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

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:
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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:
  • Elevated levels of late-night salivary cortisol
  • 24 hours UFC threefold greater than the upper reference range.
  • Early morning (8 am) sample having serum cortisol 1.8 mcg/dL or higher after overnight DST
 
 
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:
  • CRH or desmopressin stimulation test
  • High dose (8mg) overnight DST
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pituitary irradiation carried out in patients with:
  • Failure to resect tumor completely by surgery.
  • The location of the tumor cannot be determined.
  • The patient wishes to conceive in the future.
 
 
 
Resection of the primary tumor
 
 
Medical therapy:
  • Inhibit the synthesis of adrenocortical enzymes: ketoconazole, metyrapone, and etomidate.
  • Inhibits the secretion of ACTH from the ectopic site: Octreotide
  • Inhibits hyperglycemia secondary to hypercortisolism: Mifepristone
  •  
    Unilateral adrenalectomy
     
     
    Bilateral adrenalectomy
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
    Bilateral adrenalectomy is performed in patients with severe refractory hypercortisolism despite surgical and radiation therapy.
     
     
     
     
     
     
     
     
     
     
     
     
     

    Do's

    Don'ts

    References

    1. 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.
    2. 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.
    3. 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.
    4. 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.
    5. 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. 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.
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    8. 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.
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    12. 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.
    13. 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. 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.
    15. 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.
    16. 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.
    17. 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.
    18. 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.
    19. 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.
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