Subclinical Cushing's Syndrome Research Articles

Adrenal incidentaloma: A case of pheochromocytoma with sub-clinical Cushing's syndrome

Adrenal incidentaloma: A case of pheochromocytoma with sub-clinical Cushing's syndrome

Clinical characteristics and prognosis of primary aldosteronism associated with subclinical Cushing syndrome

Objective: To analyze the clinical characteristics and prognosis of patients with primary aldosteronism (PA) associated with subclinical Cushing syndrome (SCS). Methods: This retrospective cohort study was conducted at the First Affiliated Hospital of Chongqing Medical University in China. Patients with PA were included between January 2014 and December 2022. According to the results of 1-mg overnight dexamethasone suppression test, the patients were divided into the PA group and PA associated with SCS (PA/SCS) group. The demographic information, hormone levels, and follow-up results were analyzed. Independent sample t-test, chi-square test and Mann-Whitney U test were used for data comparison. Results: A total of 489 PA patients were enrolled in this study, of which 109 had PA/SCS (22.3%). Patients with SCS were on average older (54.4±10.7 vs. 47.4±11.0, P<0.001); had a larger proportion of women (69.7%, 76/109 vs. 57.4%, 218/380; P=0.020); and a longer duration of hypertension [96 (36, 180) vs. 60 (12, 120) months, P=0.001] than patients without SCS. There were 215 and 51 patients in the PA group and PA/SCS group, who completed adrenalectomy and follow-up, respectively. The remission rate of autonomous cortisol secretion in the PA/SCS group was 85.3% (29/34). There was no significant difference in the remission rate of autonomous aldosterone secretion among patients between the PA/SCS and PA group (94.1%, 48/51 vs. 94.4%, 203/215; P=1.000), while the clinical remission rate in the PA/SCS group was lower than that in the PA group (39.2%, 20/51 vs. 61.9%, 133/215; P=0.003). Conclusions: SCS is common in PA patients (22.3%), and the clinical remission rate is low. Screening using the 1-mg overnight dexamethasone suppression test is recommended for all patients with PA.

Clinical, Biochemical, and Radiological Retrospective Analysis in Patients with Adrenal Incidentaloma – A Secondary Publication

Objective: To evaluate the epidemiological, demographic, clinical features, treatment approaches, and survival of patients followed up for adrenal incidentaloma. Methods: Data from 46 patients who were treated and followed up due to adrenal incidentaloma in the Endocrinology Department of Mersin University Health Research and Application Hospital between 2010 and 2014 were retrospectively analyzed. Results: Of the cases included in the study, 13 were male, 33 were female, and the mean age was 54.09 ± 10.7 years. The most common reason for admission was abdominal pain in 34.78% of the patients, the most commonly diagnosed radiological method was dynamic adrenal CT in 60.87%, and the most common location was the left adrenal gland. The mean lesion diameter was between 26.8 ± 16.5 mm. The frequency of hypertension was 50%, obesity 47.8%, type 2 diabetes 21.7%, osteoporosis 42.8%, and metabolic syndrome 41.3%. According to hormonal evaluation results, non-functional adrenal adenoma (NFAA) was found in 82.61%, subclinical Cushing’s syndrome (SCS) in 15.21%, and aldosteronoma in 2.1%. Myelolipoma, pheochromocytoma, and adrenocortical adenoma were diagnosed in 8 cases undergoing adrenalectomy. One patient died due to liver failure. No hormonal activation or growth in lesion size was detected during the follow-up of the patients. Conclusion: Due to the very different pathological and radiological appearances of adrenal incidentaloma, it is important to evaluate demographic, etiological, clinical, laboratory, and radiological data as a whole in the treatment and follow-up.

Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11β-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

Long-term outcome of retroperitoneoscopic partial versus total adrenalectomy in patients with Cushing's syndrome.

We analyze the long-term outcome of surgery for Cushing's syndrome (CS) and the influence of the extent of surgical resection on the duration of postoperative cortisone substitution. One-hundred forty-one patients (129 female, 12 males; mean age: 45.7±12.8years) operated between January 2000 to June 2020 were included in the analysis. Patients suffered from manifest (124) or subclinical (17) CS due to benign unilateral adrenal neoplasia. All tumors were removed by the posterior retroperitoneoscopic approach. 105 patients had total (TA) and 36 partial (PA) adrenalectomies. All patients were discharged with ongoing corticosteroid supplementation therapy. Follow-up data could be obtained for 83 patients. Twenty-four (1male, 23 females; mean age 42.3years) underwent PA and 59TA (6 males, 53 females; mean age 44.6years). Mean follow-up time was 107±68months (range: 6-243months). The median duration of postoperative corticosteroid therapy was 9.5months after PA and 11months after TA (p=0.1). Significantly, more patients after total adrenalectomy required corticosteroid therapy for more than 24months (25% vs. 4%; p=0.03). Recurrent ipsilateral disease occurred in one case after partial adrenalectomy and was treated by completion adrenalectomy. A case of contralateral recurrence associated with subclinical Cushing's syndrome was observed after total adrenalectomy. The risk of local recurrence after partial adrenalectomy in CS is low. Cortical-sparing surgery may shorten corticosteroid supplementation therapy after surgery.

