Independent Cushing's Syndrome Research Articles

A case of ACTH independent Cushing's syndrome with bilateral adrenal nodules

A case of ACTH independent Cushing's syndrome with bilateral adrenal nodules

P-03 A report of recurring pregnancy-induced Cushing's Syndrome

Abstract Introduction The incidence of pregnancy-induced Cushing's syndrome (CS) is very low. However, the diagnosis of CS in pregnant patients is very difficult because of an overlapping signs and symptoms. Clinical Case A 20-year-old woman with polycystic ovarian syndrome (PCOS) was successfully treated with clomiphene for infertility and pregnant in September of 2016 for the first time. She experienced out of proportion abdominal obesity, excessive striosis, exacerbation of hirsutism and myasthenia during the first trimester of her pregnancy. Initial diagnosis of ovarian hyperstimulation syndrome (OHSS) was made and due to concomitant intrauterine growth retardation (IUGR), the pregnancy was electively terminated at the 8th week. All associated symptoms spontaneously regressed within 2-3 months after the abortion. The second pregnancy was induced with a pulse treatment of letrozole 5 mg, followed by 3 every other day injections of 100 units recombinant follicle-stimulating hormone. Within the first 4 weeks into the second pregnancy, the patient developed recurrence of OHSS symptoms. In addition to the prior symptoms and progressive proximal myasthenia, the patient developed hypertension, round moon-like face, back hump, and suprasternal fat pad consistent with the typical features of CS. In week 14 of pregnancy, the patient complained from acute-onset bilateral blindness and hypertension (blood pressure of 180/120 mmHg), which soon progressed into loss of consciousness and grand-mal seizure. She was admitted to the intensive care unit (ICU). Admission laboratory testing included those to assess the function of the pituitary-adrenal axis (HPA) due to the presence of symptoms related to CS. Based on available clinical information a diagnosis of hemolysis, elevated liver enzymes, and a low platelet count (HELLP) syndrome was made and emergency termination of pregnancy was carried out at the gestational age of 14 weeks. The patient`s clinical signs such as hypertension and acute blindness were totally subsided soon after the therapeutic abortion. Diagnosis of ACTH independent CS was made based on elevated 8 a.m. serum cortisol level unresponsive to low-dose dexamethasone (45-41 µg/ dL). Conclusion Diagnosis of CS in pregnancy is challenging as the physiological changes during pregnancy may mimic those of CS. Long-term treatment of gestational CS has not been as successful. However, in the case of adrenal hyperplasia, bilateral adrenalectomy offers a certain cure. Our patient had a therapeutic abortion due to severe maternal complications and development of CS during the early gestational age. The patient was reeducated on the subject of contraception and the possibility of adrenalectomy for future pregnancies. Due to the temporal relation between the occurrence of CS after each pregnancy the diagnosis of gestational hypercortisolism was made, and for further pregnancies bilateral adrenalectomy was recommended.

SAT330 Recurrence of Acth Independent Cushing Syndrome In Patient With Previously Operated On For Primary Bilateral Macronodular Adrenal Hyperplasia And Co-existence Of Papillary Thyroid Carcinoma

