Risk Of Adrenal Insufficiency Research Articles

Adrenal insufficiency in pediatric kidney transplantation recipients.

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. 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. 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 (β = -16.3, p < .001), 6-month hospitalization days (β = -3.3, p = .013), creatinine variability (β = -2.4, p = .025), and occurrence of acute kidney injury (β = -70.6, p = .01). 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.

A schedule for tapering glucocorticoid treatment in patients with severe SARS-CoV 2 infection can prevent acute adrenal insufficiency in the geriatric population.

Glucocorticoids (GCs) have been widely used in symptomatic patients for the treatment of COVID-19. The risk for adrenal insufficiency must be considered after GC withdrawal given that it is a life-threatening condition if left unrecognized and untreated. Our study aimed to diagnose adrenal insufficiency early on through a GC reduction schedule in patients with COVID-19 infection. From November 2021 to May 2022, 233 patients were admitted to the Geriatric Division of the University Hospital of Padova with COVID-19 infection. A total of 122 patients were treated with dexamethasone, after which the GC tapering was performed according to a structured schedule. It consists of step-by-step GC tapering with prednisone, from 25mg to 2.5mg over 2 weeks. Morning serum sodium, potassium, and cortisol levels were assessed 3 days after the last dose of prednisone. At the end of GC withdrawal, no adrenal crisis or signs/symptoms of acute adrenal insufficiency were reported. Median serum cortisol, sodium, and potassium levels after GC discontinuation were, respectively, 427 nmol/L, 140 nmol/L, and 4 nmol/L (interquartile range 395-479, 138-142, and 3.7-4.3). A morning serum cortisol level below the selected threshold of 270 nmol/L was observed in two asymptomatic cases (respectively, 173 and 239 nmol/L, reference range 138-690 nmol/L). Mild hyponatremia (serum sodium 132 to 134 nmol/L, reference range 135-145 nmol/L) was detected in five patients, without being related to cortisol levels. A structured schedule for the tapering of GC treatment used in patients with severe COVID-19 can reduce the risk of adrenal crisis and acute adrenal insufficiency.

Osilodrostat in cushing's disease: Risk of adrenal insufficiency should be monitored

Osilodrostat in cushing's disease: Risk of adrenal insufficiency should be monitored

Total dose, fraction dose and respiratory motion management impact adrenal SBRT outcome

Purpose/Objective(s)Stereotactic body radiotherapy (SBRT) is an effective treatment for oligometastatic disease in multiple sites. However, the optimal radiation dose for long-term local control of adrenal metastases has yet to be determined. The aim of this study is to evaluate outcomes of adrenal SBRT and to evaluate factors that correlate with local control. Materials/MethodsAfter IRB approval, a retrospective data review of patients treated with SBRT for adrenal metastases at a medical center in Israel between 2015 and 2021 was conducted. A biological effective dose was calculated using an alpha beta ratio of 10. Kaplan Meier and Cox regression were calculated using SPSS software to describe the hazard ratio for local control and survival. Results83 cases of adrenal SBRT were identified. The average age was 67 (range 42–92 years old). Non-small cell lung cancer was the primary site in 44 % of patients. A total of 70 % of the patients had oligometastatic disease (less than five lesions), and the rest were polymetastatic, responding to systemic therapy with oligo progression in the adrenal. The average gross tumor volume (GTV) was 42 ml. Respiratory control was applied in 88 % of cases; 49.3 % used 4-D/ITV, and 38.5 % used breath-hold or continuous positive airway pressure (CPAP) with free breathing. On multivariable analysis, Dose above 75 Gy (biological effective Dose) (HR = 0.41, p = 0.031), Dose above 8 Gy per fraction (HR = 0.53p = 0.038), and breath-holds or CPAP (HR = 0.65, p = 0.047) were significant for local control. From multivariable analysis, we computed a predicted nomogram curve using seven clinical parameters to evaluate local control odds. ConclusionIn this single institution series reported to date, we found unilateral adrenal SBRT safe, yet bilateral treatment harbors a risk of adrenal insufficiency. Biological effective Dose > 75 Gy (BED), motion management with breath-hold or CPAP, and Dose per fraction > 8 Gy were the enhanced local controls. We propose a nomogram to help in decision-making regarding total Dose and Dose per fraction when treating adrenal SBRT.

