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Cushing's syndrome; hypercortisolism; hyperadrenocorticism; pluriglandular syndrome

Endogenous Cushing's syndrome due to increased cortisol by adrenal gland. Etiology: 1) ACTH-secreting pituitary adenoma (Cushing's disease) a) 80% of cases b) bilateral adrenal hyperplasia c) slow to progress (> 3 months), weight gain [11] 2) cortisol-producing adrenal tumors (ACTH-independent) a) adenomas generally secrete only cortisol b) carcinomas generally secrete multiples hormones i.e. cortisol, aldosterone &/or DHEA 3) ACTH- or CRH-producing non endocrine tumors a) bronchogenic carcinoma b) carcinoid c) pancreatic carcinoma d) bronchial adenoma e) faster progression than pituitary adenoma (< 3 months), weight loss [11] 4) iatrogenically induced via glucocorticoid administration (most common cause) - HIV1 protease inhibitors (ritonavir) in combination with fluticasone* 5) ACTH-independent macronodular adrenal hyperplasia * ritoavir inhibits CYP3A4 that metabolizes fluticasone (NEJM) [11], replace with beclomethasone (can be used to treat asthma in combination with HIV1 protease inhibitor) Pathology: - excess glucocorticoid - prednisone equivalents of > 10-20 mg/day can cause hypothalamic-pituitary-adrenal axis suppression afer > 3 weeks of use Clinical manifestations: 1) truncal (centripedal) obesity* 2) rounded, puffy face, facial plethora* 3) fat deposits in supraclavicular fossa & over posterior neck (buffalo hump)* 4) wide (> 1 cm) violaceous striae* 5) thick skin with excessive skin fragility 6) easy bruising, ecchymoses 7) hyperpigmentation (if secondary to increased ACTH) 8) psychiatric disturbances - depression is most common - memory impairment [4] 9) proximal muscle weakness 10) hirsutism (virilism)#, feminization 11) amenorrhea# 12) temporal balding# 13) hyperphagia 14) weight gain 15) hypertension * specific findings # due to androgen excess with adrenal adenoma or adrenal carcinoma [4] Laboratory: 1) serum chemistries a) serum cortisol: elevated with loss of diurnal variation b) serum glucose: hyperglycemia c) serum K+, serum bicarbonate - hypokalemic metabolic alkalosis (if secondary to increased ACTH) d) plasma ACTH > 10 pg/mL at a time when excess cortisol secretion is known to exist defines ACTH-dependent Cushing's syndrome 2) urine chemistries a) 24 hour urine cortisol (24 hour urinary free cortisol)* 1] > 250 ug/day makes the diagnosis 2] < 65 ug/day excludes Cushing's disease 3] not affected by sleep patterns, shift work or estrogen therapy [4] 4] 2 weeks after hospital discharge best test for hospitalized patient [11] b) increased urinary 17-ketosteroids c) increase urinary 17-hydroxysteroids 3) overnight dexamethasone suppression test* a) measure serum cortisol b) 1 mg of dexamethasone given PO at 2300 hours c) serum cortisol at 0800 AM the next day d) serum cortisol < 3-5 ug/dL at 0800 & > 5 ug/dL prior to dexamethasone is normal e) false positives with obesity, alcohol abuse, psychosocial stress [4] 4) low dose dexamethasone test if overnight test is abnormal a) dexamethasone 0.5 mg PO every 6 hours for 48 hours b) urine cortisol is measured for the final 24 hours c) urine cortisol > 20 ug/24 hours is diagnostic of Cushing's syndrome 5) 8 mg dexamethasone suppression test after serum ACTH a) serum cortisol suppresses with ACTH-secreting pituitary adenoma b) serum cortisol does not suppress with ectopic ACTH-secreting tumor 6) serial late night salivary cortisol* 7) inferior petrosal sinus sampling of ACTH following CRH stimulus (1 ug/kg) > 3 X simultaneously measured ACTH in serum if source of ACTH is pituitary 8) see ARUP consult [5] * initial diagnostic tests [4] * best time for evaluation of patient with suspected Cushing's syndrome in a hospitalized patient is 2 weeks after hospital discharge & recovery from stress of hospitalization Radiology: 1) pituitary MRI for ACTH-dependent hypercortisolism 2) CT of head for enlargement of sella turcica secondary to pituitary adenoma 3) abdominal CT for adrenal tumor a) adenomas are generally < 3 cm b) lesions > 6 cm are frequently malignant 4) CT of thorax for ectopic ACTH production 5) bone mineral density (DEXA scan) - patients at high risk for osteoporosis & fracture [4] Differential diagnosis: - polycystic ovary syndrome - also see etiology (above) Complications: - Cushing's disease during pregnancy is associated with risk of prematurity & stillbirth [4] - osteoporosis & osteonecrosis - diabetes mellitus may develop - nephrolithiasis - increased cardiovascular risk [6] - venous thromboembolism - deep vein thrombosis, pulmonary embolism [4] Management: 1) Cushing's disease a) trans-sphenoidal surgical adenectomy or subtotal hypophysectomy b) post-operatively persistent disease 1] radiation therapy 2] osilodrostat (Isturisa) inhibits cortisol synthesis 3] other treatments for inhibition of steroidogenesis - ketoconazole, metyrapone, mitotane, or etomidate 4] inhibit ACTH secretion with cabergoline 5] inhibit glucocorticoid receptor with mifepristone 6] bilateral adrenalectomy a] lifelong glucocorticoid & mineralocorticoid replacement b] monitor for Nelson's syndrome c) if coadministration of HIV1 protease inhibitor (ritonavir) & fluticasone, replace fluticasone with beclomethasone (see Etiology: above & fluticasone) 2) adrenal adenoma: a) unilateral adrenalectomy b) all hormonally-active adrenal lesions should be surgically removed [4] 3) bilateral adrenalectomy for rare syndrome of bilateral micronodular dysplasia 4) suppression of the pituitary-adrenal axis a) occurs after removal of the causative tumor b) generally lasts 3-12 months, but may last 1-2 years c) treat with stress-dose glucocorticoids (hydrocortisone) as for adrenal insufficiency d) begin when morning (0800) cortisol is < 5 mg/dL e) increase glucocorticoids with stressful events, trauma, surgery 5) bisphosphonate therapy for osteoporosis caused by hypercortisolism [4] Notes: - 'pluriglandular syndrome' a term introduced by Harvey Cushing [10]