Abstract Disclosure: N. Vashakmadze: None. D. Nikoleishvili: None. Background: Cushing syndrome is a rare and usually sporadic endocrine disorder. Herein we describe a case of ACTH-independent Cushing syndrome and ACTH-dependent Cushing disease in non-identical twins. Moreover, recurrence of Cushing syndrome after 25 years of non-complete resection of adrenal glands and co-existence of papillary thyroid cancer. Clinical Case: A 57-year woman presented with hypertension, depression, easy bruising, proximal muscle weakness, fatigue, and facial plethora. According to the patient, Cushing’s syndrome caused by bilateral macronodular adrenal hyperplasia was diagnosed in 1997. Surgical treatment - left adrenalectomy and right adrenal gland resection was performed. She was receiving HRT during the first 6 months, since then she was not receiving HRT and her cortisol was normal. It is extremely interesting that her nonidentical twin sister was diagnosed with ACTH-dependent Cushing disease in 2006 and was successfully treated with transsphenoidal surgery. In 2019 patient was diagnosed with papillary thyroid cancer (PTC), thyroidectomy was performed and multifocal PTC pT1b(m)N0M0 was diagnosed. Patient received adjuvant therapy with 80 mCi of RAI. In 2019 cortisol and ACTH levels were routinely evaluated, ACTH was undetectable <3 ng/dl (N: 7.2-63); 1 mg dexamethasone suppression test showed no suppression of cortisol 116 ng/ml (N: <1.8 ng/ml). However, patient did not consult an endocrinologist with the results of the mentioned investigations. She admitted to our clinic in December 2022 with above-mentioned complains to determine the tactics of further investigation/treatment. The data obtained during our consultation was consistent to recurrence of Cushing syndrome: midnight salivary cortisol– 0.46 mcg/dl (0.02-0.34), ACTH– 4.2 ng/l (7.2-63), 1 mg of dexamethasone suppression test – 217 nmol/l (<50). CT showed right adrenal noduls (2.5 cm and 1.2 cm). These data confirmed the diagnosis of recurrence of Cushing’s syndrome and right adrenalectomy with steroid coverage and postoperative hormone replacement therapy was recommended. Other data showed normal OGTT, moderate hypercholesterolemia, taking into account Cushing’s syndrome and smoking, statins were initiated. DXA showed osteoporosis (forearm T-score = -3.9 SD). 25(OH)D3 – 22.35 ng/ml, Ca – 1.09 mmol/l (1.1-1.3). Denosumab, calcium and vitamin D supplements were started to the patient. In addition, TSH was markedly suppressed on 125 mcg LT4 therapy, TSH – 0.005 mIU/l (0.4-3.8); Tg <0.17 g/l, anti-Tg - N and neck ultrasound was normal, that is consistent with excellent response and the target TSH was established 0.5-2.0 mIU/l. The dose of LT4 was reduced to 100 mcg. Conclusion: To our knowledge existence of Cushing syndrome and Cushing disease in non-identical twins has not been reported yet. Also, co-existence of Cushing syndrome and thyroid cancer is rare, and no connection is established yet. Presentation: Saturday, June 17, 2023

The effects of hypercortisolism on the frequency and magnitude of sleep EEG waves in patients with Cushing syndrome: A spectral analysis study

ObjectivesOur aim was to investigate the effects of endogenous chronic hypercortisolism on sleep electroencephalogram (EEG) and differences between the adrenocorticotropic hormone (ACTH)-dependent and independent Cushing Syndrome (CS) patients through a sleep spectral analysis program. MethodsA total of 32 patients diagnosed as having endogenous CS (12 ACTH-dependent and 20 ACTH-independent) and a control group comprising 16 healthy individuals were included in the study. Polysomnographic analysis was performed. Blood samples were collected at 08:00 AM for analysis of ACTH and basal cortisol, and at 00:00 AM for midnight cortisol levels. The frequency and power of the slow wave activity (SWA), theta, alpha, and beta waves of the first and last non-rapid eye movement (NREM) cycles were measured with a spectral analysis program. ResultsThe CS patient group had higher SWA power, especially in the first NREM cycle. In the ACTH-dependent group, SWA maximum and mean power values were higher in the frontal channels in the first NREM, compared to the last NREM sleep stage (p<0.05). ConclusionCortisol has been found to be associated with SWA waves, making these waves higher in power, especially in the first NREM phase. This difference was much less pronounced in the final NREM sleep stage. The difference between the first and last NREM sleep stages with respect to the power of SWA in the frontal channel in the ACTH-dependent group suggests that not only cortisol but also high levels of ACTH affect the power of slow waves during sleep.

Impact of Morphology in the Genotype and Phenotype Correlation of Bilateral Macronodular Adrenocortical Disease (BMAD): A Series of Clinicopathologically Well-Characterized 35 Cases.

