Residency · Residency · Internal Medicine
Adrenal Insufficiency and Steroid Management
Overview
Adrenal insufficiency (AI) is a potentially life-threatening condition resulting from inadequate cortisol production. It is classified as primary (adrenal gland failure), secondary (pituitary ACTH deficiency), or tertiary (hypothalamic CRH deficiency or chronic exogenous steroid suppression). Tertiary AI from chronic glucocorticoid use is by far the most common form encountered on the wards. Adrenal crisis is a medical emergency requiring immediate IV hydrocortisone.
Classification
Primary Adrenal Insufficiency (Addison Disease)
Primary AI involves destruction or dysfunction of the adrenal cortex, resulting in loss of cortisol, aldosterone, and adrenal androgens. Autoimmune adrenalitis accounts for 80% of cases in developed countries and is often part of polyglandular autoimmune syndromes. Infections include tuberculosis (the most common cause worldwide), CMV in immunocompromised patients, histoplasmosis, and HIV. Bilateral adrenal hemorrhage occurs in Waterhouse-Friderichsen syndrome (meningococcemia), with anticoagulant use, or in DIC. Infiltrative causes include metastatic disease (lung, breast), lymphoma, and amyloidosis. Drugs such as ketoconazole, etomidate, mitotane, and immune checkpoint inhibitors can cause AI. Congenital adrenal hyperplasia is a genetic cause. Distinguishing features of primary AI include hyperpigmentation (elevated ACTH stimulates melanocytes), hyperkalemia, hyponatremia, salt craving, and hypotension.
Secondary Adrenal Insufficiency
Secondary AI results from pituitary ACTH deficiency leading to decreased cortisol production. Aldosterone is preserved because it is regulated by RAAS rather than ACTH, so hyperkalemia does not occur. Causes include pituitary tumors, surgery, or radiation; Sheehan syndrome (postpartum pituitary necrosis); lymphocytic hypophysitis; craniopharyngioma; sarcoidosis; and checkpoint inhibitor-induced hypophysitis. Hyperpigmentation is absent because ACTH is low.
Tertiary Adrenal Insufficiency
Tertiary AI is the most common form in clinical practice. Chronic exogenous glucocorticoid use suppresses CRH and ACTH, leading to adrenal atrophy. Risk develops after 3 or more weeks of prednisone at 5 mg/day or higher (or equivalent), any dose for longer than 1 month, or repeated steroid injections. HPA axis recovery can take 6-12 months after steroid discontinuation. Aldosterone is preserved and hyperpigmentation is absent.
<image>Classification of adrenal insufficiency showing primary (adrenal), secondary (pituitary), and tertiary (hypothalamic/exogenous) causes with distinguishing laboratory and clinical features</image>
Diagnosis
Clinical Presentation
Chronic AI presents with fatigue, weakness, weight loss, anorexia, nausea, orthostatic hypotension, hyperpigmentation (primary only), and salt craving (primary only). Adrenal crisis manifests as hypotension or shock refractory to fluids and vasopressors, altered mental status, abdominal pain, fever, hyponatremia, hyperkalemia (primary only), and hypoglycemia. Crisis precipitants include intercurrent illness, surgery, trauma, abrupt steroid cessation, and physiologic stress in patients with undiagnosed AI.
Laboratory Clues
Hyponatremia occurs because cortisol deficiency impairs free water excretion and aldosterone deficiency causes sodium wasting. Hyperkalemia is seen only in primary AI due to aldosterone deficiency. Hypoglycemia reflects loss of cortisol's counter-regulatory function. Eosinophilia and lymphocytosis result from loss of cortisol's immunosuppressive effect. A mild normocytic anemia may be present.
Cosyntropin (ACTH) Stimulation Test
The standard test involves administering 250 mcg cosyntropin (synthetic ACTH) IV or IM and measuring cortisol at 0 and 30 (or 60) minutes. A normal response (cortisol of 18 mcg/dL or above at 30 or 60 minutes) rules out primary AI. An abnormal result (cortisol below 18) confirms adrenal insufficiency. The test cannot distinguish secondary from primary AI, so ACTH level must be checked: elevated ACTH indicates primary AI while low or normal ACTH indicates secondary or tertiary AI. An important limitation is that the test may be falsely normal in early or recent-onset secondary AI when the adrenals have not yet atrophied.
Morning Cortisol
A random morning cortisol below 3 mcg/dL is highly suggestive of AI and may not require cosyntropin testing. A level above 15-18 makes AI unlikely. Values between 3 and 15 are indeterminate and require cosyntropin stimulation.
Additional Workup
For primary AI, 21-hydroxylase antibodies assess for autoimmune etiology, and CT of the adrenals evaluates for infections, hemorrhage, or infiltration. For secondary AI, pituitary MRI and evaluation of other pituitary hormone axes is appropriate. For tertiary AI, a detailed steroid exposure history is essential.
<image>Cosyntropin stimulation test algorithm showing administration, cortisol measurement at baseline and 30 minutes, interpretation of results, and subsequent ACTH level to distinguish primary from secondary adrenal insufficiency</image>
Treatment
Chronic Replacement Therapy
Glucocorticoid replacement for all types of AI uses hydrocortisone 15-25 mg/day in 2-3 divided doses (such as 10 mg in the morning, 5 mg at noon, and 5 mg in the late afternoon), or prednisone 3-5 mg/day (once daily for simpler dosing but less physiologic). Dose adjustments are based on clinical response, not cortisol levels. Mineralocorticoid replacement with fludrocortisone 0.05-0.2 mg/day is needed only in primary AI, monitored with blood pressure, potassium, and plasma renin activity. It is not needed in secondary or tertiary AI where the aldosterone axis remains intact. DHEA supplementation (25-50 mg/day) in women with primary AI may improve well-being and libido, though evidence is modest.