E076 Incidence of adrenal insufficiency in patients with giant cell arteritis tapering glucocorticoids with the Norwich prednisolone regimen

Abstract Background/Aims Glucocorticoids continue to be the main treatment for giant cell arteritis (GCA). It is widely recognised that treatment with oral glucocorticoids is associated with adverse events including adrenal insufficiency. Reports suggest the risk of adrenal insufficiency is dependent on the dose and the duration of therapy. The Norwich regimen has been devised to deliver prednisolone at a rate 1mg/kg of lean body mass tapering over 100 weeks. We report the incidence of adrenal insufficiency related to the Norwich regimen. Methods The Norwich regimen has been used in all patients diagnosed with GCA from 01/01/2012. A notes review of all patients diagnosed after that date was undertaken to look for evidence of adrenal insufficiency. We routinely check 9am cortisol when symptoms of adrenal insufficiency were reported. The 9am cortisol was recorded as normal, indeterminate, or low. Patients with a low 9am cortisol remained on long term prednisolone; no further test was required. Patients with an indeterminate result were referred for a short synacthen test (SST). If the results of the SST were normal patients were weaned off prednisolone, patients with an inadequate SST result remained on long term prednisolone. Results From 01/01/2012-31/05/2022 353 patients diagnosed with GCA were treated with the Norwich regimen. 9am cortisol was checked in 76 patients (21.5%). Of these, 34 patients (9.6%) had a normal result, 35 patients (9.9%) had an indeterminate result requiring SST. 7 patients (2.0%) had a low 9am cortisol. Of the 35 patients referred for SST: 27 patients (7.6%) had an adequate result, 8 patients (2.3%) had an inadequate result resulting in long term prednisolone. Conclusion We report the incidence of adrenal insufficiency in patients diagnosed with GCA, tapering prednisolone using the Norwich regimen. In total 15/353 (4.3%) patients developed adrenal insufficiency because of long-term glucocorticoid use. Disclosure G. Ducker: None. C.B. Mukhtyar: None.

Risk and Incidence of Endocrine Immune-Related Adverse Effects Under Checkpoint Inhibitor Mono- or Combination Therapy in Solid Tumors: A Meta-Analysis of Randomized Controlled Trials.

Few meta-analyses on incidence of endocrine immune-related adverse effects (eirAEs) have been published and many trials have been published since. We performed a comprehensive meta-analysis with updated literature to assess risk and incidence of eirAEs of any grade and grade 3 to 5 by immune checkpoint inhibitor (ICI) monotherapy or combination therapy in solid tumors. An electronic search using PubMed/Medline, Embase, and the Cochrane Library was performed. Randomized controlled studies (RCTs) assessing eirAEs under ICI monotherapy or ICI combination therapy were selected. Stata software (v17) was used for statistical analyses and risk of bias was evaluated using Review Manager version 5.3. A total of 69 RCTs with 80 independent reports, involving 42 886 patients, were included in the study. Meta-analysis revealed the following pooled estimates for risk ratio and incidence, respectively: for any grade hypothyroidism 7.81 (95% CI, 5.68-10.74, P < .0001) and 7.64% (95% CI, 6.23-9.17, P < .0001); significantly increased also for hyperthyroidism, hypophysitis/hypopituitarism, and adrenal insufficiency; and for insulin-dependent diabetes mellitus 1.52 (95% CI, 1.07-2.18, P = .02), and 0.087% (95% CI, 0.019-0.189, P = .0006), respectively. Meta-regression showed that combination of ICIs (nivolumab plus ipilimumab; durvalumab plus tremelimumab) is an independent risk factor for any grade hypophysitis/hypopituitarism, and that ICI agent is an independent factor of risk for adrenal insufficiency, but that cancer type is not an independent risk factor for eirAEs. We showed that risk, independent from cancer type, and incidence of eirAEs are substantially increased with ICI therapy. Combination of ICIs increases risk for eirAEs, especially for hypophysitis/hypopituitarism.

FRI220 Primary Bilateral Macronodular Adrenal Hyperplasia: A Rare Cause Of Cushing Syndrome