Bilateral macronodular adrenocortical disease (BMAD) is characterized by the development of adrenal macronodules resulting in a pituitary-ACTH independent Cushing's syndrome. Although there are important similarities observed between the rare microscopic descriptions of this disease, the small series published are not representative of the molecular and genetic heterogenicity recently described in BMAD. We analyzed the pathological features in a series of BMAD and determined if there is correlation between these criteria and the characteristics of the patients. Two pathologists reviewed the slides of 35 patients who underwent surgery for suspicion of BMAD in our center between 1998 and 2021. An unsupervised multiple factor analysis based on microscopic characteristics divided the cases into 4 subtypes according to the architecture of the macronodules (containing or not round fibrous septa) and the proportion of the different cell types: clear, eosinophilic compact, and oncocytic cells. The correlation study with genetic revealed subtype 1 and subtype 2 are associated with the presence of ARMC5 and KDM1A pathogenic variants, respectively. By immunohistochemistry, all cell types expressed CYP11B1 and HSD3B1. HSD3B2 staining was predominantly expressed by clear cells whereas CYP17A1 staining was predominant on compact eosinophilic cells. This partial expression of steroidogenic enzymes may explain the low efficiency of cortisol production in BMAD. In subtype 1, trabeculae of eosinophilic cylindrical cells expressed DAB2 but not CYP11B2. In subtype 2, KDM1A expression was weaker in nodule cells than in normal adrenal cells; alpha inhibin expression was strong in compact cells. This first microscopic description of a series of 35 BMAD reveals the existence of 4 histopathological subtypes, 2 of which are strongly correlated with the presence of known germline genetic alterations. This classification emphasizes that BMAD has heterogeneous pathological characteristics that correlate with some genetic alterations identified in patients.

PSAT025 Functional Adrenocortical Oncocytic Neoplasm: A Rare Cause of ACTH Independent Cushing's Syndrome

Abstract Background Adrenal oncocytomas (AOCs) or adrenocortical oncocytic neoplasms (ACONs) are extremely rare tumors of adrenal glands characterized by the presence of oncocytes, which are epithelial cells with eosinophilic cytoplasm. Only about 140 cases have been reported in literature so far. AOCs are more common in females (2.5: 1), more prevalent on the left adrenal gland (3.5: 1), and tumor size ranges from 3 to 17 cm. About two thirds of AOCs are reported to be nonfunctioning, and only less than 6% of functioning are cortisol secreting. The malignant potential of these tumors has been described quite variably in current literature. Based on the most recent systematic literature review, about 35% were found to be benign, 24% malignant, and 41% borderline, based on the Lin Weiss Bisceglia system. The mainstay of treatment is surgical resection. Here we describe a case where biochemical workup and pathology revealed a functional AOC with uncertain malignant potential. Clinical Case A 68 year old female with hypertension was found to have an incidental left 3 cm adrenal nodule on CT abdomen and pelvis during a workup for hematuria. The nodule was biopsied and initially found to be benign. Afterwards, she was referred to endocrinology where biochemical testing was consistent with ACTH-independent Cushing's syndrome. She had three elevated late night salivary cortisol - 0.10 mcg/dL, 0.14 mcg/dL, and 0.19 mcg/dL (≤0. 09 mcg/dL), three abnormal 1 mg dexamethasone suppression tests - 16.4 mcg/dL, 15.1 mcg/dL, and 17.1 mcg/dL (&amp;lt;1.8 mcg/dL), two normal 24 hour urinary cortisol - 22.5 and 31.5 mcg/24h (4-50 mcg/24h), and ACTH &amp;lt;5 pg/mL (6-50 pg/mL). She was then referred to surgery and was treated by laparoscopic adrenalectomy. Surgical pathology showed a 3.5 cm adrenal cortical tumor with oncocytes infiltrating into the periadrenal adipose tissue, with positive staining for synaptophysin and negative for P53. On Ki67 staining, some hot spots were greater than 5%. Therefore, the tumor was characterized as AOC with undetermined malignant potential or a low grade, oncocytic adrenocortical carcinoma. She was evaluated by oncology and radiation oncology, and it was decided to monitor the patient without systemic therapy or adjuvant radiation therapy. A surveillance approach was favored given that the risks of adjacent bowel and kidney toxicity outweighed the benefits of radiation. Conclusion We hereby report a case of AOC with undetermined malignant potential. This case highlights many challenges in the diagnosis, management and long-term surveillance of patients with AOCs, and need for further research. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

