitis, 4 with Crohn’s disease, 1 with IBD-U,2 with early-onset IBD. Median age at diagnosis was 10 years (range 8 months -14 years). Duration of GT was for an average 3 months (range 6 - 16 weeks). 42%(n=6) initiated GT with IV methylprednisolone before switching to 2mg/kg oral prednisolone (maximum 40mg) for 2 weeks, weaning 5mg every week. At the end of initial GT, morning cortisol was deficient in 42% (n=6), insufficient in 35% (n=5) requiring SST. Of those undergoing a SST at this stage, 60% (n=3) had a normal response, 40% (n=2) demonstrating AI. Overall, 57% (n=8) had significant AI at the end of initial treatment. Repeat adrenal axis testing was offered at 3 months (5 of 8) and at 6 months (4 of 4). AI was noted in 100% and 75% at 3 and 6-month respectively. No child suffered an adrenal crisis during the study period Conclusion AI following glucocorticoid therapy is common in this small cohort. Screening for AI should be considered in pIBD patients receiving conventional doses of glucocorticoids longer than 3 weeks, with appropriate advice given. The incidence and risks of iatrogenic adrenal insufficiency (AI) requires further investigation

The utility of a baseline morning cortisol measurement, in the screening for adrenal insufficiency amongst non-critically ill hospital inpatients

BackgroundSerum cortisol levels vary according to the daily circadian cycle, with peak levels seen in the morning. There is evidence in ambulatory patients that a morning cortisol level can predict an adequate cortisol response to Synacthen (tetracosactide) stimulation. AimThe aim of this study is to determine the utility of baseline analysis of the serum cortisol levels in the morning “baseline morning cortisol”, determined using a newer immunoassay, in the screening for adrenal insufficiency amongst non-critically ill hospital inpatients. MethodsThis is a retrospective cross-sectional cohort study. Results64 adult inpatients had undergone a short Synacthen test (SST) (measurement of serum cortisol levels 30 and 60 min after administration of tetracosactide) during the study period. 17 patients returned an abnormal SST result. The measured level of cortisol in the morning correlated to both the 30 min and 60 min stimulated cortisol values (r = 0.612, p < 0.001 and r = 0.639, p < 0.001). After inspecting the receiver operating characteristic curve, a cortisol concentration of 200nmmol/L measured in the morning was selected as a threshold for predicting the SST result. Using this cut off, sensitivity for predicting a normal SST was 100 %, specificity 56 %, positive predictive value 45 % and negative predictive value 100 %. ConclusionA morning cortisol measurement, determined using a newer immunoassay, is sufficient in most cases to screen for adrenal insufficiency amongst non-critically ill hospital inpatients. Use of clinical judgement in conjunction with single morning cortisol measurement is likely to reduce the need for SST testing amongst inpatients.

Adrenal functional reserve in the full spectrum of chronic kidney disease.

Altered cortisol levels have been associated with an increase in mortality and a decrease in health-related quality of life in patients with chronic kidney disease (CKD); however, adrenal response to adrenocorticotropic hormone (ACTH) stimulation test has not been evaluated in patients with stage 3a to 5 CKD with and without renal replacement therapy (RRT). To evaluate adrenal function in patients with CKD. Adults with CKD underwent a low-dose cosyntropin stimulation test (1 µg synthetic ACTH), with serum cortisol levels being measured at 0, +30 and +60 minutes post-test. Sixty participants with stage 3, 4 and 5 CKD (with and without RRT) were included. None of the patients had adrenal insufficiency (AI). The correlation observed between cortisol concentration at baseline and 30 minutes and 1 hour after stimulation and glomerular filtration rate (GFR) was negative and statistically significant (r: -0.39 [p = 0.002], r: -0.363 [p = 0.004], r: -0.4 [p = 0.002], respectively). Since CKD early stages, cortisol levels increase as GFR decreases. Therefore, we conclude that systematic screening for AI is not necessary in CKD patients.

Screening for adrenal insufficiency using home waking salivary cortisone is accurate and lowers NHS costs

Screening for adrenal insufficiency using home waking salivary cortisone is accurate and lowers NHS costs

Swallowed Steroids and Adrenal Insufficiency in Eosinophilic Esophagitis

Swallowed Steroids and Adrenal Insufficiency in Eosinophilic Esophagitis

Adrenal insufficiency due to bilateral adrenal metastases – A systematic review and meta-analysis

ObjectiveBilateral 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. MethodA 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. ResultsTwenty 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 = 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. ConclusionThe 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.

