scholarly journals Ectopic ACTH-Producing Pheochromocytoma as a Rare Cause for Rapid Progressing Cushing Syndrome: A Case Report

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A128-A128
Author(s):  
Daniela Salazar ◽  
Cláudia Fernandes Costa ◽  
Joana Oliveira ◽  
Liliana Violante ◽  
Ana Luísa Cunha ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Cushing Syndrome ◽  
Somatostatin Receptors ◽  
Osteoporotic Fractures ◽  
Urinary Free Cortisol ◽  
Hand Tremor ◽  
Ectopic Acth ◽  
Late Night ◽  
Free Cortisol ◽  
The Right

Abstract Background: Cushing syndrome due to ectopic CRH or ACTH secretion can be rarely caused by pheochromocytoma, commonly as part of genetic conditions. Case: A 21 year-old male, previously healthy, with no usual medication, went to the physician assistant for hematuria. The kidney US revealed, besides lithiasis, a highly vascularized mass in the right adrenal gland with 10 cm. In his first evaluation the patient had no complaints or pheochromocitoma/hypercortisolism stigmata, other than hand tremor and slight rounding of the face. Blood pressure was 149/88 mmHg, and heart rate 86 bpm. There was no family history of endocrine disease. He rapidly developed increased appetite, insomnia, and severe myalgias, with filling of supraclavicular fossae, facial plethora, and cervical and truncal acne. Laboratory analysis showed abnormal overnight dexamethasone suppression test (57.4 µg/dL, N < 1.8), elevated ACTH 378 pg/mL (N 9.0–52.0), 24h-urinary free cortisol (UFC) (5334.0 µg/24h, N 4.3–176.0), and late-night salivar cortisol (1.44 µg/dL, N < 0.32), hypokalemia (2.8 mEq/L, N 3.8–5.0), and leukocytosis (22.4*109/L, N 4.0–11.0); DHEA-S 962 µg/dL (N 80–560), 4-androstenedione 380 ng/dL (N 70–360), 17-OH progesterone 4.5 ng/mL (N 0.59–3.44), cromogranine A 6063 ng/mL (N 0–100), and markedly elevated urinary amines (adrenaline 173 nmol/24h, N 0–109; noradrenaline 5033 nmol/24h, N 89–473; normetanephrine 334605 nmol/24h, N 480–2424; metanephrine 15998 nmol/24h, N 264–1729; dopamine 4808 nmol/24h, N 424–2612). Hypercalcemia with hypophosphatemia and supressed PTH level was also detected. 68Ga-DOTANOC PET revealed a mass of the right adrenal gland with overexpression of somatostatin receptors (likely pheochromocytoma), without evidence of other tumor lesions of neuroendocrine origin. Pituitary MRI showed normal pituitary gland. Potassium supplementation, alpha-blockade with phenoxybenzamine, and metyrapone were initiated. Due to severe back pain, a CT scan of the spine was performed detecting compressive osteoporotic fractures in the mid dorsal and low dorsal segments. The patient was submitted to right adrenalectomy. Histology revealed pheochromocytoma with 11.2*9mm, with capsular and vascular invasion, extra-adrenal extension, necrosis, and atypical mitosis, with Ki67 of 9.5% and PASS score of 16. Postoperative analysis showed ACTH 45.6 pg/mL (N 7.2-63,3), late-night salivar cortisol < 0,0544 µg/dL (N < 0,32) and free urinary cortisol 41.4 µg/24h (N 4.3–176.0). Discussion: Ectopic cushing syndrome caused by pheochromocytoma is a rarely described entity. In this young patient, it caused rapid clinical progression of hypercortisolism with important hydroelectrolytic disturbances and compressive vertebral fractures, requiring prompt surgical intervention for clinical remission and improvement.

