General Principles

• Adrenal failure may be due to disease of the adrenal glands (primary adrenal failure, Addison disease), with deficiency of both cortisol and aldosterone and elevated plasma adrenocorticotropic hormone (ACTH), or due to ACTH deficiency caused by disorders of the pituitary or hypothalamus (secondary adrenal failure), with deficiency of cortisol alone.
• Primary adrenal failure is most often due to autoimmune adrenalitis, which may be associated with other endocrine deficits (e.g., hypothyroidism).
• Adrenal failure may also develop in patients with infiltrative or infectious diseases of the adrenal glands, such as adrenal lymphoma, metastases, disseminated cytomegalovirus, mycobacterial infection, or fungal infection. Some of the causative infections are more common in immunosuppressed individuals.
• Hemorrhagic adrenal infarction may occur in the postoperative period, in coagulation disorders and hypercoagulable states, and in sepsis. Adrenal hemorrhage often causes abdominal or flank pain and fever; CT scan of the abdomen reveals high-density bilateral adrenal masses.
• Less common etiologies include adrenoleukodystrophy that causes adrenal failure in young men and drugs such as ketoconazole and etomidate that inhibit steroid hormone synthesis.
• Secondary adrenal failure is most often due to glucocorticoid therapy. Any patient who has been treated with greater than physiologic replacement doses of glucocorticoids for more than a few months should be considered to have secondary adrenal failure until proven otherwise. This can be investigated by tapering to a physiologic steroid dose and then performing a cosyntropin stimulation test. ACTH suppression may persist for a year after therapy is stopped. Any disorder of the pituitary or hypothalamus can cause ACTH deficiency, but other evidence of these disorders is usually obvious.
• Checkpoint inhibitors commonly used for immunotherapy to treat various cancers can cause hypophysitis or, less commonly, adrenalitis, potentially leading to secondary or primary adrenal failure, respectively.