Cushing's Syndrome Patients Research Articles

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality.

ObjectiveWe aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS).MethodsThe protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies.ResultsSMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

The Association of Serum Total Bile Acids With Bone Mineral Density in Chinese Adults Aged 20-59: A Retrospective Cross-Sectional Study.

ObjectiveAccording to a recent study, serum total bile acids (TBA) may preserve lumbar bone mineral density (BMD) in Cushing syndrome patients, and BMD is directly linked to bone health. We were interested in examining the association between TBA and in Chinese adults aged 20–59 years.MethodsWe retrospectively analyzed the physical examination results of 2,490 general healthy subjects in Hainan West Central Hospital. Femoral neck BMD and TBA were measured, and the relationship between TBA and femoral neck BMD was evaluated by curve fitting, a generalized additive model, and multiple linear regression analysis.ResultsThe fitted smooth curve and generalized additive model showed a nonlinear relationship between TBA and femoral neck BMD, and a positive correlation between TBA and femoral neck BMD was found after we made adjustments for the potential confounders.ConclusionTBA is positively associated with femoral neck BMD in Chinese adults aged 20–59 years.

The Importance of DHEA-S Levels in Cushing's Syndrome; Is There a Cut-off Value in the Differential Diagnosis?

The purpose of this study was to determine possible cut-off levels of basal DHEA-S percentile rank in the differential diagnosis of patients with Cushing's syndrome (CS) with ACTH levels in the gray zone and normal DHEA-S levels. In this retrospective study including 623 pathologically confirmed CS, the DHEA-S percentile rank was calculated in 389 patients with DHEA-S levels within reference interval. The patients were classified as group 1 (n=265 Cushing's disease; CD), group 2 (n=104 adrenal CS) and group 3 (n=20 ectopic ACTH syndrome).ROC-curve analyses were used to calculate the optimal cut-off level of DHEA-S percentile rank in the reference interval in the differential diagnosis of CS, and the effectiveness of this cut-off level in the identification of the accurate etiology of CS was assessed in patients who were in gray zone according to their ACTH levels. The DHEA-S percentile rank in the reference interval were significantly lower in group 2 compared to the other two groups (p<0.001), while group 1 and group 3 had similar levels. The optimal cut-off level of DHEA-S percentile rank in the reference interval providing differential diagnosis between group 1 and group 2 was calculated as 19.5th percentile (80.8% sensitivity, 81.5% specificity) and the level demonstrated the accurate etiology in 100% of CD and 76% of adrenal CS patients who were in the gray zone. This study showed that the cut-off value of DHEA-S level less than 20% of the reference interval could be used for differential diagnosis of CD and adrenal CS with high sensitivity and specificity, and it should be taken into the initial evaluation.

Ketoconazole- and Metyrapone-Induced Reductions on Urinary Steroid Metabolites Alter the Urinary Free Cortisol Immunoassay Reliability in Cushing Syndrome.

