What is the best course of action for a patient with resistant hypertension, hypokalemia, and a high serum aldosterone to renin ratio, despite being on an angiotensin-converting enzyme (ACE) inhibitor, calcium channel blocker, and long-acting diuretic, with potassium supplements?

Primary Hyperaldosteronism in Resistant Hypertension with Hypokalemia

A serum aldosterone to renin ratio (ARR) of 521 with plasma aldosterone concentration of 8 mg and plasma renin activity of 3 ng strongly supports the diagnosis of primary hyperaldosteronism, especially in the context of resistant hypertension and persistent hypokalemia despite potassium supplementation.

Diagnostic Interpretation

The patient presents with classic features of primary hyperaldosteronism:

1. Resistant hypertension: Uncontrolled blood pressure despite three medications (ACE inhibitor, calcium channel blocker, and diuretic)
2. Persistent hypokalemia: Despite potassium supplementation
3. Elevated aldosterone-to-renin ratio (ARR): 521, which is significantly above the diagnostic threshold

According to the American Heart Association guidelines, an ARR greater than 20-30 is considered elevated and suggestive of primary hyperaldosteronism, with a sensitivity of over 90% when properly performed 1. The 2018 AHA Scientific Statement specifically notes that "a high ratio (> 20) when the serum aldosterone is >16 ng/dL and PRA is <0.6 ng/mL per hour is suggestive of primary aldosteronism" 2.

Clinical Significance

Primary aldosteronism is present in 8-20% of patients with resistant hypertension 1. The condition is characterized by:

• Autonomous aldosterone production independent of renin-angiotensin system
• Sodium retention leading to volume expansion and hypertension
• Potassium wasting leading to hypokalemia (though up to 50% of patients may be normokalemic)

Next Steps in Management

1. Confirm the diagnosis:

   • Additional testing such as fludrocortisone suppression test or saline infusion test should be performed to confirm the diagnosis 1
   • These confirmatory tests should be done while the patient is potassium-replete

2. Refer to specialist:

   • The 2018 AHA Scientific Statement recommends: "In adults with hypertension and a positive screening test for primary aldosteronism, referral to a hypertension specialist or endocrinologist is recommended for further evaluation and treatment" 2

3. Imaging studies:

   • Proceed to imaging only after biochemical confirmation
   • CT scan of adrenal glands to identify potential adenoma 1
   • Consider adrenal vein sampling to distinguish between unilateral and bilateral disease, especially in patients >40 years 1

4. Treatment options:

   a) For unilateral disease:

   • Laparoscopic adrenalectomy is the treatment of choice, improving blood pressure in virtually 100% of patients and achieving complete cure of hypertension in ~50% 1

   b) For bilateral disease or non-surgical candidates:

   • Add a mineralocorticoid receptor antagonist (spironolactone or eplerenone)
   • Initial dose of spironolactone 12.5-25 mg daily, titrating up to 100 mg daily as needed 1
   • Eplerenone can be used at 50-100 mg daily if spironolactone is not tolerated 3
   • Monitor for hyperkalemia, especially in patients with reduced renal function 4

Important Considerations

• Medication interactions: The ARR interpretation may be affected by the patient's current medications. ACE inhibitors can increase renin levels, potentially lowering the ARR and masking primary aldosteronism 1. The fact that the ARR is still elevated despite ACE inhibitor use strengthens the diagnosis.

• Potassium status: Ensure the patient is potassium-replete before confirmatory testing, as hypokalemia can suppress aldosterone production and lead to false-negative results 1.

• Monitoring: Regular monitoring of blood pressure, serum potassium levels, and renal function is essential, particularly when initiating mineralocorticoid receptor antagonist therapy 4.

• Caution with mineralocorticoid receptor antagonists: When adding spironolactone or eplerenone to a regimen already containing an ACE inhibitor, monitor for hyperkalemia. The risk increases when eplerenone is used in combination with an ACE inhibitor, especially in patients with impaired renal function 4.

Primary hyperaldosteronism is significantly underdiagnosed, with screening rates as low as 2-4% even in high-risk groups 1. Early diagnosis and appropriate treatment can significantly improve outcomes by reducing cardiovascular and renal complications.