What is the appropriate workup for a primary insufficiency in an adult or elderly patient, considering potential underlying causes such as autoimmune disorders, pituitary gland issues, or genetic conditions?

Primary Adrenal Insufficiency Workup

Begin the diagnostic workup with paired measurement of early morning (8 AM) serum cortisol and plasma ACTH, followed by etiologic investigation starting with 21-hydroxylase autoantibodies. 1

Initial Diagnostic Testing

Biochemical Confirmation

• Measure early morning serum cortisol and plasma ACTH simultaneously as the primary diagnostic test 1, 2

  • Serum cortisol <250 nmol/L (<5 µg/dL) with elevated ACTH confirms primary adrenal insufficiency 1, 2
  • Serum cortisol 250-400 nmol/L (5-10 µg/dL) with elevated ACTH raises strong suspicion and requires further testing 1

• Add DHEAS measurement to the initial panel, as low DHEAS supports the diagnosis of primary adrenal insufficiency 2

• Perform cosyntropin stimulation test if morning cortisol is equivocal (250-500 nmol/L) 1

  • Administer 0.25 mg cosyntropin (tetracosactide) intramuscularly or intravenously 1
  • Measure serum cortisol at 30 and 60 minutes 1
  • Peak cortisol <500 nmol/L (<18 µg/dL) is diagnostic of primary adrenal insufficiency 1

Critical Clinical Indicators

Look for these specific findings that increase clinical suspicion 1:

• Hyperpigmentation (particularly in skin creases, scars, and mucous membranes)
• Hyponatremia (sodium <135 mEq/L)
• Hyperkalemia (potassium >5.0 mEq/L)
• Metabolic acidosis
• Hypoglycemia

Important caveat: Never delay treatment with intravenous hydrocortisone 100 mg and isotonic saline if acute adrenal crisis is suspected—obtain blood samples for cortisol and ACTH before treatment but do not wait for results 1, 3

Etiologic Investigation

Step 1: Measure 21-Hydroxylase Autoantibodies

• Order 21-hydroxylase (anti-adrenal) autoantibodies as the first etiologic test 1, 3
• Positive antibodies confirm autoimmune Addison's disease, which accounts for approximately 85% of primary adrenal insufficiency cases in Western populations 4, 3

Step 2A: If 21-Hydroxylase Antibodies Are POSITIVE

Screen for autoimmune polyendocrine syndrome type 1 (APS-1) in children and young adults, particularly if other manifestations are present 1, 3:

• Hypoparathyroidism
• Chronic mucocutaneous candidiasis
• Dental enamel dysplasia
• Keratitis
• Autoimmune hepatitis
• Malabsorption
• Premature ovarian insufficiency

Confirm APS-1 diagnosis with 1, 3:

• Anti-interferon omega antibodies or anti-IL-22 antibodies
• AIRE gene mutational analysis

Screen for associated autoimmune conditions 1, 3:

• Thyroid function tests (TSH, free T4) and thyroid peroxidase antibodies—check annually 1
• Fasting glucose or HbA1c for diabetes mellitus 1
• Vitamin B12 levels for pernicious anemia 1
• Tissue transglutaminase antibodies if diarrhea is present (celiac disease) 1

Step 2B: If 21-Hydroxylase Antibodies Are NEGATIVE

Order CT imaging of the adrenal glands to identify 1, 3:

• Tumors or masses
• Calcifications (suggesting tuberculosis)
• Adrenal hemorrhage
• Bilateral adrenal metastases
• Infiltrative processes

In male patients, measure very long-chain fatty acids (VLCFA) to screen for adrenoleukodystrophy, an X-linked condition with variable presentation 1, 3

Consider infectious causes based on clinical context 1:

• Tuberculosis: Quantiferon test, PCR, culture
• HIV testing
• Fungal infections (Pneumocystis, histoplasmosis)
• Cytomegalovirus, herpes simplex virus

Evaluate for genetic causes 1, 4:

• Congenital adrenal hyperplasia: urine steroid profile, sequencing of steroidogenic genes (CYP21B)
• NR0B1 (DAX1) gene mutations if hypogonadotropic hypogonadism is present
• Familial glucocorticoid deficiency (ACTH resistance syndrome)
• Mitochondrial disorders (Kearns-Sayre syndrome)

Review medication history for drugs causing adrenal insufficiency 1:

• Ketoconazole
• Etomidate
• Mitotane
• Metyrapone

Consider infiltrative diseases 1:

• Amyloidosis
• Hemochromatosis
• Sarcoidosis
• Lymphoma

Common Pitfalls to Avoid

• Do not interpret cortisol levels without considering ACTH—secondary adrenal insufficiency will show low or inappropriately normal ACTH, while primary shows elevated ACTH 2

• Do not miss 21-hydroxylase antibody-negative autoimmune disease—antibodies can become negative over time in previously positive patients 1

• Do not forget to check for adrenoleukodystrophy in males—this X-linked condition requires specific VLCFA testing and has important genetic counseling implications 1

• Do not overlook APS-1 in young patients—the presence of even one other component (hypoparathyroidism, candidiasis) should trigger specific testing 1, 3

• Do not delay emergency treatment for diagnostic testing—if acute adrenal crisis is suspected, give hydrocortisone 100 mg IV immediately and draw blood samples simultaneously 1, 3