Diagnosing Primary Adrenal Insufficiency
The diagnosis of primary adrenal insufficiency requires paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, with cortisol <250 nmol/L (<9 μg/dL) and elevated ACTH being diagnostic in the setting of acute illness. 1
Initial Diagnostic Approach
When to Suspect Primary Adrenal Insufficiency
- Consider the diagnosis in any patient presenting with unexplained collapse, hypotension, vomiting, or diarrhea 1
- Hyperpigmentation is a key distinguishing feature of primary (not secondary) adrenal insufficiency 1
- Hyponatremia is present in 90% of newly diagnosed cases, but hyperkalemia occurs in only ~50% of patients—do not rely on electrolytes alone to make or exclude the diagnosis 2
- Fatigue (50-95%), nausea/vomiting (20-62%), and weight loss (43-73%) are common but nonspecific presenting symptoms 3
Critical First Step
Treatment of suspected acute adrenal insufficiency should NEVER be delayed by diagnostic procedures. 1, 2 If the patient is clinically unstable with suspected adrenal crisis, immediately administer:
- IV hydrocortisone 100 mg bolus, followed by 100 mg every 6-8 hours 1, 4
- 0.9% sodium chloride solution at 1 L/hour until hemodynamic improvement 1
- Draw blood for cortisol and ACTH before treatment if possible, but do not delay therapy 2
Diagnostic Testing Algorithm
Step 1: Baseline Morning Cortisol and ACTH
Obtain early morning (8 AM) paired measurements of serum cortisol and plasma ACTH 1, 3:
Diagnostic thresholds for primary adrenal insufficiency:
- Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness = diagnostic 1, 2
- Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH in acute illness = strong suspicion 1
- Cortisol >500 nmol/L (>18 μg/dL) effectively rules out adrenal insufficiency 2
Important caveat: Approximately 10% of patients with confirmed primary adrenal insufficiency may present with normal cortisol concentrations but clearly elevated ACTH—do not dismiss the diagnosis based on cortisol alone if clinical suspicion is high 5
Step 2: Cosyntropin (Synacthen) Stimulation Test
When to perform: If baseline cortisol is indeterminate (between 250-500 nmol/L or 9-18 μg/dL) 1, 2
Protocol:
- Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 1, 2
- Measure serum cortisol at baseline and at 30 and/or 60 minutes post-administration 1
- Peak cortisol <500-550 nmol/L (<18-20 μg/dL) is diagnostic of adrenal insufficiency 1, 2
- Peak cortisol >550 nmol/L (>20 μg/dL) is considered normal 1, 2
Critical pitfall: Exogenous steroids (oral prednisolone, dexamethasone, inhaled fluticasone) can suppress the HPA axis and confound test results 1, 2. If you must treat suspected adrenal crisis but still need diagnostic testing, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 2
Step 3: Additional Laboratory Findings
Supportive findings in primary adrenal insufficiency:
- Elevated plasma ACTH (distinguishes primary from secondary) 1, 3
- Low DHEAS levels 3
- Hyponatremia (90% of cases) 2
- Hyperkalemia (~50% of cases) 1, 2
- Metabolic acidosis 1
- Hypoglycemia 1
- Mildly elevated TSH (4-10 IU/L) due to lack of cortisol's inhibitory effect on TSH production 1
Determining the Etiology
Step 1: Measure 21-Hydroxylase (Anti-Adrenal) Autoantibodies
This is the first test to determine etiology, as autoimmunity accounts for ~85% of primary adrenal insufficiency cases in Western populations 1, 2
Step 2: If Autoantibodies Are Negative
- Obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, fungal infections, or other structural abnormalities 1, 2
- In male patients, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy 1, 2
Step 3: Consider APS-1 in Children and Young Adults
The diagnosis of autoimmune polyglandular syndrome type 1 (APS-1) should be considered in children and young persons presenting with primary adrenal insufficiency plus other manifestations (hypoparathyroidism, chronic mucocutaneous candidiasis) 1:
Special Diagnostic Considerations
Distinguishing Primary from Secondary Adrenal Insufficiency
Primary adrenal insufficiency:
- Low cortisol + high ACTH 2, 3
- Mineralocorticoid deficiency present (hyponatremia, hyperkalemia) 1, 3
- Hyperpigmentation present 1
Secondary adrenal insufficiency:
- Low cortisol + low or inappropriately normal ACTH 2, 3
- No mineralocorticoid deficiency 3
- No hyperpigmentation 3
Adrenal Insufficiency vs. SIADH
Both conditions present with euvolemic hypo-osmolar hyponatremia and can be clinically indistinguishable 2. The cosyntropin stimulation test is medically necessary to rule out adrenal insufficiency before diagnosing SIADH, as hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases 2
Treatment Initiation
Chronic Replacement Therapy
Glucocorticoid replacement:
- Hydrocortisone 15-25 mg daily in split doses (first dose immediately upon waking, last dose at least 6 hours before bedtime) 1, 6, 4, 7
- Alternative: Prednisone 3-5 mg daily 3, 7
- In children: Hydrocortisone 6-10 mg/m² body surface area 1
Mineralocorticoid replacement (primary adrenal insufficiency only):
- Fludrocortisone 50-200 μg daily as a single dose 1, 6, 3
- Children and younger adults may require higher doses 1
- Advise patients to take salt and salty foods ad libitum 1
Patient Education and Safety
All patients must receive:
- Medical alert identification jewelry and steroid alert card 1, 2
- Education on stress dosing during illness 2, 3
- Injectable hydrocortisone 100 mg for self-administration or emergency use 1, 3
- Instructions to double or triple glucocorticoid dose during minor to moderate concurrent illnesses 1
Follow-Up Monitoring
Annual review should include: 1