Abstract Disclosure: Y. Ortiz: None. A.M. Aviles Melendez: None. M.M. Mangual Garcia: None. J.M. Garcia-Mateo: None. Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogenous entity whose pathophysiology remains largely unclear, representing less than 2% of Cushing syndrome (CS) cases, which leads to a challenging diagnosis. Many patients have a mild clinical picture and remain undiagnosed until abdominal imaging for unrelated reasons reveals bilateral adrenal enlargement. Hereby, we describe the case of a patient presented with abdominal pain and clinical hypercortisolism due to PBMAH. Case of a 42-year-old female with past medical history of arterial hypertension, referred for evaluation due to bilateral adrenal masses found on abdominal CT scan performed after patient presented with abdominal discomfort. On initial evaluation, patient refers a 50 pounds weight gain, increase in abdominal circumference, muscle weakness and sudden onset of facial and abdominal hair growth. Physical examination reveals dorsocervical fat pad, proximal muscle weakness, moon facies, facial and abdominal hirsutism. Abdominal CT scan with adrenal protocol showed bilateral adrenal lesions, with largest measuring 2.8 and 3.9 cm on the left side, with attenuation of 16 and 7.4 Hounsfield units. The absolute and relative washouts for the first were 76.6% and 61.6%, and for the second 73.5% and 67.1%, both consistent with adenomas. Laboratory results showed late night salivary cortisol levels of 4.60 ug/dl and 4.80 ug/dl, values which may be high or even normal due to ineffective steroidogenesis on PBMAH. Other labs consisted of low dose 1 mg dexamethasone suppression test: 4.80 ug/dl, and ACTH level: 9.60 pg/ml, which confirms clinical hypercortisolism, indeterminate for ACTH-independent cause. Desmopressin test was not performed, since levels may not be fully suppressed in PBMAH due to ectopic production by adrenal glands, leading to an erroneous diagnosis of ACTH-dependent CS. DHEA level of 618 ug/dl can also be increased, which could lead to a diagnosis of adrenocortical carcinoma. Considering risk of recurrence, risk for adrenal insufficiency, and lower documented complications, unilateral left-sided adrenalectomy was chosen as the best surgical treatment, despite bilateral adrenalectomy being the gold standard for diagnosis. Surgical pathology report showed Adrenocortical adenoma with associated myelolipomatous foci of 7.5 cm in greatest dimension. Despite limited data regarding unilateral adrenalectomy, it appears to convey clinical and biochemical benefits in most cases. Initial remission reported reaches more than 90% with low risk of recurrence between 10-15%. Adrenal insufficiency, despite the presence of residual hyperplastic adrenal tissue, occurs in about one-third of patients and is usually transient. Our case is a great example of the importance of individualization of management options based on therapy benefits, and decreased risks of future complications. Presentation: Friday, June 16, 2023

THU611 Circadian Misalignment Of Melatonin Secretion In Adrenal Insufficiency (AI)

Abstract Disclosure: M. Darji: None. S. Pannain: None. S. Sam: None. E. Van Cauter: None. E.C. Hanlon: None. Background: Despite glucocorticoid replacement, the mortality risk of AI remains markedly elevated. Under normal conditions, the circadian rhythm of endogenous cortisol levels is a major internal synchronizing signal between central and peripheral circadian clocks. There is increasing evidence indicating that circadian misalignment has a host of adverse effects, including increased cardio-metabolic risk. The present study aimed to assess circadian function in AI patients, as compared to individually-matched healthy subjects, under controlled laboratory conditions. The 24-h profile of melatonin, normally secreted exclusively at night, was used as the marker of central circadian timing. The 24-h profile of leptin was used as a marker of peripheral circadian function. Methods: Plasma cortisol, melatonin, and leptin were measured over a 24-h period every 30-60 minutes under controlled light-dark, sleep-wake and dietary conditions. A best-fit curve was calculated for each individual hormonal profile using a locally weighted nonlinear regression procedure with a window of 4 hours. The peak and the nadir were defined as the maximum and minimum of the best-fit curve, respectively. The amplitude was defined as half of the difference between the peak and the nadir. Sleep was polygraphically recorded. During daytime hours, the participants completed validated questionnaires assessing Vigor, Mood and Sleepiness. Results: Complete data sets were obtained in 15 AI patients (12 women; age: 47.9 ±12.5 years, BMI: 26.6 ± 12.5 kg/m2; mean ± SD). Twelve AI patients were on hydrocortisone treatment (total dose range: 20 to 40mg/day, number of doses: 1-5 /day) and 3 were on prednisone treatment. Controls (n=15, 12 women) were aged 48.5 ±14.5 years with BMI of 26.5 ± 5.4 kg/m2. The amplitude of the cortisol profile was wider in AI patients, relative to controls, with a higher morning peak and an extended and lower nocturnal nadir. Unexpectedly, we observed a marked difference in the melatonin profile in AI patients as compared to controls. A daytime phase of elevated melatonin levels, culminating prior to lights off while the patients were awake, was detected in 9 of the 15 AI patients. The nocturnal elevation persisted with a similar amplitude to that observed in controls but was advanced by 1-2 hours. The 24-h leptin profile was similar in the two groups. The presence of a daytime melatonin peak in AI patients was associated with lower ratings of vigor and mood, and higher ratings of sleepiness. Conclusion: Glucocorticoid treatment to replace the endogenous levels and circadian rhythmicity of cortisol in AI may impact central circadian timing, resulting in daytime, in addition to nighttime, release of melatonin. This finding suggests that exogenous cortisol replacement that does not mimic a normal 24-h rhythm, may cause central circadian dysfunction and contribute to alterations in mood, vigor and sleepiness. Presentation: Thursday, June 15, 2023

