Addison Disease Workup

A quick review of the clinical presentation, physical examination findings, and laboratory findings (when available) quickly heightens the index of suspicion and possibly leads to more appropriate tests and diagnosis. A high index of suspicion is necessary for diagnosis.

• The diagnosis of adrenocortical insufficiency rests on the assessment of the functional capacity of the adrenal cortex to synthesize cortisol. This is accomplished primarily by use of the rapid ACTH stimulation test (Cortrosyn, cosyntropin, or Synacthen). ^[3]

  • ACTH, through complex mechanisms, activates cholesterol esterase enzymes and leads to the release of free cholesterol from cholesterol esters. It also activates the 20,22-desmolase enzyme, which catalyzes the rate-limiting step in adrenal steroidogenesis and increases the NADPH (nicotinamide adenine dinucleotide phosphate) levels necessary for the various hydroxylation steps in steroidogenesis.

  • Within 15-30 minutes of ACTH infusion, the normal adrenal cortex releases 2-5 times its basal plasma cortisol output.

  • Although ACTH stimulation is not normally the major stimulus for aldosterone production, it increases aldosterone production to peak levels within 30 minutes. This response, however, is affected by dietary sodium intake.

  • An increase in the plasma cortisol and aldosterone levels above basal levels after ACTH injection reflects the functional integrity of the adrenal cortex.

• Performing the rapid adrenocorticotrophic hormone test ^[43]

  • Blood is drawn in 2 separate tubes for baseline cortisol and aldosterone values.

  • Synthetic ACTH (1-24 amino acid sequence) in a dose of 250 mcg (0.25 mg) is given IM or IV. Smaller doses of synthetic ACTH, as low as 1 mcg, have been used with accuracy approaching the standard test. Proponents of this modified test argue that a dose of 1 mcg or lower is more physiologic, whereas the 250-mcg dose is pharmacologic. However, the modified test is more sensitive only for the 30-minute samples, not the 60-minute samples.

  • Thirty or 60 minutes after the ACTH injection, 2 more blood samples are drawn; one for cortisol and one for aldosterone. No significant reason exists to draw both the 30-minute and 60-minute samples because the sensitivity of the 30-minute value for accurate diagnosis is well documented. The baseline and 30-minute samples usually are adequate to establish the diagnosis.

• Interpreting the rapid adrenocorticotrophic hormone test ^{[44, 45, 46, 47]}

  • Two criteria are necessary for diagnosis: (1) an increase in the baseline cortisol value of 7 mcg/dL or more and (2) the value must rise to 20 mcg/dL or more in 30 or 60 minutes, establishing normal adrenal glucocorticoid function.

  • A low aldosterone value of less than 5 ng/100 mL that fails to double or increase by at least 4 ng/100 mL 30 minutes after ACTH administration denotes abnormal mineralocorticoid function of the adrenal cortex.

  • The 30-minute aldosterone value is more sensitive than the 60-minute value because aldosterone levels actually have been shown to decrease in the 60-minute sample.

  • The absolute 30- or 60-minute cortisol value carries more significance than the incremental value, especially in patients who may be in great stress and at their maximal adrenal output. These patients may not show a significant increase in cortisol output with ACTH stimulation.

  • A normal 30- or 60-minute rapid ACTH test excludes Addison disease but may not adequately exclude mild impairment of the hypothalamic pituitary adrenal axis in secondary adrenal insufficiency.

  • In patients with Addison disease, both cortisol and aldosterone show minimal or no change in response to ACTH, even with prolonged ACTH stimulation tests lasting 24-48 hours.

  • When the results of the rapid ACTH test are equivocal and do not meet the 2 criteria mentioned above, further testing might be required to distinguish Addison disease from secondary adrenocortical insufficiency. Plasma ACTH values and prolonged ACTH stimulation tests may be useful in making this distinction.

  • ACTH levels often are elevated to higher than 250 pg/mL in patients with Addison disease. However, ACTH is unstable in plasma, and specimen collection and storage may require special attention. The specimen should be collected in iced anticoagulated plastic containers and frozen immediately.

  • Importantly, note that ACTH levels also may be high in patients recovering from steroid-induced secondary adrenocortical insufficiency and in patients with ACTH-refractory syndromes.

  • ACTH-inducing tests such as metyrapone stimulation and insulin-induced hypoglycemia, which may be useful in the evaluation of some cases of secondary adrenocortical insufficiency, have no role in the diagnosis of Addison disease and may in fact be lethal to the patient with Addison disease.

• In acute adrenal crisis, where treatment should not be delayed in order to do the tests, a blood sample for a random plasma cortisol level should be drawn prior to starting hydrocortisone replacement.

