Adrenal Insufficiency in Adults

Background

• Adrenal insufficiency is a life-threatening clinical syndrome caused by either primary adrenocortical failure or secondary adrenal disease due to impairment of the hypothalamic-pituitary-adrenal axis that results in deficient production or action of glucocorticoids, with or without concurrent mineralocorticoid and adrenal androgen deficiency.
  • Primary adrenal insufficiency (also called Addison disease) is due to adrenocortical failure.
  • Central adrenal insufficiency is due to impaired adrenal regulation by the pituitary gland (in secondary disease) or the hypothalamus (in tertiary disease).
  • Critical illness-related adrenal insufficiency is a relative insufficiency, wherein cortisol production is inadequate to control the inflammatory response or to meet an elevated metabolic demand.

Evaluation

• Adrenal insufficiency may present acutely with hypotension or volume depletion (adrenal crisis), or with slow onset of nonspecific symptoms.
• If acute adrenal insufficiency is suspected, begin treatment immediately (before diagnostic test results are available).
• Perform diagnostic testing to exclude primary adrenal insufficiency in patients who are acutely ill or present with otherwise unexplained symptoms or signs suggestive of primary adrenal insufficiency, including volume depletion, hypotension, hyponatremia, hyperkalemia, fever, abdominal pain, hyperpigmentation, or hypoglycemia (Strong recommendation).
• Diagnosis of adrenal insufficiency is based on low basal cortisol levels when suggestive symptoms and signs are present, and/or post-adrenocorticotropin (ACTH) stimulation test serum cortisol levels at any time.
  • When patient's condition allows, perform ACTH stimulation test to confirm diagnosis of primary adrenal insufficiency if suggestive clinical symptoms or signs are present (Strong recommendation).
  • Suspect adrenal insufficiency in patients who have basal serum cortisol (usually 6 AM-9 AM) < 80 nmol/L (3 mcg/dL)
  • Basal salivary cortisol (8 AM) < 5 nmol/L (0.18 mcg/dL) suggests adrenal insufficiency, but is not diagnostic.
  • Diagnose adrenal insufficiency if poststimulation serum cortisol < 500 nmol/L (18 mcg/dL) 30-60 minutes after ACTH administration.
  • Adrenal insufficiency is unlikely if any of:
    • 8 AM basal cortisol > 415 nmol/L (15 mcg/dL)
    • peak cortisol > 500-550 nmol/L (18-20 mcg/dL) 30-60 minutes after ACTH administration
    • 8 AM salivary cortisol > 16 nmol/L (5.8 mcg/L)
  • Distinguish between primary and secondary/tertiary adrenal insufficiency by measuring plasma ACTH at 8 AM
    • Primary adrenal insufficiency:
      • plasma ACTH concentration > 22 pmol/L (100 pg/mL) (> 45 pmol/L in most cases)
      • high plasma renin activity and low aldosterone concentrations
      • hyponatremia and hyperkalemia
    • Secondary and tertiary adrenal insufficiency:
      • plasma ACTH concentration < 12 pmol/L (52 pg/mL)
      • normal renin and aldosterone concentrations
  • In critically ill patients, consider diagnosis of adrenal insufficiency if total cortisol is < 275 nmol/L (10 mcg/dL), or change in cortisol is < 250 nmol/L (9 mcg/dL) after ACTH 250 mcg administration with peak cortisol levles below 18 mcg/dl (assay dependent) at 30 or 60 minutes..
• Measure plasma ACTH level at 8 AM to distinguish between primary and secondary adrenal insufficiency (Strong recommendation).
  • ACTH > 22 pmol/L (100 pg/mL) indicates primary adrenal insufficiency.
  • ACTH < 12 pmol/L (52 pg/mL) indicates secondary adrenal insufficiency.
• In patients with primary adrenal insufficiency, perform simultaneous measurement of plasma renin and aldosterone to determine the presence of mineralocorticoid deficiency (Strong recommendation).
• If the patient's biochemical profile suggests primary adrenal insufficiency:
  • Consider measuring autoantibody titers against 21-hydroxylase, adrenal cortex, and other autoantigens associated with autoimmune adrenalitis.
  • Consider measuring very long chain fatty acids in young male patients without autoantibodies.
  • Perform adrenal computed tomography (CT) to assess for infection, infiltration, hemorrhage, calcifications, malignancy, or other rare causes of adrenal insufficiency in patients who do not have associated autoimmune disease or evidence of autoantibodies.
• If secondary adrenal insufficiency is suspected, perform pituitary magnetic resonance imaging (MRI) to assess for hypothalamic-pituitary lesions.

