What is the differential diagnosis and workup for drug-resistant hypertension?

Differential Diagnosis and Workup for Drug-Resistant Hypertension

The comprehensive evaluation of drug-resistant hypertension requires systematic exclusion of pseudoresistance, identification of secondary causes, and assessment of contributing factors before optimizing therapy with a structured approach to medication management.

Definition and Confirmation of True Resistant Hypertension

Resistant hypertension is defined as:

• Blood pressure that remains above goal (≥140/90 mmHg) despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, with one being a diuretic 1
• OR blood pressure controlled but requiring 4 or more medications 1, 2

Exclude Pseudoresistance First

• Improper BP measurement technique: Ensure correct cuff size, patient position, and measurement protocol
• White coat hypertension: Confirm with home or ambulatory BP monitoring 1, 2
• Medication nonadherence: Assess adherence through direct questioning and pharmacy refill records 2
• Inadequate medication dosing: Verify optimal dosing of all medications 1
• Interfering substances: Identify and discontinue NSAIDs, oral contraceptives, sympathomimetics, licorice, and other interfering medications 1, 2

Differential Diagnosis: Secondary Causes

1. Primary Aldosteronism

• Screening: Elevated aldosterone/renin ratio 1
• Clinical clues: Hypokalemia (spontaneous or diuretic-induced), metabolic alkalosis
• Prevalence: Present in 10-20% of resistant hypertension cases 1

2. Obstructive Sleep Apnea

• Screening: Sleep questionnaires, polysomnography if indicated
• Clinical clues: Snoring, witnessed apnea, excessive daytime sleepiness 1
• Prevalence: Very common in resistant hypertension patients 1, 2

3. Chronic Kidney Disease

• Screening: eGFR, urinalysis, urine albumin-to-creatinine ratio
• Clinical clues: Elevated creatinine, proteinuria, abnormal urinalysis 1
• Mechanism: Volume overload, increased sympathetic activity, RAAS activation 1

4. Renal Artery Stenosis

• Screening: Duplex ultrasound, CT angiography, or MR angiography
• Clinical clues: Young female (fibromuscular dysplasia), atherosclerotic disease, worsening renal function with ACEi/ARB, flash pulmonary edema 1
• High-risk groups: Peripheral arterial disease, unexplained renal insufficiency 1

5. Pheochromocytoma

• Screening: Plasma or 24-hour urine metanephrines and catecholamines
• Clinical clues: Episodic hypertension, palpitations, diaphoresis, headache 1
• Prevalence: Rare but important not to miss 1

6. Cushing's Syndrome

• Screening: Overnight dexamethasone suppression test, 24-hour urinary free cortisol
• Clinical clues: Moon facies, central obesity, abdominal striae, inter-scapular fat deposition 1

7. Thyroid Disorders

• Screening: TSH, free T4
• Clinical clues: Hyperthyroidism (tachycardia, weight loss) or hypothyroidism (bradycardia, weight gain)

8. Aortic Coarctation

• Screening: CT angiography, MRA, or echocardiography
• Clinical clues: Differential in brachial or femoral pulses, systolic bruit 1

Comprehensive Workup Algorithm

Initial Evaluation

1. Confirm BP measurements:

   • Office measurements with proper technique
   • 24-hour ambulatory BP monitoring or home BP monitoring 1, 2

2. Medication review:

   • Verify adherence to prescribed regimen
   • Document all current medications including OTC and herbal supplements
   • Identify interfering substances 1, 2

3. Laboratory testing:

   • Basic metabolic panel (electrolytes, BUN, creatinine)
   • Urinalysis and urine albumin-to-creatinine ratio
   • Fasting glucose and lipid panel
   • TSH
   • Aldosterone/renin ratio (morning sample, fasting) 1

4. Additional testing based on clinical suspicion:

   • 24-hour urine collection for metanephrines, catecholamines (if pheochromocytoma suspected)
   • Overnight dexamethasone suppression test (if Cushing's suspected)
   • Sleep study (if OSA suspected) 1

Imaging Studies

• Renal ultrasound: Assess kidney size, structure, and rule out hydronephrosis
• Renal artery imaging: Duplex ultrasound, CT angiography, or MR angiography if renal artery stenosis suspected
• Echocardiography: Assess for LVH, systolic and diastolic function 1
• Additional imaging: Adrenal CT (if primary aldosteronism or pheochromocytoma suspected) 1

Management Approach

Optimize Current Therapy

1. Ensure optimal dosing of current medications
2. Consider single-pill combinations to improve adherence 2
3. Verify diuretic appropriateness: Consider switching from hydrochlorothiazide to chlorthalidone or indapamide for more potent and longer-acting diuresis 2

Add Fourth Agent

• Spironolactone is the preferred fourth agent (25-50 mg daily) 1, 2
• Alternatives if spironolactone not tolerated:
  • Eplerenone (50-100 mg daily)
  • Amiloride (5-10 mg daily)
  • Doxazosin (4-8 mg daily)
  • Beta-blockers 2

Monitor and Follow-up

• Check electrolytes and renal function 1-2 weeks after medication changes 2
• Schedule follow-up within 1 month of medication changes 2
• Continue to monitor for development of target organ damage 1

Common Pitfalls to Avoid

1. Failing to confirm true resistance: Always rule out pseudoresistance before extensive workup
2. Overlooking medication adherence: This is a major cause of apparent treatment resistance
3. Inadequate diuretic therapy: Ensure appropriate diuretic type and dosing for volume management
4. Missing secondary causes: Systematic screening for common secondary causes is essential
5. Inappropriate medication combinations: Avoid redundant mechanisms of action

By following this systematic approach to differential diagnosis and workup, clinicians can identify the underlying causes of resistant hypertension and implement effective management strategies to improve blood pressure control and reduce cardiovascular risk.