Diagnosis Of Cushing's Disease Research Articles

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Letter: Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

High prevalence of vertebral fractures associated with preoperative cortisol levels in patients with recent diagnosis of Cushing disease

Background/objective Morphometric vertebral fractures (VFs) and osteopathy are prevalent and clinically significant complications of Cushing disease (CD). However whether they represent an early occurrence in the natural progression of the disease is an ongoing debate. This study aimed to assess the prevalence and determinants of VFs in patients newly diagnosed with CD. Patients and methods This cross-sectional case–control study recruited 75 newly diagnosed CD patients and compared them with a control group of individuals without pituitary disorders or secondary forms of osteoporosis. Demographic, clinical and biochemical data were collected. The VFs were assessed using preoperative lateral chest radiography. Results We found a significantly higher prevalence of VFs in the CD group than in the control group (58.7% vs. 14.5%; P < 0.001). Among the CD patients with VFs, 27 (61.4%) showed moderate/severe VFs. The CD patients with VFs had significantly higher preoperative 8 am serum cortisol (8ASC) levels than those without VFs (P < 0.001). The preoperative 4 pm adrenocorticotropic hormone (ACTH) levels (P = 0.031), preoperative 0 am ACTH levels (P = 0.021) and systolic blood pressure were slightly higher in CD patients with VFs than in those without VFs (P = 0.028). A binary multiple logistic analysis showed that 8ASC was an independent predictor of VF risk (P = 0.003). The optimal cut-off value of the preoperative serum 8ASC level for predicting VFs was 22.18 ng/mL. Conclusions This is the first study reporting a high prevalence of radiologic VFs in recently diagnosed CD patients. VFs may represent an early manifestation of CD and may be related to cortisol levels. Therefore, VF assessment should be included in the workup during CD diagnosis.

SAT598 7mg-dexamethasone Suppression Test For The Differential Diagnosis Of Cushing’s Syndrome

Abstract Disclosure: D. Cuevas Ramos: None. G. Garza García: None. W. Hernández Núñez: None. F.J. Gómez Pérez: None. Introduction: Establishing the cause of Cushing’s syndrome remains challenging. Bilateral Inferior Petrosal Sinus Sampling (BIPSS) is the gold standard for distinguishing between Cushing's disease (ACHT-secreting pituitary adenoma) and an ectopic source of ACTH. However, BIPSS is an invasive test and is not widely available. Therefore, we sought to explore the diagnostic efficacy of the 7 mg dexamethasone suppression test (7mg-dexa) for establishing the diagnosis of Cushing's disease (CD). Methods: We reviewed 1375 cases with pituitary adenomas. From them, 191 cases had confirmed diagnosis of CD from 1999 to 2022. Of these, 25 patients underwent 7 mg dexamethasone suppression test together with BIPSS during their diagnosis workup. A diagnosis of CD was established in 21 patients, confirmed after neurosurgery, with a pathology report of ACTH+ secreting pituitary adenoma, and a biochemical resolution of CS. The additional 4 cases showed an adrenal source of CS. Suppression of 50% or more in the afternoon (of day 1 after 7 mg-dexa IV infusion by 7h starting at 7:00 hrs at 1 mg/hr) was considered consistent with CD. A central-to-peripheral plasma ACTH gradient of ≥2 before and after desmopressin stimulation was also considered consistent with CD during the BIPSS. We calculated kappa index to evaluate concordance between diagnostic test. Also, sensitivity (S), specificity (E), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) were calculated. Results: The mean age was 43±12.1 years, with a BMI of 30±5.6 kg/m2, 86% females. For the basal ACTH values during BIPSS, the S=76%, E=75%, PPV=94%, NPV=37%, LR+=3, LR-=0.3. For the post-stimulation BIPSS, the S=95%, E=75%, PPV=95%, NPV=75%, LR+=3, LR-=0.06. Using the 7mg-dexa, a S=91%, E=75%, PPV=95%, NPV=60%, LR+=3.6, LR-=0.12. Kappa between test was 0.6 before stimulation, and 0.7 after desmopressin stimulation showing acceptable concordance. Conclusion: The 7 mg-dexa showed similar and acceptable diagnostic performance in comparison with basal or stimulated BIPSS. Since 7mg-dexa inhibition test is less invasive and less expensive, further clinical research to evaluate its utility in CD diagnostic approach is in order. Presentation: Saturday, June 17, 2023