Bilateral co-secretory lesions presenting with coexisting Cushing syndrome and primary aldosteronism: a case report

BackgroundThere is an increasing number of cases of aldosterone- and cortisol-producing adenomas (A/CPAs) reported in the context of primary aldosteronism (PA). Most of these patients have PA complicated with subclinical Cushing's syndrome; cases of apparent Cushing's syndrome (CS) complicated with aldosteronism are less reported. However, Co-secretory tumors were present in the right adrenal gland, a cortisol-secreting adenoma and an aldosterone-producing nodule (APN) were present in the left adrenal gland, and aldosterone-producing micronodules (APMs) were present in both adrenal glands, which has not been reported. Here, we report such a case, offering profound insight into the diversity of clinical and pathological features of this disease.Case presentationThe case was a 45-year-old female from the adrenal disease diagnosis and treatment centre in West China Hospital of Sichuan University. The patient presented with hypertension, moon-shaped face, central obesity, fat accumulation on the back of the neck, disappearance of cortisol circadian rhythm, ACTH < 5 ng/L, failed elevated cortisol inhibition by dexamethasone, orthostatic aldosterone/renin activity > 30 (ng/dL)/(ng/mL/h), and plasma aldosterone concentration > 10 ng/dL after saline infusion testing. Based on the above, she was diagnosed with non-ACTH-dependent CS complicated with PA. Adrenal vein sampling showed no lateralization for cortisol and aldosterone secretion in the bilateral adrenal glands. The left adrenocortical adenoma was removed by robot-assisted laparoscopic resection. However, hypertension, fatigue and weight gain were not alleviated after surgery; additionally, purple striae appeared in the lower abdomen, groin area and inner thigh, accompanied by systemic joint pain. One month later, the right adrenocortical adenoma was also removed. CYP11B1 were expressed in the bilateral adrenocortical adenomas, and CYP11B2 was also expressed in the right adrenocortical adenomas. APN existed in the left adrenal gland and APMs in the adrenal cortex adjacent to bilateral adrenocortical adenomas. After another surgery, her serum cortisol and plasma aldosterone returned to normal ranges, except for slightly higher ACTH.ConclusionsThis case suggests that it is necessary to assess the presence of PA, even in CS with apparent symptoms. As patients with CS and PA may have more complicated adrenal lesions, more data are required for diagnosis.

THU009 Subclinical Cushing’s Syndrome In An ACTH-secreting Pituitary Macroadenoma

Abstract Disclosure: N.G. Akabogu: None. D. Kumar: None. N. Sheung: None. A. Akofu: None. A. Uddin: None. S. Dejhansathit: None. F. Marium: None. L.G. Kurukulasuriya: None. Background: Subclinical Cushing’s syndrome (SCS) is characterized by subtle cortisol hypersecretion, which does not result in the typical signs and symptoms of Cushing’s syndrome (CS). While many of the signs and symptoms of CS are common in the general population, there are some that are discriminatory and specific for CS: supraclavicular fat pads, proximal muscle weakness, facial plethora, and violaceous striae. SCS manifests mostly as obesity, type 2 diabetes, and hypertension. Diagnosing SCS is challenging; however, the best screening test to uncover the subtle hypercortisolism is the dexamethasone suppression test (DST). Case presentation: We report a case of SCS in a 62 years old Caucasian postmenopausal patient with a medical history of total thyroidectomy for Graves’ disease, post-surgical hypothyroidism, 7.4cm right pheochromocytoma status post partial right adrenalectomy, incidentally discovered pituitary macroadenoma (during imaging to look for subarachnoid hemorrhage), untreated type 2 diabetes mellitus (A1c 6.6% and stable for 1 year before treatment), hypertension, atrial fibrillation, cerebrovascular accident, and worsening migraines. Patient’s physical exam was mostly unremarkable; she had central obesity and bilateral lower extremity swelling. Pituitary work-up showed evidence of secondary hypogonadism and secondary hypothyroidism with elevated adrenocorticotropic hormone (ACTH) of 130 (AM range: 7.2-63) and cortisol of 12.6, at 11:52AM. Further work-up for hypercortisolism revealed non-suppressed 8AM cortisol (5.83mcg/dL) on the low dose DST and 49% suppression of 8AM cortisol and ACTH on the high dose DST. 24hour urinary cortisol was normal. Patient did not perform the midnight salivary cortisol. Patient subsequently underwent trans-sphenoidal resection of the pituitary macroadenoma. Pathology analysis of the pituitary mass showed weak to moderate immunoreactivity for ACTH. Conclusion: Our patient had abnormal DST but normal 24hour urine cortisol. We may have missed her SCS if we screened her only with a 24hour urine cortisol. This confirms the fact that dexamethasone suppression test should be the first test in the evaluation of subclinical Cushing’s syndrome. Presentation: Thursday, June 15, 2023

