What are the next steps in managing a patient with primary adrenal insufficiency and no adrenal masses on abdominal CT, who is on hydrocortisone (corticosteroid) and fludrocortisone (mineralocorticoid) replacement therapy?

Management of Primary Adrenal Insufficiency with No Adrenal Masses on CT

Continue hydrocortisone and fludrocortisone replacement therapy with regular monitoring of blood pressure, electrolytes, and plasma renin activity, while investigating the underlying etiology and providing comprehensive patient education on stress-dose adjustments to prevent adrenal crisis. 1

Etiologic Investigation

Since the abdominal CT showed no adrenal masses, the next critical step is determining the underlying cause:

• Test for 21-hydroxylase autoantibodies (21OH-Ab), which are positive in autoimmune Addison disease, accounting for approximately 85% of primary adrenal insufficiency cases in Western Europe 2
• If 21OH-Ab is negative, measure very long chain fatty acids (VLCFA) to evaluate for adrenoleukodystrophy 2
• Consider testing for tuberculosis and other infiltrative processes if clinically indicated, though the negative CT makes these less likely 1

The absence of adrenal masses on CT effectively rules out hemorrhage, tumor, and most infiltrative processes, making autoimmune adrenalitis the most probable diagnosis 2.

Optimization of Replacement Therapy

Glucocorticoid Monitoring

• Maintain hydrocortisone 15-25 mg daily in 2-3 divided doses (typically 10 mg morning, 5 mg afternoon, 5 mg evening or 10 mg morning, 5 mg afternoon) 1
• Monitor for signs of under-replacement: weight loss, fatigue, hyperpigmentation, postural hypotension 1
• Monitor for signs of over-replacement: weight gain (especially truncal), peripheral edema, hypertension 3
• Perform morning cortisol day curve (before and 2,4, and 6 hours after morning dose) if rapid cortisol clearance is suspected 1

Mineralocorticoid Optimization

Fludrocortisone 50-200 µg daily (typically 100 µg) taken as a single morning dose is the standard replacement 1, 4. The dose should be titrated based on:

• Blood pressure measurement in both supine and standing positions - postural hypotension indicates insufficient mineralocorticoid replacement 1, 4
• Serum sodium and potassium levels - aim for normal electrolytes 1
• Plasma renin activity (PRA) - target the upper normal range 5, 6
• Absence of salt craving - persistent salt craving suggests under-replacement 1
• Absence of peripheral edema - edema suggests over-replacement 1

Under-replacement of mineralocorticoids is common and sometimes compensated for by over-replacement of glucocorticoids, which predisposes patients to recurrent adrenal crises 1, 3. This is a critical pitfall to avoid.

Regular Monitoring Schedule

Annual Follow-up Should Include:

• Thyroid function tests (TSH, FT4, TPO-Ab) every 12 months, as autoimmune hypothyroidism frequently develops in patients with autoimmune adrenal insufficiency 1
• Fasting glucose and HbA1c to screen for diabetes mellitus 1
• Complete blood count to detect pernicious anemia or other autoimmune cytopenias 1
• Serum sodium, potassium, and creatinine to assess adequacy of mineralocorticoid replacement 1

At Each Visit:

• Measure blood pressure supine and standing - orthostatic hypotension is an early warning sign of inadequate mineralocorticoid replacement 4, 2
• Assess weight trends - weight loss suggests under-replacement, weight gain suggests over-replacement 1
• Evaluate skin pigmentation - normal skin color indicates adequate replacement 1

Critical Patient Education to Prevent Adrenal Crisis

The frequency of acute adrenal crises is 6-8 per 100 patient-years, with precipitating events often being vomiting/diarrhea, infections, surgical procedures, or injuries 1. Patient education is paramount to preventing these life-threatening emergencies 2.

Stress-Dose Guidelines:

• Minor illness (fever, cold, gastroenteritis): Double or triple the usual hydrocortisone dose 2, 5
• Vomiting or inability to take oral medications: Use parenteral hydrocortisone immediately and seek emergency care 1, 2
• Major surgery or severe illness: Requires hospitalization with IV hydrocortisone 100 mg bolus followed by 100-300 mg/day 1

Essential Patient Instructions:

• Provide medical alert jewelry and emergency steroid card to trigger stress-dose corticosteroids by emergency personnel 2
• Instruct patient to carry adequate supply of medication for emergencies 1
• Teach patient and family members how to administer intramuscular hydrocortisone for emergencies when oral intake is impossible 2
• Emphasize unrestricted sodium intake and avoidance of potassium-containing salt substitutes 1, 3

Important Drug Interactions to Avoid

• Diuretics, acetazolamide, NSAIDs, licorice, and grapefruit juice should be avoided as they interact with fludrocortisone 1, 3, 7
• Anti-epileptics, barbiturates, rifampin increase hydrocortisone metabolism and may require dose increases 1
• Never start thyroid hormone replacement before ensuring adequate glucocorticoid replacement, as this can trigger adrenal crisis 2

Special Considerations

• Chronic under-replacement with fludrocortisone combined with low salt consumption is a recognized cause of recurrent adrenal crises 1, 4
• Fludrocortisone dose may need adjustment in younger adults (sometimes requiring up to 500 µg daily) or during pregnancy (increased in third trimester due to progesterone's anti-mineralocorticoid effects) 1, 3
• If essential hypertension develops, add a vasodilator rather than stopping mineralocorticoid replacement, though consider dose reduction 1