LBSAT63 Cushing Syndrome As A Presentation Of Adrenocortical Carcinoma.Case Report

Abstract Introduction adrenocortical carcinoma is a rare endocrine malignancy (1) Case: 44 year old afro American female with no past medical history. No regular medications. Amenorrhea for 2 years. smokes cigarettes. Irrelevant family history. She presented with itchiness after cat scratch and was found to have hypertension urgency 229/123. Review of systems was positive for weight gain and easy bruises. Physical examination alert and oriented with body mass index of 31 kg/m2 heart rate 75 beats per minute normal heart sounds and clear lungs with scratch marks on left hand. bilateral lower extremities pitting edema, supraclavicular fat pad and violet abdominal striae. No facial plethora or hirsutism or lymphadenopathy or acne. Laboratory work up was remarkable for hypokalemia and metabolic alkalosis. High plasma morning cortisol level 53.6ug/dl normal between 6.2 and 29, 24hour urine cortisol and DHEAS and low ACTH FSH and LH. Estradiol 261pg/ml 17hydroxyprogesterone 49ng/dl and prolactin 31.7ng/ml. HBA1C 6.7. Normal renin aldosterone TSH and plasma and 24hour metanephrine and normetanephrine. Normal creatinine liver function and complete blood count. CT abdomen and pelvis with contrast showed large lobular heterogeneously enhancing mass in the left adrenal gland of 9. 0×10.1×10.1cm with left kidney posterior displacement and left renal vein compression. The pancreatic tail and splenic vein were draped over the mass. The right adrenal gland and other abdominal organs were unremarkable. DEXA scan showed osteopenia. CT chest showed 5mm right lower lobe nodule and compression fracture in the 7th thoracic vertebrae. Echocardiogram showed dilated left ventricle dimension with reduced ejection fraction 45%. The diagnosis was made for ACTH independent Cushing syndrome with adrenal mass. She underwent open left adrenalectomy distal pancreatectomy splenectomy and left nephrectomy in another institution. Histopathology showed 12×7.5×7 cm stage III adrenal cortical malignancy T3N0M0. Extensive necrosis and capsular invasion but negative surgical margins. Possibility of lung metastasis. Postoperative cortisol level 6. 02ug/dl. She was kept on postoperative slow tapering hydrocortisone with plan of chemotherapy and Mitotane. Conclusion adrenocortical carcinoma has a poor prognosis. It usually metastasizes to distant organs at time of diagnosis and rarely presents as Cushing syndrome. Surgical resection is the main management of localized tumors with controlling the effects of secreted hormones. Adjuvant therapies are chemotherapy radiotherapy and Mitotane according to the tumor stage and size. Mitotane is adrenal cytotoxic agent showed increase survival of advanced stages(1).

Subtype-specific pattern of white blood cell differential in endogenous hypercortisolism.

Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count. A retrospective monocentric cohort study was carried out in patients with overt endogenous Cushing's syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver-operating characteristics analysis. In total, 253 patients were analyzed (Cushing's disease (CD); n = 88; ectopic CS (ECS), n = 31; cortisol-producing adrenal adenomas (CPA), n = 40; ACS, n = 45; adrenocortical carcinomas (ACC), n = 49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r = 0.314 and r = 0.428), while a negative correlation was observed for lymphocytes and eosinophils (r = -0.374 and r= -0.380) (each P < 0.0001). Similar observations were made for 24 h-urinary free cortisol. CD and ECS differed in numbers of neutrophils and lymphocytes (P < 0.0001) and were well differentiated at a cut-off of 6.1 for the neutrophil/lymphocyte ratio (sensitivity 90.0%, specificity 89.4%, and areas under the curve (AUC) 0.918). For adrenocorticotropic hormone (ACTH)-independent CS, the best diagnostic outcome was obtained for the discrimination of CPA and ACC at a cut-off of 187.9 for the platelet/lymphocyte ratio (sensitivity 59.6%, specificity 80.6%, and AUC 0.713). For ECS, CPA, and CD, neutrophils decreased (delta -47.0, -29.7, and -26.2%) and lymphocytes increased (+123.2, +78.1, and +17.7%) already 3 months after remission. Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified 3 months after remission from endogenous hypercortisolism.

