What is the recommended treatment protocol for tuberculosis adrenalitis, including anti‑TB therapy and glucocorticoid/mineralocorticoid replacement?

Treatment Protocol for Tuberculosis Adrenalitis

Tuberculosis adrenalitis requires standard four-drug anti-TB therapy for 6–9 months combined with lifelong glucocorticoid and mineralocorticoid replacement, with critical attention to increased hydrocortisone dosing during rifampicin therapy due to accelerated cortisol metabolism.

Anti-Tuberculosis Chemotherapy

Initial Intensive Phase (First 2 Months)

• Administer daily isoniazid, rifampicin, pyrazinamide, and ethambutol for the first 2 months in all adults with TB adrenalitis 1
• This four-drug regimen is necessary because of the relatively high proportion of isoniazid-resistant organisms 1
• Ethambutol can be discontinued once drug susceptibility confirms full susceptibility to isoniazid and rifampicin 1

Continuation Phase (Months 3–6 or longer)

• Continue daily isoniazid and rifampicin for an additional 4–7 months (total treatment duration 6–9 months) 1
• For extrapulmonary TB including adrenal involvement, some experts recommend extending therapy toward 9 months rather than the standard 6-month pulmonary regimen 2
• Daily dosing is strongly preferred over intermittent regimens to maximize treatment completion 1

Drug Dosing

• Follow standard TB dosing guidelines as outlined in Tables 3,4, and 5 of the ATS/CDC/IDSA guidelines 1
• Monitor for hepatotoxicity from isoniazid, rifampicin, and pyrazinamide throughout therapy 1

Glucocorticoid Replacement Therapy

Initial Dosing

• Start hydrocortisone 15–25 mg daily divided into 2–3 doses (typically 10 mg morning, 5 mg afternoon, 5 mg evening) or equivalent glucocorticoid 3, 4
• Alternatively, use prednisone 5–7.5 mg daily or dexamethasone 0.5–0.75 mg daily 1

Critical Dose Adjustment During Rifampicin Therapy

• Increase hydrocortisone dosage by 50–100% (typically double the dose) when rifampicin is initiated because rifampicin is a potent CYP3A4 inducer that accelerates cortisol metabolism 4, 5
• This interaction can precipitate life-threatening adrenal crisis if not anticipated 4, 5
• Monitor for signs of adrenal insufficiency (fatigue, hypotension, hyponatremia) throughout rifampicin therapy 4, 5
• Return to standard replacement doses after completing rifampicin therapy 5

Stress Dosing

• Provide stress-dose steroids (hydrocortisone 100 mg IV every 8 hours) for acute illness, surgery, or trauma 3
• Educate patients to double or triple their usual dose during minor illnesses 5

Mineralocorticoid Replacement Therapy

Standard Dosing

• Initiate fludrocortisone 0.05–0.2 mg daily (typically 0.1 mg) for mineralocorticoid replacement 5
• TB adrenalitis causes primary adrenal insufficiency affecting both cortisol and aldosterone production 3, 4

Monitoring

• Monitor serum sodium, potassium, and blood pressure to guide fludrocortisone dosing 5
• Hyponatremia is present in 83.3% of TB patients with adrenal dysfunction and should normalize with appropriate replacement 6
• Measure plasma renin activity if mineralocorticoid dosing is uncertain 6

Biochemical Monitoring and Diagnosis Confirmation

Baseline Assessment

• Measure morning (8 AM) serum cortisol and paired plasma ACTH before initiating therapy 6
• Perform standard-dose ACTH stimulation test (250 mcg cosyntropin) to confirm primary adrenal insufficiency 2, 6
• Check plasma renin activity to assess mineralocorticoid deficiency 6

Imaging

• Obtain CT or MRI of the adrenal glands showing bilateral adrenal enlargement with peripheral rim enhancement ± calcifications, which are characteristic of TB adrenalitis 3
• Consider 18-FDG PET/CT if diagnosis is uncertain, which will show bilateral adrenal nodules with tracer accumulation 5

Follow-Up Testing

• Repeat ACTH stimulation tests every 6 months during and after anti-TB therapy 2
• Nearly 50% of TB patients have subclinical adrenal insufficiency at baseline, and 97% show recovery of adrenal function by 24 months of therapy 2
• However, patients with established TB adrenalitis (bilateral adrenal destruction) typically require lifelong hormone replacement even after successful TB treatment 3

Common Pitfalls and How to Avoid Them

Rifampicin-Induced Adrenal Crisis

• Never start rifampicin without simultaneously increasing glucocorticoid dosing in patients with known or suspected adrenal insufficiency 4, 5
• This is the most dangerous drug interaction in TB adrenalitis management 4, 5
• Patients may present with drowsiness, dehydration, and hypotension within days of starting rifampicin if hydrocortisone is not increased 4

Delayed Diagnosis

• Symptoms of adrenal insufficiency (fatigue, weight loss, hyperpigmentation) overlap with TB symptoms, leading to delayed recognition 3, 6
• Maintain high clinical suspicion in any TB patient with hyponatremia, hypotension, or nonspecific constitutional symptoms 6
• Adrenal dysfunction correlates with TB severity and duration—82.5% of patients with moderately advanced disease and 80% with far-advanced disease have adrenal dysfunction 6

Premature Discontinuation of Steroids

• Do not stop glucocorticoid replacement based on clinical improvement or completion of anti-TB therapy 3
• Assess adrenal recovery with ACTH stimulation testing before considering steroid withdrawal 2
• Most patients with established TB adrenalitis require lifelong replacement despite microbiological cure 3

Inadequate Patient Education

• Provide an Addison's emergency card documenting the need for stress-dose steroids and listing drug interactions (especially rifampicin) 5
• Instruct patients on sick-day rules and when to seek emergency care 5

Special Considerations

HIV Co-Infection

• Use corticosteroids with caution in HIV-positive patients with TB adrenalitis 1
• Monitor for opportunistic infections and hyperglycemia more closely 1

Pregnancy

• Pyrazinamide may be withheld in pregnancy, requiring a modified regimen of isoniazid, rifampicin, and ethambutol for 2 months followed by isoniazid and rifampicin for 7 months (total 9 months) 1
• Glucocorticoid and mineralocorticoid replacement should continue throughout pregnancy with stress-dose coverage for labor and delivery 1

Monitoring During Therapy

• Check liver function tests regularly due to hepatotoxicity risk from isoniazid, rifampicin, and pyrazinamide 1
• Monitor visual acuity if using ethambutol 1
• Assess electrolytes, blood pressure, and weight to guide mineralocorticoid dosing 5, 6

Prognosis and Recovery

• Subclinical adrenal insufficiency (impaired ACTH stimulation response) occurs in approximately 50% of TB patients and reverses with anti-TB therapy in 97% by 24 months 2
• However, patients with overt TB adrenalitis (bilateral adrenal destruction visible on imaging) typically have permanent adrenal failure requiring lifelong replacement 3
• Adrenal function recovery correlates inversely with disease severity and duration 6