Prevalence of Secondary Adrenal Insufficiency in Recipients of Pediatric Hematopoietic Stem Cell Transplant: A Single Center Study

Background Data on adrenal function following pediatric allogeneic hematopoietic cell transplantation (HCT) is limited. Therefore, a single-institution retrospective study was performed to determine the prevalence of secondary adrenal insufficiency (AI) and identify associated risk factors in pediatric HCT recipients. Methods All allogeneic HCT patients from January 2007 through December 2014, with a minimum of two years of post-HCT follow up were included. AI was diagnosed when testing done at either clinical presentation of AI or routine yearly screening in the long term follow up clinic, revealed a morning cortisol level Results Eighty patients (48 male, 32 female) with malignant (n=38) and non-malignant diagnoses (n=42) were included. Median age at HCT and length of follow up were 7.6 years (range 0.1- 20.5 years) and 4.1 years (range 2-10 years), respectively. Twelve (12, 15%) patients developed secondary AI at a median of 16 months post-HCT (range 2-61 months), with an equal number presenting with clinical AI (n=6) and biochemical AI (n=6) respectively. In univariate analysis (Table 1), occurrence of graft-versus-host disease (GvHD), and post-HCT corticosteroid exposure were significant risk factors for development of secondary AI. Age, gender, type of diagnosis, total body irradiation (TBI)-containing and myeloablative conditioning were not. Conclusion: GvHD, and post-HCT steroid exposure were significant risk factors for AI, with one-third patients with post-HCT corticosteroid exposure diagnosed with AI. As half of patients with AI in this cohort were asymptomatic, routine screening for AI should be performed in pediatric allogeneic HCT recipients for timely diagnosis of AI to prevent morbidity associated with this complication.

Smith-Lemli-Opitz syndrome: clinical and biochemical correlates

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by mutations in the DHCR7 gene that result in reduced cholesterol biosynthesis. The aim of the study was to examine the biochemical and clinical features of SLOS in the context of the emerging evidence of the importance of cholesterol in morphogenesis and steroidogenesis. We retrospectively reviewed the records of 18 patients (including four fetuses) with confirmed SLOS and documented their clinical and biochemical features. Seven patients had branchial arch abnormalities, including micrognathia, immune dysfunction and hypocalcemia. Thymic abnormalities were found in three fetuses. All four patients with a cholesterol level of ≤0.35 mmol/L died. They all had electrolyte abnormalities (hyperkalemia, hyponatremia, hypocalcemia), necrotizing enterocolitis, sepsis-like episodes and midline defects including the branchial and cardiac defects. Patients with cholesterol levels ≥1.7 mmol/L had milder features and were diagnosed at 9 months to 25 years of age. All 10 patients had intellectual disability. One patient was found to have a novel mutation, c.1220A>G (p.Asn407Ser). We suggest that screening for adrenal insufficiency and for hypoparathyroidism, hypothyroidism and immunodeficiency, should be done routinely in infants diagnosed early with SLOS. Early diagnosis and intervention to correct these biochemical consequences may decrease mortality and improve long-term outcome in these patients.

The Diagnostic Approach to Central Adrenocortical Insufficiency (CAI) in Thalassemia.

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Inhaled corticosteroids and secondary adrenal insufficiency.

Inhaled corticosteroids (ICS) have been used as first line treatment of asthma for many decades. ICS are a form of exogenous glucocorticosteroids that can suppress the endogenous production of glucocorticosteroids, a condition known as adrenal suppression (AS). As a result, cessation, decreasing the dose or changing the type of ICS may trigger features of adrenal insufficiency (AI). AI may cause a spectrum of presentations varying from vague symptoms of fatigue to potentially life threatening acute adrenal crises. This article reviews the current literature on ICS and AI particularly in adults (although majority of data available is from the paediatric population). It aims to increase awareness of the potential risk of AI associated with ICS use, delineate the pathogenesis of AI and to provide recommendations on screening and management. From our literature review, we have found numerous case reports that have shown an association between ICS and AI particularly in children and patients using high doses. However, there have also been reports of AI in adults as well as in patients using low to moderate doses of ICS. To conclude, we recommend screening for AI in select patient groups with an initial early morning serum cortisol. If results are abnormal, more definitive testing such as the low dose corticotropin stimulation test may be done to confirm the diagnosis.

