What are the guideline sources, guidelines and references for Cushing_s syndrome ?
Guideline sources The following summarized guidelines for the evaluation and management of Cushing's syndrome (CS) are prepared by our editorial team based on guidelines from the American Association of Endocrine Surgeons (AAES 2022), the European Society of Endocrinology (ESE 2021), and the Endocrine Society (ES 2020; 2015; 2008). 1 2 3 4 5 6 6 6 6 Definition CS is a rare disorder resulting from chronic exposure to excess glucocorticoids characterized by obesity, moon face, facial plethora, and hypertension. 6 Epidemiology CS is caused by ACTH production from a pituitary adenoma (Cushing's disease; 75-80%), ACTH production from nonpituitary tumors (ectopic ACTH syndrome; 15-20%), and corticotropin-releasing hormone (CRH)-producing tumors (<1%). 6 https://web.pathway.md/diseases/recTgTOpnhjZgalO3 1/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Disease course Glucocorticoid excess results in CS, which causes clinical manifestations of obesity, moon face, supraclavicular/dorsocervical fat pads, hirsutism, alopecia, facial plethora, violaceous striae, acne, easy bruising, menstrual irregularity, decreased libido, emotional lability, depression, psychosis, cognitive dysfunction, muscle weakness, muscular atrophy, osteopenia, fractures, decreased linear growth in children, hypertension, glucose intolerance, hyperlipidemia, hepatic steatosis, and nephrolithiasis. 6 Prognosis and risk of recurrence CS is associated with a standard mortality ratio of 3.7 (95% CI 2.3-5.3). 6 Calculator Diagnostic criteria for Cushing's Guidelines 1. Screening and diagnosis Indications for testing: test for CS in patients with an adrenal adenoma. B Show 3 more 2. Diagnostic investigations Corticosteroid exposure history: obtain a thorough drug history to exclude iatrogenic CS (due to excessive exogenous corticosteroid exposure) prior to undertaking further diagnostic investigations. A Initial laboratory testing: Obtain one of the following tests to evaluate for CS, based on its suitability for a given patient: urinary free cortisol late-night salivary cortisol 1-mg overnight dexamethasone suppression test longer low-dose dexamethasone suppression test. B Subsequent laboratory testing: confirm abnormal results on initial laboratory testing using a different test drawn from the recommended initial tests (urine free cortisol, late-night salivary cortisol, 1-mg overnight dexamethasone suppression test, or longer low-dose dexamethasone suppression test). B https://web.pathway.md/diseases/recTgTOpnhjZgalO3 2/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Show 2 more Adrenal gland imaging: consider evaluating patients with an adrenal mass that has a radiodensity of 10 Hounsfield on noncontrast CT scan for malignancy, using further imaging. C Dexamethasone-CRH test: Consider obtaining the dexamethasone-CRH test only in specific clinical situations. B The dexamethasone-CRH test can be useful in patients with equivocal results for urinary free cortisol. Midnight serum cortisol test: Consider obtaining the midnight serum cortisol test only in specific situations. B The midnight serum cortisol test may be useful in the following situations: patients with a high clinical index of suspicion of CS, but normal urinary free cortisol and dexamethasone suppression testing patients with a low clinical index of suspicion of CS, but abnormal dexamethasone suppression testing and mildly elevated urinary free cortisol patients who fail to suppress on dexamethasone testing due to anticonvulsant medication. Desmopressin test: consider avoiding the use of the desmopressin test, except in research studies, until additional data validate its utility. D Evaluation of cardiovascular risks: obtain cardiovascular risk assessment and initiate treatment in adult patients with cured CS as in the general population. B Show 2 more 3. Medical management General principles: perform surgical resection of any primary lesion identified as the cause of cortisol excess (pituitary, ectopic or adrenal) as the first-line and definitive treatment for CS, unless surgery is not possible or is unlikely to significantly reduce corticosteroid excess. A Show 2 more Indications for treatment: treat patients with overt CS by normalizing cortisol levels, or blocking the action of cortisol at its receptors, in order to eliminate the signs and symptoms of CS. B Show 2 more Corticosteroid antagonists: consider initiating a corticosteroid antagonist (mifepristone) in patients with diabetes or glucose intolerance who are not surgical candidates or who have persistent disease after transsphenoidal selective adenomectomy. C Pituitary-directed therapy: consider pituitary-directed medical treatments (cabergoline, pasireotide) in patients with Cushing's disease who are not surgical candidates or who have persistent disease after transsphenoidal surgery. C Steroidogenesis inhibitors: Initiate steroidogenesis inhibitors (such as ketoconazole, metyrapone, mitotane, etomidate) in the following clinical scenarios: https://web.pathway.md/diseases/recTgTOpnhjZgalO3 3/8 6/23/23, 3:37 AM Cushing's syndrome Pathway as second-line treatment after transsphenoidal surgery in patients with Cushing's disease, either with or without RT/radiosurgery as primary treatment of ectopic ACTH secretion in patients with occult or metastatic ectopic ACTH secretion as adjunctive treatment to reduce cortisol levels in adrenocortical carcinoma. B Management of ectopic ACTH syndrome: consider targeted therapies (octreotide, cabergoline, vandetanib, sorafenib) to treat ectopic ACTH syndrome. C Statin therapy: consider initiating statin therapy as adjunct to lifestyle modification, to reduce cardiovascular risk, irrespective of the cardiovascular risk score, in adult patients with persistent endogenous CS. C 4. Therapeutic procedures Radiotherapy: Consider radiation therapy / radiosurgery in patients with Cushing's disease who have failed transsphenoidal surgery or display evidence of disease recurrence. C Confirm that medical therapy is effective in normalizing cortisol prior to initiating radiation therapy for Cushing's disease, given that a response to medical therapy is required for disease control while awaiting the effect of radiation. B 5. Perioperative care Perioperative thromboprophylaxis: consider administering perioperative prophylaxis for VTE in patients with CS undergoing surgery. C Perioperative sodium monitoring: measure serum sodium frequently during the first 5-14 days after transsphenoidal surgery. B 6. Surgical interventions Adrenal gland resection, adrenal gland disease: As per AAES 2022 guidelines: Consider performing unilateral laparoscopic adrenalectomy in patients with bilateral macronodular hyperplasia with CS as an attempt to achieve biochemical remission of hypercortisolism without causing permanent adrenal insufficiency. C Administer empirical postoperative corticosteroid replacement therapy in all patients with overt CS after unilateral adrenalectomy. Obtain morning cortisol or corticotropin stimulation testing on the first postoperative day to determine the need for corticosteroid replacement therapy in patients with mild autonomous cortisol secretion. B As per ES 2015 guidelines, perform surgical resection as the treatment of choice for CS in patients with unilateral cortisol-secreting adrenal disease. B https://web.pathway.md/diseases/recTgTOpnhjZgalO3 4/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Show 2 more Adrenal gland resection, occult ACTH secreting-tumors: As per AAES 2022 guidelines, perform laparoscopic adrenalectomy for anticipated significant improvements in cardiometabolic comorbidities in patients with mild autonomous cortisol secretion secondary to a unilateral adenoma. B Show 2 more As per ES 2015 guidelines, consider performing bilateral adrenalectomy for occult or metastatic ectopic ACTH secretion, or as a life-preserving emergency treatment in patients with very severe ACTH-dependent disease who cannot be promptly controlled by medical therapy. C Transsphenoidal selective adenomectomy: perform transsphenoidal selective adenomectomy as the treatment of choice for Cushing's disease in patients who are fit for surgery. A Ectopic ACTH-secreting tumor resection: perform surgical resection (with node dissection as appropriate) in patients with ectopic ACTH-secreting tumors. A 7. Specific circumstances Pregnant patients, evaluation: As per ESE 2021 guidelines: Consider obtaining testing for a new diagnosis of Cushing's disease during pregnancy only in case of high clinical suspicion. C Obtain neuro-ophthalmologic evaluation in pregnant patients with pituitary adenomas impinging visual pathways or in case of suspected tumor progression or pituitary apoplexy. Obtain MRI without contrast in case of symptoms of tumor progression or apoplexy. B As per ES 2008 guidelines: Assess urine free cortisol as the initial diagnostic test in pregnant patients with suspected CS. B Do not obtain dexamethasone testing in the initial evaluation of pregnant patients with suspected CS. D Pregnant patients (management): manage pregnant patients with active or medically treated Cushing's disease by a multidisciplinary team expert in high-risk pregnancies. B Show 3 more Pregnant patients (monitoring): monitor pregnant patients with a known pituitary adenoma, particularly in large sizes (> 1 cm) and with Cushing's disease, by an endocrinologist and an advanced nurse practitioner where relevant. Decide on the frequency based on the underlying condition and individualized needs. B Pregnant patients (delivery and breastfeeding): consider providing standard obstetrical care with close maternal and fetal surveillance in pregnant patients with pituitary adenomas. C Show 2 more https://web.pathway.md/diseases/recTgTOpnhjZgalO3 5/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Patients