FRI173 Investigation Of Cut Off Values For Identifying Cortisol Excess In Adrenal Venous Blood Sampling

Abstract Disclosure: K. Watanabe: None. K. Nakai: None. Y. Tsurutani: None. R. Hirose: None. J. Saito: None. T. Nishikawa: None. Objective: Primary aldosteronism (PA) is sometimes accompanied by subclinical Cushing’s syndrome (SCS). However, there is no defined cutoff value for excess cortisol (Cort) in adrenal venous blood sampling (AVS). Meanwhile, some reports have shown AVS usefulness in overt Cushing’s syndrome. This study analyzed AVS parameters to determine the cutoff value of excess Cort in AVS. Methods: The Cort-producing adenoma (CPA) group included patients with adrenal tumors who had a Cort level of ≥ 5 mg/dL after a 1 mg dexamethasone suppression test (DST) and underwent segmental AVS (sAVS) at our hospital from 2009-2020 (n = 75). Patients who underwent AVS on only one side had an adrenocorticotropic hormone (ACTH) level of &amp;gt; 10 pg/mL after 1 mg DST, a midnight Cort level of &amp;lt; 5.0 mg/dL, bilateral cortisol-producing tumors, and/or adrenal cancer, were excluded (n = 26). The control group with normal Cort secretion included patients with Cort level of &amp;lt; 1.8 mg/dL after 1 mg DST who underwent sAVS and whose resected adrenal tumor was negative or weakly positive in 11β-hydroxylase cytochrome P450 staining (n = 45). We compared the various sAVS values between the CPA and control groups. Results: Forty-nine patients in the CPA and 45 in the control groups were analyzed. Compared with the control, the CPA group had a significantly higher maximum Cort level in the tributary veins flowing from the tumor (1220 [860.1-1584.4] vs. 928 [695.5-1350.0], p = 0.016). Meanwhile, Cort levels in the central vein on the tumor side were not significantly different between the two groups (895 [614.7-1312.7] vs. 820 [590.5-1065.0], p = 0.202). The CPA group had a significantly lower minimum Cort level in all tributary veins (117 [73.1-241.5] vs 559 [386.0-794.0], p &amp;lt; 0.001), and Cort level in the central vein on the non-tumor side (176 [93.9-394.0] vs 766 [499.5-1090.0], p &amp;lt; 0.001). The ratio of each value showed that the maximum Cort level in tributary veins flowing from the tumor/minimum Cort level in all tributary veins (9.59 [3.75-21.23] vs 1.65 [1.45-2.06], p &amp;lt; 0.001) and Cort level in the central vein on the tumor side/Cort level in the central vein on the non-tumor side (4.44 [1.95-11.35] vs 1.04 [0.73-1.34], p &amp;lt; 0.001) were significantly higher in the CPA group. The former had the largest area under the curve for the receiver operating characteristic curve in various indices (AUC = 0.948, 81.6% sensitivity and 97.8% specificity when 3.28 was set as the cut-off value). Conclusion: Novel cutoff values were proposed to identify excess cortisol in AVS. Presentation: Friday, June 16, 2023

FRI198 Acute Pancreatitis And Diabetic Ketoacidosis As A Presentation Of Subclinical Cushing Syndrome

