Definition

Impairment of adrenal glands, rendering them unable to produce adequate steroid hormones. Typically referring to cortisol, but can also indicate aldosterone deficiency.

Adrenal Anatomy 

• Can be remembered as: salty, sweet, sex hormones.
• Outermost zone = zona glomerulosa: secretes aldosterone.
  • Responsible for renin-angiotensin system.
  • Not impaired in secondary and tertiary AI.
• Middle zone = zona fasciculata: secretes cortisol.
  • Regulated by CRH and ACTH.
• Innermost zone = zona reticularis: secretes adrenal androgens.

Etiologies

Primary adrenal insufficiency (Addison’s disease): adrenal glands fail to produce cortisol.

• Autoimmune adrenalitis: destruction of adrenal cortex, most common in developed countries. Can be isolated or as part of a polyglandular autoimmune syndrome.
• Infectious: TB (most common in world), histoplasmosis, paracoccus, HIV, CMV.
• Vascular: hemorrhage/infarction (seen in sepsis/meningococcemia, coagulopathy or trauma) or thrombosis (in APLS).
• Drugs: ketoconazole (impairs steroidogenesis), etomidate (even single dose can interfere with cortisol synthesis for 24 hours), rifampin (increases cortisol metabolism).
• Infiltrative disease: sarcoidosis, hemochromatosis, or amyloidosis.
• Malignancy: rare because must destroy ~90% of glands to lead to insufficiency.

Secondary adrenal insufficiency: pituitary failure to produce ACTH.

• Iatrogenic: most commonly from exogenous steroids (feedback suppression of ACTH).
• Primary pituitary problem (usually pan-hypopituitarism): pituitary adenoma, pituitary apoplexy, Sheehan’s syndrome, infiltrative pituitary disease, empty sella syndrome, autoimmune pituitary destruction, pituitary metastases.
• Drugs: megestrol acetate (suppresses ACTH at doses >160 mg/day), ipilimumab.

Tertiary adrenal insufficiency: hypothalamic failure to produce CRH.

• Chronic steroid exposure: exogenous from high dose chronic steroid use or endogenous in Cushing’s syndrome. Seen during withdrawal of chronic exogenous steroids or cure of Cushing’s’ syndrome.
• Tumors.
• Cranial radiation.
• Infiltrative diseases as above.

Evaluation

Chronic symptoms: can be vague and nonspecific including weakness, fatigue, malaise, anorexia, weight loss, abdominal discomfort, nausea, or salt cravings.

Acute symptoms: hypotension/shock (in adrenal crisis), altered mental status, fever, abdominal/flank/back pain.

Physical exam

• Orthostatic hypotension, distributive shock (in adrenal crisis).
• Abdominal/flank/back tenderness.
• Skin hyperpigmentation (in primary adrenal insufficiency as ACTH stimulates melanocytes).
• May see signs of other autoimmune process such as vitiligo, tender thyroid, pale skin/conjunctiva.
• Fever/hypothermia.

Laboratory evaluation in hospitalized patients

• Hyponatremia, hyperkalemia, hypoglycemia, eosinophilia (rare).
• ACTH: increased in primary AI, decreased in secondary AI. If concern for secondary AI or planning to start steroids immediately, get ACTH with initial cortisol. See CST below.
• Cortisol
  • Has a diurnal variation and is higher in the morning.
  • Random level >18 mcg/dL reflects intact adrenal function.
  • Morning level (better test) <3 mcg/dL is strongly suggestive of AI and <10 is suggestive. Level >18 consistent with normal adrenal function.
  • Cosyntropin stimulation test (CST) (see below for order details)
    • Post-stimulation cortisol >18 mcg/dL confirms intact adrenal function.
    • In early acute secondary or tertiary adrenal insufficiency, the test is not reliable because it takes several days for the adrenal cortex to atrophy.
    • A percentage of cortisol is bound to albumin. Hypoalbuminemia makes this test difficult to interpret.

