Adrenal Failure8,9

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 fl ank 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.

DIAGNOSIS

Clinical Presentation

• Adrenal failure should be suspected in patients with otherwise unexplained hypotension, weight loss, persistent nausea, hyponatremia, hyperkalemia, or hypoglycemia.

• Clinicalfindings in adrenal failure are nonspecific, and without a high index of suspicion, the diagnosis of this potentially lethal but readily treatable disease is easily missed.

î Symptoms include anorexia, nausea, vomiting, weight loss, weakness, and fatigue. Orthostatic hypotension and hyponatremia are common.

î Symptoms are usually chronic, but shock may develop suddenly and is fatal unless promptly treated. Often, this adrenal crisis is triggered by illness, injury, or surgery. All these symptoms are due to cortisol deficiency and occur in both primary and secondary adrenal failure.

• Hyperpigmentation (because of marked ACTH excess) and hyperkalemia and volume depletion (because of aldosterone deficiency) occur only in primary adrenal failure.

Diagnostic Testing

• The cosyntropin (Cortrosyn) stimulation test is used for diagnosis. Cosyntropin, 250 #956;g, is given IV or IM, and plasma cortisol is measured 30 and 60 minutes later. The normal response is a stimulated plasma cortisol gt;18 #956;g#8725;dL. Newer monoclonal antibody immune assays or liquid chromatography­mass spectrometry (LC-MS)#8725;MS assays are more specific for cortisol, so a stimulated cortisol of 14­15 mg/dL is normal with these assays. This test detects primary and secondary adrenal failure, except within a few weeks of onset of pituitary dysfunction (e.g., shortly after pituitary surgery; see “Pituitary Adenomas and Hypopituitarism” section). Note that plasma cortisol is protein bound, and in situations where patients have very low albumin levels, cortisol levels may appear falsely low; thus, cosyntropin stimulation tests in these patients should be interpreted with caution.

• The clinical presentation usually helps to distinguish between primary and secondary adrenal failure. Hyperkalemia, hyperpigmentation, or other autoimmune endocrine deficits are more suggestive of primary adrenal failure, whereas deficits of other pituitary hormones, symptoms of a pituitary mass (e.g., headache, visual field loss), or known pituitary or hypothalamic disease are more suggestive secondary adrenal failure.

• If the cause is unclear, the plasma ACTH level distinguishes primary adrenal failure (in which it is markedly elevated) from secondary adrenal failure. High renin and low aldosterone levels are suggestive of primary adrenal insufficiency.

• Most cases of primary adrenal failure are due to autoimmune adrenalitis, but other causes should be considered. Radiographic evidence of adrenal enlargement or calcification indicates that the cause is infection or hemorrhage.

• Patients with secondary adrenal failure should be tested for other pituitary hormone deficiencies and should be evaluated for a pituitary or hypothalamic tumor (see “Pituitary Adenomas and Hypopituitarism” section).

TREATMENT

• Adrenal crisis with hypotension must be treated immediately. Patients should be evaluated for an

underlying illness that precipitated the crisis.

• If the diagnosis of adrenal failure is known, hydrocortisone, 100 mg IV q8h, should be given, and 0.9% saline with 5% dextrose should be infused rapidly until hypotension is corrected. The dose of hydrocortisone is decreased gradually over several days as symptoms and any precipitating illness resolve and then changed to oral maintenance therapy. Mineralocorticoid replacement is not needed until the dose of hydrocortisone is lt;100 mg/d.

• If the diagnosis of adrenal failure has not been established, a single dose of dexamethasone, 10 mg IV, should be given, and a rapid infusion of 0.9% saline with 5% dextrose should be started. A Cortrosyn stimulation test should be performed, regardless of the time of day.

• High-dose hydrocortisone provides sufficient mineralocorticoid activity to cover for suspected primary adrenal insufficiency until diagnosis is clarified.

• Maintenance therapy in all patients requires cortisol replacement with prednisone or hydrocortisone. Most patients with primary adrenal failure also require replacement of aldosterone with fludrocortisone.

î Prednisone, 5 mg PO every morning, or hydrocortisone 10 mg Qam and 5 mg Qpm should be started. The dose is then adjusted with the goal being the lowest dose that relieves the patient's symptoms, to prevent osteoporosis and other signs of Cushing syndrome. Most patients require doses between 4.0 and 7.5 mg PO daily. Concomitant therapy with rifampin, phenytoin, or phenobarbital accelerates glucocorticoid metabolism and increases the dose requirement.

° During illness, injury, or the perioperative period, the dose of glucocorticoid must be increased. For minor illnesses, the patient should double the dose of prednisone for 2-3 days. If the illness resolves, the maintenance dose is resumed.

î Vomiting requires immediate medical attention, with IV glucocorticoid therapy and IV fluid. Patients can be given a 4-mg vial of dexamethasone to be self-administered IM for vomiting or severe illness if medical care is not immediately available.

î For severe illness or injury, hydrocortisone, 50 mg IV q8h, should be given, with the dose tapered as severity of illness wanes. The same regimen is used in patients undergoing surgery, with the first dose of hydrocortisone given preoperatively. The dose can be tapered to maintenance therapy by 2-3 days after uncomplicated surgery.

• In primary adrenal failure, fludrocortisone, 0.1 mg PO daily, should be given. The dose is adjusted to maintain blood pressure (supine and standing) and serum potassium within the normal range; the usual dosage is 0.05-0.20 mg PO daily.

• Patients should be educated in management of their disease, including adjustment of prednisone dose during illness. They should also wear a medical identification tag or bracelet.