Reversible Adrenal Insufficiency in Three Patients With Post-Roux-en-Y Gastric Bypass Noninsulinoma Pancreatogenous Hypoglycemia Syndrome.

Objective. Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS) is a disorder of endogenous hyperinsulinemia that is clinically distinguishable from insulinoma, with a greater preponderance after Roux-en-Y gastric bypass (RYBG). Hyperinsulinemic hypoglycemia can predispose to attenuation of counterregulatory hormone responses to hypoglycemia, and consequent suppression of the hypothalamic–pituitary–adrenal (HPA) axis. This case series describes 3 individuals who were diagnosed with adrenal insufficiency (AI) after undergoing RYGB, complicated by NIPHS. Methods. A retrospective chart review was performed for each individual. Chart review applied particular attention to the onset of hyperinsulinemic hypoglycemia following bariatric surgery and the dynamic testing leading to the diagnoses of NIPHS and AI. Results. In each case, reactive hypoglycemia ensued within months to years after RYGB. Cosyntropin stimulation testing confirmed the diagnosis of AI. Hydrocortisone therapy reduced the frequency and severity of hypoglycemia and was continued until successful medical and/or surgical management of hyperinsulinism occurred. Follow-up testing of the HPA axis demonstrated resolution of AI. In all cases, hydrocortisone therapy was finally discontinued without incident. Conclusion. We speculate that transient AI is a potential complication in patients who experience recurrent hyperinsulinemic hypoglycemia after RYGB. The putative mechanism for this observation may be attenuation of the HPA axis after prolonged exposure to severe, recurrent hypoglycemia. We conclude that biochemical screening for AI should be considered in individuals who develop post-RYGB hyperinsulinemic hypoglycemia. If AI is diagnosed, supportive treatment should be maintained until hyperinsulinemic hypoglycemia has been managed effectively.

Cortisol Response To Low Dose Versus Standard Dose (Back-to-Back) Adrenocorticotrophic Stimulation Tests In Children and Adolescents With Thalassemia Major

Patients with thalassemia major(TM ), especially those with inadequate iron chelation, have high prevalence of endocrinopathies. Several studies reported a significant prevalence of subclinical “biochemical” adrenal insufficiency, ranging from 18–45%, in patients with thalassemia. This variability may be due to the different severity of TM, iron overload status, the test used for assessing adrenal function, and the cutoff value used to define subnormal cortisol response. The low dose (LD) 1-microg (ug) ACTH test follows the insulin tolerance test (ITT) has been shown to be more closely and more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic-pituitary-adrenal axis. Therefore the 1 ug ACTH test may be more appropriate for screening for secondary AI in TM patients. Measurements of serum dehydroepiandrosterone sulfate (DHEA-S) levels during LD simulation provide additional valuable information that improves the diagnostic accuracy of LDC in patients suspected to have central adrenal insufficiency (AI). The aim of this study was to compare cortisol and DHEA-S responses to LD and SD ACTH tests in patients with TM. Patients and Methods This cross-sectional controlled study was conducted at the Departments of Pediatrics and Hematology, Hamad Medical Center (HMC). 10 children and 13 adolescents (age 8 to 26 years ) were randomly recruited. They had been receiving blood transfusion at a regular basis every 4 wk. Iron chelation therapy was suboptimal in most of them. Patients were excluded if they had any other endocrine or systemic disease or drugs known to affect adrenal functions. 13 healthy children and adolescents with normal variant short stature served as controls. Serum cortisol and DHEA-S concentrations were determined in each subject before blood transfusion both in basal condition and after low dose (LD) (1 microgram) followed by standard dose (SD) (250 micrograms) respectively) with synthetic corticotrophin beta 1-24 ACTH (Synacthen Ciba). Normal controls were a group of 13 age and sex matched normal subjects. Results Using a peak total cortisol cutoff level of 550 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 8 patients after the LD ACTH and in 2 patients after SD ACTH test and in none of the controls. Using a peak total cortisol cutoff level of 420 nmol/L and increments of 200 ug above basal cortisol, AI was demonstrated in 5 patients after the LD ACTH and in 2 patients after SD ACTH test but none of controls. All patients with biochemical AI were asymptomatic with normal serum Na and K concentrations and no history suggestive of adrenal pathology. The peak cortisol concentrations in thalassemic patients with impaired adrenal function both after 1ug and 250 ug cosyntropin, ( 294 +/- 51 nmol/L and 307 +/- 58.6) were significantly lower than those with patients with normal ( 454 +/- 79.7 nmol/L and 546.1 +/- 92.2 nmol/L respectively) and controls (460.2 +/- 133.4 nmol/L and 554.3 +/- 165.8 nmol/L respectively). Adolescents but not children with TM had significantly lower peak cortisol concentration after SD cosyntropin test versus controls. Peak cortisol response to LD cosyntropin test was correlated significantly with peak cortisol response to SD in all patients (r = 0.83, p &lt; 0.0001). In adolescents with thalassemia DHEA-S levels before and after LD ACTH stimulation were significantly lower and the cortisol/DHEA-S ratios significantly higher than controls. In conclusion, the use of LD ACTH test diagnoses more adrenal abnormalities versus SD ACTH in thalassemic patients. The relatively high prevalence of AI in thalassemic adolescents necessitates that these patients have to be investigated for AI before major surgery and those with impaired cortisol secretion should receive stress doses of corticosteroids during the stressful event. Disclosures: No relevant conflicts of interest to declare.

