What is the differential diagnosis and management for resistant hypertension?

Differential Diagnosis for Resistant Hypertension

First exclude pseudoresistance (poor BP measurement, white coat effect, medication nonadherence, suboptimal drug choices), then systematically evaluate for secondary causes, with primary aldosteronism and obstructive sleep apnea being the most common culprits. 1, 2, 3

Initial Step: Confirm True Resistant Hypertension

Before pursuing an extensive differential, you must rule out pseudoresistance:

• Verify BP measurements using proper technique and confirm with 24-hour ambulatory BP monitoring or home BP monitoring to exclude white coat hypertension 1, 3
• Assess medication adherence through direct questioning, pill counts, or if available, blood/urine drug level testing 3
• Review the current regimen to ensure optimal doses of three different drug classes (ideally a RAS blocker, calcium channel blocker, and diuretic) 1, 2
• Identify interfering substances: NSAIDs, oral contraceptives, decongestants, stimulants, immunosuppressive agents, excessive alcohol (≥30 drinks/week), and excessive dietary sodium (>10g/day) 1, 3

Common Secondary Causes (High Yield)

Obstructive Sleep Apnea

• Most prevalent in resistant hypertension, affecting 83% of patients in specialized centers 1
• Screen with: Berlin Questionnaire or Epworth Sleepiness Scale, confirm with polysomnography 3
• Mechanism: Intermittent hypoxemia causes sustained sympathetic nervous system activation 1

Primary Aldosteronism

• Screen ALL patients with resistant hypertension using plasma aldosterone-to-renin ratio, even with normal potassium 2, 4
• Positive screen: Ratio >20-30 (when aldosterone in ng/dL and renin activity in ng/mL/h) 2
• Prevalence: Approximately 20% of resistant hypertension cases 4, 5
• Confirm with: 24-hour urinary aldosterone excretion 1, 5

Renal Parenchymal Disease

• Evaluate with: Serum creatinine, eGFR calculation, and urinalysis with dipstick for proteinuria 1
• More common in elderly patients 1

Renal Artery Stenosis

• High suspicion in: Young women (fibromuscular dysplasia) or older patients with atherosclerotic risk factors 1
• Screen with: Renal ultrasound followed by duplex ultrasound, CT angiography, or MR angiography 3
• Avoid: Diagnostic arteriography without positive noninvasive imaging 1

Uncommon But Important Secondary Causes

Pheochromocytoma

• Screen with: 24-hour urinary metanephrines or plasma metanephrines 1
• Do NOT order abdominal CT to screen for adrenal adenomas without biochemical confirmation first 1

Cushing's Disease

• Consider in: Patients with characteristic physical findings (central obesity, striae, moon facies) 1

Other Rare Causes

• Hyperparathyroidism, aortic coarctation, intracranial tumor 1

Lifestyle and Dietary Contributors

Excessive Dietary Sodium

• Assess with: 24-hour urinary sodium excretion (>10g/day is excessive) 1
• Target: <1500 mg/day sodium intake 3

Heavy Alcohol Use

• Definition: ≥30 drinks per week 1
• Screen with: Liver transaminase levels as surrogate marker 1

Obesity

• Associated with: Sleep apnea, volume expansion, and increased sympathetic tone 6, 5

Systematic Evaluation Algorithm

1. Confirm diagnosis with out-of-office BP monitoring 1, 2
2. Basic screening for all patients: comprehensive metabolic panel (sodium, potassium, creatinine/eGFR), TSH, urinalysis, fasting glucose or HbA1c, lipid profile, ECG 1, 3
3. Universal screening: Aldosterone-to-renin ratio and sleep apnea questionnaire 2, 3, 4
4. Targeted imaging: Only pursue renal artery imaging if clinical suspicion exists (young age, abrupt onset, refractory disease) 1, 3
5. Specialized testing: Reserve pheochromocytoma screening for patients with paroxysmal symptoms or incidental adrenal masses 1

When to Refer

Refer to a hypertension specialist (nephrologist, cardiologist, or endocrinologist) if: 2, 3

• BP remains uncontrolled after 6 months of optimized therapy
• Early-onset hypertension (<30 years of age) even with normal initial screening 1, 3
• Known or suspected secondary cause requiring specialized management
• BP requires 4+ medications for control

Critical Pitfalls to Avoid

• Do not skip aldosterone screening just because potassium is normal—most patients with primary aldosteronism are normokalemic 4, 5
• Do not order abdominal CT for adrenal screening without biochemical confirmation first—poor specificity leads to incidental findings 1
• Do not assume young patients (<30 years) have essential hypertension—secondary causes are highly prevalent in this age group 1, 3
• Do not forget that resistant hypertension is almost always multifactorial—multiple secondary causes often coexist in the same patient 1, 6