SAT312 CT-guided Cryoablation Of Hereditary Pheochromocytoma

Abstract Disclosure: E. Griffing: None. B. Reading: None. F. De Luca: None. Background: Guidelines surrounding the management of hereditary pediatric pheochromocytomas (PHEO) are lacking. This is the first report of a pediatric patient with bilateral hereditary PHEO treated with right adrenalectomy and computed tomography (CT) percutaneous-guided cryoablation (CRA) of the left-sided lesion.Clinical case: A previously healthy 15 years-old male presented to a tertiary care hospital with a months-long history of episodic chest pain, flushing, shortness of breath, diaphoresis, and tremulousness. Paternal family history was significant for PHEO and brain stem hemangioblastoma in grandmother and PHEO in the great-grandfather. Targeted familial mutation analysis of the von Hippel-Lindau tumor suppressor gene was positive for pathogenic mutation c.500G&amp;gt;A (p.R167Q). Plasma free normetanephrine level was 4,625 pg/mL (nl: &amp;lt;145 pg/mL), while free metanephrines were normal. Magnetic-resonance imaging of the abdomen visualized a 4.4 x 3.4 x 5.3 cm right adrenal mass and a 1.4 x 1.4 x 1.4 cm left adrenal mass, consistent with bilateral PHEO. He underwent right adrenalectomy after initiation of alpha-receptor blockade and later addition of beta-receptor blockade due to heart rates in the 150’s. After discussion with parents, it was decided to observe the smaller left-sided adrenal lesion. Plasma free normetanephrines initially decreased to 338 pg/mL, but then increased to 507 pg/mL five months post-operatively. Six months after surgery, due to the persistence of hypertension with systolic blood pressure in the 140’s as well as tachycardia with heart rates in the 150’s, he underwent CT-guided CRA of the left-sided PHEO. A 12-minute freeze, 5-minute thaw, and 10-minute freeze, followed by an active thaw were performed. There was an increase in blood pressure during the initial thaw with systolic blood pressure in the 230s, accompanied by bradycardia to the 30s, treated with nitroprusside, phentolamine, and increased sedation. He required continuation of nitroprusside infusion for five hours post-procedure. He was discharged the following day with normal blood pressure and heart rate. He was able to completely wean off anti-hypertensive medications within one month and symptoms of chest pain and tachycardia resolved. In the four years since his procedure, he has not had a recurrence of PHEO nor development of adrenal insufficiency. Plasma free normetanephrines and metanephrines have remained within normal limits. Conclusion: Percutaneous ablation of hereditary PHEO has not been reported before in the pediatric population and may represent a novel treatment strategy that reduces the risk of adrenal insufficiency. Presentation: Saturday, June 17, 2023

SAT277 Intracellular Cortisol Control: An Approach To Reduce Cushing’s Syndrome Morbidity With Minimal Adrenal Insufficiency Risk?

Abstract Disclosure: F.S. Czerwiec: Employee; Self; Sparrow Pharmaceuticals, Inc. Stock Owner; Self; Sparrow Pharmaceuticals, Inc. D.A. Katz: Employee; Self; Sparrow Pharmaceuticals, Inc. Stock Owner; Self; Sparrow Pharmaceuticals, Inc. P.M. Stewart: Advisory Board Member; Self; Sparrow Pharmaceuticals, Inc. Consulting Fee; Self; Sparrow Pharmaceuticals, Inc. Endocrinologists focus on circulating and excreted cortisol to diagnose and to assess severity and treatment response in Cushing’s syndrome (Cs), but tissue action that drives morbidity is mediated by cortisol binding to intracellular glucocorticoid (GC), mineralocorticoid, and non-genomic receptors. Patients with severe hypercortisolism and deficiency in 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) (an enzyme that generates active GC in target tissues) had no cortisol-related morbidity. Mice without the Hsd11b1 gene (which encodes HSD-1) or given a HSD-1 inhibitor were protected from glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, dermal atrophy, and trabecular bone loss associated with GC administration. The HSD-1 inhibitor AZD4017 prevented detrimental prednisolone effects on glycemic control and osteocalcin in a Phase 1 clinical trial. Although patients with cortisone reductase (i.e., HSD-1) deficiency show no signs or symptoms of adrenal insufficiency (AI), the theoretical possibility of AI in HSD-1 inhibitor treated patients has been raised. Healthy adults received the HSD-1 inhibitor SPI-62 or placebo for 14 days. Data after last dose were analyzed by ANCOVA with baseline as covariate. SPI-62 reduced 24h urinary cortisol metabolites (4.6 +/- 0.3 v 8.0 +/- 0.5 nmol), indicative of a 42% intrahepatocellular cortisol decrease. Results from other inhibitors support HSD-1 as the source of nearly half of intrahepatocellular cortisol in human. Morning serum (293.9 +/- 18.9 v 273.4 +/- 39.3 nM) and 24h urinary (100.7 +/- 6.9 v 89.6 +/- 14.0 nmol) cortisol did not differ between SPI-62 and placebo. No pattern of adverse events suggestive of AI has been observed in SPI-62, nor other HSD-1 inhibitor, clinical trials. Administration of a HSD-1 inhibitor to patients with GC excess could reduce Cs morbidity via reduction of cortisol or GC medication (e.g., prednisolone) available to intracellular receptors. Unlike current Cs treatments that are all associated with substantial AI risk, under HSD-1 inhibition ACTH-mediated cortisol secretion maintains normal circulatory cortisol available to enter cells and thus prevent AI. Data suggest that AI will not be an issue in patients treated with HSD-1 inhibitors. That prediction is under evaluation in Phase 2 clinical trials of SPI-62 in patients with ACTH-dependent Cs, autonomous cortisol secretion, and (together with prednisolone) polymyalgia rheumatica. Until more experience is gathered, caution in patients with modest autonomous cortisol secretion, suppressed ACTH, and atrophied adrenal tissue is advised. In situations that require GC rescue dosing during HSD-1 inhibitor administration, prodrug GCs (i.e., cortisone acetate, prednisone) will not be effective a. s they require HSD-1 for activation. Those patients require active agents (e.g., hydrocortisone, prednisolone). Presentation: Saturday, June 17, 2023

