Cushings

• Cushing’s syndrome is caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids (cortisol)
• Cushing’s disease is caused by a pituitary adenoma that secrets excessive adrenocorticotropic hormone (ACTH). This leads to excess cortisol release from the adrenal cortex
• Cushing’s syndrome is either caused by ACTH dependent or ACTH independent factors
• ACTH dependent causes of Cushing’s syndrome:

  • Cushing’s disease
  • paraneoplastic syndrome - most commonly a small cell lung cancer that secrets ACTH
• ACTH independent causes of Cushing’s syndrome:

  • adrenal adenoma secreting cortisol
  • exogenous steroids
• Symptoms of cushing‘s syndrome:

  • weakness
  • weight gain
  • low mood
  • decreased libido
  • Polyuria
  • polydipsia
  • increased frequency of infections
• Clinical signs of Cushing’s syndrome:

  • truncal obesity
  • buffalo hump
  • moon face
  • abdominal striae
  • proximal muscle wasting
  • hypertension
  • oedema
  • Headaches, visual field defects and galactorrhoea in Cushing's disease
  • facial hair in women
• Investigations for Cushing’s syndrome:

  • FBC - raised WCC
  • U&Es - raised sodium and low potassium
  • dexamethasone suppression test
  • 24 hour urinary free cortisol
  • MRI brain for pituitary adenoma
  • CT for adrenal tumours or small cell lung cancer
• In high concentrations, cortisol exhibits mineralocorticoid effects - increased sodium and water retention

  increases potassium excretion
• Low dose dexamethasone suppression test:

  • 1mg at 11pm and measure cortisol at 8am
  • cortisol not suppressed in Cushing’s syndrome
  • shows the negative feedback mechanism is not working
• High dose dexamethasone test is used to distinguish between ACTH independent and dependent causes of cushing‘s syndrome:

  • 8mg given
  • cortisol is suppressed if pituitary adenoma (Cushing’s disease)
  • cortisol not suppressed if adrenal adenoma or ectopic ACTH
• Management of Cushing’s disease is to surgically remove the underlying cause

  if this is not possible then both adrenal glands can be removed and the patient is placed on life long steroid replacement therapy
• Complications of Cushing’s :

  • hypertension
  • diabetes
  • obesity
  • osteoarthritis
• Functions of cortisol:

  • Synthesis of glucose (gluconeogenesis)
  • Break down of proteins - can result in muscle wasting
  • Chronic elevation promotes lipogenesis (synthesis of fatty acids)
  • Downregulation of the immune response
  • Reduction in bone formation - can result in osteoporosis
  • In high concentrations exhibits mineralocorticoid effects - sodium and water retention, increased potassium excretion
• The most common cause of Cushing's syndrome is the use of exogenous glucocorticoids
• Once diagnosis of Cushing's syndrome is confirmed via 24-hour urinary free cortisol and low-dose dexamethasone suppression test, the underlying cause can be identified via:

  • Plasma ACTH
  • High dose dexamethasone suppression test - distinguish between pituitary and ectopic (adrenal) ACTH production
• Medical management:

  • Ketoconazole, metyrapone and mitotane
  • Inhibit glucocorticoid synthesis and secretion in the adrenal gland
  • Temporarily reduce cortisol levels to help prepare the patient for surgery
  • May be long term for patients unsuitable for surgery