Diagnostic Considerations

Diagnosis of Cushing syndrome can sometimes be very challenging, especially in cases of pseudo-Cushing, subclinical, mild or cyclic Cushing syndrome.

A pseudo-Cushing is defined as having some of the clinical features and biochemical evidence of Cushing syndrome. However, resolution of the primary condition results in disappearance of the cushingoid features and biochemical abnormalities.

In patients who chronically abuse alcohol, clinical and biochemical findings suggestive of Cushing syndrome are often encountered. Discontinuation of alcohol causes disappearance of these abnormalities, and, therefore, this syndrome is often specifically referred to as alcohol-induced pseudo-Cushing syndrome. Patients with depression often have perturbation of the HPA axis, with abnormal cortisol hypersecretion. These patients rarely develop clinical Cushing syndrome. Because excess glucocorticoids can lead to emotional liability and depression, distinguishing between depression and mild Cushing syndrome is often a diagnostic challenge.

See Pseudo-Cushing Syndrome.

Differential Diagnoses

Alcoholism
Anorexia Nervosa
Bulimia Nervosa
Concurrent ritonavir and inhaled fluticasone in patients with HIV - Interferes with dexamethasone suppression testing (false positive)
Depression
Obesity
Pseudo-Cushing Syndrome
Psychiatric Illness