Primary pigmented nodular adrenocortical disease: Unusual histology in children- A report of 3 cases

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of adrenocorticotropin independent Cushing Syndrome. Majority cases are diagnosed in second or third decade of life. Presentation of PPNAD in early childhood is very rare. It is characterized by adrenocorticotrophic hormone [ACTH] independent, hypersecretion of cortisol by multiple, pigmented nodules of hyperplastic adrenocortical cells. The histology varies with age, the pigmentation increasing with age. More than ninety percent of reported cases of PPNAD occur as one of the manifestation of Carney’s complex.

Large adrenal tumor in paucisymptomatic ACTH - independent Cushing syndrome's patient - a clinical case

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

Recent Advances in the Clinical Application of Adrenal Vein Sampling.

We reviewed clinical research investigating the applications of adrenal vein sampling (AVS). AVS could be applied not only to primary aldosteronism (PA) but also to other endocrine diseases, such as adrenocorticotropic hormone (ACTH) independent Cushing syndrome (AICS) and hyperandrogenemia (HA). However, the AVS protocol requires improvements to increase its success rate. Using the computed tomography image fusion, coaxial guidewire technique, and fast intraprocedural cortisol testing (CCF) technique could improve the success rate of catheterization in AVS for PA. ACTH loading could be considered in medical centers with a low selectivity of AVS for PA but is not essential in those with mature AVS technology. The continuous infusion method should be recommended for ACTH stimulation in AVS for PA to reduce adverse events. AVS has not been routinely recommended before management decisions in AICS, but several studies verified that AVS was useful in finding out the source of excess cortisol, especially for distinguishing unilateral from bilateral disease. However, it is necessary to reassess the results of AVS in AICS with the use of reference hormones to fully normalize cortisol levels. In addition, it is essential to determine the optimal model that combines AVS results and mass size to guide the selection of surgical plans, including identifying the dominant gland and presenting the option of staged adrenalectomy, to minimize the impact of bilateral resection. For HA, AVS combined with ovarian intravenous sampling to locate excess androgens could be considered when imaging results are equivocal.

VP07.09: ACTH independent Cushing's syndrome: a diagnostic dilemma

VP07.09: ACTH independent Cushing's syndrome: a diagnostic dilemma

ACTH independent cushing's syndrome secondary to a right adrenal adenoma masked by pregnancy

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

Incidence of Venous Thromboembolic Events in Patients With Endogenous Cushing Syndrome