scholarly journals A Challenging Case of an Ectopic Cushing Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Joana Menezes Nunes ◽  
Elika Pinho ◽  
Isabel Camões ◽  
João Maciel ◽  
Pedro Cabral Bastos ◽  
...  
Keyword(s):  
Cushing Syndrome ◽  
Lung Resection ◽  
Signs And Symptoms ◽  
Urinary Free Cortisol ◽  
Community Acquired Pneumonia ◽  
Interesting Case ◽  
Ectopic Acth Syndrome ◽  
Ectopic Acth ◽  
Free Cortisol ◽  
Fdg Pet Scan

Bronchopulmonary carcinoids are rare pulmonary neoplasms although they account for most cases of ectopic ACTH syndromes. When feasible, the mainstay treatment is surgical resection of the tumor. We report the case of a 52-year-old woman with signs and symptoms suggestive of hypercortisolism for 12 months, admitted to our department because of community acquired pneumonia. Blood hormone analysis showed increased levels of ACTH and urinary free cortisol and nonsuppressibility to high- and low-dose dexamethasone tests. Pituitary MRI showed no lesion and no central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. CRH stimulation test suggested an ectopic ACTH source. Thoracic CT scan revealed a nodular region measuring 12 mm located in the inferior lingular lobule of the left superior lung with negative uptake by18-FDG-PET scan and negative SRS. The patient was successfully treated with an atypical lung resection and histology revealed an atypical bronchial carcinoid tumor with positive ACTH immunoreactivity. This was an interesting case because the patient was admitted due to pneumonia that may have been associated with her untreated and chronic hypercortisolism and a challenging case of ectopic ACTH syndrome due to conflicting results on the diagnostic exams.

Accuracy of Laboratory Tests for the Diagnosis of Cushing Syndrome

2020 ◽  
Vol 105 (6) ◽  
pp. 2081-2094 ◽  
Author(s):  
Brandon P Galm ◽  
Nidan Qiao ◽  
Anne Klibanski ◽  
Beverly M K Biller ◽  
Nicholas A Tritos
Keyword(s):  
Likelihood Ratio ◽  
Diagnostic Tests ◽  
Cushing Syndrome ◽  
Data Extraction ◽  
Positive Likelihood Ratio ◽  
Negative Likelihood Ratio ◽  
Serum Cortisol ◽  
Urinary Free Cortisol ◽  
Late Night ◽  
Free Cortisol

Abstract Context The diagnosis of Cushing syndrome (CS) can be challenging. It remains to be determined which diagnostic tests are the most accurate. Objective To summarize the accuracy of diagnostic tests for CS using contemporary meta-analytic techniques (hierarchical models). Data Sources PubMed, Embase, Scopus, Web of Science, and the Cochrane Database of Systemic Reviews (inception until August 3, 2018). Study Selection Studies performed in adults that determined the accuracy of one or more diagnostic tests: overnight 1-mg dexamethasone suppression test (DST), 2-day low-dose DST (2d DST), 24-hour urinary free cortisol (UFC), late-night salivary cortisol (LNSC), midnight serum cortisol (MSC), and the dexamethasone-suppressed CRH (dex-CRH) and desmopressin (dex-DDAVP) tests. Data Extraction Two authors independently extracted data and performed methodological assessments. Data Synthesis One hundred thirty-nine studies (14 140 participants) were included in the analysis. The respective sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio (95% confidence interval [CI]) estimates include the following: DST 98.6% (96.9%-99.4%), 90.6% (86.4%-93.6%), 10.5 (7.2-15.3), and 0.016 (0.007-0.035); 2d DST 95.3% (91.3%-97.5%), 92.8% (85.7%-96.5%), 13.2 (6.47-27.1), and 0.051 (0.027-0.095); UFC 94.0% (91.6%-95.7%), 93.0% (89.0%-95.5%), 13.3 (8.47-21.0), and 0.065 (0.046-0.092); LNSC 95.8% (93.%-97.2%), 93.4% (90.7%-95.4%), 14.6 (10.3-20.7), and 0.045 (0.030-0.066); MSC 96.1% (93.5%-97.6%), 93.2% (88.1%-96.3%), 14.2 (7.96-25.2), and 0.042 (0.026-0.069); and dex-CRH 98.6% (90.4%-99.8%), 85.9% (67.6%-94.7%), 7.0 (2.80-17.6), and 0.016 (0.002-0.118). A single study evaluated dex-DDAVP. Meta-regression and a novel network meta-analytic approach suggest that DST is the most sensitive while UFC is the least sensitive. Conclusions All of the included diagnostic tests for CS are highly sensitive and specific. It appears that the DST is the most sensitive while the UFC is less sensitive. The specificity of all first-line tests appears comparable.