THU037 Diagnostic Accuracy Of Bilateral Inferior Petrosal Sinus Sampling In Adrenocorticotropin-dependent Cushing’s Syndrome, And The Utility Of Maximum-stimulated Petrosal Sinus ACTH To Baseline Petrosal Sinus ACTH Ratio

Abstract Disclosure: A.N. Maldar: None. P.H. Chauhan: None. A. Kulkarni: None. N.F. Shah: None. B.K. Misra: None. M. Chadha: None. Methods: The diagnosis of Cushing’s Syndrome (CS) was made as per the prevalent endocrine society guidelines. CS patients with serum ACTH&amp;gt;15 pg/mL were considered as ACTH-dependent CS. Baseline ACTH (both inferior petrosal sinuses and peripheral) values were obtained, and since 2014, stimulated ACTH values (5 and 10 minutes post one unit iv vasopressin) were obtained as standard protocol. Prolactin corrected ACTH ratios were additionally being calculated since 2016. The highest central to peripheral ACTH gradient &amp;gt;2 in baseline samples (bC:P), &amp;gt;3 in samples after vasopressin stimulation (sC:P), and &amp;gt;0.8 in PRL-corrected ratios (pC:P) was used as reference value indicative of Cushing’s Disease (CD). An inter-petrosal gradient &amp;gt;1.4 was considered to be suggestive of an adenoma located on the side of the petrosal sinus with the higher ACTH concentration. Results: Of the 51 patients with ACTH-dependent CS who underwent BIPSS, four patients with incomplete data, one patient with unilateral petrosal sinus catheterization, one patient with Cortisol Resistance Syndrome were excluded from the analysis. Mean age of our cohort was 37.5 years, with 77.8% females. 39 patients had CD (positive histopathology-immunohistochemistry in 34, and remission post-surgery in additional five with hyperplasia), while six had ectopic CS (one each of bronchial carcinoid, lung NET, thymic NET, pancreatic NET, and two with undiagnosed ectopic source). bC:P&amp;gt;2 (N=45) demonstrated 92.3% sensitivity, 83.3% specificity, 97.3% PPV and 62.5% NPV, while sC:P&amp;gt;3 (N=31) demonstrated 96.3% sensitivity, 100% specificity, 100% PPV and 80% NPV to diagnose CD. pC:P&amp;gt;0.8 (N=20) improved the sensitivity and NPV to 100%, with a 75% specificity and 94.1% PPV. On ROC analysis, cut-point ratio of 2.55 for bC:P value gave a sensitivity of 89.7% and specificity of 100% (AUC=0.964); sC:P ratio of 2.95 had 96.3% sensitivity and 100% specificity (AUC=0.991); 0.93 for pC:P ratio provided a sensitivity of 93.8% and specificity of 100% for diagnosis of CD (AUC=0.984). Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio of &amp;lt;1.11 provided a 100% sensitivity, while a ratio &amp;gt;1.75 provided 100% specificity towards diagnosis of CD. 71.4% (10/14) patients with left sided adenoma, and 85% (17/20) patients with right sided adenoma were correctly lateralised on BIPSS. In patients whom adenoma was detected on pituitary MRI, 66.7% (6/9) were correctly lateralised to the left side, and 94.1% (16/17) to the right side. Conclusion: BIPSS provides high sensitivity and specificity to diagnose CD. Vasopressin stimulation improves the sensitivity and specificity, while prolactin correction improves the sensitivity of BIPSS, as compared to baseline ratios. Maximum-stimulated petrosal sinus ACTH to baseline petrosal sinus ACTH ratio can be additionally used, especially in CD patients suspected of false negative localization. Presentation: Thursday, June 15, 2023

THU213 Posterior Reversible Encephalopathy Syndrome As A Rare Presentation Of ACTH-dependent Cushing Syndrome In A Pediatric Patient