Abstract Disclosure: W.H. Alkhidady: None. N. Almefgaie: None. A. Ekhzaimy: None. Case Report: A 43-year-old Saudi woman, presented to the emergency department with two days history of right upper quadrant pain, radiating to the back. Associated with nausea and vomiting with no history of diarrhea, constipation, or constitutional symptoms. She has a 4-year history of hypertension on 5 mg amlodipine with no history of endocrine or malignant tumors. On Examination she was alert, severely dehydrated with temperature of 37 °C, pulse of 124 per minute, blood pressure of 147/61 mmHg. The abdomen was tender in the right upper quadrant area. A laboratory examination showed lipemic sample with high triglycerides level 11mmol/L (0.4-1.48), high amylase 763nu/l (25-115), lipase 5773 u/l (73-393), low potassium level 2.6 mmol/l (3.50-5.10) and low calcium level 1.25 mmol/l (2.10-2.55). The urine analysis showed 4+ glucosuria and ketonuria. Her venous blood gas showed pH of 7.18 and bicarbonate of 10 mmol/L, random blood glucose was 16 mmol/L and anion gap could not be calculated at that time. A diagnosis of DKA secondary to acute pancreatitis secondary to high triglycerides level was made and management was started along with plasmapheresis. A CT pancreatitis protocol was done which showing a 4.2 x 3.5 cm well-circumscribed left adrenal lesion. An MRCP showed 4.3 cm well defined collision tumor in left adrenal gland, its peripheral part is suggestive of adenoma. further work up showed negative 24-hours urine metanephrins, normal Aldosterone Renin ratio, High 24-hour urine cortisol level 644 nmol/l, low ACTH 0.6 pmol/l and morning cortisol level post 1 mg DST was not suppressed on two different occasions. Since the patient had no phenotypical presentation of Cushing’s a diagnosis of SCS was made. She underwent left robotic assisted adrenalectomy, with pathological diagnosis of adrenocortical adenoma. 2 days later, AM cortisol level reduced to 230 nmol/L. while blood pressure and serum potassium remained normal with no signs of adrenal insufficiency. Her Diabetes mellitus and Hypertriglyceridemia resolved after left adrenalectomy. Conclusion: This case report demonstrates the uncommon association of subclinical Cushing syndrome and acute pancreatitis as a first presentation therefore it highlights the significant role of endocrine evaluation of any young patient with unexplained acute metabolic presentations. Presentation: Friday, June 16, 2023

Utilizing dehydroepiandrosterone sulfate and its ratio for detecting mild autonomous cortisol excess in patients with adrenal incidentaloma.

Subclinical Cushing syndrome is a condition of mild autonomous cortisol excess (MACE) that lacks typical features of Cushing syndrome but is associated with many complications. It represents a common hormonal dysfunction among patients with adrenal incidentaloma (AI), defined as unexpected masses or lesions found in the adrenal glands during radiological examinations of the chest or abdomen unrelated to adrenal gland assessment. The study evaluated the accuracy of dehydroepiandrosterone sulfate (DHEA-S) and dehydroepiandrosterone sulfate ratio (calculated by dividing the DHEA-S value by the age and sex-adjusted normal range of DHEA-S) in detecting MACE in AI patients. A cross-sectional study was conducted from April 2021 to July 2022 at the Faiha Specialized Diabetes, Endocrine, and Metabolism Centre (FDEMC) in Basrah, southern Iraq, involving 38 AI patients. Comprehensive laboratory and radiological evaluations were performed, including tests for adrenocorticotropic hormone (ACTH), renin, aldosterone, aldosterone/renin ratio (ARR), metanephrine, normetanephrine, cortisol, DHEA-S, and the 1-mg overnight dexamethasone suppression test (1-mg ONDST). Among the AI patients, 14% had MACE. Both DHEA-S ≤75 µg/dL and a DHEA-S ratio ≤1.7 exhibited a sensitivity of 80% each, with specificities of 73.3% and 76.6%, respectively, in diagnosing MACE in individuals aged ≤65 years. The negative predictive values were 95.7% and 95.8%, respectively. Low DHEA-S and DHEA-S ratio had high sensitivity and specificity in predicting MACE among AI patients aged ≤65 years, with strong negative predictive value.

Cardiovascular risk assessments in patients with cortisol-producing adenoma: impact of clinical features and genetic characteristics.

The causes of adrenal Cushing's syndrome (CS) encompass a wide spectrum of adrenal cortisol proliferations that exhibit clinical and molecular heterogeneity. The aims of our study were to investigate whether clinical and molecular heterogeneity influences endothelial function and metabolic abnormalities in patients with cortisol-producing adenoma (CPA). We retrospectively enrolled 25 patients with CPA and 45 patients with essential hypertension (EH). All CPAs were studied by direct sequencing of PRKACA. Flow-mediated vasodilation (FMD), an index of vascular endothelial function, was significantly lower in CS and subclinical CS (SCS) groups than in the EH group. FMD impairment did not differ significantly between CS and SCS groups. No differences in FMD were seen between PRKACA mutant and wild-type groups. FMD correlated negatively with hemoglobin A1c (HbA1c) in both PRKACA mutant and wild-type groups, as well as in CS and SCS groups. After adrenalectomy, systolic blood pressure (SBP) and HbA1c decreased significantly from baseline in the CS group, and SBP and low-density lipoprotein cholesterol (LDL-C) decreased significantly from baseline in the SCS group. While SBP and LDL-C decreased significantly from baseline in patients with wild-type PRKACA, only HbA1c decreased from baseline in patients harboring PRKACA mutations. Our data showed that patients with CPA have impaired endothelial function compared with EH patients and suggest the need for strict monitoring of atherosclerosis, even in patients with SCS or without PRKACA mutation.