IntroductionTwenty-four-hour urinary free cortisol (24h-UFC) is the most used test for follow-up decision-making in patients with Cushing syndrome (CS) under medical treatment. However, 24h-UFC determinations by immunoassays (IA) are commonly overestimated because of steroid metabolites’ cross-reaction. It is still uncertain how ketoconazole (KTZ)- and metyrapone (MTP)-induced changes on the urinary steroid metabolites can alter the 24h-UFC*IA determinations’ reliability.Methods24h-UFC was analyzed by IA and gas chromatography-mass spectrometry (GC-MS) in 193 samples (81 before treatment, 73 during KTZ, and 39 during MTP) from 34 CS patients. In addition, urinary steroidome was analyzed by GC-MS on each patient before and during treatment.ResultsBefore treatment, 24h-UFC*IA determinations were overestimated by a factor of 1.75 (95% CI 1.60–1.94) compared to those by GC-MS. However, during KTZ treatment, 24h-UFC*IA results were similar (0.98:1) to those by GC-MS (95% CI, 0.83–1.20). In patients taking MTP, IA bias only decreased 0.55, resulting in persistence of an overestimation factor of 1.33:1 (95% CI, 1.09–1.76). High method agreement between GC-MS and IA before treatment (R2 = 0.954) declined in patients under KTZ (R2 = 0.632) but not in MTP (R2 = 0.917). Upper limit normal (ULN) reductions in patients taking KTZ were 27% larger when using 24h-UFC*IA compared to 24h-UFC*GC-MS, which resulted in higher false efficacy and misleading biochemical classification of 15% of patients. Urinary excretion changes of 22 urinary steroid metabolites explained 86% of the 24h-UFC*IA interference. Larger urinary excretion reductions of 6β-hydroxy-cortisol, 20α-dihydrocortisol, and 18-hydroxy-cortisol in patients with KTZ elucidated the higher 24h-UFC*IA bias decrement compared to MTP-treated patients.ConclusionKTZ and MTP alter the urinary excretion of IA cross-reactive steroid metabolites, thus decreasing the cross-reactive interference of 24h-UFC*IA determinations present before treatment. Consequently, this interference reduction in 24h-UFC*IA leads to loss of method agreement with GC-MS and high risk of overestimating the biochemical impact of KTZ and MTP in controlling CS because of poor reliability of reference ranges and ULN.

Endogenous Cushings syndrome is associated with impaired myocardial work efficiency

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): German Ministry of Research and Education within the Comprehensive Heart Failure Center, Würzburg OnBehalf STAAB Cohort Study and CV-CORT-EX Study Background Endogenous Cushing’s syndrome (CS) is associated with increased cardiovascular morbidity and mortality. Long-term remission (LTR) after successful treatment is considered to positively affect the cardiovascular system including the heart. Left ventricular (LV) myocardial work (MyW) based on pressure-strain loops is a novel tool to non-invasively assess LV performance and is considered less load-dependent than LV ejection fraction (LVEF) and global longitudinal strain (GLS). We analyzed LV function in patients with overt CS and CS in LTR in comparison to healthy individuals derived from a local population-based cohort. Methods/Results: In a cross-sectional analysis, we compared n = 31 comprehensively characterized patients with overt CS (mean age 48 ± 12 years, 71% women) and 49 patients with CS in LTR (53 ± 12 years, 77% women) with a control group who underwent transthoracic echocardiography. As control group, we analyzed a population-based sample of apparently healthy individuals (in sinus rhythm, free from CV risk factors, and no significant valve disease) from a population-based cohort: n = 439, 49 ± 11 years, 56% women. MyW assessment was performed off-line using EchoPAC (GE, version 202). Systolic and diastolic blood pressure, HbA1c, and body mass index were significantly higher in patients with either overt CS or CS in LTR when compared to healthy participants (without significant differences between both patient groups). LVEF was equal between all three groups, but GLS was significantly lower in healthy participants and tended to be lower in LTR when compared to patients with CS. Global work index was equal between all three groups, but global wasted work was significantly higher in CS patients when compared to healthy participants, resulting in lower global work efficiency (Table). Conclusion In contrast to LVEF as established parameter of cardiac function, myocardial work analysis revealed functional alterations in patients with current and previous cortisol excess when compared to healthy individuals derived from a population-based sample. CS patients´ hearts appear to perform larger amounts of wasted work even during long-term remission. Abstract Figure.

Clinical Spectrum of Adrenal Cushing's Syndrome and the Caution for Interpretation of Adrenocorticotrophic Hormone: A Single-Center Experience.

