Cosyntropin Stimulation Test for Evaluation of Posaconazole Induced Inhibition of 11 Beta-Hydroxylase

Antifungals, keto- and itra-conazole, cause primary adrenal insufficiency (PAI) due to inhibition of the steroidogenesis enzymes including 11 beta-hydroxylase (CYP11B1). Posaconazole (POS), a second-generation triazole agent with broad-spectrum antifungal activity is preferred for prevention and treatment of invasive fungal infection. However, POS has also been associated with PAI. Here we present a case describing the evaluation of adrenal insufficiency (AI) with a cosyntropin stimulation test (CST) in a patient who had both exposure to long term exogenous steroids and POS. PAI versus POS induced CYP11B1 inhibition was evaluated by the level of 11-deoxycortisol (Compound “S”), and the ratio of cortisol (compound “F”) to 11-deoxycortisol (i.e., F/S ratio) after CST.

Case Description:

70-year-old man with acute myelocytic leukemia, post bone marrow transplantation, on treatment for graph versus host disease with chronic prednisone (5mg daily) and budesonide (3mg TID), and on chronic POS prophylaxis (300 mg daily), was admitted for weakness and symptom of orthostatic hypotension, hyponatremia, and an episode of hypoglycemia after glargine insulin 15 units (glucose 40mg/dL). Physical examination was significant for cachexia. There was no hyperpigmentation. To evaluate for causes of possible adrenal insufficiency, a 250 mcg intravenous CST was performed 2 hours after administering his usual dose of POS. Serum cortisol levels were 2.0 mcg/dL (55 nmol/L) at baseline, and 7.7 mcg/dL (213 nmol/L) at 60 minutes (normal response >18 mcg/dL, 500 nmol/L), and serum 11- deoxycortisol levels were < 10 ng/dL ( < 0.3 nmol/L) at baseline and 121 ng/dL (3.3 nmol/L) at 60 minutes, and the F/S ratio after CST was 64. Clinically significant CYP11B1 blockade has been previously defined as a baseline 11- deoxycortisol >8 nmol/L and a post CST F/S ratio of < 21. After Palliative Medicine consultation, patient was converted to comfort care, and he expired two days later.

Discussion:

A CST was performed. It was expected that in PAI both “F” and “S” would be suppressed after cosyntropin. A normal range for non-stimulated 11- deoxycortisol is < 8 nmol/L and F/S ratios have been described as >100 to >300. Post CST, a normal response is F/S ratio >21. In this case, the low baseline level of cortisol with a partial increase post CST suggested that the prolonged steroid use was associated with secondary AI. This case did not confirm that POS was involved in causing PAI through blockade of CYP11B1. Future CST studies should be performed to assess the appropriate range of responses of cortisol and 11-deoxycortisol in controls and in those patients on azole type anti-fungal agents.