Cushing's syndrome resident survival guide
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mydah Sajid, MD[2]
Overview
Cushing’s syndrome is characterized by elevated circulating levels of glucocorticoid (i.e. cortisol) in blood. It presents with a wide range of clinical spectrum ranging from mild to severe. The clinical symptoms are characterized by central obesity, facial edema, buffalo hump, proximal myopathy, hypertension, hyperglycemia, mood changes, skin thinning, abdominal striae, and easy bruising. The physician should aim to diagnose the cause of Cushing’s syndrome and treat it accordingly. This section provides a short and straight to the point overview of the Cushing's syndrome.
Causes
Life Threatening Causes
Life-threatening causes include conditions that may result in death or permanent disability within 24 hours if left untreated.
- Does not include any known cause.
Common Causes
- Iatrogenic or factitious Cushing's syndrome due to administration of exogenous glucocorticoids.
- Cushing's disease (due to excess secretion of Adrenocorticotropic hormone from anterior pituitary).
- Paraneoplastic: due to ectopic secretion of ACTH (includes, small cell lung cancer, benign carcinoid tumors, Ewing's sarcoma). [1][2][3]
- Ectopic secretion of Corticotropin-releasing hormone (CRH).
- Adenoma and carcinoma in the adrenal cortex
- Primary pigmented nodular adrenocortical disease (PPNAD)[4]
- Bilateral macronodular adrenal hyperplasia (BMAH)[5]
Diagnosis
Shown below is an algorithm summarizing the diagnosis of Cushing's syndrome according to the Endocrine Society clinical guidelines.[6][7][8][9][10][11][12][13]
Symptoms suggestive of Cushing’s syndrome:
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| Take a detailed history of the patient including medication history. Rule out the use of any exogenous topical, oral, parenteral, or inhaled glucocorticoid and synthetic progesterone. | |||||||||||||||||||||||||||||||||||||
Perform any two of the following three laboratory investigations:
| |||||||||||||||||||||||||||||||||||||
Two of the following abnormal results:
| Any one abnormal result | ||||||||||||||||||||||||||||||||||||
| High suspicion for Cushing's syndrome | Low suspicion for Cushing's syndrome | ||||||||||||||||||||||||||||||||||||
| Measure late night plasma ACTH levels | Refer to endocrinologist | ||||||||||||||||||||||||||||||||||||
| Low value plasma ACTH <5 pg/mL | Indeterminate values of plasma ACTH between 5 to 20 pg/mL | High value plasma ACTH >20 pg/mL | |||||||||||||||||||||||||||||||||||
| CRH or desmopressin stimulation test | |||||||||||||||||||||||||||||||||||||
| No ACTH response | + ACTH response | ||||||||||||||||||||||||||||||||||||
| ACTH independent Cushing's syndrome | ACTH dependent Cushing's syndrome | ||||||||||||||||||||||||||||||||||||
| CT scan/ MRI of adrenal glands to look for adrenal tumors or hyperplasia. | Perform both tests:
| ||||||||||||||||||||||||||||||||||||
| Adequate suppresion of early morning serum cortisol (with levels less than 5 mcg/dL) and stimulation with CRH | Negative or equivocal response | ||||||||||||||||||||||||||||||||||||
| MRI of the pituitary | |||||||||||||||||||||||||||||||||||||
| Tumor >6mm | Tumor <6mm or no mass lesion | ||||||||||||||||||||||||||||||||||||
| Cushing's disease | Perform Inferior petrosal sinus sampling. | ||||||||||||||||||||||||||||||||||||
| Central step-up | No Central step-up | ||||||||||||||||||||||||||||||||||||
| Ectopic ACTH production | |||||||||||||||||||||||||||||||||||||
Treatment
Shown below is an algorithm summarizing the treatment of Cushing's syndrome according the the Endocrine Society clinical practice guidelines.[14][15][16]
| The treatment depends upon the underlying etiology | |||||||||||||||||||||||||||||||||||||||||||||||
| Cushing's disease | Paraneoplastic Cushing's syndrome | ACTH-independent Cushing's syndrome | |||||||||||||||||||||||||||||||||||||||||||||
| Transsphenoidal surgery: Treatment of choice in patients with pituitary adenoma with distinct margins. | Resectable tumor | Nonresectable tumor | Adrenal adenoma | Bilateral adrenal hyperplasia | |||||||||||||||||||||||||||||||||||||||||||
| Resection of the primary tumor | Medical therapy:
| Unilateral adrenalectomy | Bilateral adrenalectomy | ||||||||||||||||||||||||||||||||||||||||||||
| Bilateral adrenalectomy is performed in patients with severe refractory hypercortisolism despite surgical and radiation therapy. | |||||||||||||||||||||||||||||||||||||||||||||||
Do's
- In ACTH-independent Cushing’s syndrome, glucocorticoid therapy should be given to patients post-operatively due to suppression of the hypothalamic-pituitary axis. Patients with medication-induced Cushing’s syndrome should taper the dose of glucocorticoid instead of sudden withdrawal of the medications.