Laboratory evaluation in critically ill patients (functional adrenal insufficiency)

• Cortisol
  • No established consensus, but a random level <10 mcg/dL is suggestive of AI and treatment would be reasonable. If >34 mcg/dL, there is sufficient adrenal function. In between these values, or to further assess a value <10 mcg/dL, do a CST.
• CST: if the cortisol does not increase by at least 9 mcg/dL, AI is likely.

Cosyntropin stimulation test (CST)

• Patient must be off glucocorticoids for ≥12 hours.
• Dexamethasone is not detected by many cortisol assays. Use for initial therapy if CST will be performed after the initial dose of steroids is given (unstable patient).
• Performing CST:
  • Draw baseline serum cortisol level and ACTH level, and send to lab immediately on ice.
  • Immediately after labs are drawn, inject cosyntropin 0.25 mg IV x 1 (it can also be given IM).
  • Draw repeat serum cortisol 45 minutes after dose.

Imaging

• CT of adrenals if suspected primary AI.
  • Especially if acute onset or immunosuppressed/HIV with higher risk of infection.
• Pituitary protocol MRI if suspected secondary AI and not steroid-induced.

Management 

Chronic treatment

• Primary AI:
  • Must replace both glucocorticoid and mineralocorticoid.
  • Typically, glucocorticoid maintenance: 15-25 mg hydrocortisone daily = 5 mg prednisone daily = 0.5 mg dexamethasone daily. Hydrocortisone is usually dosed 2/3 in the AM and 1/3 in afternoon, other steroids are once daily.
  • Mineralocorticoid maintenance: 0.05-0.20 mg fludrocortisone daily depending on type of glucocorticoid used.
• Secondary AI: only require glucocorticoid replacement given that there is loss of ACTH but mineralocorticoid activity remains normal. May require replacement for other pituitary hormone deficiencies.
• Glucocorticoids are metabolized by the P450 CYP3A4 system. Higher doses are needed if the patient is on phenytoin, rifampin, or barbiturates. Lower doses needed if on protease inhibitors.

Stress dosing

• When a patient on chronic steroids presents with mild to moderate acute illness, frequent practice is to double the maintenance dose for three days and taper back to baseline as illness improves (little evidence).
• Acute adrenal crisis: give hydrocortisone 100 mg IV stat followed by 50 mg IV q6. Continue q4-6 hours while tapering dose over the next 3-5 days as patient improves. However, if a patient has persistent complications maintain or increase to a daily total of 200-300 mg.
• Relative adrenal insufficiency/septic shock: no consensus. Can consider hydrocortisone 50-100 mg IV q8 hours with a rapid taper if patient improves and stabilizes. This may help with treatment of shock but may not improve mortality. Also see Critical Care: Corticosteroid Supplementation in the Critically Ill Patient.
• Mineralocorticoid replacement: only needed in primary AI. Not needed if hydrocortisone dose > 50mg per 24h. If total daily hydrocortisone is reduced to 50 mg or below, give mineralocorticoid replacement with fludrocortisone 0.1 mg daily.

Patients with AI undergoing surgery: no clear consensus.

• Minor procedures (e.g., hernia repair): can double or triple the usual replacement dose the day of and day after surgery before returning to maintenance.
• Intermediate procedures (e.g., joint replacement): hydrocortisone 50 mg IV x 1 immediately prior to surgery, then 25 mg IV q 8 hours x 24 hours, then resume normal dose.
• Major procedures (e.g., CABG): patient’s usual dose 2 hours before surgery, plus hydrocortisone 100 mg IV x 1 with induction of anesthesia, then hydrocortisone 50 mg IV q 8 hours x 48-72 hours after surgery, then taper of 50% each day down to maintenance dose.

Key Points

• If you suspect AI in an unstable patient, give steroids first. Dexamethasone is a good initial steroid since it does not cross-react with cortisol assay. Perform a CST ASAP. Once the cortisol is measured, switch to a more typical steroid (e.g. hydrocortisone).
• Best way to diagnose AI in the hospital is with a morning cortisol level followed by CST.

*

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Annane D, Sébille V, Charpentier C, et al. Effects of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-871.

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