What laboratory findings are consistent with primary adrenal insufficiency (Addison’s disease)?

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Laboratory Findings Consistent with Addison's Disease

The diagnostic hallmark of primary adrenal insufficiency is low serum cortisol paired with markedly elevated plasma ACTH, typically exceeding twice the upper limit of normal, along with hyponatremia in 90% of cases. 1

Core Diagnostic Laboratory Findings

Hormonal Abnormalities

Cortisol and ACTH:

  • Serum cortisol is usually below the normal range at diagnosis 1
  • Plasma ACTH is clearly increased, typically exceeding 2-fold the upper limit of the reference range 2
  • In acute illness, cortisol <250 nmol/L (9 µg/dL) with elevated ACTH is diagnostic of primary adrenal insufficiency 1
  • Cortisol <400 nmol/L (14.5 µg/dL) with elevated ACTH raises strong suspicion 1
  • Important caveat: Approximately 10% of patients may present with cortisol levels in the normal range, but these levels are inappropriately low for the disease state (such as during sepsis), and the presence of clearly elevated ACTH in this context is still indicative of early primary adrenal insufficiency 1, 3

Mineralocorticoid Axis:

  • Plasma renin activity (PRA) is increased 1, 4
  • Serum aldosterone is low or inappropriately normal despite elevated renin 1, 2, 4
  • The elevated PRA/aldosterone ratio is highly suggestive of mineralocorticoid deficiency 4

Adrenal Androgens:

  • Dehydroepiandrosterone sulfate (DHEAS) levels are low 1

Electrolyte and Metabolic Abnormalities

Sodium and Potassium:

  • Hyponatremia is present in 90% of newly presenting cases 1
  • Hyperkalaemia occurs in approximately 50% of patients at diagnosis 1
  • Critical pitfall: The classical combination of hyponatremia and hyperkalemia is NOT reliable for diagnosis because sodium levels are often only marginally reduced and potassium may be normal 1
  • In the presence of severe vomiting, hypokalemia and alkalosis may be present instead of the expected hyperkalemia 1

Other Metabolic Findings:

  • Hypercalcemia (mild to moderate) occurs in 10-20% of patients at presentation 1
  • Acidosis may be present 1
  • Hypoglycemia is common in children but rare in adults, though hypoglycemic seizures can occur 1

Hematologic and Other Laboratory Abnormalities

  • Anemia may be present 1
  • Mild eosinophilia 1
  • Lymphocytosis 1
  • Increased liver transaminases 1

Thyroid Function

  • TSH levels are typically in the range of 4-10 IU/L due to the lack of inhibitory effect of cortisol on TSH production 1
  • This represents a mildly elevated TSH that normalizes with glucocorticoid replacement 1

Diagnostic Algorithm

Step 1: Initial Screening

  • Measure morning (0800-0900h) serum cortisol and plasma ACTH simultaneously 1, 2, 4
  • If cortisol <140 nmol/L (5 µg/dL) with ACTH >300 pg/mL (66 pmol/L), this is highly predictive of primary adrenal insufficiency 2, 4

Step 2: Confirmatory Testing (if initial results equivocal)

  • Perform ACTH stimulation test (cosyntropin 0.25 mg IM or IV) 1, 2
  • Peak serum cortisol <500 nmol/L (18 µg/dL) is diagnostic of primary adrenal insufficiency 1, 2

Step 3: Mineralocorticoid Assessment

  • Measure plasma renin and aldosterone simultaneously to determine mineralocorticoid deficiency 2, 4
  • Elevated renin with low or inappropriately normal aldosterone confirms mineralocorticoid deficiency 2, 4

Step 4: Etiological Workup

  • Measure 21-hydroxylase (anti-adrenal) autoantibodies as first-line test for etiology 1, 5
  • Autoantibodies are present in 65-66% of cases and have 92% probability of correct classification 5

Important Clinical Caveats

Confounding Factors:

  • Exogenous steroid use (oral prednisolone, dexamethasone, or inhaled fluticasone) may confound interpretation of low cortisol levels 1
  • These medications should be discontinued before testing when possible, or results interpreted with caution

Early Disease Recognition:

  • Elevated ACTH with cortisol in the normal range can be the first sign of early-stage primary adrenal insufficiency 2, 3
  • In early evolving disease, mineralocorticoid deficiency may predominate and be the only initial sign 2

Assay Variability:

  • ACTH assays demonstrate significant analytical bias between laboratories 2
  • Results should be interpreted based on the specific laboratory's reference intervals 2

References

3
Research

On Primary Adrenal Insufficiency with Normal Concentrations of Cortisol - Early Manifestation of Addison's Disease.

Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme, 2024

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