Abstract Disclosure: E.E. Bell-Sambataro: None. C. Tatsi: None. P. Chittiboina: None. S.A. Bowden: None. Background: Cushing disease (CD), caused by ACTH-secreting pituitary adenoma, is the most common cause of Cushing Syndrome (CS) in children &amp;gt; 5 years of age. Hypertension is reported in up to 50% of pediatric cases with CS. We report a challenging pediatric case with a rare presentation of hypertensive emergency associated with CD. Clinical Case: A 6-year-old female with 3 month-history of rapid weight gain (8 kg), round face, and hypertrichosis presented to emergency department for abdominal pain from nephrolithiasis and was noted to have severe hypertension. While in ED, she developed status epilepticus and altered mental status. Brain MRI findings were consistent with posterior reversible encephalopathy syndrome (PRES). Her hypertensive encephalopathy gradually improved with aggressive anti-hypertensive and anti-epileptic therapy. Further studies confirmed hypercortisolism with markedly elevated urine free cortisol of 1288 ug/day (&amp;lt;18 ug/day) and lack of diurnal variation of serum cortisol (8 AM cortisol of 47.9 ug/dL, midnight cortisol of 20.3 ug/dL). ACTH level of 23 pg/mL suggested ACTH-dependent CS. Low dose (1 mg) dexamethasone suppression test (DST) failed to suppress 8 am cortisol (31.4 ug/dL). High dose DST (120 mcg/kg) suppressed serum cortisol to 67%- borderline threshold for CD, likely due to increased dexamethasone clearance by anticonvulsant. Pituitary MRI did not reveal a visible lesion. Desmopressin stimulation test showed stimulation of ACTH by 700% and cortisol by 160% suggesting pituitary source. Inferior petrosal sinus sampling showed a mildly increased gradient in central to peripheral plasma ACTH of 1.7 at baseline (&amp;gt;2) and post-stimulation of 2.5 (&amp;gt;3). ACTH gradient did not reach cutoffs for pituitary source, likely due to insufficient catheterization of petrosal sinus from anatomically small blood vessels. Given her severity, she underwent surgical pituitary exploration. Postoperative morning cortisol was &amp;lt;5 mcg/dL, with decreased midnight salivary cortisol level obtained 2 months after surgery. She developed post-operative central hypothyroidism but did not have diabetes insipidus. She had a 4 kg weight loss with increased height percentile 5 months after surgery and remains under close monitoring. Conclusion: PRES is a clinical-radiographic disorder characterized by seizures, encephalopathy with neuroimaging findings of reversible cortical and subcortical vasogenic edema. Hypertension induced by marked hypercortisolism precipitated by pain is likely the etiologic factor. Prompt recognition and treatment of PRES are crucial to prevent further life-threatening complications and permanent neurological damage. Early diagnosis and treatment of CD are critical to prevent associated morbidities. Pituitary exploration by expert neurosurgery team should be considered in patients with MRI-negative CD. Presentation: Thursday, June 15, 2023

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.

The relationship between temporal muscle thickness and disease activity in Cushing's disease.

This study aimed to investigate the relationship between hypercortisolism and temporal muscle thickness (TMT) in Cushing's disease (CD). A retrospective review of medical records was conducted for patients with CD who presented to our clinic between 2012 and 2022. Biochemical data and TMT measurements from sella imaging were evaluated during diagnosis and the first postoperative year. A total of 44 patients were included in the study, with an average age of 43.9years, of which 38 were female. The mean TMT at the time of diagnosis was 19.07 ± 1.71mm, with no significant difference between males and females (p = 0.097), and no correlation between the TMT and age at diagnosis (p = 0.497). There was an inverse relationship between TMT and serum cortisol levels, 24-h UFC, and midnight salivary cortisol at the time of diagnosis of CD (p < 0.05, for all). One year after surgery, TMT significantly increased in all patients compared to baseline (p < 0.001). Furthermore, patients who achieved postoperative remission had significantly higher TMT values compared to those who did not achieve remission (p = 0.043). Among the patients who achieved remission, those who achieved remission through surgery had significantly higher TMT compared to those who could not reach remission with surgery and patients who started medical treatment and achieved biochemical remission (p = 0.01). Patients with severe myopathy and sarcopenia had significantly lower TMT values than the others (p < 0.001). Temporal muscle thickness was found to be associated with disease activity and disease control in Cushing's disease.

P15 A rare case of paediatric Cushing disease presenting as acne

Abstract Cushing disease in children and adolescents is rare. Early detection and treatment are vital to reduce morbidity and mortality. We present the case of a 13-year-old female who was referred to dermatology with an acneiform rash on her face. During the consultation it was made apparent that the patient had noticed changes to her face over the past 6 months in which she described her face becoming swollen and ‘puffy’. She also reported irregular menstruation and hirsutism mainly to her back. Serum baseline tests at the time demonstrated no abnormalities, but further serum cortisol and free urinary cortisol were exceedingly high. Subsequently an MRI pituitary scan demonstrated a 3-mm microadenoma, in keeping with a diagnosis of Cushing disease. She has now been transferred to a tertiary paediatric endocrinology unit. This case highlights the importance of the dermatological manifestations of rare conditions such as this, and that the skin is often the window to many underlying medical conditions.