Fraction Size, Total Dose and Respiratory Control Impact Local Control in Adrenal SBRT

Stereotactic body radiotherapy (SBRT) is an effective treatment for oligometastatic disease in multiple sites, however, the optimal radiation dose for long term local control of adrenal metastases has not yet been determined. The aim of this study is to evaluate outcomes of adrenal SBRT and to evaluate factors that correlate with local control MATERIALS/METHODS: After IRB approval, a retrospective data review of patients treated with SBRT on adrenal metastases was conducted, at a medical center in Israel between 2015 and 2021. Biologic Equivalent Dose (BED) were calculated using an alpha beta ration of 10. Kaplan Meier and Cox regression were calculated to describe the hazard ratio for local control and survival using statistical software. Fifty-eight cases of adrenal SBRT were identified. The average age was 67 years (ranging 42-92). Forty-three percent of primary tumor was non-small cell lung cancer. The lesions were equally distributed between the right and left adrenal gland. Six patients had bilateral radiation treatment. Fifty-eight percent of the cases were in the setting of oligometastatic disease (less than 5 lesions) with the rest having progression in the adrenal. PET-CT scans were available for follow up in 55% of patients and CT in the rest. The average GTV volume was 42 cm2 respiratory control through 4D and breath hold was performed in 86% of cases. The median follow up time, for local control, was 10 months with a range of 1-54 mos. Univariate analysis local control, during the last follow up, was seen in 74% of cases. Total dosage was equal to or above 72 Gy and dosage per fraction was equal to or above 8 Gy. The use of respiratory motion was found significant for local control. Only a fraction size equal to or above 8 Gy and a total dosage equal to and above 72 Gy were found significant for local failure (HR = 0.26, p = 0.024 and HR = 0.28, p = 0.019). With multivariable analysis the dosage per fraction ≥8 Gy continued to be significant after adjusting for total dose, histology, side, and motion management. Two patients had clinical signs of adrenal insufficiency and both received bilateral adrenal radiation. Bowel toxicity was low: 1 patient had >G3 toxicity. In the largest single institution series reported to date, we found unilateral adrenal SBRT to be safe, however, bilateral treatment harbors a risk of adrenal insufficiency. Dose per fraction ≥8 Gy was the most powerful predictor of local control, and a total dose ≥72gy and motion management were also significant. In conclusion, we propose a treatment regimen with a fraction size of at least 8 Gy and a total dosage of at least 72 Gy for evaluation, in a prospective clinical trial.

Statin treatment is not associated with an increased risk of adrenal insufficiency in real-world setting.

Statins could reduce the synthesis of steroid hormones, thereby could cause adrenal insufficiency. We investigated this risk in a large nationwide database. We conducted a nested case-control study using a cohort of individuals affiliated to the French health insurance system in 2010, ≥18y and without adrenal insufficiency history. Each case had a first event of adrenal insufficiency between 2015 and 2017 and was matched to up to ten controls on age, sex, and prior treatment with corticosteroids. Statin exposure was measured over the five years preceding the index date, considering a six-month censoring lag-time. Association was estimated using a conditional logistic regression adjusted for confounders included in a disease risk score. Analyses were stratified on age, sex and corticosteroid history of use. 4 492 cases of adrenal insufficiency were compared with 44 798 controls (median age 66y, 58% women), of which 39% vs. 33% were exposed to statins, respectively. No association between statin use and adrenal insufficiency was found when adjusting the model for confounders (adjusted odds ratio 0.98; 95% confidence interval 0.90-1.05). These results were consistent regardless of the exposure definition and stratifications considered. Statin-related adrenal insufficiency risk, if any, seems to be very limited and does not compromise the benefit of statin treatment.

Machine Learning Approaches for Assessing Risk Factors of Adrenal Insufficiency in Patients Undergoing Immune Checkpoint Inhibitor Therapy.