Abstract #1413755: Subclinical Cushing’s Syndrome in an ACTH-secreting Pituitary Macroadenoma

Subclinical Cushing’s syndrome (SCS) is characterized by subtle cortisol hypersecretion, which does not result in the typical signs and symptoms of Cushing’s syndrome (CS). While many of the signs and symptoms of CS are common in the general population, there are some that are discriminatory and specific for CS: supraclavicular fat pads, proximal muscle weakness, facial plethora, and violaceous striae. SCS manifests mostly as obesity, type 2 diabetes, and hypertension. Diagnosing SCS is challenging; however, the best screening test to uncover the subtle hypercortisolism is the dexamethasone suppression test (DST). We report a case of SCS in a 62 years old Caucasian postmenopausal patient with a medical history of total thyroidectomy for Graves’ disease, post-surgical hypothyroidism, 7.4cm right pheochromocytoma status post partial right adrenalectomy, incidentally discovered pituitary macroadenoma (during imaging to look for subarachnoid hemorrhage), untreated type 2 diabetes mellitus (A1c 6.6% and stable for 1 year before treatment), hypertension, atrial fibrillation, cerebrovascular accident, and worsening migraines. Patient’s physical exam was mostly unremarkable; she had central obesity and bilateral lower extremity swelling. Pituitary work-up showed evidence of secondary hypogonadism and secondary hypothyroidism with elevated adrenocorticotropic hormone (ACTH) of 130 (AM range: 7.2-63) and cortisol of 12.6, at 11:52AM. Further work-up for hypercortisolism revealed non-suppressed cortisol (5.83mcg/dL) on the low dose DST and 49% suppression of cortisol and ACTH on the high dose DST. 24-hour urinary cortisol was normal. Patient did not perform the midnight salivary cortisol. Patient subsequently underwent trans-sphenoidal resection of the pituitary macroadenoma. Pathology analysis of the pituitary mass showed weak to moderate immunoreactivity for ACTH. Our patient had abnormal DST but normal 24hour urine cortisol. We may have missed her SCS if we screened her only with a 24hour urine cortisol. This confirms the fact that dexamethasone suppression test should be the first test in the evaluation of subclinical Cushing’s syndrome.

Primary bilateral macronodular adrenocortical hyperplasia (PBMAH) patient with ARMC5 mutations

BackgroundPrimary bilateral macronodular adrenocortical hyperplasia (PBMAH) is a highly heterogeneous disease with divergent manifestations ranging from asymptomatic subclinical Cushing syndrome (CS) to overt Cushing syndrome with severe complications. ARMC5 mutations occur in 20 to 55% PBMAH patients usually with more severe phenotypes. Different ARMC5 mutations might be associated with diverse phenotypes of PBMAH.Case presentationA 39-year-old man was admitted to our hospital with progressive weight gain and severe hypertension. He presented typical CS and its classical metabolic and bone complications like hypertension and osteoporosis. The laboratory results showed high levels of cortisol and low levels of ACTH. Low- and high-dosed dexamethasone suppression tests were negative. Contrast-enhanced computed tomography (CT) revealed multiple bilateral irregular macronodular adrenal masses. Adrenal venous sampling (AVS) confirmed that the right adrenal gland with larger nodules secreted more hormone that the left side did. Right adrenalectomy and subsequent contralateral subtotal resection were conducted. His blood pressure and CS symptoms as well as comorbidities including backache and muscle weakness improved. Whole exome sequencing identified one ARMC5 germline mutation (c.1855C > T, p. R619*), five ARMC5 somatic mutations (four novel mutations) in his right and left adrenal nodules.ConclusionsThis PBMAH patient was identified with one ARMC5 germline mutation and five different somatic ARMC5 mutations (four novel mutations) in the different nodules of the bilateral adrenal masses. AVS combined with CT imagine could be helpful to determine the dominant side for adrenalectomy. Genetic testing is important for the diagnosis and management of the patient with PBMAH.

