Cushing syndrome

Cushing syndrome, or hypercortisolism, is an endocrine disorder that is most often caused iatrogenically by the exogenous administration of glucocorticoids. Less commonly, Cushing 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 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.

Exogenous (iatrogenic) Cushing syndrome

• Prolonged glucocorticoid therapy → hypercortisolism → decreased ACTH → bilateral adrenal atrophy
• Most common cause of hypercortisolism

Endogenous Cushing syndrome

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

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

• Skin ^[2]
  • Thin, easily bruisable skin with ecchymoses
  • Stretch marks (classically purple abdominal striae)
  • Hirsutism
  • Acne
  • If secondary hypercortisolism: often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity)
    • Caused by excessive ACTH production because melanocyte-stimulating hormone (MSH) is cleaved from the same precursor as ACTH called proopiomelanocortin (POMC)
    • Not a feature of primary hypercortisolism
  • Delayed wound healing
  • Flushing of the face
• Neuropsychological: : lethargy, depression, sleep disturbance, psychosis
• Musculoskeletal ^[2]
  • Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head
  • Muscle atrophy/weakness
• Endocrine and metabolic ^[3]
  • Insulin resistance; → hyperglycemia (see “Diabetes mellitus”) → mild polyuria in the case of severe hyperglycemia
  • Dyslipidemia
  • Weight gain characterized by central obesity, moon facies, and a buffalo hump
  • ♂: Decreased libido
  • ♀: Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea)
  • Growth delay (in children)
• Other features ^[1]
  • Secondary hypertension (∼ 90% of cases)
  • Increased susceptibility to infections (due to immunosuppression)
  • Peptic ulcer disease
  • Cataracts

“CUSHINGOID” is the acronym for side effects of corticosteroids: Cataracts, Ulcers, Striae/Skin thinning, Hypertension/Hirsutism/Hyperglycemia, Infections, Necrosis (of the femoral head), Glucose elevation, Osteoporosis/Obesity, Immunosuppression, Depression/Diabetes.

Patients with secondary hypercortisolism due to ectopic ACTH production may present with rapid onset of hypertension and hypokalemia without other typical features of Cushing syndrome.Consider a diagnosis of hypercortisolism in patients who present with proximal muscle weakness, central obesity, thinning skin, weight gain, sleep disturbance, and/or depression.

General laboratory findings ^[4]

• Hypernatremia, hypokalemia, metabolic alkalosis
• Hyperglycemia: due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue
• Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia)
• Leukocytosis (predominantly neutrophilic), eosinopenia ^[5][6]

Screening for hypercortisolism ^[7]

Any of the following can be used as a screening test for hypercortisolism :

• ↑ 24-hour urine cortisol (> 3 times the normal value i.e. > 300 μg/24 h) ^[2]
• ↑ Early morning serum cortisol levels (> 50 nmol/L) following a low-dose dexamethasone suppression test ^[8]
• ↑ Midnight salivary cortisol (> 4 nmol/L) ^[9]
• ↑ Midnight serum cortisol (> 7.5 μg/dL) ^[10]

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 screening 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 disease and ectopic ACTH production
   • High-dose dexamethasone suppression test
     • Adequate suppression of cortisol levels to less than 50% of baseline: Cushing disease
     • No suppression: ectopic ACTH production
   • CRH stimulation test
     • ACTH and cortisol levels increase further: Cushing disease
     • No increase in ACTH or cortisol levels: ectopic ACTH production

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

Imaging to localize the tumor

• CT and/or MRI of the abdomen: for adrenal tumors (if primary hypercortisolism is suspected)
  • The adrenal cortex contralateral to the tumor shows atrophy due to reduced ACTH stimulation.
  • In Cushing disease, CT and/or MRI of the abdomen shows bilateral hyperplasia of both the zona fasciculata and zona reticularis.
• CT and/or MRI of the skull: if Cushing disease is suspected
  • If no findings are present on neuroimaging, perform bilateral sampling of the inferior petrosal sinus in order to measure ACTH levels. ^[12]
  • See also “Diagnostics” in “Pituitary adenoma”.
• Other tests: if ectopic ACTH production is suspected
  • Chest x-ray and/or CT
  • Abdominal CT
  • Pelvic CT
  • Thyroid ultrasound

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.

Exogenous Cushing syndrome

• Consider lowering the dose of glucocorticoids
• Consider the use of alternatives to glucocorticoids (e.g., azathioprine)

Endogenous Cushing syndrome ^[2]

• Inoperable disease: (e.g., inoperable adrenal carcinomas, advanced small cell carcinoma of the lung): drugs to suppress cortisol synthesis; (e.g., metyrapone, mitotane, ketoconazole)
• Operable disease: Surgical therapy is the treatment of choice.
  • Adrenocortical tumor: laparoscopic or open adrenalectomy (a surgical procedure to remove one or both adrenal glands)
  • Pituitary adenoma: transsphenoidal resection of the pituitary adenoma (see “Therapy” in “Pituitary adenoma”)
  • ACTH-secreting ectopic tumor: resection of the ectopic foci (e.g., bronchial carcinoid)

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

Patients who develop severe hypokalemia due to the mineralocorticoid effect of cortisol may be treated with spironolactone (aldosterone antagonist).

Nelson syndrome (post adrenalectomy syndrome)

• Etiology: bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma
• Pathophysiology: bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and MSH → symptoms of pituitary adenoma and ↑ MSH
• Clinical features: headaches, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation
• Diagnostics
  • High levels of beta-MSH and ACTH
  • Pituitary adenoma on MRI confirms the diagnosis.
• Treatment: surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g, in the case of tumor residues after surgery)