Background: Hypercortisolemia is a hypercoagulable state associated with increased risk of venous thromboembolic events (VTE). The reported incidence of VTE in patients with ACTH-dependent or independent Cushing Syndrome (CS) is variable, ranging from 3 to 14%. Our aim was to assess the incidence of clinically significant VTE among patients with endogenous CS and to identify risk factors for the development of VTE. Methods: We conducted a single center retrospective longitudinal study of adult patients diagnosed with endogenous CS between 2010 and 2020. Patients with a known prothrombotic disease (e.g. Factor V Leiden), insufficient data, or non-neoplastic hypercortisolism were excluded. Data collected included patient demographics, presenting symptoms, biochemical and radiological workup, treatment details, and incidence of clinically significant VTE. Results: A total of 114 patients (mean age of 45.55 ± 14.78 years, 79.8% women) followed for mean of 3.26 ± 2.9 years were included. Of the 114 patients, 58 (50.9%) had Cushing disease (CD), 40 (35.1%) had CS due to adrenal adenoma/hyperplasia, 6 (3.5%) had adrenocortical carcinoma (ACC), and 10 (8.8%) had ectopic Cushing syndrome (eCS). The overall incidence of VTE at any time point was 14/114 (12.3%); 11 (79%) VTEs were associated with presence of an additional VTE risk factor (8 surgery and 3 malignancy). Prior to any intervention for CS, 3 of 114 (2.6%) patients had a VTE. Surgery for CS (adrenalectomy, transsphenoidal surgery, tumor resection) was performed in 97 patients (85.1%) whereas 17 were treated medically (n=10), died before treatment (n=1) or observed (n=6). VTE occurred in 2 patients receiving medical therapy for CS. The post-operative incidence of VTE was 9 (9.3%; 4 in CD, 1 in adrenal CS, 3 in ACC, and 1 in eCS). VTE occurred ≤ 3-month post-operative in 4 patients (44.4%). Among the 5 patients in whom VTE occurred >3 months post-operative, 3 had recurrent metastatic ACC with hypercortisolemia and 2 were in remission (1 with CS and 1 with eCS). The median time from surgery to VTE occurrence was 315 days (8-1006). Compared to those who did not develop VTE, those who developed VTE had higher mean 24-hour urine free cortisol (4663.6 vs 558.21 mcg/dL; n = 100, P < 0.0001) and mean 1 mg overnight dexamethasone suppression test (36.3 vs 11.8 mcg/dL; n = 69, P = 0.0003), but similar mean late-night salivary cortisol (0.591 vs 0.790 ng/dL, n = 84, P = 0.71) at diagnosis of CS. Discussion: Among those with CS, the overall incidence of VTE was 12.3% and the majority of VTE were provoked (surgery, malignancy). Moreover, VTE was more likely in those with higher UFC and 1 mg overnight dexamethasone suppression test in our cohort. This suggests that in patients with CS who have an active malignancy, severe CS or those undergoing a surgical procedure may be at increased risk of VTE. Future studies should investigate the optimal type and duration of the VTE prophylaxis.

Recurrent Cushing Syndrome Secondary to Metastatic Adrenocortical Carcinoma in a Patient With Previously Resected Adenoma

Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH <12 pg/mL (n<46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n <0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n<45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n<32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.

Abstract No. 191 Adrenal venous sampling for lateralization of cortisol hypersecretion in patients with adrenocorticotropic hormone–independent Cushing syndrome and bilateral adrenal masses

To evaluate adrenal venous sampling (AVS) in guiding surgical management of patients with adrenocorticotropic hormone (ACTH) independent Cushing syndrome (CS) and bilateral adrenal masses 28 patients with bilateral adrenal masses and ACTH independent autonomous cortisol secretion who underwent AVS from January 1, 2008, to August 1, 2020, were identified. Methodology and data interpretation were performed as previously described. Cortisol and epinephrine levels were measured from each adrenal vein (AV) and the inferior vena cava (IVC). AVS was technically successful if plasma epinephrine concentration in AV-IVC was > 100 pg/mL. AV/IVC cortisol ratio for each adrenal gland and cortisol lateralization ratio (CLR) were calculated. Previously described parameters were utilized for interpretation: AV/IVC cortisol ratio of > 6.5 on one side and ≤3.3 on the contralateral side with CLR ≥ 2.3 was consistent with a unilateral cortisol-secreting adenoma whereas bilateral AV/IVC cortisol ≥ 4.1 with CLR < 2 was consistent with bilateral cortisol hypersecretion. Clinical, imaging, laboratory, pathology and follow-up data were collected. Primary outcome measure was hypercortisolism recurrence. 28 patients underwent AVS. Patients underwent subsequent right (n = 12) or left (n = 9) total, right total and left partial (n = 1) or bilateral total (n = 3) adrenalectomy. 3 patients were recommended adrenalectomy but were lost to follow up and not included in outcome analysis. Initial presentation included incidental adrenal masses (12%), subclinical CS (64%), overt CS (24%). Sequela included hypertension (88%), osteoporosis/osteopenia (38%), diabetes mellitus (36%), hyperlipidemia (56%), weight gain (76%), depression (52%). AVS was successful in all 28 patients. Data were interpreted as described above to guide laterality of adrenalectomy. Mean AV/IVC cortisol for unilateral adrenalectomies was 12 with mean CLR 3.7. Mean AV/IVC for bilateral adrenalectomies was 8.67 right and 6.33 left with CLR 0.76. Among 29 resected adrenal glands, pathology demonstrated benign adrenocortical adenomas (52%) and macronodular hyperplasia (48%) and mean dominant nodule maximum diameter of 2.7cm and mean weight of 18.2g. At a mean follow-up of 21.8 months, there was no clinical or biochemical recurrence of ACTH-independent hypercortisolism with most recent cortisol of 12.8 ± 7.5 mcg/dL and ACTH of 19.7 ± 13.1 pg/mL. AVS can be used to guide surgical management in patients with ACTH independent Cushing syndrome and bilateral adrenal masses, with favorable midterm outcomes.

