What is the most likely diagnostic test for a 38-year-old man with resistant hypertension (high blood pressure) and hypokalemia (low potassium) on maximum dose losartan (angiotensin II receptor antagonist) and amlodipine (calcium channel blocker) and 25mg of hydrochlorothiazide (HCTZ) (thiazide diuretic)?

Diagnostic Testing for Resistant Hypertension with Hypokalemia

The most appropriate diagnostic test for this 38-year-old man with resistant hypertension and hypokalemia is a plasma aldosterone-to-renin ratio (ARR) test. 1

Clinical Presentation Analysis

This patient presents with several key findings that strongly suggest primary aldosteronism:

• Resistant hypertension (BP 150/78 despite maximum doses of three antihypertensive medications)
• Hypokalemia (potassium 3.2 mEq/L)
• Young age (38 years)
• Current medication regimen includes:
  • Losartan (ARB) at maximum dose
  • Amlodipine (CCB) at maximum dose
  • Hydrochlorothiazide 25 mg (thiazide diuretic)

Diagnostic Approach

Primary Aldosteronism Screening

• The American College of Cardiology/American Heart Association guidelines specifically recommend screening for secondary hypertension when unprovoked or excessive hypokalemia is present, especially in the context of resistant hypertension 2
• Primary aldosteronism is present in 8-20% of patients with resistant hypertension 2
• The combination of resistant hypertension and hypokalemia is highly suggestive of primary aldosteronism, particularly in a young patient 1

Test Preparation

Before performing the ARR test:

• The patient should be potassium-replete (correct the hypokalemia first)
• Morning collection is preferred (8-10 AM)
• Patient should be seated for 5-15 minutes before collection 1

Medication Considerations

• Current medications may affect ARR results:
  • Losartan (ARB) may cause false-negative results in up to 23.5% of cases 3
  • Amlodipine has minimal effect on ARR (1.8% false-negative rate) 3
  • Hydrochlorothiazide can cause hypokalemia, which may be exacerbating an underlying primary aldosteronism 4

Diagnostic Algorithm

1. First-line test: Plasma aldosterone-to-renin ratio (ARR)

   • An ARR >20-30 (when plasma aldosterone is reported in ng/dL and plasma renin activity in ng/mL/hour) with plasma aldosterone ≥15 ng/dL is considered positive 1

2. Confirmatory testing (if ARR is positive):

   • Fludrocortisone suppression test or saline infusion test 1

3. Localization studies (after biochemical confirmation):

   • CT scan of adrenal glands
   • Adrenal vein sampling (gold standard for distinguishing unilateral from bilateral disease) 1

Alternative Diagnostic Considerations

While primary aldosteronism is the most likely diagnosis, other causes to consider include:

• Renovascular disease (5-34% prevalence in resistant hypertension) 2
• Pheochromocytoma (rare, 0.1-0.6% prevalence) 2
• Cushing's syndrome (rare, <0.1% prevalence) 2

Management Implications

If primary aldosteronism is confirmed:

• Unilateral disease: Laparoscopic adrenalectomy (potentially curative)
• Bilateral disease: Medical therapy with mineralocorticoid receptor antagonists (spironolactone or eplerenone) 1

Common Pitfalls to Avoid

1. Failing to correct hypokalemia before testing: Hypokalemia can suppress aldosterone production and lead to false-negative results 1

2. Not considering medication effects on test results: ARBs like losartan can cause false-negative ARR results 3

3. Attributing hypokalemia solely to hydrochlorothiazide: While thiazide diuretics commonly cause hypokalemia (12.6% of users) 4, the combination of resistant hypertension and hypokalemia should prompt evaluation for primary aldosteronism

4. Proceeding directly to imaging without biochemical confirmation: This can lead to unnecessary procedures for incidental adrenal findings 1

5. Delaying diagnosis: Primary aldosteronism is significantly underdiagnosed, with screening rates as low as 2-4% even in high-risk groups 1