Enhancing Cushing's disease diagnosis: exploring the impact of desmopressin on ACTH gradient during BIPSS.

The differential diagnosis between Cushing's disease (CD) and ectopic ACTH syndrome (EAS) is complex, and bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold-standard test. However, BIPSS with corticotropin-releasing hormone (CRH) stimulation is rarely available. This retrospective cohort study aimed to assess the accuracy of the inferior petrosal sinus to peripheral ACTH gradient (IPS:P) before and after desmopressin stimulation for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), applying different cutoff values. A total of 50 patients (48 with CD and 2 with EAS) who underwent BIPSS were included in this study. The sensitivity and specificity of IPS:P in BIPSS before and after desmopressin stimulation were evaluated. Various cutoff values for IPS:P were examined to determine their diagnostic accuracy. Using the traditional IPS:P cutoff, the sensitivity was 85.1% before stimulation, 89.6% after stimulation, and a combined sensitivity of 91.7%. Applying cutoff values of IPS:P >1.4 before and >2.8 after stimulation, the sensitivity was 87.2% and 89.6%, respectively, with a combined sensitivity of 91.7%. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values of 1.2 before stimulation and 1.57 after stimulation, resulting in a sensitivity of 93.6% and 93.8%, respectively, with a combined sensitivity of 97.9%. Specificity remained at 100% throughout all analyses. Among the 43 patients who responded positively to stimulation, 42 (97.7%) did so within the first three minutes, and all 43 (100%) did so within the first five minutes. None of the assessed clinical variables predicted the ACTH response to stimulation in BIPSS with statistical significance. ACTH stimulation with desmopressin during BIPSS improves the accuracy of IPS:P, making it a valuable tool for investigating ACTH-dependent Cushing's syndrome. Considering the low risk of complications, we recommend the use of desmopressin stimulation during BIPSS for the differential diagnosis of ACTH-dependent CS.

Ovine CRH Stimulation and 8 mg Dexamethasone Suppression Tests in 323 Patients With ACTH-Dependent Cushing's Syndrome.

Determining the etiology of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available. Evaluate the performance of the corticotropin-releasing hormone stimulation test (CRH-ST) and the 8 mg high-dose dexamethasone suppression test (HDDST) in distinguishing Cushing's disease (CD) from ectopic ACTH syndrome (EAS). Retrospective review in a tertiary referral center. A total of 323 patients with CD or EAS (n = 78) confirmed by pathology or biochemical cure (n = 15) in 96% underwent CRH-ST and HDDST performed between 1986 and 2019. We calculated test sensitivity (Se), specificity (Sp), positive predictive value (PPV), negative predictive value, and diagnostic accuracy (DA) for the diagnosis of CD, and determined optimal response criteria for each test, alone and in combination. The CRH-ST performed better than the HDDST (DA 91%, 95% CI 87-94% vs 75%, 95% CI 69-79%). Optimal response criteria were a ≥40% increase of ACTH and/or cortisol during the CRH test and a ≥69% suppression of cortisol during the HDDST. A ≥40% cortisol increase during the CRH test was the most specific measure, PPV 99%. Seventy-four percent of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95%, and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS. CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current worldwide unavailability impedes optimal management of these patients.

Cushing disease in pediatrics: an update.

Cushing disease (CD) is the main cause of endogenous Cushing syndrome (CS) and is produced by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma. Its relevance in pediatrics is due to the retardation of both growth and developmental processes because of hypercortisolism. In childhood, the main features of CS are facial changes, rapid or exaggerated weight gain, hirsutism, virilization, and acne. Endogenous hypercortisolism should be established after exogenous CS has been ruled out based on 24-hour urinary free cortisol, midnight serum or salivary cortisol, and dexamethasone suppression test; after that, ACTH dependence should be established. The diagnosis should be confirmed by pathology. The goal of treatment is to normalize cortisol level and reverse the signs and symptoms. Treatment options include surgery, medication, radiotherapy, or combined therapy. CD represents a challenge for physicians owing to its multiple associated conditions involving growth and pubertal development; thus, it is important to achieve an early diagnosis and treatment in order to control hypercortisolism and improve the prognosis. Its rarity in pediatric patients has led physicians to have limited experience in its management. The objective of this narrative review is to summarize the current knowledge about the pathophysiology, diagnosis, and treatment of CD in the pediatric population.

