A 49-year-old man presents with 3 months of generalized weakness. He has had a chronic cough and a 20 pound unintentional weight loss over the past 6 months. He has a medical history significant for high blood pressure, hyperlipidemia, and seasonal allergies with no prior surgical history. He has no history of tobacco use. He moved from India 7 years prior to presentation. He currently lives in Oregon and has not left the west coast since moving. His temperature is 99°F (37.2°C), blood pressure is 100/70 mmHg, pulse is 76/min, and respirations are 16/min. His physical exam is significant for hyperpigmentation of the oral mucosa and temporal muscle wasting. Radiography of the abdomen demonstrates bilateral adrenal calcifications. Laboratory values are as follows:

Serum:
Na+: 130 mEq/L
Cl-: 96 mEq/L
K+: 5.2 mEq/L
HCO3-: 24 mEq/L
Morning cortisol: 2 ug/dL
30-minute cortisol during cosyntropin test: 8 ug/dL (normal > 18 ug/dL)
Morning adrenocorticotropic hormone (ACTH) concentration (serum): 80 pg/mL (normal 10-60 pg/mL)

Which of the following is the most appropriate next step in management?
Prednisone taper
Bilateral adrenalectomy, prednisone, and fludrocortisone
Rifamycin, isoniazid, pyrazinamide, ethambutol, and hydrocortisone therapy
Hydrocortisone and immunoglobulin therapy
Rifamycin, isoniazid, pyrazinamide, ethambutol, and hydrocortisone therapy
This man from India presents with generalized weakness, chronic cough, unintentional weight loss, skin hyperpigmentation, hyponatremia, hyperkalemia, hypocortisolism, cosyntropin stimulation test failure, elevated ACTH, and bilateral adrenal calcifications on radiography. These symptoms and signs in this patient are most consistent with adrenal tuberculosis requiring RIPE therapy (rifamycin, isoniazid, pyrazinamide, ethambutol) as well as glucocorticoid and mineralocorticoid therapy.

Adrenal insufficiency occurs when the adrenal glands do not produce enough cortisol and aldosterone. Primary adrenal insufficiency is due to dysfunction at the level of the adrenal glands themselves, as opposed to upstream factors such as the pituitary gland. Primary adrenal insufficiency in developed nations is most often caused by autoimmune disease. In developing nations, adrenal tuberculosis is a significant cause of primary adrenal insufficiency. Adrenal tuberculosis often presents with a history of tuberculosis or tuberculosis symptoms, as well as symptoms of adrenal insufficiency such as fatigue, unintentional weight loss, and hyperpigmentation. Patients often have hyponatremia, hyperkalemia, low morning cortisol, a failed cosyntropin test, and high ACTH concentrations. Radiography may demonstrate bilateral adrenal calcifications, and/or adrenal enlargement. Tuberculosis can infect all cortices of the adrenal glands bilaterally, and therefore treatment requires eradicating the infection with multi-drug therapy (RIPE therapy) as well as replacement of glucocorticoids and mineralocorticoids, which may be achieved by high-dose hydrocortisone or other combinations of steroids that together provide glucocorticoid and mineralocorticoid replacement.

Vinnard and Blumberg outline the signs and symptoms, histopathology, lab results, imaging, differential diagnosis, and treatments associated with adrenal tuberculosis. They recommend early recognition and treatment.

Incorrect Answers:
Answer A: Bilateral adrenalectomy, prednisone therapy, and fludrocortisone therapy are incorrect because medical therapy should first be attempted to eradicate the infection before undergoing surgery. Bilateral adrenalectomy may be considered if there is suspicion of lung cancer with metastasis to the bilateral adrenal glands. Patients will require lifelong replacement therapy.

Answer B: Dexamethasone alone is incorrect because this patient likely has tuberculosis and should be treated for it. Additionally, this patient has signs of mineralocorticoid deficiency (hyponatremia, hyperkalemia), and patients often require mineralocorticoid therapy or a high dose of a glucocorticoid with mineralocorticoid activity (e.g., hydrocortisone). Dexamethasone has minimal to absent mineralocorticoid activity.

Answer C: Hydrocortisone therapy and immunoglobulin therapy are incorrect because this patient has adrenal tuberculosis. Although autoimmune adrenalitis can cause primary adrenal insufficiency, immunoglobulins are not used to treat this condition.

Answer D: Prednisone taper would be appropriate for acute conditions such as an asthma or COPD exacerbation. While prednisone will treat the symptoms of primary adrenal insufficiency, it will not treat active tuberculosis infection. Primary adrenal insufficiency in developed nations is most often caused by autoimmune adrenalitis (Addison disease) and presents with fatigue, unintentional weight loss, abdominal pain, hyperpigmentation, and muscle weakness. In this condition, long-term steroid therapy is indicated.

Bullet Summary:
Patients with adrenal tuberculosis should be treated with rifamycin, isoniazid, pyrazinamide, ethambutol, as well as glucocorticoid and mineralocorticoid replacement.