PD03-02 NOVEL STRUCTURAL VARIANTS IN CTNNB1 AND MOLECULAR CLASSIFICATION IN CORTISOL-PRODUCING ADENOMA

You have accessJournal of UrologyCME1 Apr 2023PD03-02 NOVEL STRUCTURAL VARIANTS IN CTNNB1 AND MOLECULAR CLASSIFICATION IN CORTISOL-PRODUCING ADENOMA Yoichi Fujii, Seiichiro Higuchi, Yusuke Sato, Yuichi Shiraishi, Kenichi Yoshida, Satoru Miyano, Haruki Kume, Tomohiko Ichikawa, Atsushi Iwama, Tomoaki Tanaka, and Seishi Ogawa Yoichi FujiiYoichi Fujii More articles by this author , Seiichiro HiguchiSeiichiro Higuchi More articles by this author , Yusuke SatoYusuke Sato More articles by this author , Yuichi ShiraishiYuichi Shiraishi More articles by this author , Kenichi YoshidaKenichi Yoshida More articles by this author , Satoru MiyanoSatoru Miyano More articles by this author , Haruki KumeHaruki Kume More articles by this author , Tomohiko IchikawaTomohiko Ichikawa More articles by this author , Atsushi IwamaAtsushi Iwama More articles by this author , Tomoaki TanakaTomoaki Tanaka More articles by this author , and Seishi OgawaSeishi Ogawa More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003220.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cortisol-producing adenoma (CPA) is the most common hormone-producing adrenal tumor. Although several hotspot mutations of driver genes (PRKACA, GNAS, and CTNNB1) have been identified in the previous studies, genotypes have not been confirmed in approximately 30% of CPAs. In addition, the association between genotypes and clinical characteristics of CPAs are poorly understood. METHODS: Genomic DNA and RNA was extracted from 125 surgical specimens of adrenal CPAs, including 60 cases with Cushing’s syndrome (CS) and 65 with subclinical Cushing’s syndrome (SCS), and subjected to targeted-capture sequencing and RNA sequencing. RESULTS: Novel structural variants (SVs) in CTNNB1, including long deletion and inversion, were identified in 8% (10/125) of CPA cases. All these SVs resulted in the lack of exon 3, which encodes the phosphorylation site of beta-catenin and plays an important role in its degradation, leading to the constitutive activation of the Wnt pathway by disrupting the degradation of beta-catenin. In addition, several mutations in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA), were identified around the known hotspot p.L206. Subsequent functional assay showed that these PRAKACA mutants abolished its binding ability to PRKAR1A, the regulatory subunit of PKA, leading to the constitutive, cAMP-independent PKA activation. In total, 82.4% (103/125) of CPAs had alterations in PRKACA, GNAS, and wnt pathway genes (CTNNB1, APC, and MED12) in almost mutually exclusive manner, based on which CPAs are classified into three distinct subgroups. These mutational subtypes showed distinct genetic and clinical characteristics. RNA sequencing revealed that the expression level of steroidogenic enzymes such as CYP17A1 and CYP21A2 were more upregulated in PRKACA-mutated subtype than wnt-mutated subtype. Consistent with this observation, PRKACA-mutated subtype showed significantly higher cortisol-producing autonomous secretion level, more frequent CS than wnt-mutated subtype. In contrast, wnt-mutated subtype more tended to be SCS, showed lower cortisol-producing ability and largar tumor volume compared to the other two subtypes. CONCLUSIONS: Novel CTNNB1 structural variants were identified. CPAs showed distinct genetic landscape, associated with various clinical features. Source of Funding: No © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e74 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoichi Fujii More articles by this author Seiichiro Higuchi More articles by this author Yusuke Sato More articles by this author Yuichi Shiraishi More articles by this author Kenichi Yoshida More articles by this author Satoru Miyano More articles by this author Haruki Kume More articles by this author Tomohiko Ichikawa More articles by this author Atsushi Iwama More articles by this author Tomoaki Tanaka More articles by this author Seishi Ogawa More articles by this author Expand All Advertisement PDF downloadLoading ...