Retrospective, single-center, observational study. Fifty-eight adrenal CS patients [Adrenocortical carcinoma (ACC), n=30; Adenoma (ACA), n=15; Primary pigmented nodular adrenocortical disease (PPNAD), n=10; ACTH independent macronodular adrenal hyperplasia (AIMAH), n=3) evaluated at a tertiary care center in western India between January 2006 to March 2020 were included. Data on demography, clinical evaluation, biochemistry, imaging, management, histopathology, and outcome were recorded in a standard format and analyzed. Cortisol secreting ACC presented at 38(1-50) years with abdominal mass in 26/30 (86.7%) and 16/30 (53.3%) had metastases at presentation. ACA with autonomous cortisol excess presented at 25(4.9-40) years with discriminating features of CS in 14/15 (93.3%), sex steroid production in 2/15, unenhanced HU <10 in only one, and relative washout >40% in 8/11 (72.7%). One ACA and eight ACC patients had plasma ACTH (by Siemens Immulite assay) > 20 pg/ml, despite hypercortisolemic state. Cortisol-secreting ACC and ACA most often present with mass effects and florid CS, respectively. Baseline HU has low sensitivity to differentiate cortisol-secreting ACA from ACC. Plasma ACTH measured by Seimens Immulite is often unsuppressed, especially in ACC patients, which can be addressed by measuring ACTH by more accurate assays.

Association between Neutrophilic Granulocyte Percentage and Diabetes Mellitus in Cushing's Syndrome Patients: A Cross-Sectional Study.

Background Glucose metabolism is frequently impaired in patients with Cushing's syndrome (CS) due to chronic exposure to excess glucocorticoids. Inflammation plays an essential role in the pathophysiology of diabetes mellitus (DM). The present study aimed to investigate the potential associations of inflammatory blood cell parameters, including white blood cell (WBC) count, neutrophil count, neutrophilic granulocyte percentage (NEUT%), lymphocyte count (LYM), and lymphocyte proportion (LYM%), with diabetes mellitus in Cushing's syndrome patients. Materials and Methods The cross-sectional study was conducted in Zhongshan Hospital of Fudan University, China. A total of 150 patients with Cushing's syndrome were retrospectively screened from 2017 to 2019. The demographic data, clinical data, and blood samples (lipids, adrenal, glucose, and inflammatory blood cell parameters) were recorded. Statistical analyses were carried out by using the SPSS software package, version 13.0. Results In this study, the prevalence of diabetes mellitus was 38.7% in patients with Cushing's syndrome. Patients with DM had higher WBC, neutrophil, NEUT% levels than patients without DM (p < 0.05). As the NEUT% increased, a stepwise increase in glucose and glycated hemoglobin (HbA1c) level was observed. In addition, in the multivariate logistic regression, NEUT% was a significant independent risk factor for DM, regardless of gender, age, body mass index (BMI), and triglyceride and 12 midnight cortisol (12 MN cortisol) level (OR = 2.542, 95% CI 1.337–4.835, p < 0.001). Conclusions In conclusion, elevated NEUT% level was linked to diabetes in patients with Cushing's syndrome. The neutrophilic granulocyte percentage may be referred to as a new predictor for diabetes in Cushing's syndrome patients.

Cortisol and Phosphate Homeostasis: Cushing's Syndrome Is Associated With Reversible Hypophosphatemia.

ObjectivesThe influence of hypercortisolism on phosphate homeostasis is relatively unknown. A few previous studies have reported on patients with Cushing’s syndrome (CS) with hypophosphatemia in whom serum phosphate normalized after initiation of treatment for CS. We aimed to investigate the prevalence of hypophosphatemia in CS, the association between the degree of hypercortisolism and serum phosphate and the change in serum phosphate after remission of CS. We compared the prevalence of hypophosphatemia in CS with the prevalence in the population-based Rotterdam Study (RS).MethodsPatients diagnosed with CS and treated at the Department of Endocrinology of Erasmus MC in the period of 2002-2020 were included and data was collected on age at diagnosis, sex, serum phosphate, calcium and potassium levels, kidney function and BMI. Using multivariate linear regression, we analyzed the association between 24h urinary free cortisol excretion (UFC) and serum phosphate. Changes in serum phosphate and covariates were tested with a repeated measurement ANOVA, using mean levels of laboratory values for the periods before remission, and 0-14 days and 15-180 days after remission.ResultsHypophosphatemia before treatment was present in 16% of the 99 CS patients with data on serum phosphate, 24h UFC and covariates. In comparison, the prevalence of hypophosphatemia in RS was 2.0-4.2%. Linear regression showed a negative association between the level of UFC and serum phosphate at diagnosis, which remained significant after adjusting for covariates [β -0.002 (95%CI -0.004; -0.0004), p=0.021]. A subset of 24 patients had additional phosphate measurements at 0-14 days and 15-180 days after remission. In this subgroup, serum phosphate significantly increased from 1.03 ± 0.17 mmol/L prior to remission to 1.22 ± 0.25 mmol/L 15-180 days after remission (p = 0.008). BMI decreased after remission [-1.1 kg/m2, (95%CI -2.09 to -0.07), p=0.037]. Other covariates did not show an equivalent change over time.ConclusionIn this retrospective study, we found that 16% of patients with CS had hypophosphatemia. Moreover, serum phosphate was related to the level of cortisoluria and increased after remission of CS. Potential underlying mechanisms related to urinary phosphate excretion and possibly involving FGF23, BMI and parathyroid hormone levels should be further explored.

