What are the differences in diagnosis, laboratory tests, and confirmatory tests between primary aldosteronism and Addison's disease?

Differences Between Primary Aldosteronism and Addison's Disease: Diagnosis and Testing

Primary aldosteronism and Addison's disease represent opposite ends of the adrenal function spectrum, with primary aldosteronism characterized by excessive aldosterone production and Addison's disease characterized by adrenal insufficiency affecting both cortisol and aldosterone production.

Pathophysiology and Clinical Presentation

Primary Aldosteronism

• Definition: Excessive, autonomous aldosterone production, typically from adrenal adenoma or bilateral adrenal hyperplasia
• Clinical presentation:
  • Hypertension (often resistant to conventional treatment)
  • Hypokalemia (in ~50% of patients)
  • Muscle weakness or cramping
  • Metabolic alkalosis
  • Normal or increased sodium levels

Addison's Disease (Primary Adrenal Insufficiency)

• Definition: Insufficient production of adrenal hormones due to adrenal cortex destruction
• Clinical presentation:
  • Hypotension or orthostatic hypotension
  • Hyponatremia (present in ~90% of cases)
  • Hyperkalemia
  • Hyperpigmentation (due to elevated ACTH)
  • Fatigue, weight loss, and weakness
  • Nausea, vomiting, abdominal pain

Laboratory Testing

Primary Aldosteronism

Initial Screening

• Plasma aldosterone and renin activity:
  • Elevated aldosterone levels
  • Suppressed renin activity
  • Aldosterone-to-renin ratio (ARR) >30 when plasma aldosterone is reported in ng/dL and plasma renin activity in ng/mL/h 1
  • Plasma aldosterone should be at least 10 ng/dL to interpret the test as positive 1

Confirmatory Testing

• Saline suppression test or oral salt-loading test 1
  • Failure to suppress aldosterone production with sodium loading confirms diagnosis

Subtype Determination

• Adrenal CT or MRI imaging
• Adrenal venous sampling (gold standard to differentiate unilateral from bilateral disease) 1
  • Essential for determining surgical candidacy

Addison's Disease (Primary Adrenal Insufficiency)

Initial Testing

• Morning serum cortisol and ACTH:
  • Low cortisol (usually below normal range)
  • Elevated ACTH levels 1
  • Low aldosterone levels
  • Elevated plasma renin activity 1

Confirmatory Testing

• ACTH stimulation test (Synacthen/cosyntropin test) 1, 2
  • Normal response: peak cortisol ≥18 μg/dL (≥500 nmol/L)
  • Subnormal response confirms adrenal insufficiency

Additional Testing

• Adrenal antibodies (to confirm autoimmune etiology)
• Electrolytes: Hyponatremia, hyperkalemia
• Adrenal imaging (CT/MRI) to rule out structural causes

Diagnostic Algorithms

Primary Aldosteronism

1. Screening: Measure plasma aldosterone and renin activity, calculate ARR

   • ARR >30 with aldosterone ≥10 ng/dL suggests primary aldosteronism 1
   • Ensure proper test conditions: unrestricted salt intake, normal potassium levels, and withdrawal of mineralocorticoid receptor antagonists for at least 4 weeks 1

2. Confirmation: Perform saline suppression test or oral salt-loading test 1

3. Subtype Determination:

   • Adrenal imaging (CT/MRI)
   • Adrenal venous sampling if surgery is being considered 1

Addison's Disease

1. Screening: Measure morning serum cortisol and ACTH

   • Low cortisol with elevated ACTH suggests primary adrenal insufficiency 1

2. Confirmation: ACTH stimulation test

   • Failure to achieve cortisol ≥18 μg/dL confirms diagnosis 2

3. Etiology Determination:

   • Adrenal antibodies (autoimmune etiology)
   • Adrenal imaging to rule out structural causes
   • Consider testing for other autoimmune conditions (thyroid, diabetes)

Interpretation of Laboratory Results

Primary Aldosteronism

Test	Result
Aldosterone	Elevated
Renin	Suppressed
ARR	>30
Sodium	Normal or elevated
Potassium	Normal or low
ACTH	Normal
Cortisol	Normal

Addison's Disease

Test	Result
Cortisol	Low
ACTH	Elevated
Aldosterone	Low
Renin	Elevated
Sodium	Low
Potassium	Elevated
DHEAS	Low

Common Pitfalls and Caveats

Primary Aldosteronism

• False positive ARR can occur with very low renin levels
• Medications affecting results:
  • Beta-blockers, NSAIDs can suppress renin
  • Diuretics, ACE inhibitors, ARBs can increase renin
• Hypokalemia should be corrected before testing

Addison's Disease

• Exogenous steroid use can suppress ACTH and cortisol
• Critical illness may affect cortisol levels
• TSH elevation (4-10 IU/L) is common due to lack of cortisol's inhibitory effect 1

Imaging Considerations

Primary Aldosteronism

• CT/MRI can identify adrenal adenomas but cannot reliably distinguish functioning from non-functioning adenomas
• Adrenal venous sampling is essential to determine unilateral vs. bilateral disease, especially in patients >40 years 1

Addison's Disease

• Adrenal imaging may show atrophied adrenals in autoimmune disease or enlarged adrenals in infiltrative diseases
• Not always necessary for diagnosis but helpful for determining etiology

By understanding these key differences in laboratory findings and diagnostic approaches, clinicians can accurately distinguish between primary aldosteronism and Addison's disease, leading to appropriate treatment strategies and improved patient outcomes.