scholarly journals Severe Cushing Syndrome Due to Ectopic ACTH Secretion by Pheochromocytoma

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A156-A156
Author(s):  
Rafael Buck Giorgi ◽  
Rayssa Fabiana Chamma ◽  
Rayssa F Chamma ◽  
Ituo Filho ◽  
Giane Cristina Garcia ◽  
...  
Keyword(s):  
Ct Scan ◽  
Adrenal Mass ◽  
Cushing Syndrome ◽  
Urinary Free Cortisol ◽  
Secondary Hypertension ◽  
Ectopic Acth ◽  
Ectopic Acth Secretion ◽  
Free Cortisol ◽  
Ectopic Acth Production ◽  
History Of

Abstract Introduction: Ectopic ACTH production is a very unusual cause of Cushing Syndrome (CS). When it occurs, lung cancer is the main cause. Very rarely, this ectopic source of ACTH can arise from a Pheochromocytoma (Pheo). A recent literature review identified less than 100 cases described. We present a case of 28 years old woman who was referred for adrenalectomy for CS with notorious adrenal mass. However, during the investigation, ectopic ACTH due a Pheo was identified. Case Report: A 28-year-old woman required emergency care for ecchymosis and asymptomatic hypertension (BP: 230x130mmHg). Hyperpigmentation of the skin was evident on physical examination. Severe hypokalemia (K: 2.5mEq/liter) was detected. She denied taking any medication and was unaware of any previous illness. She always had normal BP measurements as well as laboratory tests. No family history of adrenal disease or secondary hypertension causes. During hospitalization, the hypothesis of CS was made and confirmed after: cortisol after 1mg dexamethasone: 44.5mcg/dl (<1.8mcg/dl) and 24h urinary free cortisol: 6228 mcg/dl (28-213mcg/dl). Concomitantly, a CT scan of the abdomen exhibited a left adrenal mass (3.1x2.8x3.5cm) of uncertain etiology and ACTH: 352pg/ml (<46pg/ml). Additionally, the patient presented hyperglycemia during hospitalization. After confirmation of the ACTH dependent CS, pituitary MRI was performed with normal results and a chest CT scan ruled out lung masses. As there was still no etiological confirmation and due to clinical deterioration, it was decided to start Ketoconazole 200mg/day, rising until 600mg and spironolactone with doses up to 250mg/day with a significant improvement in hypokalemia, decreased cortisol levels and optimal BP control. Due to the extremely high levels of ACTH and indeterminate adrenal mass, the hypothesis of ACTH ectopic due Pheo was postulated. Patient underwent abdomen MRI with left adrenal mass with hypersignal at T2 and urinary metanephrines levels: 6132mcg/24h (<289mcg/24h), urinary normetanephrines: 1808mcg/24h (<732mcg/24h). Once the diagnosis was elucidated, she received preoperative preparation with alpha blocker (Doxazosin) and underwent adrenalectomy without complications. After discharge, she received prednisone 10mg/day. The patient presented normalization of BP levels, as well as glycemic control with a slight improvement in skin hyperpigmentation. The pathology department confirmed Pheo and an ACTH expression was observed in immunohistochemistry. A genetic panel for Pheo is running with no results so far. Conclusion: Despite an extremely rare cause of CS, the ectopic production of ACTH by a Pheo has extremely high mortality rates, especially when not diagnosed or managed correctly. The clinicians must always remain alert and suspect this syndrome when the patient has a confirmed ACTH dependent CS associated with adrenal masses.

