What is the diagnosis for a patient with resistant hypertension on (Angiotensin-Converting Enzyme Inhibitor) ACEI and (Calcium Channel Blocker) CCB, with hypokalemia and hyperbicarbonatemia, undergoing diagnostic tests including serum and urine metanephrine, renin-aldosterone ratio, and 24-hour urine cortisol?

Diagnosis: Primary Aldosteronism

The most likely diagnosis is primary aldosteronism, which presents with resistant hypertension, hypokalemia, and metabolic alkalosis (high bicarbonate), and is confirmed by an elevated aldosterone-to-renin ratio. 1

Clinical Presentation and Diagnostic Rationale

This patient's presentation is classic for primary aldosteronism:

• Resistant hypertension (uncontrolled on ACEI + CCB) is the hallmark, with primary aldosteronism occurring in approximately 20% of patients with resistant hypertension 1
• Hypokalemia is present, though importantly, serum potassium levels are rarely low in early primary aldosteronism and hypokalemia represents a late manifestation 1, 2
• High bicarbonate indicates metabolic alkalosis, which occurs due to aldosterone's mineralocorticoid effects causing renal potassium excretion and hydrogen ion loss 3

Recommended Diagnostic Tests (In Order of Priority)

First-Line Test: Aldosterone-to-Renin Ratio (ARR)

• The aldosterone-to-renin ratio is the primary screening test for primary aldosteronism in patients with resistant hypertension and hypokalemia 1
• This test should be performed despite the patient being on ACEI and CCB, though these medications can cause false-negative results by suppressing aldosterone and increasing renin 1
• Important caveat: ACEIs and CCBs lower the ARR and may produce false-negative results, but the clinical presentation is so suggestive that testing should proceed 1

Secondary Tests Based on Clinical Context

24-hour urine metanephrines (serum and urine):

• Screen for pheochromocytoma, which represents 0.1-0.6% of resistant hypertension cases 1
• Critical distinction: Pheochromocytoma characteristically presents with orthostatic hypotension alongside hypertension, which is NOT described in this patient 2
• This makes pheochromocytoma less likely but still worth excluding given the resistant hypertension 1

24-hour urine cortisol:

• Screens for Cushing's syndrome, which can present with hypertension and hypokalemia 1, 3
• Cushing's syndrome causes hypertension in 78-80% of cases, with 45% requiring ≥3 medications 3
• However, primary aldosteronism is far more common (20% prevalence in resistant hypertension vs. much rarer Cushing's) 1

Why Primary Aldosteronism is Most Likely

Epidemiologic evidence strongly favors this diagnosis:

• Primary aldosteronism prevalence in resistant hypertension: 17-23% across multiple studies 1
• The combination of resistant hypertension + hypokalemia + metabolic alkalosis creates a very high pre-test probability 1, 4
• Autonomous aldosterone production causes sodium retention, volume expansion, and suppressed renin activity 2

Common Diagnostic Pitfalls to Avoid

Medication interference with ARR testing:

• The patient's current ACEI will suppress aldosterone and markedly increase renin, potentially causing a false-negative ARR 1
• However, given the strong clinical presentation (hypokalemia + resistant HTN), proceed with testing rather than stopping medications, as the 2024 ESC guidelines note that helpful information can be obtained from reviewing prior potassium levels 1
• If ARR is equivocal, consider repeating after medication adjustment under specialist guidance 1

Don't assume normal potassium excludes primary aldosteronism:

• Hypokalemia is a late finding; most confirmed cases have normal potassium initially 1, 2
• The presence of hypokalemia in this patient actually suggests more severe or prolonged aldosterone excess 2

Next Steps After Diagnosis

If primary aldosteronism is confirmed:

• Differentiate unilateral vs. bilateral disease with adrenal CT and potentially adrenal vein sampling 1, 4
• Unilateral disease: Laparoscopic adrenalectomy is curative 1, 4
• Bilateral disease: Mineralocorticoid receptor antagonists (spironolactone or eplerenone) are first-line medical therapy 1, 3

Treatment with mineralocorticoid receptor antagonists:

• Spironolactone starting at 25 mg daily, titrating to 50 mg as tolerated 5
• This directly addresses the pathophysiology and will correct both hypertension and hypokalemia 1, 3
• Monitor for hyperkalaemia, especially given concurrent ACEI use 5, 6