What are the features of steroid-induced adrenal insufficiency?

Features of Steroid-Induced Adrenal Insufficiency

Steroid-induced adrenal insufficiency presents with nonspecific symptoms including fatigue, nausea, vomiting, and anorexia, and is characterized biochemically by low or intermediate morning cortisol (5-10 µg/dL) with low or inappropriately normal ACTH levels, distinguishing it from primary adrenal insufficiency. 1

Clinical Presentation

Common Symptoms

• Fatigue occurs in 50-95% of patients with adrenal insufficiency and is the most frequent presenting complaint 1
• Nausea and vomiting affect 20-62% of patients, often accompanied by poor appetite and weight loss 1
• Anorexia and weight loss occur in 43-73% of cases, representing significant glucocorticoid deficiency 1
• Morning nausea and lack of appetite are particularly common and may indicate under-replacement of glucocorticoids 2

Gastrointestinal Features

• Nonspecific gastrointestinal symptoms are common presenting features after steroid withdrawal or tapering 3
• Periumbilical abdominal pain may occur, particularly in acute presentations 4
• Vomiting can be prominent and contributes to electrolyte disturbances 4

Cardiovascular Manifestations

• Unexplained hypotension should raise immediate suspicion for adrenal insufficiency in any patient taking ≥20 mg/day prednisone or equivalent for at least 3 weeks 2
• Hypotension may progress to shock if untreated, representing adrenal crisis 1

Laboratory Features

Cortisol and ACTH Patterns

• Low or intermediate morning cortisol levels (5-10 µg/dL) are characteristic, distinguishing steroid-induced from primary adrenal insufficiency which typically shows cortisol <5 µg/dL 1
• ACTH levels are low or inappropriately normal (not elevated as in primary adrenal insufficiency), confirming central suppression of the hypothalamic-pituitary-adrenal axis 1, 5
• Low DHEAS levels accompany the low cortisol and ACTH 1

Electrolyte Abnormalities

• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, making it a highly sensitive marker 2, 4
• Hyperkalemia is notably ABSENT in steroid-induced adrenal insufficiency because aldosterone secretion is preserved (unlike primary adrenal insufficiency where it occurs in ~50% of cases) 6, 4
• If vomiting is present, hypokalemia may occur instead of hyperkalemia due to gastrointestinal losses masking any tendency toward hyperkalemia 4
• Hypoglycemia may occur, particularly during acute illness or stress 6

Metabolic Features

• Hypercalcemia is a rare but well-documented complication of glucocorticoid-induced adrenal insufficiency, occurring when steroids are withdrawn 5
• Metabolic acidosis may be present in severe cases 6

Diagnostic Considerations

Key Distinguishing Features from Primary Adrenal Insufficiency

• Absence of hyperpigmentation (no elevated ACTH to stimulate melanocytes) 6
• Preserved aldosterone function (no hyperkalemia or significant salt wasting) 4
• Low or normal ACTH rather than elevated 1, 5
• No associated autoimmune conditions typically seen with primary adrenal insufficiency 2

Confounding Factors

• Exogenous steroids including oral prednisolone, dexamethasone, and inhaled fluticasone confound interpretation of cortisol levels and must be considered when interpreting diagnostic tests 6, 2
• Morning cortisol measurements in patients currently on corticosteroids are not diagnostic, as therapeutic steroids may cross-react in cortisol assays 6
• Hydrocortisone must be held for 24 hours and other steroids for longer before endogenous adrenal function can be accurately assessed 6

Routes of Steroid Administration That Cause HPA Suppression

All Routes Can Suppress the HPA Axis

• Oral corticosteroids are the most common cause, particularly doses ≥20 mg/day prednisone equivalent for ≥3 weeks 6, 2
• Inhaled corticosteroids (particularly fluticasone) can suppress the HPA axis even at commonly prescribed doses in a dose-dependent manner 6, 7
• Intra-articular steroid injections can cause systemic absorption and subsequent HPA axis suppression, with recovery occurring within 2 weeks to months 3
• Intrathecal steroid administration has been documented to cause secondary adrenal insufficiency, with elevated steroid levels persisting in cerebrospinal fluid for up to 2 months 8
• Topical, intranasal, and intrabursal routes can all potentially suppress the HPA axis 6

Time Course and Recovery

Duration of HPA Suppression

• HPA axis suppression may persist for up to 12 months after discontinuation of therapy following large doses for prolonged periods 9
• Recovery of the HPA axis should be tested after 3 months of maintenance hydrocortisone therapy 6
• In some cases, recovery can occur as quickly as 2 weeks after diagnosis, though this is variable 3

Risk Factors for Prolonged Suppression

• Higher doses of glucocorticoids increase risk 6
• Longer duration of therapy increases risk 6
• Potent synthetic glucocorticoids (dexamethasone, betamethasone) carry higher risk than hydrocortisone 6

Critical Clinical Pitfalls

Common Diagnostic Errors

• Do not rely on the absence of hyperkalemia to exclude adrenal insufficiency—it is absent in steroid-induced cases and present in only ~50% of primary adrenal insufficiency 6, 4
• Do not assume normal electrolytes exclude the diagnosis—10-20% of patients have normal electrolytes at presentation 2
• Do not attempt laboratory confirmation of adrenal insufficiency in patients currently on high-dose corticosteroids until treatment is ready to be discontinued 6
• The threshold to test for adrenal insufficiency should be low in any patient with nonspecific symptoms after steroid use or withdrawal 3

Management Imperatives

• Treatment of suspected acute adrenal insufficiency should NEVER be delayed for diagnostic procedures if the patient is clinically unstable 6, 2
• If unstable, give 100 mg IV hydrocortisone immediately without waiting for test results 2, 4
• If diagnosis is uncertain but testing is still needed, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2
• All patients require education on stress dosing, emergency injectable steroids, and should wear medical alert identification 6, 1