Adrenal Insufficiency

Indications for Testing

The early symptoms of adrenal insufficiency are nonspecific, which may lead to delayed diagnosis. They include

• Weakness
• Fatigue
• Loss of appetite and weight loss
• Nausea
• Musculoskeletal pain
• Dizziness

Symptoms suggestive of PAI include

• Extracellular fluid volume reduction
• Abdominal pain
• Hypotension
• Hyponatremia
• Hyperkalemia
• Fever
• Hyperpigmentation
• Hypoglycemia, especially for pediatric patients

If untreated, patients may experience adrenal crisis and death. Clinicians should use a low threshold for diagnostic evaluation in 

• Acutely ill patients
• Patients with predisposing factors (eg, type 1 diabetes mellitus, autoimmune gastritis, HIV, tuberculosis)
• Patients taking certain medications, such as adrenal enzyme inhibitors, phenytoin, and St. John’s wort
• Pregnant women with unexplained fatigue, constant nausea, and hypotension

Laboratory Testing                            

Patients in acute adrenal crisis require prompt treatment and stabilization prior to diagnostic evaluation.  

Initial Diagnostic Testing

ACTH Stimulation Test

The recommended initial diagnostic tool to determine adrenal insufficiency (and gold standard for diagnosing primary adrenal insufficiency) is the short corticotropin test (also called ACTH stimulation test) with cortisol response measurements at 0, 30, and/or 60 minutes.   The recommended standard dose of cosyntropin is 250 μg for adults and children 2 years and older, 125 μg for children younger than 2 years, and 15 μg/kg for infants.  A low-dose (1 μg) version of the test should be used only when the corticotropic agent is in short supply.  Intravenous administration is recommended over intramuscular administration. 

Serum Cortisol and Plasma ACTH

When a short corticotropin test is not possible or feasible, the combination of morning cortisol and ACTH measurement is a preliminary option until the stimulation test can be performed to confirm the diagnosis, unless the combined results of the two tests (morning cortisol and ACTH measurement) are unquestionable.  Special consideration should be given to results of pregnant women and those with critical illness, as cortisol levels are naturally altered in these conditions.

Additional Testing

Once a diagnosis of adrenal insufficiency has been established, further testing should be performed to identify the underlying cause  of the insufficiency and determine other medical implications. Imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) may also be necessary when an adenoma, lesion, or infection is suspected as the cause. 

Aldosterone/Renin Testing

Simultaneous measurement of aldosterone and plasma renin in adrenal insufficiency is recommended to determine whether the patient has mineralocorticoid deficiency.  Such testing also helps with diagnosis in the early phase of PAI development (when the deficiency may be the only indication) and in differentiating primary from secondary adrenal insufficiency.  A high plasma renin activity measurement with a low or inappropriately normal serum aldosterone concentration is suggestive of PAI.   Both aldosterone and renin levels are typically normal in secondary insufficiency.  Furthermore, aldosterone deficiency leads to low levels of sodium and high levels of potassium in the blood.

21-Hydroxylase Antibody Testing

A positive 21-hydroxylase antibody test result confirms an autoimmune etiology of PAI, in which the body’s own immune response attacks adrenal tissue. If the 21-hydroxylase test result is negative, other causes should be investigated. 

17-Hydroxyprogesterone Testing

For infants and also children and adults with PAI with suspected CAH, consider 17-hydroxyprogesterone testing to determine CAH or genetic syndromes as the etiology. 

Pituitary Function Evaluation

In cases of secondary adrenal insufficiency, assess the hypothalamic-pituitary axis with imaging.  See the Hypopituitarism topic for further testing information.

Monitoring

Monitoring of glucocorticoid replacement should be based on clinical assessment; hormonal monitoring is generally not recommended.  For patients on mineralocorticoid replacement, monitoring includes clinical assessment and blood electrolyte measurements.  Women receiving dehydroepiandrosterone (DHEA) replacement should be monitored with morning serum DHEA sulfate levels.