with suspected cyclic Cushing's syndrome: consider using urinary free cortisol or midnight salivary cortisol, rather than performing a dexamethasone suppression test, as the diagnostic tests of choice in patients suspected of having cyclic CS. C Patients with renal failure: consider using the 1-mg overnight dexamethasone suppression test, rather than urinary free cortisol, as the diagnostic test of choice for in patients with severe renal failure who are suspected of having CS. C Patients with epilepsy: Use measurements of cortisol in blood, saliva, or urine as the diagnostic tests of choice in patients with suspected CS who are receiving antiepileptic drugs known to enhance dexamethasone clearance. B Avoid the use of dexamethasone testing in patients receiving antiepileptic drugs known to enhance dexamethasone clearance. D Patients with life-threatening complications: treat hypercortisolism urgently (within 24-48 hours) in patients with life-threatening complications of CS, including cardiovascular, infectious, or thromboembolic complications, as well as acute psychosis. B 8. Patient education General counseling: Counsel patients on the nature of their disease, available treatment options, and what to expect after remission. B Provide education about adrenal insufficiency to hypocortisolemic patients. A Preconception counseling: advise patients with active CS not to get pregnant. B Show 5 more 9. Preventative measures Immunizations: provide age-appropriate immunizations to patients with CS - particularly influenza, Herpes zoster, and pneumococcal immunizations - due to an increased risk of infection. B 10. Follow-up and surveillance Indications for specialist referral: refer patients with a high pretest probability of CS in whom biochemical testing is negative for further evaluation by an endocrinologist. B Serial clinical assessment: manage the specific comorbidities associated with CS (including cardiovascular risk factors, osteoporosis and psychiatric symptoms) on a lifelong basis, until resolution. B https://web.pathway.md/diseases/recTgTOpnhjZgalO3 6/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Serial laboratory assessment: obtain testing for recurrent disease throughout life, except in patients who underwent resection of an adrenal adenoma with a CT density of < 10 HUs. B Serial imaging assessment: Obtain a pituitary MRI within 1-3 months of surgery in patients who have undergone successful transsphenoidal selective adenomectomy. B Obtain follow-up tests for cardiac myxoma and other associated disease (testicular tumors, acromegaly, thyroid lesions) on a lifelong basis in patients with Carney complex. A Serial endocrine assessment: measure free T4 and prolactin within 1-2 weeks of surgery, to evaluate for overt hypopituitarism. B Show 2 more Management of recurrent disease: provide an individualized management approach in patients with recurrent disease, based upon whether the postoperative serum cortisol values categorize the patient's condition as hypocortisolism, hypercortisolism, or eucortisolism. B Likelihood Ratios Pertinent positives The following findings increase the probability of Cushing's syndrome in adults. 1 1 1 Finding LR+ Value Increased urine free cortisol 15.7 Increased saliva late-night salivary cortisol (> 7.5 g/dL) 13.1 Abnormal overnight dexamethasone suppression test (plasma cortisol < 1.8 g/dL at 48h after 2 mg dex) 11.5 Abnormal low-dose dexamethasone suppression test (cortisol < 1.4 mg/dL at 12 h after 1 mg dex) 3 Show 1 more Pertinent negatives The following findings decrease the probability of Cushing's syndrome in adults. 1 1 1 Finding LR- Value Normal low-dose dexamethasone suppression test (cortisol 1.4 mg/dL at 12 h after 1 mg dex) 0.01 urine free cortisol not increased 0.1 saliva late-night salivary cortisol not increased ( 7.5 g/dL) 0.1 Normal overnight dexamethasone suppression test (plasma cortisol 1.8 g/dL at 48h after 2 mg dex) 0.1 https://web.pathway.md/diseases/recTgTOpnhjZgalO3 7/8 6/23/23, 3:37 AM Cushing's syndrome Pathway Show 1 more References 1. Nieman LK, Biller BM, Findling JW et al. The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May;93 5 1526 40. Open 2. Nieman LK, Biller BM, Findling JW et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Aug;100 8 2807 31. Open 3. A Luger, L H A Broersen, N R Biermasz et al. ESE Clinical Practice Guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur J Endocrinol. 2021 Aug 23;185 3 G1 G33. Open 4. Linwah Yip, Quan-Yang Duh, Heather Wachtel et al. American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022 Aug 17. Open 5. Connie B Newman, Michael J Blaha, Jeffrey B Boord et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020 Dec 1;105 12):dgaa674. Open 6. Susmeeta T Sharma, Lynnette K Nieman, and Richard A Feelders. Cushing s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015; 7 281 293. Open https://web.pathway.md/diseases/recTgTOpnhjZgalO3 8/8