Cushing's Syndrome and Cushing's Disease

Increased free circulating glucocorticoid

Aetiology

  • The most common cause of cortisol excess is the therapeutic administration of synthetic steroids (iatrogenic)
  • Cushing's disease is when the increased cortisol levels are caused by a functioning pituitary adenoma, all other causes are referred to as Cushing's syndrome

ACTH dependent

  • Pituitary adenoma (68%) → Cushing's disease
  • Ectopic ACTH (12%) - carcinoid/carcinoma e.g. lung, pancreas
  • Ectopic CRH (<1%)

ACTH independent

  • (Exogenous steroids)
  • Adrenal adenoma (10%) or carcinoma (8%)
  • Adrenal cortical nodular hyperplasia (1%)
  • False positive (pseudo) - severe depression, severe alcoholism

Pathophysiology

ACTH-independent

  • Autonomous over-production of cortisol by the adrenal gland due to neoplasia/nodular hyperplasia
  • Adrenal enlargement in ACTH-independent disease is usually nodular

ACTH-dependent

  • Adrenal enlargement in ACTH-dependent disease is usually diffuse
Pituitary adenomas (Cushing's disease)
  • Pituitary secretes increased ACTH → increased cortisol production by adrenal gland
Ectopic ACTH
  • Carcinoma e.g. small cell lung cancer secretes ACTH → increased cortisol production by adrenal gland
Ectopic CRH
  • Carcinoma e.g. medullary thyroid carcinoma secretes CRH → increased ACTH by pituitary → increased cortisol by adrenal gland

Consequences of increased cortisol levels

  • Protein loss
  • Altered carbohydrate and lipid metabolism
  • Excess mineralocorticoid
  • Excess androgen

Clinical presentation

General

  • Plethora (redness of the face)
  • Moon face
  • Hypertension
  • Central obesity
  • Depression/psychosis
  • Glycosuria/diabetes mellitus
  • Oedema
  • 'Buffalo hump'
  • Virilism

Skin

  • Bruising
  • Striae (purple or red)
  • Pigmentation (only occurs with ACTH-dependent causes)
  • Thin skin
  • Hirsutism
  • Acne

Musculoskeletal

  • Proximal myopathy, wasting
  • Osteoporosis, fractures

Reproductive

  • Oligo/amenorrhoea

Distinguishing between Cushing's and obesity

Cushings is characterised by:
  • Thin skin
  • Proximal myopathy
  • Frontal balding in women
  • Conjunctival oedema (chemosis)
  • Osteoporosis

Investigations

Establish cortisol excess

  • Overnight 1mg dexamethasone suppression test (oral) - first line
    • Normal: cortisol <50 nmol/l next morning
    • Abnormal: cortisol >130 nmol/l
  • 24hr urine free cortisol (24hr urine collection)
    • Total <250 is normal
    • Cortisol/creatinene ratio of<25 is normal
  • Diurnal cortisol variation (midnight/8am)
    • Loss of diurnal variation suspicious of Cushings
    • Serum/saliva/spot urine collection

Diagnostic

  • Low dose dexamethasone suppression test
    • 2 day 2mg/day dexamethasone
    • Normal: cortisol <50 nmol/l 6 hours after last dose
    • Cushing's: cortisol >130 nmol/l
  • Repeat to confirm

Differential diagnosis of the cause

  • If serum ACTH levels are low, this suggests non-ACTH-dependent disease and adrenal imaging should be planned (CT or MRI)
  • If serum ACTH levels are high, this suggests ACTH-dependent disease and pituitary MRI should be planned as well as biochemical tests to distinguish between pituitary and ectopic ACTH (high-dose dexamethasone suppression test or exogenous CRH)
notion image

Management

Pituitary

  • Hypophysectomy (transsphenoidal route)
  • External radiotherapy if recurs
  • Last line: bilateral adrenalectomy

Adrenal adenoma

  • Adrenalectomy

Ectopic

  • Remove source
  • OR bilateral adrenalectomy

Drug management

  • Metyrapone given when other treatments fail or while waiting for radiotherapy to work
    • Side effects e.g. N+V common
  • Other options include ketoconazole (hepatotoxic) and pasireotide LAR (somatostatin analogue)