Distinct serum steroid profiles between adrenal Cushing syndrome and Cushing disease.

Differentiating between adrenal Cushing syndrome (adrenal CS) and Cushing disease (CD) can be challenging if there are equivocal or falsely elevated adrenocorticotropic hormone (ACTH) values. We aim to investigate the diagnostic value of serum steroid profiles in differentiating adrenal CS from CD. A total of 11 serum steroids in adrenal CS (n=13) and CD (n=15) were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Age- and gender-specific steroid ratios were generated by dividing the actual steroid concentration by the upper limit of the relevant reference range. A principal component analysis (PCA) and an orthogonal partial least squares discriminant analysis (OPLS-DA) were performed. The PCA and OPLS-DA analyses showed distinct serum steroid profiles between adrenal CS and CD. Dehydroepiandrosterone sulfate (DHEA-S), dehydroepiandrosterone (DHEA), and androstenedione ratios were identified as biomarkers for discrimination by variable importance in projection (VIP) in combination with t-tests. The sensitivity and specificity of DHEA-S ratios<0.40 were 92.31% (95% CI 64.0%-99.8%) and 93.33% (95% CI 68.1%-99.8%), respectively, in identifying adrenal CS. The sensitivity and specificity of DHEA ratios<0.18 were 100% (95% CI 75.3%-100.0%) and 100% (95% CI 78.2%-100.0%), respectively, in identifying adrenal CS. Our data support the clinical use of the DHEA-S and DHEA ratios in the differential diagnosis of adrenal CS and CD, especially when falsely elevated ACTH is suspected.

The addition of corticotropin-releasing hormone to 2-day low dose dexamethasone suppression test provides additional case detection.

PURPOSE: The diagnostic value of adding a Corticotropin-Releasing Hormone (CRH) Stimulation Test to the 2-day Low Dose Dexamethasone Suppression Test (Dex-CRH Test) has been debated in the literature. We identified 65 patients with Cushing disease (CD) and 42 patients in whom a diagnosis of Cushing disease could not be confirmed (NCD) after a minimum follow-up of 14 months who underwent the Dex-CRH test. The female sex ratio, median (range) age, and BMI were similar between the two groups. The follow-up for patients with CD and NCD was 74 (4-233) and 52 (14-146) months, respectively. Among 65 patients with CD, 5 (7.7%) had a cortisol level ≤1.4 µg/dl after LDDST but were appropriately classified as CD with a cortisol level >1.4 µg/dL at 15-min post CRH stimulation. In contrast, 3/42 patients (7.1%) in NCD had an abnormal Dex-CRH test. In only one of three patients, the LDDST was marginally normal (cortisol was 1.4 µg/dL and increased to 3.1 µg/dL 15-min post CRH). A cortisol cutoff value of >1.4 µg/dL during the Dex-CRH test provided a sensitivity of 100%, specificity of 93%, and diagnostic accuracy of 97% to diagnose CD. When patients without a Dex level were excluded (n = 74), the sensitivity did not change, but the specificity and accuracy of the Dex-CRH test increased to 97 and 99%, respectively. The Dex-CRH Test provided additional case detection in 5/65 (7.7%) patients with CD. It resulted in one false-positive case compared to LDDST. Measurement of dexamethasone improved diagnostic accuracy of the test.

Sensitivity of Different ACTH and Cortisol Concentration Values in Corticotropin-Releasing Hormone Based Tests in Cushing’s Disease