Management of Patients With Glucocorticoid-Related Diseases and COVID-19.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing’s syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).

Glucocorticoid-induced Fingerprints on Visceral Adipose Tissue Transcriptome and Epigenome.

Chronic glucocorticoid (GC) overexposure, resulting from endogenous Cushing's syndrome (CS) or exogenous GC therapy, causes several adverse outcomes, including persistent central fat accumulation associated with a low-grade inflammation. However, no previous multiomics studies in visceral adipose tissue (VAT) from patients exposed to high levels of unsuppressed GC during active CS or after remission are available yet. To determine the persistent VAT transcriptomic alterations and epigenetic fingerprints induced by chronic hypercortisolism. We employed a translational approach combining high-throughput data on endogenous CS patients and a reversible CS mouse model. We performed RNA sequencing and chromatin immunoprecipitation sequencing on histone modifications (H3K4me3, H3K27ac, and H3K27me3) to identify persistent transcriptional and epigenetic signatures in VAT produced during active CS and maintained after remission. VAT dysfunction was associated with low-grade proinflammatory status, macrophage infiltration, and extracellular matrix remodeling. Most notably, chronic hypercortisolism caused a persistent circadian rhythm disruption in VAT through core clock genes modulation. Importantly, changes in the levels of 2 histone modifications associated to gene transcriptional activation (H3K4me3 and H3K27ac) correlated with the observed differences in gene expression during active CS and after CS remission. We identified for the first time the persistent transcriptional and epigenetic signatures induced by hypercortisolism in VAT, providing a novel integrated view of molecular components driving the long-term VAT impairment associated with CS.

Mayo Adhesive Probability Score Is Associated with the Operative Time in Laparoscopic Adrenalectomy.

Background: Laparoscopic adrenalectomy (LA) is the standard treatment for adrenal benign tumors, including primary aldosteronism (PA) or Cushing's syndrome (CS). Several obesity-related factors were associated with prolonged total operative time (OT), but perinephric fat characteristics were not assessed. We investigated whether the Mayo adhesive probability (MAP) score, which evaluates perinephric fat characteristics, was associated with OT for LA. Methods: This single-center, retrospective cohort study examined 141 consecutive patients who underwent LA for PA or CS. We reviewed patients' characteristics and OT. MAP scores were recorded using preoperative imaging. The correlation among characteristics data, MAP score, and OT was evaluated. Results: Overall, we assessed 82 women and 59 men. Adrenal tumors were found in 80 PA and 61 CS patients. There were 74 left-sided and 67 right-sided tumors. For all patients, the median age, body mass index, and tumor size were 56 years (interquartile range [IQR] 46-65), 24.1 kg/m2 (IQR 21.7-26.8), and 19 mm (IQR 13-26), respectively. A total of 91 patients had MAP scores of 0, and 50 had MAP >0. The median OT was 183.5 minutes (IQR: 156-224 minutes) in the MAP >0 group and 162 minutes (IQR: 135-194 minutes) in the MAP = 0 group. In single variable analysis (unadjusted), MAP scores >0 and left-sided tumors were correlated with longer OT. Multivariable regression analysis revealed that this correlation was only significant for MAP scores >0. Conclusions: MAP score may be useful in preoperative planning for PA or CS patients undergoing LA.

