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Abstract Disclosure: J. Saini: None. R. Nathani: None. S. Singh: None. K. Thangamuthu: None. M. Suresh: None. C. Zhang: None. A.L. Ebbehøj: None. M. Thomas: None. V. Fell: None. E. Atkinson: None. S. Achenbach: None. N. Stricker: None. I. Bancos: None. Introduction: While patients with overt Cushing syndrome are reported to have impaired cognition, the impact of milder, long-standing hypercortisolism on cognition is incompletely characterized. Objective: To determine the impact of MACS on cognition as compared to age, sex, and education-matched referent subjects. Methods: We conducted a single-center cross-sectional study of adults with MACS and referent subjects. MACS was defined as serum cortisol>1.8 mcg/dL after 1 mg dexamethasone suppression test (DST) in patients with adrenal incidentalomas. Referent subjects were included if they had abdominal imaging and had no adrenal disorders. Exclusion criteria were malignancy and exogenous glucocorticoid use within 1 year. All participants underwent a cognitive evaluation using the NIH Toolbox Cognition Battery between 1/2019 to 7/2022. NIH Toolbox assesses 8 cognitive domains using 7 tests and yields 3 composite scores: fluid cognition (executive function, episodic memory, cognitive flexibility, working memory, and processing speed), crystallized cognition (language and vocabulary), and total composite cognition (composite of all). Results are given in fully corrected T scores (adjusted for age, sex, race, and education) with an average of 50 and a standard deviation (SD) of 10. A subgroup analysis was performed based on DST cortisol. The Kruskal-Wallis test was used to compare scores between groups. Results: A total of 94 patients with MACS (median age 57.2 years, IQR 47.8-66.5, 70% women) and 94 referent subjects (median age 58 years, IQR 49.1-66.4, 70% women) were included. The median post-DST cortisol in patients with MACS was 3.3 mcg/dL (IQR, 2.4-6.2). The mean (SD) total composite T-score was lower in patients with MACS vs referent subjects (51 (9.1) vs 56.3 (9.3), P<0.001). Patients with MACS demonstrated lower mean fluid composite T-score when compared to referent subjects (49.5 (10.4) vs 56.9 (9.7), P<0.001). However, mean crystallized composite T-scores were similar in patients with MACS and referent subjects (52.3 (8.1) vs 53.9 (9.6), P=0.342). A subgroup analysis of patients with post-DST cortisol <3 mcg/dL (n=40) vs patients with post-DST cortisol >3 mcg/dL (n=54) did not show any differences in the total, fluid, or crystalized composite scores. Conclusion: Patients with MACS demonstrate lower cognitive performances than a referent group suggesting MACS has a subtle impact on cognitive functioning. The pattern of cognitive impairment in patients with MACS is similar to that seen with normal cognitive aging: impaired fluid cognitions and unaffected crystallized cognition). Cognitive performance did not differ based on the degree of MACS suggesting that in the absence of overt features of hypercortisolism, the degree of MACS is less important than the presence of MACS. Presentation: Thursday, June 15, 2023

Abstract Disclosure: L. Rahimi: None. A. Kittithaworn: None. R. Gregg Garcia: None. J. Saini: None. P. Dogra: None. E. Atkinson: None. S. Achenbach: None. A. Kattah: None. I. Bancos: None. Objective: Patients with mild autonomous cortisol secretion (MACS) have been reported to have a higher prevalence of chronic kidney disease (CKD), possibly due to the direct effect of hypercortisolism on kidney function and indirect effect of MACS-associated cardiovascular comorbidities, such as diabetes, hypertension, obesity, and dyslipidemia. Limited studies suggest improvement of kidney function following adrenalectomy in patients with MACS. In this study, we aimed to assess the factors associated and the degree and timing of change in kidney function post adrenalectomy in patients with MACS or nonfunctioning adrenal adenoma (NFA). Methods: We conducted a retrospective single-center study and included adult patients with MACS or NFA diagnosed based on a post-dexamethasone cortisol cutoff of 1.8 mcg/dL, who underwent adrenalectomy between 1999-2022. The change in estimated glomerular filtration rate (eGFR) before and up to 3.5 years after adrenalectomy was defined as the primary outcome. Demographics and comorbidities were included in univariable and multivariable analyses. Results: We included 155 (76.0%) patients with MACS and 49 (24.0%) patients with NFA treated with adrenalectomy. The proportion of women was high in both MACS and NFA (71.6% vs 69.4%, p=0.77), however, patients with MACS were older (median age 59.2 vs 54.6 years in NFA, p=0.05). The prevalence of hypertension was higher in MACS vs NFA (71.0% vs 53.1%, p=0.02), while the prevalence of diabetes (25.2% vs 28.6%, p=0.89), dyslipidemia (47.7% vs 46.9%, p=0.92), smoking (74.2% vs 68.9%, p=0.49) and obesity (median BMI 30.4 vs 31.8 kg/m2, p=0.35) was similar between the two groups. Prior to adrenalectomy, patients with MACS had lower eGFR (median 84.4 vs 89.2 ml/min/1.73m2, p=0.09) and a higher prevalence of CKD stage ≥ 3 (16.1% vs 8.2%, p= 0.16). In patients with MACS, after an initial decline of eGFR within 6 months post adrenalectomy (mean decrease 5.3 ml/min/1.73m2), eGFR increased by a mean of 4.9 points at 18-30 months, and by a mean of 8.1 points at 30-42 months post-adrenalectomy (p<0.01). Patients with NFA followed a similar eGFR change trend (p=NS). When comparing post-adrenalectomy delta eGFR in patients with MACS vs NFA, no significant differences were found. After adjusting for age, sex, pre-adrenalectomy eGFR, patient group, hypertension, antihypertensive therapy, and diabetes, there were still significant changes in eGFR over time. In a multivariable analysis, younger age (est -031, p<0.001) and lower pre-adrenalectomy eGFR (est-0.27, p=0.001) were associated with kidney function improvement post-adrenalectomy. Conclusion: Patients with MACS and NFA demonstrate improvement of eGFR over the 3.5 years of follow up post-adrenalectomy. The factors that are associated with improvement of eGFR are lower eGFR before surgery, younger age at time of adrenalectomy and longer follow up post adrenalectomy. Presentation: Friday, June 16, 2023

