How do you diagnose adrenal insufficiency in a patient with a history of chronic steroid use for conditions like asthma or rheumatoid arthritis?

Diagnosing Adrenal Insufficiency in Patients with Chronic Steroid Use

In patients with chronic steroid use for asthma or rheumatoid arthritis, you cannot reliably diagnose adrenal insufficiency while they are actively taking corticosteroids—you must wait until treatment is discontinued with adequate washout time, then obtain early morning (8 AM) cortisol and ACTH levels, followed by cosyntropin stimulation testing if results are indeterminate. 1, 2

Critical Pitfall: Testing While On Steroids

• Morning cortisol measurements in patients actively taking corticosteroids are not diagnostic because the assay measures both endogenous cortisol and therapeutic steroids, with cross-reactivity varying by assay. 1
• Patients on corticosteroids will have low morning cortisol as a result of iatrogenic secondary adrenal insufficiency, with ACTH also suppressed—this is expected and not diagnostic. 1
• Laboratory confirmation of adrenal insufficiency should not be attempted until corticosteroid treatment is ready to be discontinued and sufficient washout time has elapsed. 1
• Glucocorticoids (including prednisone) and spironolactone may falsely elevate plasma cortisol levels and must be stopped on the day of cosyntropin testing, with long-acting glucocorticoids requiring longer washout periods. 3

When to Suspect Steroid-Induced Adrenal Insufficiency

Unexplained hypotension should raise immediate suspicion for adrenal insufficiency in any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks. 1, 4

Key Clinical Features That Distinguish Steroid-Induced AI:

• Morning nausea and lack of appetite are particularly common symptoms indicating under-replacement of glucocorticoids. 4
• Absence of hyperpigmentation (no elevated ACTH to stimulate melanocytes) distinguishes this from primary adrenal insufficiency. 4
• Hyperkalemia is notably ABSENT in steroid-induced adrenal insufficiency because aldosterone secretion is preserved, unlike primary adrenal insufficiency. 4
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, making it a highly sensitive marker. 1, 4
• Fatigue (50-95%), nausea and vomiting (20-62%), and anorexia with weight loss (43-73%) are common but nonspecific. 2

Diagnostic Algorithm After Steroid Discontinuation

Step 1: Initial Morning Testing (8 AM)

• Obtain paired early morning serum cortisol and plasma ACTH measurements as first-line diagnostic tests. 1, 2
• Include basic metabolic panel to assess for hyponatremia (hyperkalemia will be absent in secondary AI). 1
• Also measure DHEAS levels—low or low-normal DHEAS with low cortisol and low/low-normal ACTH suggests secondary or glucocorticoid-induced adrenal insufficiency. 2

Step 2: Interpret Morning Cortisol Results

• Morning cortisol >13 mcg/dL (>360 nmol/L) reliably rules out adrenal insufficiency. 5
• Morning cortisol <5 mcg/dL (<140 nmol/L) with elevated ACTH indicates primary adrenal insufficiency (not steroid-induced). 2
• Morning cortisol 5-10 mcg/dL (140-275 nmol/L) with low or inappropriately normal ACTH suggests secondary or glucocorticoid-induced adrenal insufficiency and requires confirmatory testing. 1, 2
• Morning cortisol <250 nmol/L (<9 mcg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 1

Step 3: Cosyntropin Stimulation Test (If Morning Cortisol Indeterminate)

The cosyntropin stimulation test is the gold standard for confirming adrenal insufficiency when initial results are indeterminate. 1

Test Protocol:

• Administer 0.25 mg (250 mcg) cosyntropin intramuscularly or intravenously. 1, 3, 2
• Obtain baseline serum cortisol before administration. 3
• Measure serum cortisol at exactly 30 minutes and 60 minutes post-administration. 1, 3
• The test should preferably be performed in the morning, although not strictly necessary. 1

Interpretation:

• Peak cortisol <500 nmol/L (<18 mcg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency. 1, 2
• Peak cortisol >550 nmol/L (>18-20 mcg/dL) is considered normal and excludes adrenal insufficiency. 1
• The high-dose (250 mcg) test is recommended over the low-dose (1 mcg) test due to easier practical administration, comparable diagnostic accuracy, and FDA approval. 1

Important Considerations for Testing Accuracy

• Stop all glucocorticoids on the day of cosyntropin testing—long-acting glucocorticoids may need to be stopped for a longer period before testing. 3
• Estrogen-containing drugs increase cortisol binding globulin levels and should be stopped four to six weeks before testing to allow levels to return to normal. 3
• Inhaled corticosteroids (e.g., fluticasone) can also affect test results and suppress the HPA axis. 1, 4
• Approximately one-third to one-half of patients taking 5-20 mg prednisolone daily fail to achieve target cortisol concentrations on cosyntropin testing, even when they may have adequate adrenal reserve. 1

Emergency Management: Never Delay Treatment

Treatment of suspected acute adrenal insufficiency should NEVER be delayed for diagnostic procedures if the patient is clinically unstable. 1, 4, 2

If Adrenal Crisis Suspected:

• Give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour (at least 2L total). 1
• Draw blood for cortisol and ACTH before treatment if possible, but do not delay treatment. 1
• If you need to treat suspected adrenal crisis but still want to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 1

Clinical Red Flags for Adrenal Crisis:

• Unexplained collapse, hypotension, and gastrointestinal symptoms (vomiting or diarrhea). 1
• Vasopressor-resistant hypotension in critically ill patients. 1
• Severe weakness, confusion, altered mental status, or loss of consciousness. 1

Management After Diagnosis Confirmation

If Adrenal Insufficiency Confirmed:

• Lifelong glucocorticoid replacement therapy is required with hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at 12 PM, 2.5-5 mg at 4 PM) or prednisone 3-5 mg daily. 6, 1, 2
• Mineralocorticoid replacement with fludrocortisone is NOT needed in secondary/steroid-induced adrenal insufficiency because aldosterone secretion is preserved. 1, 2
• All patients require education on stress dosing (doubling or tripling dose during illness, fever, or physical stress). 1
• Prescribe injectable hydrocortisone 100 mg IM kit with self-injection training for emergencies. 1, 2
• Patients must wear a medical alert bracelet or necklace indicating adrenal insufficiency. 1, 2

Recovery Timeline:

• In cases of long-term steroid exposure, consult endocrinology for a recovery and weaning protocol using hydrocortisone rather than attempting abrupt discontinuation. 1
• Test for HPA axis recovery after 3 months of maintenance therapy with hydrocortisone in patients with isolated central adrenal insufficiency from steroid use. 1
• Wait until the patient has been weaned off corticosteroids before performing definitive HPA axis testing. 1

Special Consideration: Concurrent Hypothyroidism

If both adrenal insufficiency and hypothyroidism are present, corticosteroids must be started several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1, 7

• Starting thyroid hormone in a patient with undiagnosed adrenal insufficiency can unmask or worsen adrenal crisis by increasing metabolic demands. 7
• This is particularly important in patients with autoimmune thyroid disease who are at increased risk for developing primary adrenal insufficiency. 7