scholarly journals Adrenocorticotropic hormone-producing pheochromocytoma: analysis of clinical cases

2015 ◽  
Vol 12 (3) ◽  
pp. 46-52
Author(s):  
Evgeniya Ivanovna Marova ◽  
Iya Aleksandrovna Voronkova ◽  
Anastasiya Mikhaylovna Lapshina ◽  
Svetlana Dmitrievna Arapova ◽  
Nikolay Sergeevich Kuznetsov ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Cushing’S Syndrome ◽  
Adrenocorticotropic Hormone ◽  
Somatostatin Receptors ◽  
Pituitary Tumors ◽  
Cushing's Syndrome ◽  
Ectopic Acth Syndrome ◽  
Ki 67 ◽  
Ectopic Acth ◽  
Free Cortisol

Ectopic secretion of ACTH from non-pituitary tumors, referred to as ectopic ACTH syndrome (EAS), accounts for about 10–20% of Cushing’s syndrome (CS). Ectopic hormone-secreting pheochromocytomas (Pheo) are rare. The first publication of association between pheochromocytoma and Cushing’s syndrome by Roux is dated 1955. Pheochromocytoma represents a rare cause of hypercortisolism, accounting for less than 5 % of ectopic Cushing’s syndrome while less than 1 % of pheochromocytomas is accompanied by Cushing’s syndrome.We are reporting 4 cases of ACTH-secreting pheochromocytoma presenting as Cushing’s syndrome. Data from 4 patients were analysed. There were 4 women from 50 to 63 years old. All patients had a clinical presentation of hypercorticoidism. Their levels of adrenocorticotropic hormone in plasma, 24-hour urinary free cortisol and urinary catecholamine were high. Computed tomography scan of the abdomen in all cases revealed a mass in the left adrenal gland. Left sided adrenalectomy was performed under treatment with a-blocker doxazosin and b-blocker atenolol. Histological examination revealed in 3 cases – pheocromocytoma and in 1 case corticomedullary mixed tumor of the adrenal gland. Additional immunostaining (IHC)of these tumors showed positive immunostaining for chromogranin and ACTH. The IHC search for somatostatin receptors of subtype 2 and 5 (SSTR2, SSTR5) was performed in 3 cases and showed predominately expression SSTR2. The case index of Ki-67 ranged, from 0,5 to 4%. Biochemical signs of hypercortisolism rapidly began to disappear after surgery. Follow up of the patients during the next 2 years on average was with disease remission.

Effective Therapy of Insulinoma by Using Long-Acting Somatostatin Analogue. A Case Report and Literature Review

2011 ◽  
Vol 120 (02) ◽  
pp. 68-72 ◽  
Author(s):  
A. Jawiarczyk ◽  
M. Bolanowski ◽  
J. Syrycka ◽  
G. Bednarek-Tupikowska ◽  
M. Kałużny ◽  
...  
Keyword(s):  
Adrenal Gland ◽  
Somatostatin Receptors ◽  
Subcutaneous Administration ◽  
Pancreatic Neuroendocrine Tumor ◽  
Somatostatin Analogue ◽  
Left Adrenal Gland ◽  
Glucose Levels ◽  
Long Acting ◽  
The Right