Adrenal Crisis Management
Adrenal crisis is a medical emergency that should be treated empirically if suspected without waiting for test results. Hydrocortisone 100 mg IV bolus is given immediately, followed by 50 mg IV every 6-8 hours (or continuous infusion of 200 mg over 24 hours). Aggressive IV fluid resuscitation with 0.9% NS corrects dehydration and hyponatremia. Dextrose addresses hypoglycemia. The precipitant (usually infection) must be identified and treated. Once stable, taper to maintenance doses over 1-3 days. At stress doses of hydrocortisone (50 mg/day or above), fludrocortisone is not needed because hydrocortisone has sufficient mineralocorticoid activity.
Stress-Dose Steroids for Illness and Surgery
Patients on chronic steroids or with known AI cannot mount an appropriate cortisol response to physiologic stress. | Stress Level | Example | Steroid Coverage |
| Minor | Minor procedure, mild illness | Double daily oral dose for 2-3 days | |
|---|---|---|---|
| Moderate | Joint replacement, uncomplicated surgery | Hydrocortisone 50 mg IV pre-op, then 25 mg q8h x 24-48h | |
| Major | Cardiac surgery, sepsis, trauma | Hydrocortisone 100 mg IV q8h, rapid taper over 1-3 days |
The traditional approach is tiered: for minor illness or procedures, double the daily oral glucocorticoid dose for 2-3 days; for moderate stress (such as joint replacement or uncomplicated abdominal surgery), give hydrocortisone 50 mg IV before induction then 25 mg every 8 hours for 24-48 hours; for major stress (cardiac surgery, sepsis, trauma), give hydrocortisone 100 mg IV every 8 hours with rapid taper over 1-3 days. An emerging risk-stratified approach recognizes that not all patients on chronic steroids need stress-dose coverage, as the need depends on dose, duration, and degree of HPA axis suppression.
<image>Stress-dose steroid protocol showing tiered approach for minor, moderate, and major physiologic stress with specific hydrocortisone dosing recommendations</image>
Steroid Tapering Strategies
When to Taper
Tapering is necessary after prolonged courses (more than 3 weeks) of prednisone at 5 mg/day or higher (or equivalent), with the goal of allowing HPA axis recovery while avoiding adrenal crisis and disease flare.
General Approach
Reduction proceeds at 10-20% every 1-2 weeks (slower for longer courses). Faster reductions are possible at higher doses (such as 10 mg decrements from 60 mg to 20 mg prednisone), but the taper must slow below the physiologic dose (approximately 5 mg prednisone equals approximately 20 mg hydrocortisone). Below 5 mg prednisone, switching to hydrocortisone allows finer dose adjustments in 2.5 mg decrements. Morning cortisol or cosyntropin testing once at physiologic replacement dose assesses HPA axis recovery. Complete recovery may take 6-12 or more months.
Common Steroid Equivalencies
| Glucocorticoid | Equivalent Dose | Relative GC Potency | Relative MC Potency | Half-life |
|---|---|---|---|---|
| Hydrocortisone | 20 mg | 1 | 1 | 8-12 h |
| Prednisone | 5 mg | 4 | 0.8 | 12-36 h |
| Methylprednisolone | 4 mg | 5 | 0.5 | 12-36 h |
| Dexamethasone | 0.75 mg | 25-30 | 0 | 36-72 h |
Hydrocortisone 20 mg equals prednisone 5 mg equals methylprednisolone 4 mg equals dexamethasone 0.75 mg. Mineralocorticoid potency decreases across this spectrum: hydrocortisone has the most, followed by prednisone, then methylprednisolone, with dexamethasone having none.
Clinical Pearls
Every patient on chronic steroids should carry medical alert identification and have an emergency injection kit with instructions. Etomidate, used for rapid-sequence intubation, inhibits 11-beta-hydroxylase and can precipitate adrenal crisis; a single dose suppresses cortisol for 12-24 hours. Immune checkpoint inhibitor-induced hypophysitis is an increasingly common cause of secondary AI that may be irreversible, requiring lifelong replacement. Bilateral adrenal hemorrhage should be suspected in critically ill, anticoagulated patients with sudden hemodynamic deterioration, abdominal pain, and refractory hypotension; CT abdomen is diagnostic. Fludrocortisone is not needed when hydrocortisone doses of 50 mg/day or higher are given because hydrocortisone has intrinsic mineralocorticoid activity at high doses. The concept of "relative adrenal insufficiency" in sepsis remains controversial, but the ADRENAL and APROCCHSS trials support low-dose hydrocortisone (200 mg/day continuous or 50 mg every 6 hours) in septic shock requiring vasopressors.
References
- Bornstein SR, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101:364-389.
- Fleseriu M, et al. Hormonal Replacement in Hypopituitarism in Adults. J Clin Endocrinol Metab. 2016;101:3888-3921.
- Venkatesh B, et al. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock (ADRENAL). N Engl J Med. 2018;378:797-808.
- Annane D, et al. Hydrocortisone plus Fludrocortisone for Adults with Septic Shock (APROCCHSS). N Engl J Med. 2018;378:809-818.
- Higham CE, et al. Glucocorticoid Withdrawal -- An Update on Adrenal Insufficiency After Cessation of Therapy. Expert Rev Endocrinol Metab. 2020;15:1-12.