Management

• In patients with suspected adrenal crisis:
  • Immediately give hydrocortisone 100 mg IV followed by appropriate fluid resuscitation and hydrocortisone 200 mg/day as continuous IV infusion or 50 mg IV every 6 hours for 24 hours (Strong recommendation).
  • Decrease IV glucocorticoid dose and transition to oral maintenance dose once patient's condition is stable.
• In Chronic adrenal insufficiency
  • Primary adrenal insufficiency
    • Glucocorticoid therapy is recommended in all patients with confirmed diagnosis of primary adrenal insufficiency (Strong recommendation).
      • Consider using hydrocortisone 15-25 mg or cortisone acetate 20-35 mg orally in 2 or 3 divided doses daily (Weak recommendation).
      • Consider prednisone or prednisolone 3-5 mg/day orally once or twice daily as an alternative to hydrocortisone in patients with primary adrenal insufficiency, especially in those with reduced compliance (Weak recommendation).
      • Taper glucocorticoids slowly and if adrenal insufficiency is the only indication requiring glucocorticoid therapy, replace long-acting glucocorticoids with hydrocortisone.
    • Mineralocorticoid replacement with fludrocortisone (starting dose 50-100 mcg orally) is recommended in all patients with confirmed aldosterone deficiency (Strong recommendation).
      • Titrate dose individually based on blood pressure, serum sodium and potassium concentration, and plasma renin activity.
      • The typical fludrocortisone maintenance dose is 50-200 mcg orally daily.
      • Consider dose reduction in patients who develop hypertension while receiving fludrocortisone (Weak recommendation); consider initiating antihypertensive treatment with continued fludrocortisone if blood pressure remains uncontrolled (Weak recommendation).
    • Consider trial of dehydroepiandrosterone (DHEA) in women with primary adrenal insufficiency who have low libido, depressive symptoms, and/or low energy levels despite receiving optimized glucocorticoid and mineralocorticoid replacement therapies (Weak recommendation).
  • In patients with secondary adrenal insufficiency, the suggested dose of hydrocortisone is 15-20 mg/day orally.
• Increased doses of glucocorticoids are required in patients experiencing medical or surgical stress.
  • For minor stress, 2-3 times replacement over 24-48 hours
  • For minor to moderate surgical stress, give hydrocortisone 25-75 mg/day for 1-2 days
  • For major stress with general anesthesia, trauma, delivery, or disease that requires intensive care,
    • Give hydrocortisone 100 mg IV followed by continuous IV infusion of hydrocortisone 200 mg daily, or give 50 mg IV or intramuscular injections every 6 hours
    • Depending on patient's clinical state, taper IV treatment rapidly and switch to oral regimen (methylprednisone or prednisone).
• In patients with critical illness-related corticosteroid insufficiency:
  • Consider corticosteroid treatment regardless of cortisol testing results in patients suspected of having critical illness-related corticosteroid insufficiency (CIRCI) (Weak recommendation), including
    • septic shock, especially if the shock is poorly responsive to fluid resuscitation and vasopressors
    • early moderate to severe acute respiratory distress syndrome (ARDS) with ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen (PaO₂/FiO₂) < 200 and within 14 days
  • The optimal treatment regimen for different causes has not been established. Options for treatment include:
    • for septic shock not responsive to vasopressor therapy and fluid resuscitation, low dose and long course (IV hydrocortisone < 400 mg/day for 3 days at full dose, then if further coverage is necessary switch to a sodium-sparing glucocorticoid (methylprednisolone or prendisone).
    • for early severe ARDS, methylprednisolone 1 mg/kg/day IV for ≥ 7 days (up to 14 days)
    • for persistent severe ARDS, methylprednisolone 2 mg/kg/day IV for ≥ 7 days (up to 14 days)
  • Taper dose of corticosteroids instead of stopping treatment abruptly (Weak recommendation).
  • For additional information on treatment of critically ill patients, see Critical illness-related corticosteroid insufficiency.
• In women who are pregnant (adrenal insufficiency is rare):
  • Consider using hydrocortisone over cortisone acetate, prednisolone, or prednisone (Weak recommendation); do not use dexamethasone (Strong recommendation).
  • Monitor clinical symptoms and signs for glucocorticoid over- or under-replacement at least every trimester.
  • Consider increasing hydrocortisone dose by 20%-40% by 24 weeks.
  • Labor and delivery
    • Give hydrocortisone 100 mg IV stress dose during the active phase of labor (cervix dilation > 4 cm and/or contractions every 5 minutes for last hour) (Strong recommendation).
    • Follow with hydrocortisone 200 mg/day continuous IV or 50 mg IV or intramuscularly every 6 hours until after delivery.
    • If patient has a cesarean section, give hydrocortisone 100 mg IV every 6 hours then taper over the next 48 hours.