What are the primary biochemical abnormalities in a patient with Addison's disease?

Biochemical Abnormalities in Addison's Disease

The primary biochemical abnormalities in Addison's disease are low serum cortisol with markedly elevated plasma ACTH, hyponatremia (present in 90% of cases), hyperkalemia (in approximately 50% of cases), elevated plasma renin activity, and low aldosterone and DHEAS levels. 1

Core Hormonal Abnormalities

Cortisol-ACTH Axis

• Serum cortisol is typically below the normal range, though in some patients presenting during acute illness (such as sepsis), cortisol levels may fall within the normal range but are inappropriately low for the disease state 1
• Plasma ACTH is clearly and markedly elevated, reflecting the loss of negative feedback from the destroyed adrenal cortex 1, 2
• Critical diagnostic thresholds: Serum cortisol <250 nmol/L with elevated ACTH during acute illness is diagnostic of primary adrenal insufficiency 1, 3
• Serum cortisol <400 nmol/L with elevated ACTH during acute illness raises strong suspicion of primary adrenal insufficiency 1

Mineralocorticoid Deficiency Markers

• Plasma renin activity (PRA) is increased due to aldosterone deficiency and volume depletion 1, 2
• Serum aldosterone levels are low, reflecting destruction of the zona glomerulosa 1

Androgen Deficiency

• Dehydroepiandrosterone sulphate (DHEAS) levels are low, indicating loss of adrenal androgen production 1, 2

Electrolyte Abnormalities

Sodium and Potassium Disturbances

• Hyponatremia is present in 90% of newly presenting cases, making it the most common electrolyte abnormality 1, 3, 2
• The mechanism involves sodium loss in urine combined with increases in plasma vasopressin and angiotensin II, which impair free water clearance 1
• Hyperkalemia occurs in approximately 50% of patients at diagnosis, caused by aldosterone deficiency, impaired glomerular filtration, and acidosis 1, 2
• Important caveat: The classical combination of hyponatremia and hyperkalemia is NOT reliable for diagnosis because sodium levels are often only marginally reduced and potassium is elevated in only half of patients 1, 2
• In the presence of severe vomiting, hypokalaemia and alkalosis may be present instead, which can mislead clinicians 1

Other Electrolyte Changes

• Mild to moderate hypercalcemia occurs in 10-20% of patients at presentation 1
• Acidosis is common, contributing to the hyperkalemia 1

Additional Laboratory Findings

Hematologic Abnormalities

• Anemia may be present at diagnosis 1
• Mild eosinophilia can occur 1
• Lymphocytosis may be observed 1

Metabolic Disturbances

• Hypoglycemia is prone to occur in children (but rarely in adults), and hypoglycemic seizures may develop 1, 2
• Increased liver transaminases may be present 1

Thyroid Function

• TSH levels are usually in the range of 4-10 IU/L due to the lack of the inhibitory effect of cortisol on TSH production 1
• This represents a secondary effect rather than true thyroid disease, though true autoimmune thyroid disease is also common in these patients 1

Critical Diagnostic Pitfalls

Confounding Factors

• Exogenous steroid use (oral prednisolone or dexamethasone) and inhaled steroids (fluticasone) may confound interpretation of low serum cortisol levels 1
• Normal cortisol levels do not exclude the diagnosis when ACTH is markedly elevated and clinical suspicion is high, as approximately 10% of patients with confirmed primary adrenal insufficiency present with normal cortisol concentrations 4

Timing Considerations

• Serum and urine cortisol measurements during replacement therapy are usually impossible to interpret, so these should be obtained before treatment when possible 1
• However, treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures 1

Diagnostic Confirmation

The definitive diagnostic test is paired measurement of serum cortisol and plasma ACTH 1, 3. In equivocal cases, a synacthen (tetracosactide) stimulation test (0.25 mg IM or IV) with peak serum cortisol <500 nmol/L confirms the diagnosis 1, 3.