ABSTRACT Purpose In Cushing’s disease (CD) patients, the aim of the present study is to confirm sensitivity of several ACTH and cortisol concentration values in different time points, during corticotropin-releasing hormone (CRH) stimulation test and during CRH stimulation following dexamethasone suppression (DEX-CRH) test. Methods We retrospectively analyzed cortisol and ACTH concentration increment during CRH and DEX-CRH tests in 23 patients with confirmed CD. Cortisol and ACTH concentrations were determined immediately before, 15 min and 30 min after CRH stimulation. We evaluated the sensitivity of different cutoff values including those reported in previous studies, in the diagnosis of CD. Results During DEX–CRH test, 15 min serum cortisol concentration of 1.4 μg/dl (38 nmol/L) had a sensitivity of 90.9%, and serum cortisol concentration ≥1.27 μg/dl (35 nmol/L) had a sensitivity of 100%. For plasma ACTH, sensitivity of 100% was obtained using ACTH ≥3.5pmol/L (16 pg/ml) at 30 min. During CRH test, 35% increase from baseline in ACTH concentration had a sensitivity of 72.7%. Twenty percent increase in cortisol 30 minutes after stimulation yielded a sensitivity of 85.7%. The best sensitivity of ACTH and cortisol increment was obtained 15 min after stimulation, using 19% and 9% increase, respectively (sensitivity of 100% and 92.8%, respectively). Conclusion During CRH and DEX-CRH tests, the study findings agree with the good sensitivity of ACTH and cortisol cutoff values suggested in previous studies; yet, other cutoff values may give a higher diagnostic sensitivity.

Corticotroph tumor progression after bilateral adrenalectomy: data from ERCUSYN.

Corticotroph tumor progression after bilateral adrenalectomy/Nelson's syndrome (CTP-BADX/NS) is a severe complication of bilateral adrenalectomy (BADX). The aim of our study was to investigate the prevalence, presentation and outcome of CTP-BADX/NS in patients with Cushing's disease (CD) included in the European Registry on Cushing's Syndrome (ERCUSYN). We examined data on 1045 CD patients and identified 85 (8%) who underwent BADX. Of these, 73 (86%) had follow-up data available. The median duration of follow-up since BADX to the last visit/death was 7 years (IQR 2-9 years). Thirty-three patients (45%) experienced CTP-BADX/NS after 3 years (1.5-6) since BADX. Cumulative progression-free survival was 73% at 3 years, 66% at 5 years and 46% at 10 years. CTP-BADX/NS patients more frequently had a visible tumor at diagnosis of CD than patients without CTP-BADX/NS (P < 0.05). Twenty-seven CTP-BADX/NS patients underwent surgery, 48% radiotherapy and 27% received medical therapy. The median time since diagnosis of CTP-BADX/NS to the last follow-up visit was 2 years (IQR, 1-5). Control of tumor progression was not achieved in 16 of 33 (48%) patients, of whom 8 (50%) died after a mean of 4 years. Maximum adenoma size at diagnosis of CD was associated with further tumor growth in CTP-BADX/NS despite treatment (P = 0.033). Diagnosis of CTP-BADX/NS, older age, greater UFC levels at diagnosis of CD and initial treatment predicted mortality. In conclusion, CTP-BADX/NS was reported in 45% of the ERCUSYN patients who underwent BADX, and control of tumor growth was reached in half of them. Future studies are needed to establish effective strategies for prevention and treatment.

Dynamic Testing for Differential Diagnosis of ACTH-Dependent Cushing Syndrome: A Systematic Review and Meta-analysis.

Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.

PMON152 In Patients with Cushing's Disease and a Visible Tumor on MRI, IPSS does not Add to the Accuracy of Predicting Tumor Lateralization