AbstractWe are reporting a case of 68-year-old woman with insulinoma, after a non-successful tumor surgery and a long-term diazoxide treatment. She had a lot of hypoglycemia cases, and a weight gain of 50 kg. An abdominal CT scan demonstrated a tumor 28 mm in the diameter, in the head of the pancreas. The patient did not agree for the repeated insulinoma surgery. Furthermore, we found a lesion in the left adrenal gland (14 mm in the diameter) and in the right lung (8 mm in the diameter). Pheochromocytoma was diagnosed on the basis of hypertension, elevated levels of normetanephrine in the 24-h urine collection, and an elevated level of norepinephrine in a plasma sample. After the left adrenal gland removal we observed lower blood pressure. Since we had revealed the presence of somatostatin receptors by the somatostatin receptors scintigraphy, we decided to control hypoglycemia by a monthly subcutaneous administration of the long-acting lanreotide. Because of higher glucose levels (300–400 mg/dl) we started an intense insulin therapy. Nowadays, the patient feels better, she has lost 20 kg of her body weight, and we have observed normal blood glucose levels during the long-term lanreotide treatment. We have noticed neither side effects nor hypoglycemic episodes and we have reduced the dose of insulin. The presented case can be an evidence of the effective treatment of the pancreatic neuroendocrine tumor of insulinoma type, with somatostatin analogue.

scholarly journals Clinical Characteristics and Treatment Outcomes in Endogenous Cushing’s Syndrome: A 15-Year Experience from Thailand

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Wasita Warachit Parksook ◽  
Nitchakarn Laichuthai ◽  
Sarat Sunthornyothin
Keyword(s):  
Treatment Outcomes ◽  
Cushing’S Syndrome ◽  
Clinical Characteristics ◽  
Remission Rate ◽  
Urinary Free Cortisol ◽  
Cushing's Syndrome ◽  
Ectopic Acth Syndrome ◽  
Normal Body Mass Index ◽  
Ectopic Acth ◽  
Free Cortisol

The most common subtype of endogenous Cushing’s syndrome (CS) is Cushing’s disease (CD), with higher proportions of adrenal CS reported from Asia, compared to other continents. However, little was known about CS in this territory. This study was to investigate the distribution, clinical characteristics, and treatment outcomes of CS in a single tertiary hospital in Thailand. We performed a retrospective evaluation of 82 patients with endogenous CS during 2001–2015. The most common subtype was CD, followed by adrenal CS and ectopic ACTH syndrome (EAS), respectively. Weight gain was the most common presentation. Normal body mass index (BMI), Asian cutoff, was observed in 33% of patients. Specific features of CS (plethora, muscle weakness, bruising, and/or wide purplish striae) were documented in less than half of patients. The median age, adrenocorticotropic hormone (ACTH), and urinary free cortisol (UFC) concentrations were significantly different among 3 subtypes of CS and were highest among patients with EAS. An initial remission rate after transsphenoidal surgeries in CD was 62%, with higher rates in pituitary microadenomas compared to macroadenomas. All patients with unilateral adrenal disease achieved CS remission after adrenal surgeries. Patients with EAS achieved CS remission mostly from bilateral adrenalectomy. The highest mortality rate was observed in the EAS group. These findings were consistent with previous studies in Asia, with more proportions ACTH-independent CS.

scholarly journals Fluconazole treatment in severe ectopic Cushing syndrome

2019 ◽  
Vol 2019 ◽  
Author(s):  
Teresa M Canteros ◽  
Valeria De Miguel ◽  
Patricia Fainstein-Day
Keyword(s):  
Liver Metastases ◽  
Alternative Treatment ◽  
Cushing Syndrome ◽  
Serum Cortisol ◽  
Bilateral Adrenalectomy ◽  
Ectopic Acth Syndrome ◽  
List Type ◽  
Ectopic Acth ◽  
Free Cortisol ◽  
Cortisol Levels