The occurrence of Adrenocorticotropic hormone-independent Cushing's syndrome in a woman with the history of papillary thyroid carcinoma: a case report

BackgroundThyroid papillary carcinoma is one of the most common endocrine tumors, and it accounts for 85% of thyroid tumors. Adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome is a rare disease. In this case report, we discuss a very rare case of coexistence of papillary thyroid carcinoma and Cushing's syndrome with an adrenal origin.Case presentationThe patient was a 33-year-old Iranian/Persian woman with a history of papillary thyroid carcinoma treated with iodine 131 three years ago. She presented with weight gain, amenorrhea, and mood disorders in the last six months. She was diagnosed with an ACTH-independent Cushing's syndrome due to benign adrenal adenoma and underwent laparoscopic adrenalectomy surgery. The symptoms of the syndrome were disappeared after the surgery.ConclusionsACTH-independent Cushing's syndrome due to adrenal tumor and papillary thyroid cancer occurs sporadically. The co-occurrence of two endocrine tumors with different origins is rare. It is recommended that the occurrence of other endocrine neoplasms be considered when an endocrine tumor is diagnosed.

Prospective Evaluation of Late-Night Salivary Cortisol and Cortisone by EIA and LC-MS/MS in Suspected Cushing Syndrome.

ContextLate-night salivary cortisol (LNSC) measured by enzyme immunoassay (EIA-F) is a first-line screening test for Cushing syndrome (CS) with a reported sensitivity and specificity of >90%. However, liquid chromatography-tandem mass spectrometry, validated to measure salivary cortisol (LCMS-F) and cortisone (LCMS-E), has been proposed to be superior diagnostically.Objective, Setting, and Main Outcome MeasuresProspectively evaluate the diagnostic performance of EIA-F, LCMS-F, and LCMS-E in 1453 consecutive late-night saliva samples from 705 patients with suspected CS.DesignPatients grouped by the presence or absence of at least one elevated salivary steroid result and then subdivided by diagnosis.ResultsWe identified 283 patients with at least one elevated salivary result; 45 had an established diagnosis of neoplastic hypercortisolism (CS) for which EIA-F had a very high sensitivity (97.5%). LCMS-F and LCMS-E had lower sensitivity but higher specificity than EIA-F. EIA-F had poor sensitivity (31.3%) for adrenocorticotropic hormone (ACTH)-independent CS (5 patients with at least 1 and 11 without any elevated salivary result). In patients with Cushing disease (CD), most nonelevated LCMS-F results were in patients with persistent/recurrent CD; their EIA-F levels were lower than in patients with newly diagnosed CD.ConclusionsSince the majority of patients with ≥1 elevated late-night salivary cortisol or cortisone result did not have CS, a single elevated level has poor specificity and positive predictive value. LNSC measured by EIA is a sensitive test for ACTH-dependent Cushing syndrome but not for ACTH-independent CS. We suggest that neither LCMS-F nor LCMS-E improves the sensitivity of late-night EIA-F for CS.