Workup

Nieman LK. Recent Updates on the Diagnosis and Management of Cushing's Syndrome. Endocrinol Metab (Seoul). 2018 Jun. 33 (2):139-46. [QxMD MEDLINE Link]. [Full Text].
Chaudhry HS, Bhimji SS. Cushing Syndrome. 2018 Jan. [QxMD MEDLINE Link]. [Full Text].
Marieb NJ, Spangler S, Kashgarian M, Heimann A, Schwartz ML, Schwartz PE. Cushing's syndrome secondary to ectopic cortisol production by an ovarian carcinoma. J Clin Endocrinol Metab. 1983 Oct. 57 (4):737-40. [QxMD MEDLINE Link].
Carey RM, Varma SK, Drake CR Jr, Thorner MO, Kovacs K, Rivier J, et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing's syndrome. A clinical, morphologic, and biochemical study. N Engl J Med. 1984 Jul 5. 311 (1):13-20. [QxMD MEDLINE Link].
Tatsi C, Boden R, Sinaii N, et al. Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome. Pediatr Res. 2018 Feb. 83 (2):431-7. [QxMD MEDLINE Link]. [Full Text].
Brown RJ, Kelly MH, Collins MT. Cushing syndrome in the McCune-Albright syndrome. J Clin Endocrinol Metab. 2010 Apr. 95 (4):1508-15. [QxMD MEDLINE Link].
Assie G, Bahurel H, Coste J, Silvera S, Kujas M, Dugue MA, et al. Corticotroph tumor progression after adrenalectomy in Cushing's Disease: A reappraisal of Nelson's Syndrome. J Clin Endocrinol Metab. 2007 Jan. 92 (1):172-9. [QxMD MEDLINE Link].
Lindholm J, Juul S, Jorgensen JO, Astrup J, Bjerre P, Feldt-Rasmussen U, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. J Clin Endocrinol Metab. 2001 Jan. 86 (1):117-23. [QxMD MEDLINE Link].
Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jorgensen JO. Mortality in Cushing's syndrome: a systematic review and meta-analysis. Eur J Intern Med. 2012 Apr. 23 (3):278-82. [QxMD MEDLINE Link].
Limumpornpetch P, Morgan AW, Tiganescu A, et al. The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality. J Clin Endocrinol Metab. 2022 Jul 14. 107 (8):2377-88. [QxMD MEDLINE Link]. [Full Text].
Hara T, Akutsu H, Yamamoto T, Ishikawa E, Matsuda M, Matsumura A. Cushing's disease presenting with gastrointestinal perforation: a case report. Endocrinol Diabetes Metab Case Rep. 2013. 2013:130064. [QxMD MEDLINE Link].
Graham BS, Tucker WS Jr. Opportunistic infections in endogenous Cushing's syndrome. Ann Intern Med. 1984 Sep. 101 (3):334-8. [QxMD MEDLINE Link].
Davi' MV, Cosaro E, Piacentini S, et al. Prognostic factors in ectopic Cushing's syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017 Apr. 176 (4):451-9. [QxMD MEDLINE Link].
Pereira AM, Delgado V, Romijn JA, Smit JW, Bax JJ, Feelders RA. Cardiac dysfunction is reversed upon successful treatment of Cushing's syndrome. Eur J Endocrinol. 2010 Feb. 162 (2):331-40. [QxMD MEDLINE Link].
Tyrrell JB, Findling JW, Aron DC, Fitzgerald PA, Forsham PH. An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome. Ann Intern Med. 1986 Feb. 104 (2):180-6. [QxMD MEDLINE Link].
Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008 May. 93 (5):1526-40. [QxMD MEDLINE Link].
Meikle AW. Dexamethasone suppression tests: usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clin Endocrinol (Oxf). 1982 Apr. 16 (4):401-8. [QxMD MEDLINE Link].
Carroll T, Raff H, Findling JW. Late-night salivary cortisol for the diagnosis of Cushing syndrome: a meta-analysis. Endocr Pract. 2009 May-Jun. 15 (4):335-42. [QxMD MEDLINE Link].
Elamin MB, Murad MH, Mullan R, Erickson D, Harris K, Nadeem S, et al. Accuracy of diagnostic tests for Cushing's syndrome: a systematic review and metaanalyses. J Clin Endocrinol Metab. 2008 May. 93 (5):1553-62. [QxMD MEDLINE Link].
Elias PC, Martinez EZ, Barone BF, Mermejo LM, Castro M, Moreira AC. Late-night salivary cortisol has a better performance than urinary free cortisol in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab. 2014 Jun. 99 (6):2045-51. [QxMD MEDLINE Link].
Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA. 1993 May 5. 269 (17):2232-8. [QxMD MEDLINE Link].
Yanovski JA, Cutler GB Jr, Chrousos GP, Nieman LK. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA. 1993 May 5. 269 (17):2232-8. [QxMD MEDLINE Link].
Martin NM, Dhillo WS, Banerjee A, Abdulali A, Jayasena CN, Donaldson M, et al. Comparison of the dexamethasone-suppressed corticotropin-releasing hormone test and low-dose dexamethasone suppression test in the diagnosis of Cushing's syndrome. J Clin Endocrinol Metab. 2006 Jul. 91 (7):2582-6. [QxMD MEDLINE Link].
Wester VL, Reincke M, Koper JW, et al. Scalp hair cortisol for diagnosis of Cushing's syndrome. Eur J Endocrinol. 2017 Jun. 176 (6):695-703. [QxMD MEDLINE Link].
Elhomsy G, Staros E. Dexamethasone Suppression Test. Medscape Drugs & Diseases. Available at http://emedicine.medscape.com/article/2114191-overview. Accessed: 5/30/15.
Aron DC, Raff H, Findling JW. Effectiveness versus efficacy: the limited value in clinical practice of high dose dexamethasone suppression testing in the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab. 1997 Jun. 82 (6):1780-5. [QxMD MEDLINE Link].
Nieman LK, Oldfield EH, Wesley R, Chrousos GP, Loriaux DL, Cutler GB Jr. A simplified morning ovine corticotropin-releasing hormone stimulation test for the differential diagnosis of adrenocorticotropin-dependent Cushing's syndrome. J Clin Endocrinol Metab. 1993 Nov. 77 (5):1308-12. [QxMD MEDLINE Link].
Reimondo G, Paccotti P, Minetto M, Termine A, Stura G, Bergui M, et al. The corticotrophin-releasing hormone test is the most reliable noninvasive method to differentiate pituitary from ectopic ACTH secretion in Cushing's syndrome. Clin Endocrinol (Oxf). 2003 Jun. 58 (6):718-24. [QxMD MEDLINE Link].
Oldfield EH, Doppman JL, Nieman LK, Chrousos GP, Miller DL, Katz DA, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991 Sep 26. 325 (13):897-905. [QxMD MEDLINE Link].
Mulligan GB, Eray E, Faiman C, Gupta M, Pineyro MM, Makdissi A, et al. Reduction of false-negative results in inferior petrosal sinus sampling with simultaneous prolactin and corticotropin measurement. Endocr Pract. 2011 Jan-Feb. 17 (1):33-40. [QxMD MEDLINE Link].
Tucker ME. New guidelines address Cushing’s syndrome treatment. Medscape Medical News. Available at http://www.medscape.com/viewarticle/849084. Aug 5,2015; Accessed: Sept 3, 2015.
Aymes S. Endocrine Society releases guidelines on treatment of Cushing’s Syndrome. Endocrinology Advisor. Aug 26, 2015.
Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, 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. [QxMD MEDLINE Link].
Biller BMK, Newell-Price J, Fleseriu M, et al. OR16-2 Osilodrostat Treatment in Cushing's Disease (CD): Results from a Phase III, Multicenter, Double-Blind, Randomized Withdrawal Study (LINC 3). J Endocr Soc. 2019 Apr-May. 3(Suppl_1):[Full Text].
Johanssen S, Allolio B. Mifepristone (RU 486) in Cushing's syndrome. Eur J Endocrinol. 2007 Nov. 157 (5):561-9. [QxMD MEDLINE Link].
Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012 Jun. 97 (6):2039-49. [QxMD MEDLINE Link].
Lila AR, Gopal RA, Acharya SV, George J, Sarathi V, Bandgar T, et al. Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. Endocr Pract. 2010 Nov-Dec. 16 (6):968-76. [QxMD MEDLINE Link].
Safety and Efficacy of LC1699 for the Treatment of Patients With Cushing's Disease. ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/show/NCT02180217. Accessed: 7/13/15.
Bertagna X, Pivonello R, Fleseriu M, Zhang Y, Robinson P, Taylor A, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing's disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014 Apr. 99 (4):1375-83. [QxMD MEDLINE Link].
Tatsi C, Keil M, Lyssikatos C, Belyavskaya E, Stratakis CA, Lodish MB. Incidence of Autoimmune and Related Disorders After Resolution of Endogenous Cushing Syndrome in Children. Horm Metab Res. 2018 Apr. 50 (4):290-5. [QxMD MEDLINE Link].
Dekkers OM, Horvath-Puho E, Jorgensen JO, Cannegieter SC, Ehrenstein V, Vandenbroucke JP, et al. Multisystem morbidity and mortality in Cushing's syndrome: a cohort study. J Clin Endocrinol Metab. 2013 Jun. 98 (6):2277-84. [QxMD MEDLINE Link].
Boscaro M, Bertherat J, Findling J, Fleseriu M, Atkinson AB, Petersenn S, et al. Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study. Pituitary. 2014 Aug. 17 (4):320-6. [QxMD MEDLINE Link].

