Thomas Addison was the first to describe the clinical features of primary adrenal failure in 1855 in a paper called “Disease of the Supra-renal Capsules,” where he described the adrenal glands and adrenal insufficiency for the first time. In the 1940s, cortisone was identified, after being isolated by Edward Kendall in the 1930s and synthesized by Lewis Sarett in 1946, it became available for clinical use in 1949.
Types of Adrenal Insufficiency
- Primary adrenal insufficiency (Addison disease): disease from within adrenal gland
- Etiology
- Adrenal destruction from autoimmune causes (most common primary cause, 70-90%)
- Infectious adrenalitis (e.g., tuberculous, fungal, HIV/AIDS)
- Adrenal replacement by metastatic tumor
- Adrenal hemorrhage (Waterhouse-Friderichsen syndrome)
- Pathogenesis (three general mechanisms)
- Congenital adrenal dysgenesis/hypoplasia
- Defective steroidogenesis
- Adrenal destruction (most common)
- Etiology
- Secondary adrenal insufficiency: disease from decreased ACTH by pituitary gland
- Etiology
- Panhypopituitarism due to neoplastic or infiltrative replacement
- Pituitary surgery, radiation, infection
- Granulomatous disease
- Pituitary hemorrhage or infarction (e.g., Sheehan syndrome)
- Pathogenesis
- Results from ACTH deficiency (such as in pharmacologic steroid withdrawal)
- Risk factors: patients receiving high supraphysiologic doses of glucocorticoids for >5 days and patients receiving low supraphysiologic doses for >3 weeks
- Etiology
- Tertiary adrenal insufficiency
- Etiology
- Abrupt steroid withdrawal (most common cause of adrenal insufficiency overall)
- Tumor, radiation
- Infection
- Stroke
- Traumatic brain injury
- Etiology
- Acute adrenal insufficiency (adrenal crisis)
- Life-threatening condition occurs in patients with already marginal adrenocortical function subjected to significant acute physiologic stressor (e.g., infection, trauma)
- Pathogenesis
- Mineralocorticoid deficiency (primary mechanism) → inability to maintain sodium and intravascular volume
- Glucocorticoid deficiency → diminished cardiovascular response to catecholamines
- Presentation
- Shock
- Abdominal pain
- Fever
- Nausea, vomiting
- Electrolyte disturbances
- Occasionally hypoglycemia
- Treatment
- Must be addressed immediately
- Large-volume (1-2 L) IV resuscitation with isotonic saline
- Glucocorticoid administration → 4 mg dexamethasone followed by 50 mg hydrocortisone q8h followed by taper to standard replacement doses
- Prevention: known adrenal insufficiency should receive 100 mg hydrocortisone evening before and morning of major surgery, followed by 50-100 mg hydrocortisone q8h during first postoperative 24 hours, followed by preoperative doses in a slow or fast taper depending on clinical suspicion
Presentation
- Weakness, fatigue
- Anorexia
- Nausea, vomiting
- Confusion
- Weight loss
- Hypotension
- Hypoglycemia
- Primary adrenal insufficiency ONLY
- Hyperpigmentation
- Thought to be due to ACTH-induced melanogenesis
- ACTH converted to MSH (melanocyte-stimulating hormone)
- Mineralocorticoid deficiency
- Salt craving
- Postural hypotension
- Hyponatremia
- Hyperkalemia
- Hyperpigmentation
Labs
- Morning cortisol levels in saliva or serum (consider as screen)
- Normal morning serum cortisol is >15 µg/dL
- Normal morning salivary cortisol is >5.8 ng/mL
- Provocative testing for patients with low morning cortisol: ACTH stimulation test (standard for diagnosis)
- High-dose IV cosyntropin stimulation test → measure plasma cortisol levels after administration and then 30- and 60 minutes later → positive result is suggestive of adrenal insufficiency (normal peak cortisol level should be >20 µg/dL
- First: basal ACTH
- High ACTH = primary adrenal insufficiency
- Low ACTH = CRH stimulation test
- CRH stimulation test
- Absent/low ACTH response = secondary adrenal insufficiency
- Exaggerated ACTH response = tertiary adrenal insufficiency
Treatment
- Goal: replace physiologic glucocorticoid and mineralocorticoid levels
- Treat with IV fluids and steroids