Related

adrenal insufficiency adrenocorticotropic hormone; corticotropin; adrenocorticotropin (ACTH) corticotropin-releasing factor; corticoliberin; CRF; corticotropin-releasing hormone (CRH) cortisol; hydrocortisone (Cortef, Solu-Cortef, Alphaderm, Cetacort, Cortenema, Nutracort) Cushing, Harvey dexamethasone suppression test hyperglycemia ketoconazole (Nizoral, Xolegel) Nelson's syndrome

Specific

ACTH-independent macronodular adrenal hyperplasia (AIMAH); adrenal Cushing syndrome due to AIMAH ectopic ACTH syndrome

General

adrenal gland disease

Database Correlations

OMIM 219080

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Isselbacher et al (eds), McGraw-Hill Inc. NY, 1994, pg 1960-1
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 475-76
  3. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 225-27
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  5. ARUP: Adrenocorticotropic Hormone https://ltd.aruplab.com/Tests/Pub/0070010 - ARUP Consult: Adrenal Hyperfunction - Cushing Syndrome The Physician's Guide to Laboratory Test Selection &nInterpretation https://www.arupconsult.com/content/adrenal-hyperfunction - ARUP Consult: Adrenal Hyperfunction (Cushing Syndrome) Testing Algorithm https://arupconsult.com/algorithm/adrenal-hyperfunction-cushing-syndrome-testing-algorithm
  6. Fardet L et al Risk of cardiovascular events in people prescribed glucocorticoids with iatrogenic Cushing's syndrome: cohort study BMJ 2012;345:e4928 PMID: 22846415 http://www.bmj.com/content/345/bmj.e4928
  7. 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 PMID: 18334580
  8. Colao A, Petersenn S, Newell-Price J et al A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012 Mar 8;366(10):914-24. PMID: 22397653 Free Article
  9. Di Dalmazi G, Berr CM, Fassnacht M et al Adrenal function after adrenalectomy for subclinical hypercortisolism and Cushing's syndrome: a systematic review of the literature. J Clin Endocrinol Metab. 2014 Aug;99(8):2637-45. Review. PMID: 24878052
  10. Loriaux DL Diagnosis and Differential Diagnosis of Cushing's Syndrome. N Engl J Med 2017; 376:1451-1459. April 13, 2017 PMID: 28402781 https://www.nejm.org/doi/pdf/10.1056/NEJMra1505550
  11. NEJM Knowledge+ Endocrinology
  12. NINDS Cushing's Syndrome Information Page https://www.ninds.nih.gov/disorders/all-disorders/cushings-syndrome-information-page - NIDDK: Cushing's Syndrome http://www.niddk.nih.gov/health/endo/pubs/cushings/cushings.htm - National Institute of Child Health & Human Development Cushing's Syndrome http://www.nichd.nih.gov/publications/pubs/cushings.htm