PS-C21-4: EPIGENETIC ALTERATION OF 11B;-HYDROXYSTEROID DEHYDROGENASE 1 IN THE ADIPOSE TISSUE OF PATIENTS WITH ENDOCRINE HYPERTENSION

Objective: 11Beta-hydroxysteroid dehydrogenase 1 (11β;-HSD1) is a key enzyme involved in metabolic syndrome. The epigenetic control of 11β;-HSD1 is unclear. We examined the 11β;-HSD1 mRNA level and methylation status of the promoter region of the 11β;-HSD1 gene in the adipose tissue of patients with endocrine hypertension. Methods: We evaluated 8 adipose tissue specimens from patients with subclinical Cushing syndrome (SCS) due to cortisol-producing adenomas, 10 tissue specimens from patients with primary aldosteronism due to aldosterone-producing adenoma (APA) and 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). SCS and primary aldosteronism were diagnosed according to the guideline of the Japanese Endocrine Society. The mRNA level of 11β;-HSD1 was quantified using a real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific for the human 11β;-HSD1 promoter region. Results: The glycohemoglobin level was significantly higher in patients with SCS or APA compared with those with NFA (p &lt; 0.05). Blood pressure was significantly elevated in patients with APA compared with those with SCS or NFA (p &lt; 0.01). The 11β;-HSD1 mRNA level was significantly increased in the adipose tissues of SCS and APA compared with NFA patients (p &lt; 0.05). The methylation ratio was significantly lower in SCS compared with APA or NFA patients (p &lt; 0.05). Conclusion: 11β;-HSD1 gene expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological roles of epigenetic control of 11β;-HSD1 gene expression in adipose tissue requires further study.

Pheochromocytoma with Type 2 Diabetes Mellitus and Subclinical Cushing's Syndrome

Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal medullary chromaffin cells. It affects 1–8 per million people annually and accounts for 5% of adrenal incidentalomas. Here, we report a 62-year-old man with sudden excessive sweating, palpitations, and headaches. He has a history of type 2 diabetes mellitus, hypertension, and an adrenal mass found incidentally by ultrasonography. Clinical history and further imaging suggest a pheochromocytoma; however, the presence of subclinical Cushing's syndrome and a normal urine vanillylmandelic acid level have led to diagnostic challenges. Finally, the patient underwent a left adrenalectomy. Histopathology showed the tumor as thick nests of cells, positive chromogranin A staining, and negative inhibin staining that confirmed the diagnosis of pheochromocytoma. In conclusion, our patient had pheochromocytoma that was thought to produce adrenocorticotropic hormone ectopically, resulting in subclinical Cushing's syndrome.

PS-R03-3: INTERMITTENTLY SCANNED CONTINUOUS GLUCOSE MONITORING IN A DIFFICULT PATIENT WITH GESTATIONAL DIABETES MELLITUS AND SUBCLINICAL CUSHING'S SYNDROME: A CASE REPORT

A 41-year-old woman was admitted to the obstetrics department because of epigastric pain, nausea, and fatigue at 31 weeks of gestation. She was suspected of subclinical Cushing's syndrome based on high plasma cortisol and low ACTH levels along with an incidentally discovered tumor in the left adrenal gland 4 years prior to conception. 3 months before admission, 75 g oral glucose tolerance test yielded one point positive (81–169–174 mg/dL) and diagnosis of gestational diabetes mellitus was made. Diet and exercise therapy was started on an outpatient basis. While blood glucose control had been favorable, she discontinued visits to outpatient clinics due to difficulty in physical activity. At the time of admission, blood glucose level was running more than 200 mg/dl, and self-monitoring of blood glucose (SMBG) and insulin self-injection therapy were proposed for immediate blood glucose control accordingly. However, the patient had psychiatric symptoms that were presumably associated with delusional disorder and subclinical Cushing's syndrome. As such, she refused to implement both procedures on account of a strong fear against puncture, which caused blood glucose management difficult. Despite understanding the necessity of SMBG and potential risks to the fetus, the patient frequently expressed anxiety and could not perform SMBG. Given the difficult circumstance, intermittently scanned continuous glucose monitoring was installed to reduce invasive procedures. As a result, blood glucose levels were under good control with 0.43 U/kg of insulin per day until the delivery by cesarean section at 34 weeks of gestation. A healthy infant weighing 2442 g was delivered without complications. Here we highlight utility and efficacy of intermittently scanned continuous glucose monitoring in a difficult patient with gestational diabetes mellitus and subclinical Cushing's syndrome.

The Role of Serum Inflammation-Based Scores in Diagnosis and Assessing Remission in Cushing's Disease.