Abstract Objective Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. Design Multi-centre, cross-sectional study (March 2019-August 2022). Methods Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. Results Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio—OR 19.2, 95% confidence interval—CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). Conclusions Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Abstract Objective Prospective data on determinants of muscle strength impairment and quality of life in patients with various subtypes and severity of endogenous hypercortisolism are lacking. Design Single-center cross-sectional study, 2019 to 2022. Methods Patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) were assessed with clinical and biochemical severity scores, muscle function (nondominant hand grip strength and sit-to-stand test), and quality of life (Short Form-36 [SF36] and CushingQoL). Referent subjects were recruited from the local population undergoing abdominal imaging for reasons other than suspected adrenal disorder. Results Of 164 patients, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age was 53 years (interquartile range: 42-63 years), and 126 (77%) were women. The SF36 mental component score was similarly low in patients with MACS vs CS, but physical component score was lower in CS when compared to MACS (mean of 34.0 vs 40.5, P = .001). Compared to MACS, patients with CS had lower scores on the standardized CushingQoL (mean of 47.1 vs 34.2, P < .001). Compared to referent subjects, patients with MACS demonstrated reduced muscle strength, similar to patients with CS (mean sit to stand Z-score of −0.47 vs −0.54, P = .822). Clinical severity (r = −0.22, P = .004) but not biochemical severity was associated with sit-to-stand test performance. Conclusions Both patients with overt CS and MACS demonstrate reduced muscle strength and low quality of life. The clinical severity score utilized is associated with both physical and psychosocial components of CushingQoL and with the physical component of SF36.

Abstract Background Patients taking chronic opioids are at high risk of opioid induced adrenal insufficiency (OIAI). Previously, we showed that the prevalence of OIAI was 9% based on low morning cortisol, corticotropin (ACTH), and dehydroepiandrosterone sulfate (DHEAS). Data on the overnight metyrapone test to diagnose OIAI are sparse. We aimed to determine the prevalence of OIAI using overnight metyrapone test and identify changes in the steroid metabolome of patients treated with opioids. Methods Cross-sectional study of adult patients treated with opioid therapy of at least 20 morphine milligram equivalents (MME)/day for at least 3 months. Measurements included ACTH, cortisol, and DHEAS. Overnight metyrapone test was administered in all patients, and 24h urine steroid profiling was optional (25 steroids measured by liquid chromatography mass spectrometry1). All patients completed the quality-of-life survey (AddiQoL). Prevalence of OIAI was defined as sum of post-metyrapone 11-deoxycortisol and cortisol of <15 mcg/dL. Result: In 22 patients (median age 59 years [range, 38-74], 9, 41% women), median MME was 33 (20-161) mg, and median cumulative opioid exposure was 245 (10-2550) mg*years. Following the overnight metyrapone test, 7 (32%) patients were diagnosed with OIAI. Patients with OIAI had lower DHEAS concentrations (median of 21 mcg/dL[ 5-113] vs 54 [22-173], p =0. 03), but not cortisol (median 10[5.3-16] mcg/dL vs 13[5.3-22], p=0. 06) or ACTH (median 27[8.1-51] pg/mL vs 26[5.9-55], p=0.8). Patients with OIAI were treated with higher daily MME (100 mg[30-150] vs 30[20-161], p=0. 03) and had a higher cumulative exposure to opioids (median, 660 mg*years [250-2250] vs 150 [10-1288], p =0. 01). AddiQol scores were similar between groups (median of 68[56-84] vs 73[48-83], p= 0.97). Urine steroid profiling was performed in 18 patients. Patients with OIAI demonstrated 4 times lower total urine glucocorticoids (16334 mcg/24h vs 4377 mcg/24h, p=0. 003), all <10% of the reference range, and 3 times lower total urinary androgens (median of 805 mcg/24h vs 2320 mcg/24h, p=0.14). Conclusion Prevalence of OIAI using overnight metyrapone test is high at 32%. Patients diagnosed with OIAI were treated with higher doses of MME/day and had a higher cumulative exposure to opioids when compared to those without OIAI. Applying 24h urine steroid profiling we showed that total glucocorticoids are 4 times lower in those with OIAI (and all <10% of reference ranges) as opposed to those without OIAI. We showed that baseline measurements of ACTH, DHEAS, and cortisol may incorrectly exclude OIAI, and a dynamic test, such as overnight metyrapone test is needed when suspicion for OIAI is high. | 1. Hines JM, Bancos I, Bancos C, et al. High-Resolution, Accurate-Mass (HRAM) Mass Spectrometry Urine Steroid Profiling in the Diagnosis of Adrenal Disorders. Clin Chem. 2017;63(12): 1824-1835. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.