- Thromboprophylaxis should be initiated preoperatively in patients with Cushing’s syndrome[14]. There is a hypercoagulable state in patients with Cushing’s syndrome due to impaired fibrinolysis and activation of the coagulation cascade. These patients have an increased risk of developing deep venous thrombosis compared to the normal patient population[17].
- Rebound thymic hyperplasia can occur in patients whose hypercortisolism is controlled. On the chest imaging, it is seen as a mass in the anterior mediastinum and can be misinterpreted as tumor recurrence, or metastasis[18].
Don'ts
- The 24 hours urinary free cortisol measurement should not be used for diagnosis in subclinical hypercortisolism (mild hypercortisolism in adrenal incidentaloma) as it can yield false-negative results[6]. False-positive results are present in patients with physiological hypercortisolism (patients with a polycystic ovarian syndrome or major depressive disorder)[19][20]. High fluid intake can result in an increased fraction of excretion of free cortisol yielding false-positive results.[21]
- MRI is not a cost-effective diagnostic test. CT scan of the abdomen and adrenal glands is preferred as an imaging test to localize adrenal adenoma or carcinoma compared to MRI. On the Ct scan adrenal carcinoma has a bigger size along with hemorrhage, necrosis and calcification in the lesion[22].
References
- ↑ White A, Ray DW, Talbot A, Abraham P, Thody AJ, Bevan JS (2000). "Cushing's syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin". J Clin Endocrinol Metab. 85 (12): 4771–5. doi:10.1210/jcem.85.12.7047. PMID 11134141.
- ↑ More J, Young J, Reznik Y, Raverot G, Borson-Chazot F, Rohmer V; et al. (2011). "Ectopic ACTH syndrome in children and adolescents". J Clin Endocrinol Metab. 96 (5): 1213–22. doi:10.1210/jc.2010-2276. PMID 21346064.
- ↑ Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK (2005). "Cushing's syndrome due to ectopic corticotropin secretion: twenty years' experience at the National Institutes of Health". J Clin Endocrinol Metab. 90 (8): 4955–62. doi:10.1210/jc.2004-2527. PMID 15914534.
- ↑ Larsen JL, Cathey WJ, Odell WD (1986). "Primary adrenocortical nodular dysplasia, a distinct subtype of Cushing's syndrome. Case report and review of the literature". Am J Med. 80 (5): 976–84. doi:10.1016/0002-9343(86)90648-0. PMID 3010718.
- ↑ Lacroix A, Ndiaye N, Tremblay J, Hamet P (2001). "Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome". Endocr Rev. 22 (1): 75–110. doi:10.1210/edrv.22.1.0420. PMID 11159817.
- ↑ 6.0 6.1 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM; et al. (2008). "The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 93 (5): 1526–40. doi:10.1210/jc.2008-0125. PMC 2386281. PMID 18334580.
- ↑ Lacroix A, Feelders RA, Stratakis CA, Nieman LK (2015). "Cushing's syndrome". Lancet. 386 (9996): 913–27. doi:10.1016/S0140-6736(14)61375-1. PMID 26004339.
