• Clinical science

Cushing syndrome (Hypercortisolism)

Abstract

Cushing's syndrome, or hypercortisolism, is an endocrine disorder that is most often caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly, Cushing's syndrome can result from endogenous overproduction of cortisol. Primary hypercortisolism is the result of autonomous overproduction of cortisol by the adrenal gland (e.g., adrenal adenoma, adrenal carcinoma). Secondary hypercortisolism, on the other hand, is the result of increased production of adrenocorticotropic hormone (ACTH), either by pituitary microadenomas (Cushing's disease) or by ectopic, paraneoplastic foci (e.g., small cell lung cancer). Typical clinical features include central obesity, thin, easily bruisable skin, abdominal striae, secondary hypertension, hyperglycemia, and proximal muscle weakness. Since serum cortisol levels vary diurnally, 24-hour urine cortisol measurement, midnight saliva cortisol levels, and/or dexamethasone suppression test are used to diagnose hypercortisolism. Serum ACTH levels and CRH stimulation test are used to identify the cause of hypercortisolism, imaging is then employed to localize the tumor. Treatment of endogenous hypercortisolism primarily involves surgical removal of the source of excessive cortisol (e.g., adrenalectomy) or ACTH (e.g., transsphenoidal hypophysectomy). If surgery is contraindicated, drugs that suppress cortisol synthesis (e.g., metyrapone) may be used instead.

Etiology

Exogenous (iatrogenic) Cushing's syndrome

  • Hypercortisolism as a result of prolonged glucocorticoid therapy
  • Most common cause of hypercortisolism

Endogenous Cushing's syndrome

Types Primary hypercortisolism (ACTH-independent Cushing's syndrome) Secondary hypercortisolism
Pituitary ACTH production (Cushing's disease) Ectopic ACTH production
Relative frequency
  • 5–10%
  • ∼ 75%
  • ∼ 15%
Sex
  • < (1:4)
  • < (1:4)
  • =
Causes

While the term “Cushing's syndrome” can be applied to any cause of hypercortisolism, “Cushing's disease” refers specifically to secondary hypercortisolism that results from excessive production of ACTH by pituitary adenomas!

Secondary hypercortisolism is also called ACTH-dependent Cushing's syndrome because hypercortisolism is the result of increased ACTH levels.

References:[1][2][3][4]

Clinical features

Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression.

Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing's syndrome.

References:[2][3][4]

Diagnostics

General laboratory findings

Screening for hypercortisolism

A patient with any one of the above findings should be evaluated to identify a possible cause of hypercortisolism. The diagnosis of hypercortisolism is confirmed if at least two of the above-mentioned findings are present

Identifying the cause of hypercortisolism

Hormone analysis

Once glucocorticoid therapy has been ruled out, the following tests are used to identify the cause of hypercortisolism:

  1. Serum ACTH levels
    • Low (< 5 pg/mL): suspect primary hypercortisolism (adrenal adenoma, carcinoma)
    • Normal or elevated(> 20 pg/mL): suspect secondary hypercortisolism
  2. If secondary hypercortisolism is suspected: one of the following tests may be used to differentiate between Cushing's disease and ectopic ACTH production

Only Cushing's disease remains (partially) susceptible to suppression (high-dose dexamethasone suppression test) or stimulation (CRH test) of cortisol secretion!

ACTH levels Dexamethasone suppression test CRH test
Low-dose dexamethasone suppression test High-dose dexamethasone suppression test
Normal cortisol cortisol ACTH, cortisol
Primary hypercortisolism cortisol cortisol ACTH, cortisol
Cushing's disease cortisol cortisol ACTH, cortisol
Ectopic ACTH secretion cortisol cortisol ACTH, cortisol

Imaging to localize the tumor

In the diagnosis of hypercortisolism, hormone analysis always precedes imaging because microadenomas of the pituitary do not always appear upon imaging. Furthermore, imaging can reveal inactive adrenal tumors (incidentalomas) and pituitary tumors in many healthy individuals!

References:[5][6][7][8][2]

Treatment

Exogenous Cushing's syndrome

Endogenous Cushing's syndrome

  • Operable disease: : surgical therapy is the treatment of choice
  • Inoperable disease

Following surgical therapy, patients who develop adrenal insufficiency require lifelong glucocorticoid replacement therapy!

Patients who develop severe hypokalemia due to mineralocorticoid effect of cortisol may be treated with spirolonolactone (aldosterone antagonist)!

References:[2]

last updated 11/16/2018
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