Abstract Introduction There is controversy surrounding the value of bilateral inferior petrosal sinus sampling (BIPSS) for tumor lateralization in Cushing's disease (CD). We compare lateralization results between BIPSS and pituitary imaging against gold-standard surgical localization. Methods A retrospective chart review was conducted in patients with pathology-confirmed CD, visible tumor on MRI (with and without contrast), and who underwent BIPSS at our institution between 2003-2020. An inferior petrosal sinus to peripheral (IPS/P) prolactin ratio &amp;gt;1.8 was used to confirm appropriate IPS sampling. An inter-sinus ACTH gradient ratio greater than 1.4, adjusted for prolactin where available, was used to determine lateralization. In each case, the neurosurgeon performed a full pituitary gland exploration to avoid missing any tumors despite visible tumor on MRI. Descriptive statistics were used. Results Of 32 patients with CD, visible tumor on MRI, and BIPSS testing, 27 (84%) patients had technically successful bilateral IPSS catheterization and are the subjects of this study. All 27 of these patients had IPS/P ACTH ratio greater than 2 at baseline or 3 after CRH stimulation, consistent with CD, and all 27 lateralized. The median age at diagnosis was 42 years (range 21-69 years) and 85% were female (N=23). The median tumor size on MRI was 5 mm (range 3-8 mm). In 22/27 (81%) patients, the result of the IPSS lateralization was concordant with MRI findings. When MRI and BIPSS lateralization agreed, 21/22 (95%) were confirmed by surgical pathology. Of the 5 cases where MRI and BIPSS disagreed on laterality, the operative report was consistent with MRI lateralization in 3/5 cases, and bilateral disease in the remaining 2 cases. There were no cases where BIPSS lateralization was correct when MRI lateralization was incorrect. Overall, MRI correctly lateralized 26/27 cases (96%), whereas BIPSS correctly lateralized 23/27 (85%). In the subset of 13 patients with tumors measuring &amp;lt;6mm on MRI, MRI imaging lateralization was correct in all 13 (100%) cases and BIPSS lateralization was correct in 11/13 (85%). Adverse events associated with BIPSS were noted in 4 patients (15%) ranging from hematoma to headache. Among the 5 patients who did not have successful BIPSS cannulization, one experienced the adverse effect of transient severe headache. There were no serious complications. The surgeons performed bilateral sellar exploration in all cases regardless of BIPSS or MRI lateralization results. Conclusion When a tumor is visible on MRI, regardless of its size (≥ 3mm), BIPSS does not add to the accuracy of determining tumor lateralization. BIPSS may best be reserved for situations where the diagnosis of CD is in question. Further studies are required to determine the value of BIPSS in lateralizing the source of CD in patients without visible tumor. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

ODP304 Cyclic Cushing Disease: A Diagnostic Challenge

Abstract Background Cyclic Cushing syndrome is a clinical challenging diagnosis due to an unpredictable duration of periodic hypercortisolemia shifting with normocortisolemia periods. Only small proportion of such cases are due to a corticotroph pituitary adenoma with cyclic activity. Clinical case: 27-year-old after she stopped nursing her baby, she had no resumption of menses. She then developed mild headache and weight gain of 20kg throughout 3 months. She also developed facial hair, acne, easy bruising and striae. She was evaluated by a local physician where Cushing syndrome (CS) was suspected. Local testing showed the following results: UFC: 1117 and 1572 mcg/24h (&amp;lt;403mcg/24h), low dose DST of 595.8 nmol/l (&amp;lt;50nmol/l) and ACTH 60 pg/mL (10-100pg/mL). An MRI identified a 6 mm pituitary adenoma. The patient was sent to our pituitary clinic under the diagnosis of Cushing disease (CD). Upon examination at our institution, the patient reported asthenia, mood changes, depression and hirsutism. The physical examination revealed classical signs of CS. No other comorbidities were detected. A seven-hour 7mg dex infusion testwas performed (1), with basal cortisol of 187.5 nmol/l, early suppression of 12.6 nmol/l and late suppression of 27.5 nmol/l which is negative for hypercortisolism. As the high suspicion of CS, the patient was followed monthly with UFC and serum cortisol. During this normocortisolemia period the patient lost 10kg of weight, recovered its menses and coloration changes of striae. Laboratory follow up UFC of 67, 71 mcg/24h and serum cortisol of 124, 270, 103.4, 358.6 and 413 nmol/l ACTH 20, 21, 23, 28, 25 pg/mL. After 6 months of no clinical sign of hypercortisolism the patient reached to us as she noticed her striae changed, started gaining weight, lost menses and changed headache frequency. Laboratories revealed UFC was 754.6 mcg/24h and low dose DST was 751.1 nmol/l and ACTH of 70 pg/mL. We conducted another continuous 7mg dex infusion for seven hours with basal cortisol of 669.2 nmol/l, early suppression of 90.2 nmol/l (&amp;gt;50% suppression) and late suppression of 691.5 nmol/l which was compatible with CD. Additional testing was performed, with a 18F-NOTA-Octreotide and a full body CT that did not reveal an ectopic ACTH producing tumor neither an adrenal mass. Patient underwent a transsphenoidal surgery and reached remission of her hypercortisolism. Conclusion CD may be difficult to be confirmed but also it is important to consider that some cases showed cyclic activity. As far as we could acknowledged, this is the first case showing a 6-month period of normocortisolemia in a cyclic ACTH-secreting pituitary adenoma. Bibliography Biemond P, de Jong FH, Lamberts SW. Continuous dexamethasone infusion for seven hours in patients with the Cushing syndrome. A superior differential diagnostic test. Ann Intern Med. 1990 May 15;112(10): 738–42. Presentation: No date and time listed