Adrenal insufficiency is a rare, yet life-threatening immune-related adverse event of immune checkpoint inhibitors (ICIs). This study aimed to establish a risk scoring system for adrenal insufficiency in patients receiving anti-programmed cell death 1 (PD-1) or anti-programmed cell death-ligand 1 (PD-L1) agents. Moreover, several machine learning methods were utilized to predict such complications. This study included 209 ICI-treated patients from July 2015 to February 2021, excluding those with prior adrenal insufficiency, previous steroid therapy, or incomplete data to ensure data integrity. Patients were continuously followed up at Gyeongsang National University Hospital, with morning blood samples taken for basal cortisol level measurements, facilitating a comprehensive analysis of their adrenal insufficiency risk. Using a chi-squared test and logistic regression model, we derived the odds ratio and adjusted odds ratio (AOR) through univariate and multivariable analyses. This study utilized machine learning algorithms, such as decision trees, random forests, support vector machines (SVM), and logistic regression to predict adrenal insufficiency in patients treated with ICIs. The performance of each algorithm was evaluated using metrics like accuracy, sensitivity, specificity, precision, and the area under the receiver operating characteristic curve (AUROC), ensuring rigorous assessment and reproducibility. A risk scoring system was developed from the multivariable and machine learning analyses. In a multivariable analysis, proton pump inhibitors (PPIs) (AOR 4.5), and α-blockers (AOR 6.0) were significant risk factors for adrenal insufficiency after adjusting for confounders. Among the machine learning models, logistic regression and elastic net showed good predictions, with AUROC values of 0.75 (0.61-0.90) and 0.76 (0.64-0.89), respectively. Based on multivariable and machine learning analyses, females (1 point), age ≥ 65 (1 point), PPIs (1 point), α-blockers (2 points), and antipsychotics (3 points) were integrated into the risk scoring system. From the logistic regression curve, patients with 0, 1, 2, 4, 5, and 6 points showed approximately 1.1%, 2.8%, 7.3%, 17.6%, 36.8%, 61.3%, and 81.2% risk for adrenal insufficiency, respectively. The application of our scoring system could prove beneficial in patient assessment and clinical decision-making while administering PD-1/PD-L1 inhibitors.

Adrenal insufficiency in patients on immune checkpoint inhibitors: An All of Us Data study.

e14675 Background: Immune Checkpoint Inhibitors have revolutionized the management of cancers. Several cases are reported about their adverse effects, which include adrenal insufficiency, a life-threatening irreversible sequela in some patients. Little has been done to evaluate the burden of this adverse effect on cancer patients. This study aimed to measure the incidence rate of adrenal insufficiency in patients on immune checkpoint inhibitors in the United States using the All Of Us database. Methods: In this cross-sectional study, we included participants from the All of Us dataset version 6, which includes data collected between May 6, 2018, and January 1, 2022, who had available Electronic Health Records data (N = 258,188). We defined the cancer cohort as having at least one ICD-9/ICD-10 diagnostic code for cancer. We identified participants in the cancer cohort without or with at least one exposure to immune checkpoint inhibitors nivolumab, pembrolizumab, cemiplimab, ipilimumab, atezolizumab, avelumab, durvalumab, tremelimumab, relatlimab, tremelimumab, pidilizumab. Adrenal insufficiency was defined as having one or more ICD-9/ICD-10 codes for any adrenal insufficiency after treatment with immune checkpoint inhibitors. The calculation for the Relative Risk(RR) was with unconditional maximum likelihood estimation. Results: Among 36,377 individuals diagnosed with cancer, 418 patients had exposure to immune checkpoint inhibitors. 44(10.5%) of the 418 were diagnosed with adrenal insufficiency after exposure to immune checkpoint inhibitors. The relative risk of adrenal insufficiency after the commencement of an immune checkpoint inhibitor is five times that of patients not on immune checkpoint inhibitors. (RR 5.43, 95% CI 4.07-7.25, P &lt; 0.05). Conclusions: Our result suggests a higher incidence of adrenal insufficiency in cancer patients on immune checkpoint inhibitors compared to cancer patients, not on immune checkpoint inhibitors. Future prospective studies will be needed to confirm this finding. Physicians, particularly oncologists and endocrinologists, should have a high index of suspicion for adrenal insufficiency in patients on immune checkpoint inhibitors.

Controlling intracellular cortisol: Can HSD-1 inhibition reduce Cushing's syndrome morbidity and minimize adrenal insufficiency risk?

