What is the diagnosis and treatment for adrenal insufficiency?

Adrenal Insufficiency Diagnosis and Treatment

Immediate Clinical Recognition

If you suspect adrenal crisis (unexplained collapse, hypotension, vomiting/diarrhea), administer hydrocortisone 100 mg IV bolus immediately and infuse 0.9% saline at 1 L/hour—never delay treatment for diagnostic testing. 1, 2

High-Risk Presentations Requiring Immediate Action

• Unexplained hypotension or shock unresponsive to fluid resuscitation 2
• Vasopressor-resistant hypotension requiring multiple agents 1
• Altered mental status, confusion, or coma with hypotension 2
• Any patient on ≥20 mg/day prednisone for ≥3 weeks who develops unexplained hypotension 1
• Severe gastrointestinal symptoms (vomiting, diarrhea) with electrolyte abnormalities 1, 2

Diagnostic Approach

Initial Laboratory Testing (Before Treatment if Stable)

Draw early-morning (8 AM) serum cortisol, ACTH, and DHEAS before initiating treatment, but never delay treatment if the patient is unstable. 1, 3

Interpreting Initial Results:

• Primary adrenal insufficiency: Morning cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH 1, 3
• Secondary adrenal insufficiency: Morning cortisol 140-275 nmol/L (5-10 μg/dL) with low or inappropriately normal ACTH 1, 3
• Indeterminate results: Morning cortisol between these ranges requires confirmatory testing 1

Confirmatory Testing: Cosyntropin Stimulation Test

When initial cortisol is neither clearly normal nor clearly diagnostic, perform the cosyntropin stimulation test to definitively confirm or exclude adrenal insufficiency. 1, 4

Test Protocol:

• Administer 0.25 mg (250 μg) cosyntropin IM or IV 1, 4
• Measure serum cortisol at baseline and 30 and/or 60 minutes post-administration 1, 4
• Normal response: Peak cortisol >550 nmol/L (>18-20 μg/dL) 1, 4
• Diagnostic of adrenal insufficiency: Peak cortisol <500-550 nmol/L (<18-20 μg/dL) 1, 4

Critical Testing Considerations:

• If you need to treat suspected crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 1
• Exogenous steroids (prednisolone, inhaled fluticasone) suppress the HPA axis and confound results 1, 2
• The high-dose (250 μg) test is preferred over low-dose (1 μg) due to easier administration, comparable accuracy, and FDA approval 1

Distinguishing Primary from Secondary Adrenal Insufficiency

Primary adrenal insufficiency (Addison's disease):

• Low cortisol + high ACTH 1, 3
• Hyponatremia (present in ~90% of cases) 1, 2
• Hyperkalemia (present in ~50% of cases) 1, 2
• Hyperpigmentation in sun-exposed areas, skin creases, mucous membranes 1, 2
• Salt craving due to aldosterone deficiency 1, 2
• Mild hypercalcemia (10-20% of cases) 1, 2

Secondary adrenal insufficiency:

• Low cortisol + low or inappropriately normal ACTH 1, 3
• No hyperpigmentation (ACTH not elevated) 2
• No hyperkalemia (aldosterone production intact) 3
• May have symptoms of other pituitary hormone deficiencies (hypothyroidism, hypogonadism) 2

Etiologic Workup for Primary Adrenal Insufficiency

Test for 21-hydroxylase autoantibodies (21OH-Ab) first, as autoimmunity accounts for ~85% of primary AI cases in Western populations. 1, 4

If autoantibodies are negative:

• Obtain CT imaging of adrenals to evaluate for hemorrhage, tumor, tuberculosis, or infiltrative processes 1, 4
• In males with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1

Special Diagnostic Scenario: Hyponatremia

In patients with hypo-osmolar hyponatremia, perform cosyntropin stimulation testing to rule out adrenal insufficiency before diagnosing SIADH, as both conditions present identically. 4

Both conditions show:

• Euvolemic hypo-osmolar hyponatremia 4
• Inappropriately high urine osmolality 4
• Elevated urinary sodium 4
• The absence of hyperkalemia cannot rule out AI (present in only ~50% of cases) 4

Treatment

Acute Adrenal Crisis Management

Immediate treatment protocol:

1. Hydrocortisone 100 mg IV bolus immediately 1, 2, 3
2. Rapid IV infusion of 0.9% saline at 1 L/hour 1, 2
3. Continue hydrocortisone 100 mg IV every 6 hours until stable 1
4. Draw blood for cortisol and ACTH before treatment if possible, but never delay treatment 1, 2

Chronic Replacement Therapy

For primary adrenal insufficiency, use hydrocortisone 15-25 mg daily in 2-3 divided doses PLUS fludrocortisone 50-200 μg daily. 1, 5, 3

For secondary adrenal insufficiency, use hydrocortisone 15-25 mg daily in 2-3 divided doses alone (no fludrocortisone needed). 1, 3

Alternative Glucocorticoid Regimens:

• Prednisone 3-5 mg daily 6, 3
• Cortisone acetate 25-37.5 mg daily 1

Rationale for Hydrocortisone Preference:

• Allows recreation of diurnal cortisol rhythm 1
• Shorter half-life permits dose adjustments 7, 8

Stress Dosing Guidelines

Minor illness with fever: Double or triple the usual glucocorticoid dose 1

Moderate stress (outpatient illness):

• Hydrocortisone 30-50 mg total daily or prednisone 20 mg daily 1

Major surgery:

• Hydrocortisone 100 mg IM before anesthesia 1
• Continue 100 mg IM every 6 hours until able to take oral medications 1

Vomiting or inability to take oral medications:

• Self-administer hydrocortisone 100 mg IM injection 1, 3

Critical Treatment Pitfall: Concurrent Hypothyroidism

When treating patients with both adrenal insufficiency and hypothyroidism, start corticosteroids several days BEFORE initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1, 2

Patient Education and Safety Measures

All patients with adrenal insufficiency must:

• Wear medical alert identification jewelry 1, 2
• Carry emergency injectable hydrocortisone 100 mg IM and know how to self-administer 1, 3
• Carry a steroid alert card 2
• Be educated on doubling/tripling doses during illness, fever, or physical stress 1, 3
• Know warning signs of impending adrenal crisis 1

Practical Management of Morning Symptoms

For morning nausea and lack of appetite (common in primary AI), wake earlier to take the first hydrocortisone dose, then return to sleep. 1

This approach addresses under-replacement symptoms including:

• Morning nausea 1
• Lethargy 1
• Poor appetite 1
• Weight loss 1

Annual Monitoring and Screening

Evaluate annually:

• Symptoms, weight, blood pressure 1
• Serum sodium, potassium, glucose, HbA1c, complete blood count 1
• Thyroid function tests (TSH, FT4, TPO-Ab) for autoimmune thyroid disease 1, 4
• Vitamin B12 levels 1
• Screening for diabetes mellitus with plasma glucose and HbA1c 1

Common Pitfalls to Avoid

Never delay treatment for diagnostic procedures when adrenal crisis is suspected—mortality increases with delayed intervention. 1, 2

Under-replacement with mineralocorticoids is common and predisposes to recurrent adrenal crises. 1

Do not rely solely on electrolyte abnormalities for diagnosis:

• Hyponatremia may be only marginally reduced 1
• Hyperkalemia is present in only ~50% of cases 1, 4
• 10-20% have mild hypercalcemia at presentation 1, 2

Exogenous steroid use (including inhaled steroids) can suppress the HPA axis and confound testing. 1, 2