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Basic Information ⬇

AUTHOR: Fred F. Ferri, MD

Definition

  • Cushing syndrome is the occurrence of clinical abnormalities associated with glucocorticoid excess as a result of exaggerated adrenal cortisol production or long-term glucocorticoid therapy.
  • Cushing disease is Cushing syndrome caused by pituitary adrenocorticotropic hormone (ACTH) excess.
ICD-10CM CODES
E24Cushing syndrome
E24.2Drug-induced Cushing syndrome
E24.3Ectopic ACTH syndrome
E24.8Other Cushing syndrome
E24.9Cushing syndrome, unspecified
E24.9Pituitary-dependent Cushing disease
Physical Findings & Clinical Presentation

  • Hypertension.
  • Central obesity with rounding of the facies (moon facies); thin extremities. Fig. 1 illustrates the distribution of adipose tissue in Cushing syndrome.
  • Hirsutism, menstrual irregularities, hypogonadism.
  • Skin fragility, ecchymoses, red-purple abdominal striae (Fig. E2), acne, poor wound. healing, hair loss, facial plethora, hyperpigmentation (with ACTH excess). The frequency of individual findings in Cushing syndrome is summarized in Table 1.
  • Psychosis, emotional lability, paranoia.
  • Muscle wasting with proximal myopathy.

TABLE 1 Cushing Syndrome-Frequency of Individual Findings

Physical Finding∗Frequency (%)†
Vital Signs
Hypertension64-88
Body Habitus
Moon facies67-92
Central obesity44-97
Buffalo hump34-75
Skin Findings
Thin skin27
Plethora28-94
Hirsutism, women48-81
Ecchymoses23-75
Red or purple striae46-68
Acne21-52
Extremity Findings
Proximal muscle weakness39-68
Edema15-66
Other
Significant depression12-40

∗Diagnostic standard: For Cushing syndrome, elevated daily cortisol or corticosteroid metabolites, or both, with loss of circadian rhythm and with abnormal dexamethasone suppression tests.

† Results are overall mean frequency or, if statistically heterogeneous, the range of values.

From McGee S: Evidence-based physical diagnosis, ed 4, Philadelphia, 2018, Elsevier.

Figure 1 Distribution of adipose tissue in Cushing syndrome.

Rounding of the cheeks and prominent bitemporal fat produce the characteristic moon facies. Fat also may accumulate bilaterally above the clavicles (supraclavicular collar), in front of the sternum (episternal area, or dewlap), and over the back of the neck (dorsal cervical fat pad, or buffalo hump). In these drawings, the dotted line depicts normal contours of patients without Cushing syndrome.

From McGee S: Evidence-based physical diagnosis, ed 4, Philadelphia, 2018, Elsevier.

Note that the previously described characteristics are not commonly present in Cushing syndrome caused by ectopic ACTH production. Many of these tumors secrete a biologically inactive ACTH that does not activate adrenal steroid synthesis. These patients may have only weight loss and weakness.

Figure E2 Clinical features of Cushing syndrome.

A, Centripetal and some generalized obesity and dorsal kyphosis in a 30-yr-old woman with Cushing disease. B, Same patient as in A showing moon facies, plethora, hirsutism, and enlarged supraclavicular fat pads. C, Facial rounding, hirsutism, and acne in a 14-yr-old girl with Cushing disease. D, Central and generalized obesity and moon facies in a 14-yr-old boy with Cushing disease. E and F, Typical centripetal obesity with livid abdominal striae seen in a 41-yr-old woman (E) and a 40-yr-old man (F) with Cushing syndrome. G, Striae in a 24-yr-old patient with congenital adrenal hyperplasia treated with excessive doses of dexamethasone as replacement therapy. H, Typical bruising and thin skin of a patient with Cushing syndrome. In this case, the bruising occurred without obvious injury.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Etiology

  • Iatrogenic from long-term glucocorticoid therapy (common)
  • Pituitary ACTH excess (Cushing disease; 60%)
  • Adrenal neoplasms (30%)
  • Ectopic ACTH production (neoplasms of lung, pancreas, kidney, thyroid, thymus; 10%)
  • Table 2 summarizes the incidence of tumors associated with the ectopic ACTH syndrome
  • A classification of causes of Cushing syndrome is described in Table 3