Cushing Syndrome is Associated with Increased Stage N2 Sleep and Decreased SWS Partially Reversible After Treatment.

The aim of the present study was to evaluate the sleep parameters of patients with Cushing syndrome (CS) at the time of diagnosis and 12-months after treatment. Thirty four newly diagnosed patients with endogenous CS (17 with ACTH-secreting pituitary adenoma, 17 with adrenal CS) and 23 controls with similar age were included in the study. Two polysomnography (PSG) recordings were performed; one at the time of diagnosis and the other 12 months after resolution of hypercortisolemia. Control group had only baseline PSG. Based on the PSG findings, stage N2 sleep was found to be prolonged, stage N3 and REM sleep were shortened in patients with CS. Average heart rate and mean Apnea Hypopnea Index (AHI) score were higher in patients with CS than the control subjects. Sixteen (47.1%) patients with CS and 4 (17.4%) controls had obstructive sleep apnea (OSA; AHI ≥5). There were no significant differences in sleep parameters of patients according to the etiology of CS (adrenal vs. pituitary) patients. Following 12-months of treatment, a significant decrease in stage N2 sleep and a significant increase in stage N3 sleep were detected, but there was no change in terms of AHI. In conclusion, Cushing syndrome has disturbing effects on sleep structure and these effects are at least partially reversible after treatment. However, the increased risk of OSA was not reversed a year after treatment indicating the importance of early diagnosis and treatment of CS.

The effect of Cushing's syndrome on pregnancy complication rates: analysis of more than 9 million deliveries

Purpose The purpose of this study to evaluate the risk of Cushing’s syndrome (CS) and maternal and fetal complications using the American Nationwide Inpatient Sample database. Materials and methods This is a retrospective study using the Health Care Cost and Utilization Project-Nationwide Inpatient Sample database from 2004 to 2014. We compared pregnancies with CS versus non-CS regarding pregnancy, delivery, and neonatal outcomes using multivariate logistic regression. Results We identified 9,096,788 pregnancies during the study period. Cushing’s syndrome complicated 135 pregnancies at a rate of 1–2 cases per 100,000 births. Cushing’s syndrome subjects were more likely to be older, obese, have private insurance, chronic hypertension, and pre-gestational diabetes (p<.001). The maternal mortality rate was 0.7 and 0.007% in Cushing’s syndrome and control groups, respectively, although due to small numbers of cases, this should be interpreted with caution. Preeclampsia was higher in CS compared to controls after controlling for confounding variables, aOR 2.20. Operative vaginal delivery and blood transfusion rates were higher in CS patients than controls after controlling for confounding factors, aOR 6.49 and 3.09, respectively. The rates of preterm delivery (8.9 versus 7.2%) and gestational diabetes (8.1 versus 5.8%) were not statistically different between CS and control groups. Conclusion Cushing’s syndrome patients begin pregnancies often with maladies making them more at risk for complications including, preeclampsia, blood transfusion, and operative vaginal delivery. These patients might benefit from prevention methods for preeclampsia, and increased surveillance to decrease maternal morbidity and mortality. However, the nature of the database and its limitations, including the lack of information about CS activity and treatments received by patients, warrant careful interpretation of these results.

Cross-species Association Between Telomere Length and Glucocorticoid Exposure.