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1403717: Thyro-Adrenal Insufficiency in Severe Hypothyroidism – A Clinical Mirage? A Cross-Sectional, Propensity-Matched Case-Control Study from a Tertiary Care Centre Kalaburgi, Kalyana Karnataka

Assessment of 8:00 AM cortisol levels and predict risk of adrenal insufficiency in treatment naïve severe hypothyroidism. A cross-sectional, observational, case-control study was conducted at tertiary care teaching hospital in Kalaburagi, Kalyana Karnataka, South India between January 2017 and March 2020. We included 71 consecutive adult individuals in the age group of 18-50 years of either gender, referred to the Division of Diabetes and Endocrinology, Department of Internal Medicine. All the cases were treatment naïve, diagnosed with severe hypothyroidism defined as TSH levels > 100 μIU/ml. We excluded patients with a past history of Grave’s disease, those who had ever used anti-thyroid drugs, those who had taken radioactive iodine, received steroids for any reasons, patients with a history of thyroidectomy, pre-existing pituitary or adrenal disorders, pregnancy, patients on oral contraceptives and patients with any underlying malignancies. The control population included individuals without any known thyroid disorder or any other comorbid conditions that are known to affect the function of hypothalmo-pituitary-adrenal axis. The controls were age and gender-matched. We used SAS 9.4 version software to analyze the data. T3, T4, and cortisol have been categorized and summarized descriptively with the actual collected values. Continuous variables are presented with mean and standard deviation. Categorical parameters are summarized with counts and percentages. Correlation coefficients among the T3, T4, and cortisol were generated for the overall population. Seventy-one cases of severe hypothyroidism (TSH >100 mIU/L) were compared with age and gender-matched controls (n=40). The mean age of the patients was 30.0±9.0 years and 88.7% were females. Serum cortisol levels were significantly lower in cases than in controls (8.6±4.2 vs. 16.0±2.22 μg/dl respectively, p<0.0001). Six (8.5%) cases were identified with adrenal insufficiency. After propensity matching, T3 (20.32±16.94 vs. 39.33±38.92 ng/dl, p=0.018) and T4 (0.81±0.55 vs. 1.93±1.17 μg/dl, p=0.005) levels were comparatively lower in adrenal insufficiency cases than those without adrenal insufficiency. Serum T3 (r = -0.243, p=0.041) but not T4 (r = -0.103, p=0.391) had a significant negative correlation with serum cortisol levels. Transient adrenal insufficiency can be seen in treatment naïve severe hypothyroidism. In our cohort, the incidence of adrenal insufficiency was 8.5%. An apt clinical vigilance is needed to identify adrenal insufficiency in such patients. Further studies are needed to understand the implications of severe hypothyroidism with adrenal insufficiency. A short synaecthien test may be needed in with low cortisol at diagnosis of severe hypothyroidism.

Surgical approaches to the adrenal gland.

Review the literature on the surgical management of adrenal diseases, highlighting the various surgical approaches and their respective pros and cons. Minimally invasive adrenalectomy is commonly used for small and benign adrenal tumors, whereas open adrenalectomy is preferred for larger tumors and primary adrenal malignancy. Although minimally invasive adrenalectomy results in shorter recovery and fewer complications compared with open, the latter offers better oncologic outcomes in the setting of primary adrenal malignancy. Adrenalectomy is performed transabdominally or retroperitoneoscopically, both yielding equivalent results and recovery. Traditional laparoscopic or robotic equipment can be utilized for either minimally invasive approach. Subtotal adrenalectomy may be appropriate for patients with genetically associated pheochromocytoma to preserve cortical function and reduce the risk of adrenal insufficiency. However, the potential benefits of sparing adrenal function must be weighed against the risk of recurrence. Adrenalectomy is becoming increasingly common worldwide. For benign and small adrenal tumors, minimally invasive adrenalectomy is generally considered the standard approach, while open adrenalectomy is preferred for primary adrenal malignancy and larger tumors. Subtotal adrenalectomy may be appropriate for patients with bilateral adrenal pheochromocytoma, as it can reduce the need for lifelong glucocorticoid dependency.

Home Waking Salivary Cortisone to Screen for Adrenal Insufficiency

BackgroundWorldwide, adults and children are at risk of adrenal insufficiency as a result of adrenal suppression from use of anti-inflammatory glucocorticoids and opiates, as well as infectious diseases. The adrenocorticotropin (ACTH) stimulation test is the reference standard for diagnosis of adrenal insufficiency but requires clinic attendance and venesection. Salivary cortisone reflects free serum cortisol, and samples can be collected at home and posted to a laboratory. We tested whether home waking salivary cortisone level could be used to screen for adrenal insufficiency.MethodsA prospective, diagnostic accuracy study was performed in patients at high risk of adrenal insufficiency. Patients collected a home salivary sample on waking and then attended the clinical facility for an ACTH stimulation test. Salivary cortisone was measured by liquid chromatography–tandem mass spectrometry. Receiver-operating characteristic curves were computed, and positive and negative predictive values were calculated.ResultsTwo hundred twenty patients were recruited. As measured by an ACTH stimulation test, the prevalence of adrenal insufficiency was 44%. The area under the receiver-operating characteristic curve for waking salivary cortisone as a predictor of adrenal insufficiency was 0.95 (95% confidence interval [CI], 0.92 to 0.97). Cutoffs to ensure a minimum of 95% sensitivity and specificity gave a negative predictive value of 96% (95% CI, 90 to 99) and a positive predictive value of 95% (95% CI, 87 to 99) to exclude and confirm adrenal insufficiency, respectively. Waking salivary cortisone data provided information similar to that of an ACTH stimulation test in 70% of participants. Eighty-three percent of patients preferred home salivary collection to clinic attendance.ConclusionsHome waking salivary cortisone sampling has accuracy for the diagnosis of adrenal insufficiency similar to that of a standard ACTH stimulation test. Patients found the at-home test to be more convenient than the hospital-based test. (Funded by the National Institute for Health Research.)