TABLE 3 Classification of Causes of Cushing Syndrome

ACTH-Dependent Causes
Cushing disease (pituitary-dependent)
Ectopic ACTH syndrome
Ectopic CRH syndrome
Macronodular adrenal hyperplasia
Iatrogenic (treatment with 1-24 ACTH)
ACTH-Independent Causes
Adrenal adenoma and carcinoma
Primary pigmented nodular adrenal hyperplasia and Carney syndrome
McCune-Albright syndrome
Aberrant receptor expression (gastric inhibitory polypeptide, interleukin-1β)
Iatrogenic (e.g., pharmacologic doses of prednisolone, dexamethasone)
Pseudo-Cushing Syndromes
Alcoholism
Depression
Obesity

ACTH, Adrenocorticotropic hormone; CRH, corticotropin-releasing hormone.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

TABLE 2 Tumors Associated With the Ectopic Adrenocorticotropic Hormone Syndrome

Tumor TypeApproximate Incidence (%)
Small cell lung carcinoma50
Non-small cell lung carcinoma5
Pancreatic tumors (including carcinoids)10
Thymic tumors (including carcinoids)5
Lung carcinoids10
Other carcinoids2
Medullary carcinoma of thyroid5
Pheochromocytoma and related tumors3
Rare carcinomas of prostate, breast, ovary, gallbladder, colon10

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Alcoholic pseudo-Cushing syndrome (endogenous cortisol overproduction)
  • Obesity associated with diabetes mellitus
  • Adrenogenital syndrome
Workup

  • Initial tests include the overnight low-dose dexamethasone suppression test (LDST), 24-h urine free cortisol (UFC), and late-night (LN) salivary cortisol. The LN and UFC tend to be more convenient.
  • LN salivary cortisol: A single midnight serum cortisol level (normal diurnal variation leads to a nadir around midnight) >7.5 mcg/dl has been reported as 96% sensitive and 100% specific for the diagnosis of Cushing syndrome. This test assesses the normal diurnal rhythm of cortisol (lost in Cushing syndrome) and is not useful in patients who have inconsistent sleep patterns or do shift work. It can also be affected by tobacco use and use of topical corticosteroids.
  • In patients with a clinical diagnosis of Cushing syndrome, the classic initial screening test is the overnight dexamethasone suppression test:
    1. Dexamethasone 1 mg PO given at 11 P.M.
    2. Plasma cortisol level measured 9 h later (8 A.M.).
    3. Plasma cortisol level <5 mcg/100 ml excludes Cushing syndrome.
  • Serial measurements (two or three consecutive measurements) of 24-h urinary free cortisol and creatinine (to ensure adequacy of collection) are undertaken if overnight dexamethasone test is suggestive of Cushing syndrome. Persistent elevated cortisol excretion (>300 mcg/24 h) indicates Cushing syndrome.
  • The low-dose (2 mg) dexamethasone suppression test is useful to exclude pseudo-Cushing syndrome if the previous results are equivocal. Corticotropic-releasing hormone (CRH) stimulation after low-dose dexamethasone administration (dexamethasone-CRH test) is also used to distinguish patients with suspected Cushing syndrome from those who have mildly elevated UFC level and equivocal findings.
  • The high-dose (8 mg) dexamethasone test and measurement of ACTH by radioimmunoassay are useful to determine the etiology of Cushing syndrome.
    1. ACTH undetectable or decreased and lack of suppression indicate adrenal cause of Cushing syndrome.
    2. ACTH normal or increased and lack of suppression indicate ectopic ACTH production.
    3. ACTH normal or increased and partial suppression suggest pituitary excess (Cushing disease).
  • Bilateral inferior petrosal sinus sampling (BIPSS) can be used to distinguish pituitary Cushing disease from the ectopic ACTH syndrome.
Laboratory Tests

  • Hypokalemia, hypochloremia, metabolic alkalosis, hyperglycemia, hypercholesterolemia.
  • Increased 24-h urinary free cortisol (>100 mcg/24 h).
  • Table 4 describes the differential diagnosis of hormonal values seen in Cushing syndrome.
  • Fig. 3 describes an algorithm for the evaluation of Cushing syndrome.
Figure 3 Algorithm for the Diagnosis, Localization, and Management of Endogenous Cushing Syndrome

A biochemical diagnosis can be established with an unequivocally elevated 24-h urine-free cortisol level (greater than a threefold elevation) or an elevated late evening salivary cortisol level. Most cases of Cushing syndrome are caused by Cushing disease (pituitary corticotroph microadenoma) in which the plasma ACTH level is elevated. An undetectable ACTH level establishes the diagnosis of ACTH-independent Cushing syndrome and prompts adrenal imaging. Bilateral adrenalectomy is considered for patients with Cushing disease not cured by transsphenoidal surgery. Abd, Abdomen; CT, computed tomography; MRI, magnetic resonance imaging.