Chronic exposure to glucocorticoids (GCs) or stress increases the risk of medical disorders, including cardiovascular and neuropsychiatric disorders. GCs contribute to accelerated aging; however, while the link between chronic GC exposure and disease onset is well established, the underpinning mechanisms are not clear. We explored the potential nexus between GCs or stress exposure and telomere length. In addition to rats exposed to 3 weeks of chronic stress, an iatrogenic mouse model of Cushing syndrome (CS), and a mouse neuronal cell line, we studied 32 patients with CS and age-matched controls and another cohort of 75 healthy humans. (1) Exposure to stress in rats was associated with a 54.5% (P = 0.036) reduction in telomere length in T cells. Genomic DNA (gDNA) extracted from the dentate gyrus of stressed and unstressed rats showed 43.2% reduction in telomere length (P = 0.006). (2) Mice exposed to corticosterone had a 61.4% reduction in telomere length in blood gDNA (P = 5.75 × 10-5) and 58.8% reduction in telomere length in the dentate gyrus (P = 0.002). (3) We observed a 40.8% reduction in the telomere length in patients with active CS compared to healthy controls (P = 0.006). There was a 17.8% reduction in telomere length in cured CS patients, which was not different from that of healthy controls (P = 0.08). For both cured and active CS, telomere length correlated significantly with duration of hypercortisolism (R2 = 0.22, P = 0.007). (4) There was a 27.6% reduction in telomere length between low and high tertiles in bedtime cortisol levels of healthy participants (P = 0.019). Our findings demonstrate that exposure to stress and/or GCs is associated with shortened telomeres, which may be partially reversible.

Patient and Provider Perspectives on Postsurgical Recovery of Cushing Syndrome.

Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure. To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL. Cross-sectional observational survey. Patients (n = 341) had undergone surgery for CS and were members of the Cushing's Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS. Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P < 0.0001), exercise (40.9% vs 77.6%, P = 0.0001), and activities (44.8% vs 75.5%, P = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8). Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery.

1177-P: The Reduction in Hepatic Steatosis after Cushing’s Syndrome Treatment Is a Marker of Improving Glycemia

Cushing Syndrome (CS) is characterized by cortisol excess that leads to impaired glucose tolerance and obesity. CT imaging shows 20% of CS patients have nonalcoholic steatohepatitis (NASH). While the gold standard diagnostic test for NASH is liver biopsy, it has too much risk for CS patients. This study evaluated the ability of noninvasive, magnetic resonance spectroscopy (MRS) to measure liver fat percentage in CS patients and followed temporal changes in metabolic parameters before and after successful treatment. The primary outcome was protein density fat fraction (PDFF) by MRS at 3 timepoints: baseline, 6 months, and 12 months after treatment, which consisted of surgery as indicated based on ACTH source. The diagnosis was confirmed if there was histology consistent with corticotrope adenoma, adrenal tumor, or an ectopic source. We prospectively studied 41 consecutive patients: 85% female; 44±1.8 y; 32.6±1.5 kg/m²; urine cortisol excretion 2242.7±1806.3 [nl 3.5-45.0 mcg/24h]). Each underwent MRS at 3T where NASH was defined as &amp;gt;5% PDFF. A1c and BMI were measured. Changes over time were evaluated using Wilcoxon signed-rank test, and correlation among variables was done with Spearman’s rank test. At baseline, mean PDFF was 10.4±1.7 and correlated positively with BMI (r=0.57, P&amp;lt;0.001). NASH was present in 32% of patients. PDFF reductions were similar after 6 and 12 months of treatment (-52%, P=0.001 and -50%, P=0.02); rates of NASH declined to 13% and 11%; BMI decreased (-9%; P=0.002 and -12%, P&amp;lt;0.001). A1c was lower at 12 months (6.2±1.1 to 5.6±0.5, P&amp;lt;0.001). The reduction in liver fat correlated with changes in visceral fat mass (r=0.70, P&amp;lt;0.001). In summary, MRS-PDFF was effective at diagnosing NASH in CS. Physiologically, definitive treatment of CS reduced liver fat by 6 months after normalization of cortisol and also preceded the improvement in A1c. These results suggest that liver insulin resistance due to fat accumulation has an important role in diabetes pathophysiology in CS. Disclosure A. Pierce: None. Z. A. Sater: None. A. M. Cypess: None.

