How to diagnose and manage Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction?

Diagnosis and Management of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction

The ACTH stimulation test is the gold standard for diagnosing adrenal insufficiency, with a peak cortisol <500 nmol/L confirming the diagnosis, while the etiology is determined by measuring ACTH levels to differentiate between primary (high ACTH) and secondary (low ACTH) adrenal insufficiency. 1

Diagnostic Approach

Clinical Presentation

• Primary adrenal insufficiency (Addison's disease):

  • Fatigue, weakness, weight loss, decreased appetite
  • Hyperpigmentation, salt craving
  • Hypotension, orthostatic symptoms
  • Laboratory findings: hyponatremia (90% of cases), hyperkalemia (50% of cases) 1

• Secondary adrenal insufficiency:

  • Similar symptoms but without hyperpigmentation or electrolyte abnormalities
  • Often associated with other pituitary hormone deficiencies 1

• Cushing's syndrome (hypercortisolism):

  • Weight gain, central obesity, moon face, buffalo hump
  • Thin skin, easy bruising, purple striae
  • Hypertension, glucose intolerance 2

Diagnostic Testing Algorithm

1. First-line screening tests (choose based on clinical scenario):

   • Late-night salivary cortisol (LNSC): Preferred for most patients
   • 1mg overnight dexamethasone suppression test (DST): Preferred for shift workers or those with disrupted circadian rhythm
   • 24-hour urinary free cortisol (UFC): Obtain 2-3 collections to account for variability 2

2. Confirmatory testing:

   • ACTH stimulation test (gold standard):
     • Administer 250 μg synthetic ACTH
     • Measure cortisol at 0,30, and 60 minutes
     • Peak cortisol <500 nmol/L confirms adrenal insufficiency 1
   • Low-dose ACTH stimulation test (1 μg):
     • More sensitive for detecting subtle secondary adrenal insufficiency 3
   • Insulin tolerance test (ITT):
     • Gold standard for evaluating HPA axis stress response
     • Contraindicated in patients with seizure disorders, cardiovascular disease, or elderly 4

3. Differentiate primary vs. secondary adrenal insufficiency:

   Type	ACTH Level	Cortisol Level	Electrolytes
   Primary	High	Low	↓Na, ↑K
   Secondary	Low	Low	Normal

4. Additional testing for specific etiologies:

   • MRI of pituitary for suspected secondary adrenal insufficiency
   • Adrenal antibodies for suspected autoimmune adrenalitis
   • CRH stimulation test to differentiate between secondary and tertiary adrenal insufficiency 5

Management Approach

Adrenal Insufficiency Treatment

1. Glucocorticoid replacement:

   • Hydrocortisone 15-25 mg daily in divided doses (typically 2/3 in morning, 1/3 in afternoon)
   • Alternative: Prednisone 5-7.5 mg daily 1

2. Mineralocorticoid replacement (for primary adrenal insufficiency only):

   • Fludrocortisone 50-200 μg daily
   • Monitor blood pressure, electrolytes, and plasma renin activity 1

3. Stress dosing protocol:

   • Minor illness/stress: Double or triple usual daily dose
   • Moderate stress: Hydrocortisone 50-75 mg/day in divided doses
   • Severe stress: Hydrocortisone 100 mg IV immediately, followed by 100-300 mg/day as continuous infusion or divided doses every 6 hours 1

Cushing's Syndrome Management

1. ACTH-dependent Cushing's syndrome (pituitary or ectopic source):

   • Transsphenoidal surgery for pituitary adenomas
   • Bilateral inferior petrosal sinus sampling (IPSS) to differentiate pituitary from ectopic source 2

2. ACTH-independent Cushing's syndrome (adrenal):

   • Surgical removal of adrenal tumor(s)
   • Medical therapy if surgery contraindicated 2

Monitoring and Patient Education

1. Regular monitoring:

   • Clinical parameters: Blood pressure, weight, symptoms of under/over-replacement
   • Laboratory: Electrolytes every 3-6 months, renin levels (aim for upper normal range) 1

2. Patient education (essential for all patients with adrenal insufficiency):

   • Recognize early symptoms of adrenal crisis
   • Wear medical alert identification
   • Carry a steroid alert card
   • Have emergency hydrocortisone injection kit 1

3. Adrenal crisis management:

   • Immediate IV/IM hydrocortisone 100 mg
   • Fluid resuscitation with 3-4 L isotonic saline
   • Continuous monitoring of hemodynamic parameters and electrolytes 1

Important Considerations and Pitfalls

• Diagnostic pitfalls:

  • False positive DST results may occur with rapid absorption/malabsorption of dexamethasone, concomitant CYP3A4 inducers, or increased corticosteroid binding globulin 2
  • False negative results may occur with medications inhibiting dexamethasone metabolism 2

• Treatment pitfalls:

  • Chronic over-replacement can lead to Cushingoid features, osteoporosis, and metabolic complications 6
  • Under-replacement risks adrenal crisis during stress 1
  • HPA axis suppression can occur with exogenous glucocorticoid therapy, requiring gradual tapering 7

• Special situations:

  • Pregnancy: May require increased glucocorticoid doses
  • Surgery: Requires stress-dose steroids
  • Concurrent infections: May require increased steroid doses and prompt treatment of infection 7

Remember that HPA axis dysfunction can be life-threatening if undiagnosed or improperly managed. Early recognition and appropriate treatment are essential for preventing adrenal crisis and optimizing patient outcomes.