  • A random plasma cortisol value of 25 mcg/dL or greater effectively excludes adrenal insufficiency of any kind. However, a random cortisol value in patients who are acutely ill should be interpreted with caution and in correlation with the circumstances of each individual patient. Random cortisol levels should also be interpreted cautiously in critically ill patients with hypoproteinemia (serum albumin < 2.5 g/dL). Approximately 40% of these patients will have baseline and cosyntropin-stimulated cortisol levels below the reference range even though the patients have normal adrenal function (as evidenced by the measurement of free cortisol levels). This phenomenon is because more than 90% of circulating cortisol in human serum is protein bound.

  • Cortisol is known to be elevated by stress, but exactly how high it should rise to constitute a normal response in times of severe stress is not known.

  • An abnormal test result should prompt a proper evaluation of the hypothalamic pituitary adrenal axis after the patient's condition improves before committing a patient to lifelong steroid replacement.

  • In order to perform the ACTH stimulation test in this situation, the patient should be switched to dexamethasone and then tested 24-36 hours later. Dexamethasone does not interfere with the cortisol assay, as does hydrocortisone or prednisone. However, dexamethasone may interfere with interpretation of the random cortisol value drawn after dexamethasone already has been initiated. Dexamethasone also does not have any mineralocorticoid activity, which may be needed in patients with Addison disease.

• Other laboratory tests

  • Comprehensive metabolic panel

    • The most prominent findings are hyponatremia, hyperkalemia, and a mild non–anion-gap metabolic acidosis due to the loss of the sodium-retaining and potassium and hydrogen ion-secreting action of aldosterone.

    • Urinary and sweat sodium also may be elevated.

    • The most consistent finding is elevated blood urea nitrogen (BUN) and creatinine due to the hypovolemia, a decreased glomerular filtration rate, and a decreased renal plasma flow.

    • Hypercalcemia, the cause of which is not well understood, may be present in a small percentage of patients. However, hypocalcemia could occur in patients with Addison disease accompanied by idiopathic hypoparathyroidism.

    • Hypoglycemia may be present in fasted patients, or it may occur spontaneously. It is caused by the increased peripheral utilization of glucose and increased insulin sensitivity. It is more prominent in children and in patients with secondary adrenocortical insufficiency.

    • Liver function tests may reveal a glucocorticoid-responsive liver dysfunction.

  • CBC count

    • CBC count may reveal a normocytic normochromic anemia, which, upon initial presentation, may be masked by dehydration and hemoconcentration. Relative lymphocytosis and eosinophilia may be present.

    • All of these findings are responsive to glucocorticoid replacement.

  • Thyroid-stimulating hormone ^[48]

    • Increased thyroid-stimulating hormone (TSH), with or without low thyroxine, with or without associated thyroid autoantibodies, and with or without symptoms of hypothyroidism, may occur in patients with Addison disease and in patients with secondary adrenocortical insufficiency due to isolated ACTH deficiency. These findings may be slowly reversible with cortisol replacement. ^[49]

    • In the setting of both adrenocortical insufficiency and hypothyroidism that requires treatment, corticosteroids should be given before thyroid hormone replacement to avoid precipitating an acute adrenal crisis.

• Autoantibody testing - Thyroid autoantibodies, specifically antithyroglobulin (anti-Tg) and antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies, and/or adrenal autoantibodies may be present.

• Prolactin testing

  • Modest hyperprolactinemia has been reported in cases of Addison disease and also in secondary adrenocortical insufficiency. It is responsive to glucocorticoid replacement.

  • The cause of the hyperprolactinemia is thought to be the hyperresponsiveness of the lactotroph to thyrotropin-releasing hormone (TRH) in the absence of the steroid-induced or steroid-enhanced hypothalamic dopaminergic tone.

Chest radiograph:

• The chest radiograph may be normal but often reveals a small heart.

• Stigmata of earlier infection or current evidence of TB or fungal infection may be present when this is the cause of Addison disease.

CT scan: ^{[19, 50]}

• Abdominal CT scan may be normal but may show bilateral enlargement of the adrenal glands in patients with Addison disease because of TB, fungal infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal glands.

• In Addison disease due to TB or histoplasmosis, evidence of calcification involving both adrenal glands may be present.

• In idiopathic autoimmune Addison disease, the adrenal glands usually are atrophic.

ECG may show low-voltage QRS tracing with nonspecific ST-T wave changes and/or changes due to hyperkalemia. These changes are reversible with glucocorticoid replacement.

Sputum examination, examination of gastric washings for acid-fast and alcohol-fast bacilli, and a Mantoux or purified protein derivative (PPD) skin test may be needed if TB is thought to be the cause.

In cases due to idiopathic autoimmune adrenocortical atrophy, the adrenal glands usually are atrophic, with marked lymphocytic infiltration and fibrosis of the adrenal capsule. The adrenal medulla is spared.

In cases due to TB, the adrenal glands may be enlarged and contain caseating granulomas. Diffuse calcification may be evident, and the adrenal medulla usually is involved. ^[19]

In patients with AIDS, the adrenal glands may show necrotizing inflammation, hemorrhage, and infarction.