From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.

TABLE 4 Differential Diagnosis of Hormonal Values Seen in Cushing Syndrome

CausePlasma ACTHPlasma Cortisol (PM)High-Dose or Overnight Dexamethasone Suppression
Pituitary-dependentN-slightly ↑↑Yes
Adrenal disease↓-undetectable↑No
Ectopic Cushing∗↑↑↑↑↑Usually no
Pseudo-CushingN-slightly ↑N-↑Usually yes

ACTH, Adrenocorticotropin; N, normal.

∗ACTH levels may overlap with values seen in pituitary-dependent disease.

From McPherson RA, Pincus MR (eds): Henry’s clinical diagnosis and management by laboratory methods, ed 23, St Louis, 2017, Elsevier.

Imaging Studies

  • CT scan or MRI of adrenal glands in suspected adrenal Cushing syndrome (Fig. E1).
  • MRI of pituitary gland with gadolinium is the preferred procedure for localizing a pituitary edema in suspected pituitary Cushing syndrome.
  • Additional imaging studies to localize neoplasms of the lung, pancreas, kidney, thyroid, or thymus in patients with ectopic ACTH production.

Figure E4 Computed Tomography Scan of a Patient with Rapidly Progressing Cushing Syndrome Caused by an Adrenal Carcinoma

An irregular right adrenal mass is shown (A), and a large liver metastasis is evident (B).

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Treatment ⬆ ⬇

General Rx

The definitive treatment of Cushing syndrome is surgical removal of the tumor causing excessive production of cortisol:

  • Pituitary adenoma: Transsphenoidal microadenomectomy is the therapy of choice in adults. Pituitary irradiation is reserved for patients not cured by transsphenoidal surgery. In children, pituitary irradiation may be considered as initial therapy because 85% of children are cured by radiation. Stereotactic radiotherapy (photon knife or gamma knife) is effective and exposes the surrounding neuronal tissues to less irradiation than does conventional radiotherapy. Total bilateral adrenalectomy is reserved for patients not cured by transsphenoidal surgery or pituitary irradiation.
  • Adrenal neoplasm:
    1. Surgical resection of the affected adrenal
    2. Glucocorticoid replacement for approximately 9 to 12 mo after the surgery to allow time for the contralateral adrenal gland to recover from its prolonged suppression
    3. In nonsurgical candidates, suppression of adrenal steroid production can be accomplished with the antifungal drug ketoconazole, which inhibits several steps in cortisol synthesis. It is inexpensive but has many drug interactions. Osilodrostat a cortisol synthesis inhibitor, metyrapone, and mitotane also can be used in adults with Cushing disease when surgical resection of the pituitary adenoma is not an option or has not been curative. Cost and formulary are limiting factors. Mifepristone, an antiprogestin, can also be used for control of hyperglycemia secondary to hypercortisolism in adults with endogenous Cushing syndrome. It should be avoided in women who are or who could become pregnant
  • Bilateral micronodular or macronodular adrenal hyperplasia: Bilateral total adrenalectomy
  • Ectopic ACTH:
    1. Surgical resection of the ACTH-secreting neoplasm
    2. Control of cortisol excess with metyrapone, aminoglutethimide, mifepristone, or ketoconazole
    3. Control of the mineralocorticoid effects of cortisol and 11-deoxycorticosteroid with spironolactone
    4. Bilateral adrenalectomy: A rational approach to patients with indolent, unresectable tumors
Disposition

Prognosis is favorable in patients with surgically amenable disease.

Pearls & Considerations ⬆ ⬇

Comments

Screening for multiple endocrine neoplasia type I should be considered in patients with Cushing disease.

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  1. Loriaux D.L. : Diagnosis and differential diagnosis of Cushing’s syndromeN Engl J Med. ;376:1451-1459, 2017.