What are the causes of resistant hypertension?

Causes of Resistant Hypertension

Resistant hypertension has three major categories of causes: pseudoresistance (accounting for approximately 50% of cases), lifestyle and medication factors, and true secondary causes—with the critical first step being to exclude pseudoresistance before pursuing extensive secondary hypertension workup. 1, 2

Pseudoresistance (Most Common—~50% of Cases)

Pseudoresistance must be systematically excluded before diagnosing true resistant hypertension:

• Medication nonadherence represents approximately 50% of apparent treatment resistance and is the single most common cause 2
• White coat hypertension should be confirmed with 24-hour ambulatory blood pressure monitoring, as it accounts for roughly 50% of apparent resistant cases 2, 3
• Inadequate BP measurement technique, including using inappropriate cuff size (particularly failing to use large cuffs on large arms) or incorrect patient positioning, leads to falsely elevated readings 1, 2
• Suboptimal medication regimen, such as inadequate doses or inappropriate drug class selection for the patient's clinical profile 1

Lifestyle and Dietary Factors

These modifiable factors directly contribute to treatment resistance:

• Obesity is one of the two strongest risk factors for uncontrolled hypertension and is highly prevalent in resistant hypertension patients 2, 3
• Excessive sodium intake (averaging >10 g/day in resistant hypertension patients) directly increases BP and decreases the antihypertensive effect of most drug classes 2
• Excessive alcohol consumption significantly increases the risk of resistant hypertension 2
• Advanced age is the other strongest risk factor for uncontrolled hypertension 2, 3

Interfering Medications and Substances

A thorough medication review is essential, as these agents raise BP and contribute to treatment resistance:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common interfering medications 2, 3
• Oral contraceptives can elevate BP 1, 2
• Certain antidepressants interfere with BP control 2
• Decongestants, corticosteroids, and herbal supplements should be identified and discontinued when possible 3

Secondary Causes of Hypertension

After excluding pseudoresistance, screen systematically for these secondary causes:

Most Common Secondary Causes

• Obstructive sleep apnea affects 83% of patients with resistant hypertension and induces sustained sympathetic nervous system activation 2
• Primary aldosteronism has a prevalence of 17-23% in resistant hypertension and should be evaluated in all patients, even with normal potassium levels 2, 4
• Chronic kidney disease/renal parenchymal disease is a major contributor to resistance and requires assessment with serum creatinine and eGFR 1, 3
• Renovascular hypertension/renal artery stenosis should be considered, particularly in younger patients or those with sudden deterioration in BP control 1

Endocrine Causes

• Hypothyroidism: Screen with TSH and free T4 in patients with dry skin, cold intolerance, weight gain, and delayed ankle reflexes 1
• Hyperthyroidism: Screen with TSH in patients with heat intolerance, tremor, and weight loss 1
• Cushing's syndrome: Consider 24-hour urine cortisol in patients with characteristic features 4
• Pheochromocytoma: Screen with 24-hour urine metanephrines (represents 0.1-0.6% of resistant hypertension cases) 4
• Primary hyperparathyroidism/hypercalcemia: Check serum calcium and parathyroid hormone 1
• Congenital adrenal hyperplasia and other mineralocorticoid excess syndromes: Consider in early-onset hypertension with hypokalemia 1
• Acromegaly: Evaluate with serum growth hormone and IGF-1 in patients with acral features 1

Volume Overload States

Volume expansion is a frequently overlooked contributor:

• Inadequate diuretic therapy is extremely common—ensure thiazide-like diuretics (chlorthalidone or indapamide) are used rather than thiazides, and switch to loop diuretics when eGFR <30 mL/min/1.73m² 1
• Progressive renal insufficiency leads to volume retention 1
• Hyperaldosteronism causes sodium retention 1

High-Risk Populations

Certain demographic groups have higher prevalence:

• African Americans have higher prevalence of apparent resistant hypertension 2
• Men have higher prevalence compared to women 2
• Patients with diabetes have significantly higher risk 2
• Elderly patients have higher prevalence of sleep apnea, renal disease, and renal artery stenosis 2

Clinical Pitfalls to Avoid

• Do not pursue extensive secondary hypertension workup before confirming true resistance with ambulatory BP monitoring and verifying medication adherence 1, 3
• Do not overlook volume overload—optimize diuretic therapy before adding additional agents 1
• Screen for primary aldosteronism even when potassium is normal, as hypokalemia is a late manifestation 2, 4
• Consider referral to a hypertension specialist if BP remains elevated despite 6 months of optimized treatment, as specialists achieve control in 52-53% of resistant cases 3