Abstract #1001609: COVID-19 Response in the Cushing's Community: A Report from the Membership of the Cushing's Support & Research Foundation (CSRF), a Patient Advocacy Organization: Submitter: Leslie Edwin - Cushing's Support and Research Foundation

Cushing’s syndrome (CS) is a rare neuroendocrine disease caused by persistent, excessive cortisol secretion. Many patients suffer significant co-morbidities, and most experience delays in diagnosis and treatment. During active CS through at least the short-term post-surgical period, patients are at increased risk of infections and, frequently, poorly managed hypertension and glucose intolerance / insulin resistance. The COVID-19 pandemic thus presented this rare patient population with an unprecedented challenge to mitigate. We examined self-reported pandemic-related behaviors of CS patients who are members of the US-based patient advocacy organization Cushing’s Support & Research Foundation (CSRF). An online survey analyzing behaviors related to CS status, adverse effects of quarantine, and adaptive measures engaged as a result of the COVID-19 pandemic was designed and shared with members of CSRF. Of 274 total responses, 91.2% (n=250) of members indicated that they had not become infected with COVID-19 as of the time of survey completion, whereas 8.8% (n=24) had caught the virus. The majority of respondents (78.5%, n=215) are post-surgical and in remission; the remaining 21.5% (n=59) are experiencing recurrence, diagnosed but not yet treated, or still in the diagnostic phase. About two-thirds of respondents (66.4%, n=182) reported making changes to their routine immediately or within the first week of hearing about the pandemic. Most (89.8%, n=246) have habitually worn a mask throughout 2020 and into 2021, but in some cases it has taken adverse experiences to alter behaviors. Among the patients diagnosed with COVID, five reported not wearing a mask before getting the virus, but four of those began wearing a mask after getting infected with the virus. Some patients reported postponing labs (38.7%, n=106), postponing MRIs or other radiology appointments (21.2%, n=58), and testing for the virus (13.5%, n=37) based solely on concern for potential increased risk of infection / severity of infection due to their history with CS. About a third of respondents (34.7%, n=95) also have temporary or permanent adrenal insufficiency (AI) due to CS, and a notable 38.9% (n=37) of these patients reported shortages of their regular cortisol-replacement medication at their regular pharmacy. Changing dosage and/or cutting pills is another response to shortages reported by 13.7% (n=13) of those experiencing AI. Quarantine restrictions are at times extreme and difficult to manage. Rare disease patients such as those with CS already adapt their conditions daily to a world that often doesn’t readily support or understand those adaptations. The results of this survey confirm that the added stress and uncertainty of adjusting further to the restrictions of quarantine have added significant burden to these patients. Social isolation and postponement of needed tests and procedures in particular have contributed to a decreased quality of life for CS patients during the COVID-19 pandemic.

COVID-19: Is there an urgent need to further assess how Cushing syndrome patients have reacted to this pandemic and what mechanisms are in place to support them?