Evaluation of Adrenal Reserve in Patients with Differentiated Thyroid Cancer Receiving Thyroid Hormone Suppression Therapy- case-control Comparative Study

ABSTRACT Background Patients with differentiated thyroid cancer (DTC) are exposed to subclinical exogenous hyperthyroidism for the suppression of thyroid-stimulating hormone (TSH). In this study, we aimed to evaluate the adrenal reserve in DTC patients receiving suppression therapy. Materials and Methods The study included 55 DTC patients on suppression therapy and 32 healthy volunteers. Basal serum cortisol of all participants and adrenocorticotropic hormone (ACTH) of the patient group were measured. A standard-dose ACTH test (0.25 mg) was performed in patients with a basal cortisol <14.5 mcg/dL. Results In the patient group, TSH was lower, free thyroxine (fT4) was higher, and free triiodothyronine (fT3) was similar to those of the control group (p < .01, p < .01, p = .140, respectively). The serum cortisol of the patient group was significantly lower than the control group (12.14 ± 5.12 mcg/dL vs 18.00 ± 5.56 mcg/dL, p < .001). A total of 34 (61.8%) patients with DTC had a basal cortisol <14.5 mcg/dL. Prolonged TSH suppression (≥5 years vs <5 years) was associated with lower basal cortisol (7.46 ± 2.63 mcg/dL vs 9.48 ± 2.65 mcg/dL, p = .022). The ACTH stimulation test showed that 2 (5.8%) patients had a cortisol response <18 mcg/dL. The rate of adrenal insufficiency was 3.6% in DTC patients. A moderate negative correlation was found between ACTH and fT3 of patients with low basal cortisol (r = −0.358, p = .038) Conclusion Patients with DTC receiving TSH suppression therapy are at risk for adrenal insufficiency. The duration and severity of suppression might increase this possibility. Dynamic testing with synthetic ACTH can be used to reveal insufficient cortisol response in case of clinical suspicion.

Secondary adrenal insufficiency in patient with COVID-19 and head and neck cancer

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is an endocrinological disorder which occurs when there is an evidence of continued antidiuretic hormone (ADH) secretion in the absence of an appropriate osmotic volume stimulus. Most commonly it is caused by different types of cancer or medications (eg. diuretics, antidepressants, antipsychotics...). Secondary adrenal insufficiency is caused by the insufficient adrenocorticotropic hormone (ACTH) secretion and cortisol production. In the hypocortisolism, the inhibitory mechanism on ADH secretion vanishes causing increased ADH secretion and leading to SIADH-like state. Both conditions, SIADH and hypocortisolism, manifest in euvolemic hyponatremia, however, its cause can be misdiagnosed and result in an inadequate treatment and potentially fatal outcome. Our case is about fifty-seven-year-old male patient who was treated with chemoradiotherapy for hematological malignancy of the oropharynx and who presented with severe hyponatremia se-veral times that almost ended fatally. Considering his malignant disease, patient was diagnosed with SIADH as a cause of hypona-tremia and was treated with hypertonic saline fluids and fluid intake restriction. However, after having suffered Covid-19 infection the patient was given glucocorticoids according to the protocol at the time. The sodium levels finally corrected, and the secondary adrenal insufficiency has been declared as the real cause of hyponatremia. SIADH is often thought to be the cause of hyponatremia in patients with malignant disease. However, SIADH represents a diagnosis of exclusion. Before making a final diagnosis, thyroid and secondary adrenal insufficiency must be ruled out. Moreover, secondary adrenal insufficiency imitates SIADH and results in euvolemic hyponatremia but the management and potential outcomes of these two conditions differ significantly. In patients who have been previously treated for malignancies with the treatment options that increase the risk of adrenal insufficiency (chemotherapy, neck or skull base radiotherapy, immunotherapy), adrenal reserve must be evaluated. If introduced, the glucocorticoid therapy should be carefully deescalated in these patients because of the risk of previously unrecognized adrenal insufficiency. This especially applies to conditions that include glucocorticoid therapy in the treatment protocol, such as Covid-19 infection.