What is the appropriate diagnostic approach for a patient with suspected adrenal crisis (possible primary or secondary adrenal insufficiency)?

Diagnostic Approach for Suspected Adrenal Crisis

In a patient with suspected adrenal crisis, immediately draw blood for serum cortisol and plasma ACTH before administering treatment, but never delay emergency glucocorticoid therapy to wait for diagnostic test results 1.

Immediate Diagnostic Steps in Acute Presentation

When a patient presents with unexplained collapse, hypotension, vomiting, diarrhea, or shock, you must consider adrenal insufficiency in your differential 1. The diagnostic approach differs critically based on whether the patient is acutely ill or stable.

In the Acutely Ill Patient (Suspected Adrenal Crisis)

Draw blood immediately for:

• Serum cortisol
• Plasma ACTH
• Serum electrolytes (sodium, potassium)
• Blood glucose

Then treat immediately without waiting for results 1.

Diagnostic thresholds in acute illness:

• Serum cortisol <250 nmol/L (<9 µg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 1
• Serum cortisol <400 nmol/L (<14.5 µg/dL) with elevated ACTH raises strong suspicion of primary adrenal insufficiency 1
• In acute illness, cortisol levels within the "normal range" may still be inappropriately low for the stress state, particularly in sepsis 1

Distinguishing Primary vs Secondary Adrenal Insufficiency

Primary adrenal insufficiency is characterized by:

• Low cortisol (<140 nmol/L or <5 µg/dL)
• Markedly elevated ACTH (>2-fold above upper limit, with >66 pmol/L representing maximal stimulus) 2
• Low DHEAS (well below age and sex-adjusted normal) 2, 3
• Hyponatremia (present in 90% of cases) 1
• Hyperkalaemia (in approximately 50% of cases) 1
• Hyperpigmentation (if chronic)

Secondary adrenal insufficiency is characterized by:

• Low or intermediate cortisol (5-10 µg/dL) 3
• Low or low-normal ACTH 3
• Low or low-normal DHEAS 3
• Hyponatremia may be present, but hyperkalaemia is absent
• No hyperpigmentation

Diagnostic Approach in the Stable Patient

Step 1: Initial Screening

Measure early morning (approximately 8 AM) levels of:

• Serum cortisol
• Plasma ACTH
• DHEAS (age and sex-adjusted) 2, 3

Interpretation:

• Morning cortisol <140 nmol/L (<5 µg/dL) with ACTH elevated >2-fold confirms primary adrenal insufficiency 2
• Morning cortisol >500 nmol/L (>18 µg/dL) effectively excludes adrenal insufficiency
• Morning cortisol 140-500 nmol/L (5-18 µg/dL) requires confirmatory testing 2, 4

DHEAS adds diagnostic value: Low DHEAS (well below age/sex norms) is a useful initial sign of primary adrenal insufficiency, though it cannot be used in isolation as levels may be low in older individuals without disease 2. Recent evidence suggests age-adjusted and sex-adjusted DHEAS may help rule out primary adrenal insufficiency in indeterminate cases 4.

Step 2: Confirmatory Testing (When Initial Results Are Equivocal)

Standard-dose cosyntropin (Synacthen) stimulation test is the gold standard for confirming primary adrenal insufficiency 2, 1:

Protocol:

• Administer 250 µg cosyntropin (tetracosactide) IV or IM as bolus
• Measure serum cortisol at baseline, 30 minutes, and 60 minutes
• Can be performed at any time of day (not affected by diurnal variation) 2

Interpretation:

• Peak stimulated cortisol <500 nmol/L (<18 µg/dL) is diagnostic of primary adrenal insufficiency 1
• Peak cortisol >500 nmol/L excludes primary adrenal insufficiency

Important caveats:

• The low-dose 1 µg cosyntropin test does not provide better diagnostic accuracy than the standard 250 µg test 2
• Results may be affected by cortisol-binding globulin (CBG) deficiency, glucocorticoid resistance, or hypersensitivity 2
• Exogenous steroids (prednisolone, dexamethasone, high-dose inhaled fluticasone) confound interpretation 1

For secondary adrenal insufficiency: The cosyntropin test is less reliable. Consider insulin tolerance test or overnight metyrapone test, which remain valuable with revised cortisol thresholds 4, 5.

Step 3: Determine Etiology (Once Adrenal Insufficiency is Confirmed)

For primary adrenal insufficiency:

1. Measure 21-hydroxylase (anti-adrenal) autoantibodies first 1 - autoimmune adrenalitis is the most common cause 6
2. If antibodies are negative, obtain CT imaging of adrenals 1
3. In male patients, assay very long-chain fatty acids to check for adrenoleukodystrophy 1
4. Consider tuberculosis, fungal infections, hemorrhage, or infiltrative disease based on imaging and clinical context 3

For secondary adrenal insufficiency:

• Obtain pituitary MRI to evaluate for tumors, hemorrhage, inflammatory or infiltrative conditions 3, 6
• Review medication history for opioids or other agents suppressing corticotropin production 3

Common Pitfalls to Avoid

1. Never delay treatment for diagnostic testing in suspected adrenal crisis - mortality is high if untreated 1
2. Do not rely solely on hyponatremia and hyperkalaemia - sodium is often only marginally reduced, and potassium is elevated in only 50% of cases 1
3. Beware of hypokalaemia and alkalosis in the presence of severe vomiting, which can mask the typical electrolyte pattern 1
4. Remember that "normal" cortisol may be inappropriately low in the context of acute illness or sepsis 1
5. Consider adrenal insufficiency in patients with refractory electrolyte imbalances, unexplained hypotension, or failure to improve with standard sepsis therapy 7, 8
6. Check for exogenous steroid use including inhaled corticosteroids, which can suppress the HPA axis and confound testing 1

Emerging Diagnostic Approaches

Recent evidence supports salivary cortisone as a practical, home-based screening alternative that circumvents cortisol-binding globulin variability 4. A multimodal approach combining baseline cortisol with adjunctive markers such as DHEAS and salivary cortisone may reduce reliance on dynamic testing while maintaining diagnostic accuracy 4.