SAT-164 Pattern and Spectrum of Adrenal Disorders Seen Among Adults in Southern Iraq. A Tertiary Center Experiences

Background: Adrenal disorders is rare life-threatening conditions needed high awareness for earlier diagnosis. The aim of this study is to see the pattern and spectrum of adrenal disorders in Southern Iraq. Methods: Retrospective electronic database analysis of Faiha Specialized Diabetes, Endocrine and Metabolism Center (FDEMC) in Basrah, the largest tertiary referring Center in the Southern Iraq. Only adults 18 years and above analysed. Results: The total referred patients for presumed adrenal disorders were 5064(6%) of 83473 new patients seen over 11 years for the period of August 2008 to August 2019.The commonest adrenal disease were due to glucocorticoids misuse in 2407/5064 (47.5%),followed by adrenal endocrine hypertension in 883/5064 (17.4%),than adrenal insufficiency in 340/5064 (6.7%), hirsutism in 264/5064 (5.2%), hypopituitarism 85/5064 (1.6%) and congenital adrenal hyperplasia in 78/5064 (1.5%).Rare causes of adrenal disorder were primary aldosteronism in 30/5064 (0.5%), Addison disease in 26/5064 (0.5%), pheochromocytoma in 19/5064 (0.4%), autoimmune polyendocrine syndromes in 19/5064 (0.4%), ACTH independent Cushing syndrome in 17(0.3%), ACTH dependent Cushing syndrome in 4(0.07%), subclinical Cushing syndrome in 4(0.07%), ectopic ACTH syndrome in 1(0.01%), adrenal cyst in 9(0.1%), adrenal myelolipoma in 5(0.09%), adrenocortical carcinoma in 3(0.05%),and paraganglioma in 2(0.04%).One of the paraganglioma were secretory. Patients characteristics for those with glucocorticoids misuse showed that female forming the bulk of cases in 1708/2407 (70.9%), and mean age of 39.5±12.3 years. Urban constitutes 1306/2407 (54.3%),and 629/2407 (26.1%) were illiterates. There were 706/2407 (29.3%) with established type 2 diabetes mellitus(with all the risks of loss of glycemic control) and glucocorticoids misuse causes 105/2407 (4.3%) incident diabetes. Conclusion: Glucocorticoids misuse constituted the bulk of referral for adrenal disorders in Basrah. A lot of work needed to reduce the prevalence of this new high-risk iatrogenic disease.

Allelic Variants of ARMC5 in Patients With Adrenal Incidentalomas and in Patients With Cushing's Syndrome Associated With Bilateral Adrenal Nodules.

Objective: Germline ARMC5 mutations are considered to be the main genetic cause of primary macronodular adrenal hyperplasia (PMAH). PMAH is associated with high variability of cortisol secretion caused from subclinical hypercortisolism to overt Cushing's syndrome (CS), in general due to bilateral adrenal nodules and rarely could also be due to non-synchronic unilateral adrenal nodules. The frequency of adrenal incidentalomas (AI) associated with PMAH is unknown. This study evaluated germline allelic variants of ARMC5 in patients with bilateral and unilateral AI and in patients with overt CS associated with bilateral adrenal nodules.Methods: We performed a retrospective multicenter study involving 123 patients with AI (64 bilateral; 59 unilateral). We also analyzed 20 patients with ACTH pituitary independent overt CS associated with bilateral adrenal nodules. All patients underwent germline genotyping analysis of ARMC5; abdominal CT and were classified as normal, possible or autonomous cortisol secretion, according to the low doses of dexamethasone suppression test.Results: We identified only one pathogenic allelic variant among the patients with bilateral AI. We did not identify any pathogenic allelic variants of ARMC5 in patients with unilateral AI. Thirteen out of 20 patients (65%) with overt CS and bilateral adrenal nodules were carriers of pathogenic germline ARMC5 allelic variants, all previously described. The germline ARMC5 mutation was observed in only one patient with bilateral AI; it was associated with autonomous cortisol secretion and showed to be a familial form.Conclusion: The rarity of germline ARMC5 mutations in AI points to other molecular mechanisms involved in this common adrenal disorder and should be investigated. In contrast, patients with overt Cushing's syndrome and bilateral adrenal nodules had the presence of ARMC5 mutations that were with high prevalence and similar to the literature. Therefore, we recommend the genetic analysis of ARMC5 for patients with established Cushing's syndrome and bilateral adrenal nodules rather than patients with unilateral AI.