Chronic hypercortisolism causes diverse alterations in the immune system and inflammatory disruptions. Serum inflammation-based scores (SIBS) are indicators of systemic inflammatory status. This study aims to determine the role of SIBS in the diagnosis and evaluation of remission in patients with Cushing's disease (CD). This retrospective cross-sectional study was conducted on 195 participants; 52 patients diagnosed and followed up after treatment with CD, 65 patients with subclinical Cushing's syndrome (SCS), and 78 healthy individuals whose complete blood counts (CBC) were obtained for analysis. Participants with additional diseases or drug use that could affect CBC were excluded from the study. SIBS of the three groups were compared. Scores considered were neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). The correlations between SIBS and initial diagnostic tests for hypercortisolism were analyzed. The SIBS of patients with CD at the diagnosis were compared with those after remission. In addition, receiver operator characteristic curve analyses were used to determine the diagnostic accuracy, specificity, and sensitivity of the scores significantly high in the CD group. MLR and SII values were significantly higher in CD patients than in the healthy group (p<0.01). NLR and SII were significantly higher in patients with CD than those with SCS (p<0.05). There were no significant differences between the SCS and the control groups in all SIBS. We determine significant, positive, and moderately correlated findings between SIBS and initial diagnostic tests for hypercortisolism in the CD group (0.30<r<0.70; p<0.05). All of the scores evaluated were significantly lower in the remission of the disease compared to the active period (p<0.001). An optimal cut-off MLR value of 0.20 showed the best diagnostic value (p=0.003; sensitivity, 78.4%; specificity, 51.4%), and an optimal cut-off SII value of 776.20 showed the best diagnostic value (p=0.017; sensitivity, 54.9%; specificity, 70.0%). The SIBS, which can be easily calculated with the data obtained from CBC and do not have additional costs, can contribute to the diagnosis and assessment of remission in patients with CD.

Carney complex presenting as subclinical Cushing syndrome in a child due to a novel Phosphodiesterase 11A mutation

BackgroundSeveral disease-causing genes have been implicated in Carney complex (CNC), including PRKAR1A, PDE8B(Phosphodiesterase 8B),and PDE11A (Phosphodiesterase 11A). The purpose of this study was to describe the clinical features of CNC in a Chinese patient and identify potential pathogenic mutations. MethodsGenomic DNA was extracted from the peripheral venous blood obtained from one Chinese CNC family from Shandong province. Subsequently, targeted region sequencing (TRS) and Sanger sequencing validation were performed to identify and validate likely pathogenic mutations. ResultsGenetic analyses revealed a novel PDE11A variant that was predicted to lead to CNC. The patient's mother presented with the same genetic mutation. ConclusionThis study identifies new genetic mutation in CNC（PDE11A: NM_016953: exon11: c1921A>G (p./p.Lys641Glu). CNC patients presenting with subclinical Cushing's syndrome should be treated.

The Entity of Connshing Syndrome: Primary Aldosteronism with Autonomous Cortisol Secretion.

Connshing syndrome (CoSh) (adrenal-related synchronous aldosterone (A) and cortisol (C) excess) represents a distinct entity among PA (primary hyperaldosteronisms) named by W. Arlt et al. in 2017, but the condition has been studied for more than 4 decades. Within the last few years, this is one of the most dynamic topics in hormonally active adrenal lesions due to massive advances in steroids metabolomics, molecular genetics from CYP11B1/B2 immunostaining to genes constellations, as well as newly designated pathological categories according to the 2022 WHO classification. In gross, PA causes 4-10% of all high blood pressure (HBP) cases, and 20% of resistant HBP; subclinical Cushing syndrome (SCS) is identified in one-third of adrenal incidentalomas (AI), while CoSh accounts for 20-30% to 77% of PA subjects, depending on the tests used to confirm autonomous C secretion (ACS). The clinical picture overlaps with PA, hypercortisolemia being mild. ACS is suspected in PA if a more severe glucose and cardiovascular profile is identified, or there are larger tumours, ACS being an independent factor risk for kidney damage, and probably also for depression/anxiety and osteoporotic fractures. It seems that one-third of the PA-ACS group harbours mutations of C-related lines like PRKACA and GNAS. A novel approach means we should perform CYP11B2/CYP11B1 immunostaining; sometimes negative aldosteronoma for CYP11B1 is surrounded by micronodules or cell clusters with positive CYP11B1 to sustain the C excess. Pitfalls of hormonal assessments in CoSh include the index of suspicion (check for ACS in PA patients) and the interpretation of A/C ratio during adrenal venous sample. Laparoscopic adrenalectomy is the treatment of choice. Post-operative clinical remission rate is lower in CoSh than PA. The risk of clinically manifested adrenal insufficiency is low, but a synthetic ACTH stimulating testing might help to avoid unnecessary exposure to glucocorticoids therapy. Finally, postponing the choice of surgery may impair the outcome, having noted that long-term therapy with mineralocorticoids receptors antagonists might not act against excessive amounts of C. Awareness of CoSh improves management and overall prognosis.