Media Gallery

Physical findings in Cushing syndrome.
Diagnosis of Cushing syndrome.
Etiology of Cushing syndrome.
High power H and E of a pituitary adenoma showing a monotonous proliferation of bland cells. Not all pituitary adenomas result in Cushing syndrome, only those that produce ACTH.
Intermediate power H and E of an adrenal adenoma showing a monotonous proliferation of bland cells. Not all adrenal adenomas or carcinomas result in Cushing's syndrome; only those that produce ACTH.

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Author

Ha Cam Thuy Nguyen, MD Fellow, Department of Endocrinology, University of Pittsburgh Medical Center

Ha Cam Thuy Nguyen, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Medical Association, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Catherine Anastasopoulou, MD, PhD, FACE Associate Professor of Medicine, The Steven, Daniel and Douglas Altman Chair of Endocrinology, Sidney Kimmel Medical College of Thomas Jefferson University; Einstein Endocrine Associates, Einstein Medical Center

Catherine Anastasopoulou, MD, PhD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, American Society for Bone and Mineral Research, Endocrine Society, Philadelphia Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Gail K Adler, MD, PhD, Associate Professor of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School.

Disclosure: Nothing to disclose.

Susanna L Dipp, MD Fellow, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School

Disclosure: Nothing to disclose

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Disclosure: Nothing to disclose