Summary Severe Cushing syndrome (SCS) is considered an emergency that requires immediate treatment to lower serum cortisol levels. Fluconazole may be considered an alternative treatment in Cushing syndrome when ketoconazole is not tolerated or unavailable. We report a 39-year-old woman with a history of partial pancreaticoduodenectomy due to a periampullary neuroendocrine tumor with locoregional extension. Three years after surgery, she developed liver metastases and was started on 120 mg of lanreotide/month, despite which, liver metastases progressed in the following 6 months. The patient showed extreme fatigue, muscle weakness, delirium, moon face, hirsutism and severe proximal weakness. Laboratory tests showed anemia, hyperglycemia and severe hypokalemia. 24-h urinary free cortisol: 2152 nmol/day (reference range (RR): <276), morning serum cortisol 4883.4 nmol/L (RR: 138–690), ACTH 127.3 pmol/L (RR: 2.2–10). She was diagnosed with ectopic ACTH syndrome (EAS). On admission, she presented with acute upper gastrointestinal tract bleeding and hemodynamic instability. Intravenous fluconazole 400 mg/day was started. After 48 h, her mental state improved and morning cortisol decreased by 25%. The dose was titrated to 600 mg/day which resulted in a 55% decrease in cortisol levels in 1 week, but then had to be decreased to 400 mg/day because transaminase levels increased over 3 times the upper normal level. After 18 days of treatment, hemodynamic stability, lower cortisol levels and better overall clinical status enabled successful bilateral adrenalectomy. This case report shows that intravenous fluconazole effectively decreased cortisol levels in SCS due to EAS. Learning points: Severe Cushing syndrome can be effectively treated with fluconazole to achieve a significant improvement of hypercortisolism prior to bilateral adrenalectomy. Intravenous fluconazole is an alternative treatment when ketoconazole is not tolerated and etomidate is not available. Fluconazole is well tolerated with mild side effects. Hepatotoxicity is usually mild and resolves after drug discontinuation.

scholarly journals Relacorilant With Pembrolizumab: A Phase 1b, Open-Label Study of a Selective Glucocorticoid Receptor Modulator Combined With a Checkpoint Inhibitor for Patients With Adrenocortical Carcinoma With Excess Glucocorticoid Production

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A94-A94
Author(s):  
Mouhammed Amir Habra ◽  
Gary D Hammer ◽  
Electron Kebebew ◽  
Francis P Worden ◽  
Nitya Raj ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Adrenocortical Carcinoma ◽  
Cushing Syndrome ◽  
Checkpoint Inhibitors ◽  
Combined Treatment ◽  
Survival Duration ◽  
Progression Rate ◽  
Late Night ◽  
Free Cortisol ◽  
Phase 1B

Abstract Adrenocortical carcinoma (ACC) is an aggressive cancer with poor response to chemotherapeutic and immunotherapeutic agents. About half of ACCs produce glucocorticoids (GC), and the presence of GC excess (hypercortisolism) is correlated with decreased survival in patients with ACC. The broad immunosuppressive effects of GC may contribute to the limited efficacy of immune checkpoint inhibitors, such as pembrolizumab, in these patients. Antagonism of the glucocorticoid receptor (GR) has the potential to increase immune-related transcripts, thus promoting tumor immune response in ACC with GC excess. To test this hypothesis, we introduce a phase 1b study evaluating the combined treatment of relacorilant (CORT125134, Corcept Therapeutics) with pembrolizumab in patients with advanced ACC and hypercortisolism (NCT04373265). Relacorilant is a selective (no activity at other steroid receptors), oral GR modulator in development for Cushing syndrome and, in combination with chemotherapy, for various solid tumors. In healthy subjects, prednisone causes rapid reductions in eosinophils, lymphocytes, and osteocalcin and rapid increases in neutrophils. Relacorilant ameliorates these effects. In a phase 2 study in patients with endogenous Cushing syndrome treated with relacorilant, improvements in the signs and symptoms of GC excess were seen. The primary objective of this study is to determine the safety and efficacy of the recommended regimen of relacorilant with pembrolizumab in patients with advanced ACC and hypercortisolism. Pembrolizumab infusion will occur on day 1 of each 21-day cycle, and relacorilant will be administered once daily, starting 3 days before the first pembrolizumab infusion. Relacorilant doses will be escalated in 100-mg increments (100 mg up to 400 mg, as tolerated). Patients will receive treatment until they experience disease progression or unacceptable toxicity. Approximately 20 adults with confirmed advanced, unresectable and/or metastatic ACC will be enrolled. GC excess must be documented by either ACTH &lt;10 pg/mL and serum cortisol &gt;1.8 µg/dL after dexamethasone suppression testing (DST), or the presence of two of the following criteria: elevated urinary free cortisol; high late-night salivary cortisol; and DST cortisol &gt;1.8 µg/dL. Assessments will include safety, tolerability, and efficacy. Secondary objectives include a determination of the non-progression rate at 27 weeks, evaluation of progression-free survival, overall survival, duration of response, and an assessment of the effect of the combination on clinical manifestations of hypercortisolism. This will be the first clinical study to evaluate whether GR antagonism promotes tumor response in patients with ACC and GC excess treated with checkpoint inhibitors.