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

Hypercoagulability in ACTH-Dependent Cushing Syndrome

Introduction: ACTH-dependent Cushing syndrome (CS) is associated with hypercoagulability; however, the incidence and timing of thrombosis during evaluation and management of CS is unclear.Objective: To evaluate the incidence and timing of thrombotic events in patients with ACTH-dependent CS following diagnosis and management.Methods: We performed a retrospective, longitudinal study of patients with ACTH-dependent CS seen at Stanford University Health Care from 1998 to 2020. Thrombotic events — deep vein thrombosis (DVT), pulmonary embolism (PE), cerebral vascular accident (CVA), and myocardial infarction (MI) — were recorded between diagnosis and 12 months following therapeutic intervention.Results: Of 108 patients with ACTH-dependent CS, 97 (89.8%) were women, and the mean age at diagnosis was 43.0 years (± 15.7 years). Sixty-eight (63%) patients had hypertension, 38 (35.2%) had diabetes mellitus, and 11 (10.2%) were active smokers. Of the 108 subjects, 97 (89.8%) had Cushing Disease (CD) and 11 (10.2%) had ectopic CS. Of the 97 patients with CD, 38 (39.2%) underwent inferior petrosal sinus sampling (IPSS), 59 (60.8%) underwent transsphenoidal surgery (TSS), 19 required repeat TSS (19.6%), and 15 underwent TSS and bilateral adrenalectomy (BAL) (15.4%). Of the 11 patients with ectopic CS, 3 (27.2%) underwent IPSS, 6 (54.5%) underwent BAL, and 1 (9.1%) underwent TSS and BAL.There were 10 thrombotic events among 7 (7.2%) CD patients, but no thrombotic events among ectopic CS patients. Of the thrombotic events, there were 7 (70%) DVT/PE, 2 (20%) CVA, and 1 (10%) cortical vein thrombosis. Six (60%) occurred within 30 days after TSS (range 3-25 days), 2 (20%) between 31 days and 1 year after TSS (range 59-165 days), 1 (10%) 26 days after IPSS but prior to TSS, and 1 (10%) in a patient who did not undergo IPSS or surgery. No thrombotic events were noted after BAL. Of the 8 postoperative thrombotic events, 5 (62.5%) occurred while patients received supraphysiologic glucocorticoid replacement (defined as >25mg hydrocortisone or equivalent daily) after curative surgery, 1 (12.5%) occurred after a patient was tapered to physiologic glucocorticoid replacement, and 2 (25%) occurred in patients who had persistent disease despite surgery. The degree of hypercortisolism at baseline was not associated with risk of thrombotic events.Conclusions: In this retrospective study, 6.5% of ACTH-dependent CS patients had a thrombotic event, all in patients with CD. The majority had venous thromboembolism with DVT/PE, and the highest incidence occurred up to 30 days after surgery. The degree of hypercortisolism at baseline did not correlate with subsequent thrombotic events. Therefore, it is important to monitor all patients with ACTH-dependent CS following surgical intervention for venous thromboembolism.

The Improvement in Hepatic Steatosis After Cushing’s Syndrome Treatment Is an Early Sign of Metabolic Recovery

Context: Cushing Syndrome (CS) is characterized by cortisol excess, impaired glucose tolerance, and obesity. As assessed by CT imaging, 20% of CS patients develop steatohepatitis (NASH). The gold standard test, liver biopsy, is associated with CS complications and cannot be used to confirm the diagnosis. This study evaluated the ability of magnetic resonance spectroscopy (MRS).Objective: To identify the prevalence of NASH and its temporal changes in relation to other metabolic parameters in CS before and after successful treatment. Primary Outcome Measure: PDFF measured by MRS at 3T before, 6 and 12 months after Cushing’s syndrome treatment DESIGN: In this prospective IRB-approved study, 41 consecutive CS patients (44±1.8 y; 34(85%) females, 32.6±1.5 kg/m²; urine cortisol excretion 2242.7±1806.3 [3.5–45.0 mcg/24h]) underwent MRS before, 6 and 12months after successful treatment. PDFF was measured by MRS at 3T; NASH was defined as >5% PDFF. Metabolic markers – glycohemoglobin (A1C) and body mass index (BMI) – were measured; Wilcoxon matched-pairs signed-rank test evaluated changes over time, and spearman rank test evaluated the correlation between variables. Results: At baseline, mean PDFF was 10.4±1.7 and correlated positively with BMI (r=0.5710, p<0.0001). NASH was present in 32% of patients. After treatment, PDFF decreases were similar at 6 and 12 months (-52%, p=0.001 and -50%, p=0.02, respectively); rates of NASH declined to 13% and 11%. BMI decreased (-9%; p=0.0018 and -12%, p=0.0003) but without a statistically significant change overweight/obese status. A significant decrease in A1C followed at 12 months (-12%, p=0.0005).Conclusions: MRS-PDFF is valuable for diagnosing NASH in Cushing Syndrome, which can affect a third of this patient population. Liver fat decreases by 6 months after normalization of cortisol and precedes the improvement of A1C. Indicating that liver insulin resistance due to fat accumulation has an essential role in diabetes pathophysiology in CS.