- ↑ Weber SL (1997). "Cushing'S syndrome attributable to topical use of lotrisone". Endocr Pract. 3 (3): 140–4. doi:10.4158/EP.3.3.140. PMID 15251475.
- ↑ Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP; et al. (2003). "Diagnosis and complications of Cushing's syndrome: a consensus statement". J Clin Endocrinol Metab. 88 (12): 5593–602. doi:10.1210/jc.2003-030871. PMID 14671138.
- ↑ LIDDLE GW (1960). "Tests of pituitary-adrenal suppressibility in the diagnosis of Cushing's syndrome". J Clin Endocrinol Metab. 20: 1539–60. doi:10.1210/jcem-20-12-1539. PMID 13761950.
- ↑ Crapo L (1979). "Cushing's syndrome: a review of diagnostic tests". Metabolism. 28 (9): 955–77. doi:10.1016/0026-0495(79)90097-0. PMID 225638.
- ↑ Doppman JL, Oldfield E, Krudy AG, Chrousos GP, Schulte HM, Schaaf M; et al. (1984). "Petrosal sinus sampling for Cushing syndrome: anatomical and technical considerations. Work in progress". Radiology. 150 (1): 99–103. doi:10.1148/radiology.150.1.6316418. PMID 6316418.
- ↑ Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH (1994). "Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population". Ann Intern Med. 120 (10): 817–20. doi:10.7326/0003-4819-120-10-199405150-00001. PMID 8154641.
- ↑ 14.0 14.1 Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO; et al. (2015). "Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline". J Clin Endocrinol Metab. 100 (8): 2807–31. doi:10.1210/jc.2015-1818. PMC 4525003. PMID 26222757.
- ↑ Chow JT, Thompson GB, Grant CS, Farley DR, Richards ML, Young WF (2008). "Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing's syndrome: a review of the Mayo Clinic experience". Clin Endocrinol (Oxf). 68 (4): 513–9. doi:10.1111/j.1365-2265.2007.03082.x. PMID 17970770.
- ↑ Aniszewski JP, Young WF, Thompson GB, Grant CS, van Heerden JA (2001). "Cushing syndrome due to ectopic adrenocorticotropic hormone secretion". World J Surg. 25 (7): 934–40. doi:10.1007/s00268-001-0032-5. PMID 11572035.
- ↑ Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E; et al. (2009). "Hypercoagulable state in Cushing's syndrome: a systematic review". J Clin Endocrinol Metab. 94 (8): 2743–50. doi:10.1210/jc.2009-0290. PMID 19454584.
- ↑ Tabarin A, Catargi B, Chanson P, Hieronimus S, Corcuff JB, Laurent F; et al. (1995). "Pseudo-tumours of the thymus after correction of hypercortisolism in patients with ectopic ACTH syndrome: a report of five cases". Clin Endocrinol (Oxf). 42 (2): 207–13. doi:10.1111/j.1365-2265.1995.tb01865.x. PMID 7704966.
- ↑ Cizza G, Nieman LK, Doppman JL, Passaro MD, Czerwiec FS, Chrousos GP; et al. (1996). "Factitious Cushing syndrome". J Clin Endocrinol Metab. 81 (10): 3573–7. doi:10.1210/jcem.81.10.8855803. PMID 8855803.
- ↑ Carroll BJ, Curtis GC, Davies BM, Mendels J, Sugerman AA (1976). "Urinary free cortisol excretion in depression". Psychol Med. 6 (1): 43–50. doi:10.1017/s0033291700007480. PMID 935296.
- ↑ Mericq MV, Cutler GB (1998). "High fluid intake increases urine free cortisol excretion in normal subjects". J Clin Endocrinol Metab. 83 (2): 682–4. doi:10.1210/jcem.83.2.4555. PMID 9467592.
- ↑ Blake MA, Kalra MK, Sweeney AT, Lucey BC, Maher MM, Sahani DV; et al. (2006). "Distinguishing benign from malignant adrenal masses: multi-detector row CT protocol with 10-minute delay". Radiology. 238 (2): 578–85. doi:10.1148/radiol.2382041514. PMID 16371582.