Iatrogenic adrenal insufficiency as a side-effect of combined treatment of itraconazole and budesonide

A recent case of iatrogenic Cushing's syndrome and complete suppression of the pituitary-adrenal-axis in a patient with cystic fibrosis (CF) and allergic bronchopulmonary aspergillosis treated with itraconazole as an antifungal agent, and budesonide as an anti-inflammatory agent led to a systematic assessment of this axis and gonadal function in all patients treated with itraconazole in the authors' CF centre. Itraconazole can inhibit CYP3A, thus interfering with synthesis of gluco- and mineralocorticoids, androgens and oestradiol as well as the metabolism of budesonide. The aim of this study was to evaluate adrenal and gonadal function in patients treated with itraconazole with or without budesonide. An adrenocorticotrophic hormone (ACTH) test (250 microg tetracosactid) was performed in 25 CF patients treated with both itraconazole and budesonide, and in 12 patients treated with itraconazole alone (six patients with CF and six with chronic granulomateous disease). Mineralocorticoid and gonadal steroid function were evaluated by measurements of plasma-renin, follicle stimulating hormone, luteinising hormone, progesterone, oestradiol, testosterone, serum-inhibin A and B. ACTH tests performed as part of a pretransplantation programme in an additional 30 CF patients were used as controls. Eleven of the 25 patients treated with both itraconazole and budesonide had adrenal insufficiency. None of the patients on itraconazole therapy alone nor the control CF patients had a pathological ACTH test. Mineralocorticoid and gonadal insufficiency was not observed in any of the patients. Only one patient with an initial pathological ACTH-test subsequently normalised, the other 10 patients improved but had not achieved normalised adrenal function 2-10 months after itraconazole treatment had been discontinued. Suppression of the adrenal glucocorticoid synthesis was observed in 11 of 25 cystic fibrosis patients treated with both itraconazole and budesonide. The pathogenesis is most likely an itraconazole caused increase in systemic budesonide concentration through a reduced/inhibited metabolism leading to inhibition of adrenocorticotrophic hormone secretion along with a direct inhibition of steroidogenesis. In patients treated with this combination, screening for adrenal insufficiency at regular intervals is suggested.

Single-Dose Metyrapone Test

Subnormal plasma 11-deoxycortisol (compound S) responses to metyrapone were found in patients with adrenal insufficiency or with Cushing syndrome caused by adrenal tumors and in those receiving long-term glucocorticoid or diphenylhydantoin sodium therapy. High normal or exaggerated responses were seen in women receiving oral contraceptives, patients with Cushing syndrome caused by adrenal hyperplasia, and those with untreated hypothyroidism. Diabetes mellitus, hypoglycemia, congestive failure, and obesity also were associated with exaggerated responses. Subnormal plasma S responses were observed in 15 patients who responded normally to a repeat test or to the standard metyrapone test. The abnormal response resulted from insufficient metyrapone, administration at the wrong time, or delay in obtaining the blood sample. The single-dose metyrapone test may be the procedure of choice in screening for adrenal insufficiency.