66. Glucocorticoid hyperfunctional states

Cushing syndrome or hypercortisolism is the condition where the level of glucocorticoids in the body is elevated. We can classify them as primary or secondary, depending on whether they’re caused by increased levels of ACTH or not. We can also classify them as exogenous or endogenous.

Etiology:

Endogenous Cushing syndrome:

  • Primary hypercortisolism
    • Cortisol-producing adrenal adenoma
    • Cortisol-producing adrenal carcinoma
  • Secondary hypercortisolism
    • ACTH-producing pituitary adenoma (Cushing disease)
    • ACTH-producing paraneoplastic syndrome
      • Small cell lung cancer
      • Renal cell carcinoma

Exogenous Cushing syndrome is caused by prolonged glucocorticoid therapy and is much more common than any endogenous form. This is further discussed in the next topic.

If the hypercortisolism is caused by an ACTH-producing pituitary adenoma (and only then) the condition is called Cushing disease rather than Cushing syndrome.

Pathomechanism:

Cortisol stimulates gluconeogenesis, causing hyperglycaemia and predisposing to diabetes mellitus development. It also stimulates protein catabolism. This causes the skin to become thinner as collagen is broken down, which predisposes to development of stretch marks. These stretch marks are often purple as the dermal vessels are visible through the thin skin.

Protein catabolism also causes skeletal muscles to be broken down, which causes characteristically thin limbs and muscle weakness. The broken-down proteins provide substrates for gluconeogenesis.

Cortisol enhances leukocyte production but inhibits their function. Leukocytes are also recruited from the marginal pool, causing leukocytosis. The release of pro-inflammatory molecules is inhibited, by inhibiting the transcription factor NF-κB.

Hypercortisolism classically changes the body’s fat by moving fat from the periphery to the central area. The mechanism behind this is not well understood, especially as cortisol actually stimulates lipolysis. Compensatory hyperinsulinism may be involved in this mechanism. Central adipose tissue expresses more glucocorticoid receptors than peripheral adipose tissue, which may play a role. Increased appetite may also play a role.

Hypercortisolism causes hypertension by multiple mechanisms:

  1. The spill-over mechanism allows cortisol to induce aldosterone-like salt and water retention
  2. Cortisol increases the vessels’ sensitivity to catecholamines, essentially increasing vasoconstriction
  3. A compensatory hyperinsulinism is seen. Insulin stimulates salt and water retention and increases the vessels’ sensitivity to catecholamines
  4. In Cushing disease, the level of androgens is also high. Androgens stimulate EPO, which increases the viscosity of the blood.
  5. Cortisol increases the production of angiotensinogen in the liver, effectively increasing angiotensin II and aldosterone levels

Cortisol suppresses the release of gonadotropins like FSH and LH, causing decreased libido and irregular menses.

In secondary hypercortisolism, where ACTH is also elevated, hyperpigmentation of the skin is common. ACTH and melanocyte stimulating hormone (MSH) are produced together from the same precursor (POMC). MSH stimulates melanocytes, even in areas that are not exposed to sunlight.

Cortisol decreases calcium absorption and reabsorption from the gut and kidney. It also stimulates osteoclasts and inhibits bone formation. This causes osteoporosis.

Cortisol stimulates acid production in the stomach, causing the formation of gastric ulcers. These ulcers are not accompanied by inflammation and are characteristically painless.

Clinical features:

Hypercortisolism causes many symptoms:

  • Due to the effects of cortisol
    • Thin skin with stretch marks
    • Secondary hypertension
    • Purple striae on the abdomen
    • Depression
    • Osteoporosis
    • Leukocytosis
    • Muscle atrophy and weakness
    • Insulin resistance, potentially “other” type of diabetes mellitus
    • Central obesity
    • Moon face
    • Buffalo hump
    • Thin extremities
    • Increased susceptibility to infections
    • Painless gastric ulcers
    • Hypokalaemia
    • Metabolic alkalosis
  • Due to inhibition of FSH, LH release
    • Decreased libido
    • Irregular menses
    • Hirsutism – excessive facial hair growth in females

The triad of central obesity, moon face and buffalo hump are known as the Cushingoid appearance.

The hypertension in Cushing syndrome is more severe than in hyperaldosteronism.

Diagnosis:

Because cortisol levels change physiologically during the day, a 24-hour urine cortisol measurement is more accurate than a serum cortisol measurement.

Dexamethasone is a pharmacological glucocorticoid. If we give dexamethasone to a healthy person the cortisol level should decrease, as dexamethasone inhibits ACTH secretion by negative feedback, which again decreases cortisol production.

A person with Cushing syndrome who receives (a low dose of) dexamethasone should not see their cortisol level decreased. This is called the low-dose dexamethasone suppression test.

A person with Cushing disease who receives a higher dose of dexamethasone should see their cortisol level decreased, as the high dose of dexamethasone is enough to decrease cortisol production from the pituitary adenoma. This is the high-dose dexamethasone suppression test.

These tests are not part of the pathophysiology curriculum.

Treatment:

Surgical removal of the offending neoplasm is curative. In those cases that can’t be removed, drugs can be given that suppress cortisol synthesis. Aldosterone receptor blockers like spironolactone can be necessary if there is severe hypokalaemia.


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65. Secondary hyperaldosteronism

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67. Pathophysiological aspects of glucocorticoid therapy

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