Cushing's Syndrome

Question 1

How common is it?

Answer 1

• Prevalence = 10 to 15 people per million, with a higher incidence in people with diabetes, obesity, hypertension or osteoporosis.
• In obese patients with type 2 diabetes, especially those with poor blood glucose control and hypertension, the reported prevalence of Cushing’s syndrome is between 2% and 5%.

Question 2

What causes it?

Answer 2

• Cushing’s syndrome is the clinical state produced by chronic glucocorticoid excess and loss of the normal feedback mechanisms of the hypothalamo-pituitary-adrenal axis and loss of circadian rhythm of cortisol secretion.
• Chief cause = oral steroids.
• Endogenous causes rare – 80% due to ↑ACTH; of these a pituitary adenoma (Cushing’s disease) is the commonest cause.

1. ACTH-dependent causes (↑ACTH)
   - Cushing’s disease – Bilateral adrenal hyperplasia from an ACTH-secreting pituitary adenoma. Peak age 30-50yrs. Low dose dexamethasone test leads to no change in plasma cortisol.
   - Ectopic ACTH production – Especially small cell lung cancer and carcinoid tumours. Specific features: pigmentation (due to ↑↑ACTH), hypokalaemic metabolic alkalosis (↑↑cortisol leads to mineralocorticoid activity), weight loss, hyperglycaemia. Dexamethasone even in high doses fails to suppress cortisol production.
2. ACTH-independent causes (↓ACTH due to -ve feedback)
   - Adrenal adenoma/cancer – because the tumour is autonomous, dexamethasone in any dose won’t suppress cortisol.
   - Adrenal nodular hyperplasia – no dexamethasone suppression.
   - Iatrogenic – pharmacological doses of steroids (common)
   - Rare – Carney complex, McCune-Albright syndrome.

Question 3

Risk factors?

Answer 3

Long term steroid therapy, female gender. Predisposition to cancers?

Question 4

How does it present?

Answer 4

Symptoms
- Weight gain, mood change (depression, lethargy, irritability, psychosis), proximal weakness, gonadal dysfunction (irregular menses, hirsutism, erectile dysfunction), acne, recurrent Achilles tendon rupture, occasionally virilisation if female.

Signs
- Central obesity, plethoric moon face, buffalo neck hump, supraclavicular fat distribution, skin and muscle atrophy, bruises, purple abdominal striae, osteoporosis, ↑BP, ↑glucose, infection-prone, poor healing. Signs of the cause i.e. abdo mass.

Question 5

What other conditions may present similarly?

Answer 5

Obesity…

Question 6

Investigations?

Answer 6

• Random plasma cortisols may mislead, as illness, time of day and stress influences results. Also don’t rely on imaging to find the cause, small tumours hard to find.
• Dexamethasone suppression test (overnight and 48h).

Question 7

Treatments?

Answer 7

Depends on the cause.

1. Iatrogenic – Stop medications if possible.
2. Cushing’s disease – selective removal of pituitary adenoma (trans-sphenoidally). Bilateral adrenalectomy if source unlocatable.
3. Adrenal adeonoma or carcinoma – Adrenalectomy: ‘cures’ adenomas but rarely cures cancer. Radiotherapy and drenolytic drugs (mitotane) follow if carcinoma.
4. Ectopic ACTH – Surgery if tumour located and hasn’t spread. Metyrapone, ketoconazole and fluconazole ↓cortisol secretion pre-op or if await effects of radiation.