Hypercortisolism

Cushing syndrome - the disease resulting from chronic high exposure to endogenous corticosteroids

Aetiology

• Exogenous iatrogenic glucocorticoid administration (most common overall)
• Pituitary or supra-pituitary tumours causing ACTH excess (Cushing disease - most common endogenous source)
• Ectopic sources of ACTH (lung cancer, head and neck SCC, NET) (10%)
• Primary adrenal pathology (cortisol-secreting adrenal adenoma) (10%)

Pathophysiology

• Cortisol is produced in zona fasciculata and released in a diurnal rhythm
• Crosses cell membranes and has effects on gene transcription in nucleus
• Key impacts on gluconeogenesis, glycogenolysis, immune response, peripheral uptake of glucose, sodium transport, and other processes
• Hypercortisolism:
  • Electrolyte disturbances
  • Proteolysis
  • Lipolysis
  • Inhibition of peripheral uptake of glucose
  • Reduction of bone formation
  • Inhibited muscle formation
  • Impaired collagen formation and wound healing

Presentation

• Obesity
• HTN (>70%)
• Abnormal glucose - diabetes
• Bone density loss
• Easy bruising
• Muscle weakness
• Plethora (red facial appearance caused by thinning of the skin)
• Hirsutism

Disease classification and treatment

• ACTH-dependent Cushing's syndrome (80%)
  • Cushing's disease (pituitary adenoma) (68%)
    • Address pituitary adenoma surgically
    • Consider bilateral adrenalectomy if pituitary surgery fails
  • Ectopic ACTH syndrome) (12%)
    • Surgical excision if resectable, otherwise medical therapy
  • Ectopic CRH syndrome (<1%)
    • Same as ectopic ACTH syndrome
• ACTH-independent Cushing syndrome
  • Adrenal adenoma (10%)
    • Laparoscopic unilateral adrenalectomy
    • >90% effective
  • Adrenal carcinoma (8%)
    • Laparoscopic unilateral adrenalectomy
  • Micronodular hyperplasia/primary pigmented nodular adrenocortical disease (<1%)
  • Macronodular hyperplasia (<1%)
• Pseudo-Cushing's syndrome
  • Depression (<1%)
  • Alcoholism (<1%)

Diseases resulting in bilateral adrenal abnormalities:

• ACTH-dependent macronodular adrenal hyperplasia
  • Secondary to long-term ACTH overstimulation - either Cushing disease or ectopic ACTH
  • Adrenals are bilaterally enlarged, but not as large as in primary bilateral macronodular adrenal hyperplasia
• ACTH-independent micronodular adrenal hyperplasia
  • Most frequent variant is primary pigmented nodular adrenocortical disease (PPNAD) - can be sporadic or familial
  • Adrenal micronodules are <1cm and often adrenals are of normal size
  • Bilateral adrenalectomy is uniformly effective and medical therapy is non-curative
• ACTH-independent bilateral macronodular adrenal hyperplasia
  • Now known as primary bilateral macronodular adrenal hyperplasia
  • Uncommon
  • Adrenals contain multiple non-pigmented nodules 1-4cm in diameter
  • Related to aberrant hormone receptors, local production of ACTH and genetic mutations
  • Majority have only mild cortisol over-secretion
  • Management
    • Screen for 'aberrant receptors' - if these are found, can treat medically with targeted therapy
    • Severe Cushing's - bilateral adrenalectomy
    • Moderate Cushing's - unilateral adrenalectomy

Workup

• Diagnosis is reliant on demonstrating inappropriate cortisol secretion, or the loss of physiologic negative feedback
• Overnight low-dose dexamethasone suppression test (DMST) is a good way to start
  • 1mg at 11pm and a plasma cortisol level at 8am
  • Normal people should have cortisol <82nmol/L (<3mcg/dL) (supressed)
  • If fail to suppress, should have 24 hour urine free cortisol measurement and plasma ACTH level (low or suppressed ACTH is supportive of diagnosis)
  • 24-hour urinary cortisol can also be used as initial screening test, but less convenient for patients
  • The reference range varies between labs, but at Austin it is 60-305nm/day
  • Unequivocally high values can go straight to a diagnosis, whereas mildly elevated levels should have confirmatory testing with either DST or salivary
    • 1mg dexamethasone suppression test is commonly used, despite poor specificity
    • Late evening salivary testing is an attractive alternative
• Then test ACTH
  • Normal or elevated ACTH is indicative of ACTH-dependent Cushing syndrome, which is most likely a pituitary coriticotroph microadenoma
• Then imaging as below
• High-dose DMST (8mg) differentiates between pituitary and extra-pituitary sources of ACTH. Pituitary adenomas will be suppressed but not suppressed in ectopic tumours.

Approach to management of cortisol-secreting adrenal adenoma

• Cushing's syndrome with overt clinical features or related co-morbidities: adrenalectomy
• Mild autonomous cortisol secretion, without symptoms or signs: individualised decision, with value or adrenalectomy decreasing after age 65

Other situations

• Non-resectable pituitary disease: consider bilateral adrenalectomy
• ACTH-independent bilateral adrenal hyperplasia:
  • Primary pigmented nodular adrenocortical disease (PPNAD): bilateral adrenalectomy

Pre-operative considerations

• Optimise BP, cortisol level, electrolytes, glucose, nutrition, physical stamina (up to 6 months can be used)
• Must have careful post-operative cortisol replacement
  • Unilateral adrenalectomy for a single adenoma - will need corticosteroid supplementation if overt signs of Cushing's syndrome, usually hydrocortisone 100mg q8h, which would then be tapered to physiologic replacement levels over a few weeks, but sometimes they require supplementation for >1 year