scholarly journals OR03-05 Novel Lipidome Signature in Active Cushing Syndrome Revealed by UHPLC-MS Metabolomics

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Arturo Vega-Beyhart ◽  
Marta Iruarrizaga ◽  
Guillermo Garcia-Eguren ◽  
Adriana Pane ◽  
Oriol Giró ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cushing Syndrome ◽  
Urinary Free Cortisol ◽  
Glutamate Metabolism ◽  
Serum Samples ◽  
Topological Network ◽  
Free Cortisol ◽  
Canonical Pathways ◽  
Omega 6 ◽  
Lipid Metabolites

Abstract Background: Alterations in circulating amino acids, polyamines and acylcarnitines have been reported in patients with endogenous chronic hypercortisolism. However, lipid metabolites profiling and its interplay with the serum metabolome and degree of hypercortisolism in patients with active Cushing syndrome (CS) has not been previously assessed. Objective: To identify new metabolomic biomarkers associated with active CS. Methodology: Multiple UHPLC-MS platforms were used to analyze the metabolome of serum samples obtained from 25 patients with active endogenous CS and 25 controls subjects matched by propensity score (sex, BMI, T2D, DLP, HBP). Results: Metabolome of CS patients was deeply disrupted with 122 (27%) of the assessed metabolites significantly altered (p adj. &lt;0.05) out of which 5 bile acids resulted with the highest perturbation (&gt; 2-fold decrease). From the altered metabolites, 3 amino acids (AA), 2 acylcarnitines (ACs), 2 ceramides (CER) and 5 glycerophospholipids showed direction of effect independently associated with 24-h urinary free cortisol (MS) levels. A highly discriminant (AUC 96%) metabolome signature (n=59) characterized by lower levels of AA, ACs, polyunsaturated fatty acids (PUFA) and monoglycerophosphocolines (MGPC) together with increased levels of triacyclglycerols (TG), CER, diacylglycerophosphocholines (DGPC) and cholesteryl esters was identified and cross-validated (R2Y= 0.92, Q2Y= 0.68) using PLS-DA VIP scores &gt;1.5. PUFA omega-6, and alanine, aspartate and glutamate metabolism resulted the most impacted canonical pathways (q-stat 19.7, 10.8 (p&lt;0.001). Finally, topological network analysis detected 158 pairwise differential correlations (p &lt;0.005, 10,000-fold permutation) between 141 metabolites due to CS where the acylPC (P-18:1/0:0) resulted a key metabolite in the network (betweenness =0.117 & closeness centrality =0.467). Conclusion: Active Cushing syndrome leads to a global proatherogenic shift in the circulating ceramides, glycerophospholipids and sphingolipids metabolites which are independently associated to the levels of urinary free cortisol being potential biomarkers of patients’ cardiovascular risk.

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