PSAT002 Unilateral Adrenalectomy as a Treatment Option in Patient with Cyclical Cushing's Syndrome

Abstract Background Patients with Cyclical Cushing`s Syndrome (CSS) are at risk for a lengthy timeline of living with the untreated disease. Continual increased amounts of cortisol can lead to increased morbidity and mortality in these patients and finding effective treatments is of the utmost importance. Here we present a treatment course of the patient with CCS who eventually underwent unilateral adrenalectomy, resulting in marked improvements in excessive cortisol- mediated metabolic derangements. Clinical Case In 2014, a 51-yo female with hypertension (HTN), hyperlipidemia (HLD), and type 2 diabetes (T2D) presented to VA endocrinology clinic for the evaluation of incidentally found bilateral adrenal nodules. Based on the extensive biochemical evaluation, the patient was diagnosed with ACTH-dependent Cushing's disease (CD). In the setting of newly diagnosed CD and complex metabolic co-morbidities, in 09/2016 she underwent pituitary resection. However, she remained hypercortisolemic and in 12/2016 she had a second hypophysectomy. Despite surgical efforts, hypercortisolemia persisted. Neuroendocrine imaging studies and chest computed tomography excluded non-pituitary etiology of CD. She was subsequently started on ketoconazole but it was stopped due to side effects. Other CD-directed agents were not approved, so we continued routine management of T2D, HTN, and HLD. In 2018, the patient developed acute coronary syndrome and received percutaneous intervention despite therapy with statin and ezetimibe. Further, since her second hypophysectomy she required sequential addition of hypoglycemic agents and by the end of 2020, exenatide weekly, empagliflozin, and pioglitazone were added to her escalating basal-bolus insulin therapy due to persistent A1C elevation &amp;gt;10%. Continuous evaluation of her hypercortisolemia post-hypophysectomy suggested presence of CCS. To alleviate the metabolic burden of hypercortisolemia, the patient was offered unilateral adrenalectomy which she underwent in 03/2021. Within 6 months after the surgery, she has had unintentional 22-lb weight loss and we stopped both of her anti-HTN medications, discontinued weekly exenatide, and gradually de-escalated her initial daily insulin regimen of approximately 1.0 u/kg to an only basal insulin at 0.15 u/kg dose achieving A1C of 6.5%. There was no biochemical evidence of adrenal insufficiency since adrenalectomy was performed. Conclusion The patient with initial diagnosis of CD, which we later proved being CCS, underwent a unilateral adrenalectomy with the goal of reduction of cortisol burden. This decision was taken with the consideration that this would likely not be curative but intended to improve the course of her metabolic conditions. The 6-month observation following adrenalectomy has proven that we were able to in large extend achieve our goals. Therefore, this treatment approach should be considered for patients with CSS or CD. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Presurgical predictive factors of surgical remission in Cushing's disease. Study of 32 cases

PurposeIdentify presurgical factors associated with surgical remission in Cushing's disease (CD). MethodsAll the patients with ACTH-dependent Cushing's Syndrome in follow-up at our centre between 2014–2021 (n=40) were identified. Those patients with CD diagnosis who underwent transsphenoidal surgery by the same neurosurgeon (n=32) were included. Surgical remission was defined as plasma cortisol <1.8μg/dl and normal or low urinary free cortisol (UFC) after surgery. ResultsSixty-three per cent (n=20) were women, and the mean age at diagnosis was 42.3±17.9 years. Six patients had macroadenomas, 17 had microadenomas, and in the other 9 patients, no pituitary lesion was identified on the MRI. Seven patients were previously operated on in another centre. Surgical remission was achieved in 75% (n=24). Only three patients experienced recurrence. No association between pre-surgical demographic (age, sex, comorbidities) or hormonal (UFC, ACTH, late-night salivary cortisol levels) characteristics and the probability of surgical remission was observed. The only variable associated with a greater chance of remission was the presurgical visualisation of the adenoma on MRI (OR 8.3, P=0.02). It was also observed that patients with a history of a previous pituitary surgery had a lower tendency to achieve remission, although statistical significance was not reached (OR 0.17, P=0.09). ConclusionsIn our experience, 75% of patients with CD achieved biochemical cure after the intervention. Surgical remission was up to eight times more frequent in those patients in whom the adenoma was visualised before the intervention, but no other presurgical predictive factors of cure were identified.