What is the approach to diagnosing and treating adrenal insufficiency in adults?

Diagnosing and Treating Adrenal Insufficiency in Adults

Diagnostic Approach

The diagnosis of primary adrenal insufficiency requires paired measurement of serum cortisol and plasma ACTH, with a cortisol <250 nmol/L (<9 μg/dL) and elevated ACTH in the presence of acute illness being diagnostic. 1

Initial Clinical Suspicion

Consider adrenal insufficiency in patients presenting with:

• Unexplained collapse, hypotension, vomiting, or diarrhea 1
• Hyperpigmentation (specific to primary adrenal insufficiency) 1
• Hyponatremia (present in 90% of cases), hyperkalaemia, acidosis, or hypoglycaemia 1
• Fatigue (50-95%), nausea/vomiting (20-62%), anorexia and weight loss (43-73%) 2

Laboratory Diagnosis

Early morning (8 AM) testing:

• Serum cortisol <140 nmol/L (5 μg/dL) with elevated ACTH confirms primary adrenal insufficiency 1, 3
• Cortisol <250 nmol/L with increased ACTH in acute illness is diagnostic 1
• Cortisol <400 nmol/L with increased ACTH raises strong suspicion 1
• Measure DHEAS (low in primary adrenal insufficiency) 2

For equivocal cases (cortisol 5-10 μg/dL):

• Perform cosyntropin (synacthen) stimulation test: 0.25 mg IV or IM 1
• Peak serum cortisol <500 nmol/L (18 μg/dL) at 60 minutes is diagnostic 1, 2

Critical Rule: Never Delay Treatment

Treatment of suspected acute adrenal insufficiency must never be delayed by diagnostic procedures. 1 Draw blood for cortisol and ACTH, then immediately initiate treatment if clinical suspicion is high 1.

Determining Etiology

Step 1: Measure 21-hydroxylase (anti-adrenal) autoantibodies 1

• Positive antibodies indicate autoimmune Addison's disease (most common cause) 1

Step 2: If antibodies are negative, obtain CT imaging of adrenals 1

• Look for calcifications (tuberculosis), tumors, hemorrhage, or infiltrative disease 1

Step 3: In male patients, measure very long-chain fatty acids 1

• Screens for adrenoleukodystrophy 1

Step 4: Consider APS-1 in young patients with:

• Hypoparathyroidism, candidiasis, or other autoimmune manifestations 1
• Confirm with anti-interferon omega antibodies or AIRE gene mutation analysis 1

Treatment Approach

Glucocorticoid Replacement

Most patients require 15-25 mg hydrocortisone daily in split doses, with the first dose immediately upon waking and the last dose at least 6 hours before bedtime. 1, 4

Dosing regimen:

• Take first dose immediately after waking 1, 4
• Divide into 2-3 doses throughout the day 1
• Last dose not less than 6 hours before bedtime 1
• Use the lowest dose compatible with health and well-being 1
• Children: 6-10 mg/m² body surface area 1, 4

Alternative: Cortisone acetate 18.75-31.25 mg daily (equivalent dosing) 1

Mineralocorticoid Replacement (Primary Adrenal Insufficiency Only)

Most patients require 50-200 μg fludrocortisone as a single daily morning dose. 1, 4

Dose adjustment based on:

• Increase dose if: Hyponatremia, hyperkalemia, orthostatic hypotension despite adequate sodium intake, persistent salt cravings 5, 6
• Decrease dose if: Hypertension develops, peripheral edema, supine hypertension 5, 6
• Never stop completely even if hypertension develops—reduce dose instead 1, 6

Monitoring parameters:

• Blood pressure (supine and standing positions) 5, 6
• Serum sodium and potassium 1, 6
• Body weight 1
• Clinical symptoms (salt cravings, lightheadedness, edema) 5, 6

Dietary Recommendations

• Advise patients to take salt and salty foods ad libitum 1, 6
• Avoid liquorice and grapefruit juice (potentiate mineralocorticoid effects) 1, 6
• Avoid potassium-containing salt substitutes 6

Management of Adrenal Crisis

Adrenal crisis requires immediate treatment with IV or IM hydrocortisone 100 mg, followed by 100 mg every 6-8 hours until recovered. 1, 4

Emergency protocol:

1. Administer hydrocortisone 100 mg IV or IM bolus immediately 1
2. Continue 100 mg every 6-8 hours (or 100-300 mg/day as continuous infusion) 1
3. Infuse isotonic (0.9%) sodium chloride at 1 L/hour initially until hemodynamic improvement 1
4. Administer 3-4 L isotonic saline over 24-48 hours with frequent hemodynamic monitoring 1
5. Seek underlying precipitant (infection, trauma, surgery) once treatment initiated 1
6. Taper parenteral glucocorticoids over 1-3 days to oral maintenance dose 1
7. Restart fludrocortisone when hydrocortisone dose falls to <50 mg/day 1

Patient Education and Safety Measures

All patients must:

• Wear Medic Alert identification jewelry 1, 4
• Carry a steroid/alert card 1, 4
• Receive supplies for self-injection of parenteral hydrocortisone 1
• Learn to double or triple oral hydrocortisone during minor illnesses 1
• Understand when to seek emergency care 1

Stress Dosing

Surgery and invasive procedures require IV or IM hydrocortisone and increased oral doses. 1

• Major surgery: 100 mg hydrocortisone IV every 6-8 hours 1
• Minor procedures: Double or triple usual oral dose 1

Pregnancy adjustments:

• Small adjustments to hydrocortisone and fludrocortisone may be needed, particularly in the last trimester 1, 5
• Parenteral hydrocortisone should be given during delivery 1

Follow-Up Care

Patients should be reviewed at least annually with:

• Assessment of health and well-being 1, 4
• Measurement of weight and blood pressure 1, 4
• Serum electrolytes 1, 4
• Screening for new autoimmune disorders (particularly hypothyroidism) 1
• Bone mineral density monitoring every 3-5 years 1, 4

Common Pitfalls to Avoid

• Delaying treatment while awaiting diagnostic test results in suspected adrenal crisis 4—this can be fatal 1
• Stopping fludrocortisone completely when hypertension develops—reduce dose instead 1, 6
• Under-replacement with mineralocorticoids—this is common and predisposes to recurrent adrenal crises 6
• Failing to adjust glucocorticoid doses during illness, surgery, or stress 4
• Using plasma ACTH or serum cortisol for dose adjustment of maintenance therapy—these are not useful for monitoring 1