What investigations are recommended to evaluate secondary hypertension in a patient with resistant or atypical hypertension?

Investigation of Secondary Hypertension

When to Investigate for Secondary Causes

Screen for secondary hypertension when blood pressure remains >140/90 mmHg despite optimal doses of three antihypertensive medications (including a diuretic), when hypertension begins before age 30 or after age 50, when previously controlled blood pressure suddenly worsens, or when severe hypertension presents with grade III-IV retinopathy. 1, 2, 3

Additional red flags requiring investigation include: 2, 4, 5

• Target organ damage disproportionate to hypertension duration or severity
• Hypertensive urgency or emergency at presentation
• Specific clinical features suggesting endocrine or renovascular disease

Initial Screening Tests for All Suspected Cases

Laboratory Evaluation

Perform these baseline tests in every patient with suspected secondary hypertension: 2, 4

• Plasma aldosterone-to-renin ratio (ARR) – This is now a Class IIa recommendation for all adults with confirmed hypertension, representing a major shift in screening approach. Primary aldosteronism accounts for 8-20% of resistant hypertension cases. 2, 4
• Serum electrolytes (sodium and potassium) – Spontaneous or diuretic-induced hypokalemia strongly suggests primary aldosteronism. 1, 2, 4
• Serum creatinine and estimated glomerular filtration rate (eGFR) 2, 4
• Urinalysis with microscopy – Look for blood, protein, and casts suggesting renal parenchymal disease. 2, 4
• Urinary albumin-to-creatinine ratio 2, 4
• Fasting blood glucose or HbA1c 2, 4
• Thyroid-stimulating hormone (TSH) 1, 2
• Fasting lipid panel 2, 4

Cardiovascular Assessment

• 12-lead electrocardiogram – Assess for left ventricular hypertrophy and strain patterns. 2, 4
• Fundoscopy – Evaluate for retinal changes, hemorrhages, and papilledema, especially if blood pressure >180/110 mmHg. 4

Targeted Investigations Based on Clinical Clues

Primary Aldosteronism (Most Common Treatable Cause)

Clinical clues: Hypokalemia, muscle weakness, cramps, tetany, arrhythmias, or family history of early-onset hypertension/stroke before age 40. 1, 2, 4

Screening: Plasma aldosterone-to-renin ratio (ARR >20 with elevated aldosterone and suppressed renin is suggestive). 2, 4

Confirmatory testing: 2, 4

• Oral sodium loading test with 24-hour urine aldosterone collection
• IV saline infusion test with plasma aldosterone measured at 4 hours

Localization studies: 2, 4

• Adrenal CT scan after biochemical confirmation
• Adrenal vein sampling when surgical intervention is contemplated

Critical pitfall: ACE inhibitors and ARBs lower aldosterone and raise renin, potentially causing false-negative ARR results. Mineralocorticoid receptor antagonists raise aldosterone levels, while beta-blockers and direct renin inhibitors lower renin levels, affecting interpretation. 4

Renovascular Disease

Clinical clues: Abrupt onset or sudden worsening of previously controlled hypertension, flash pulmonary edema, serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB, severe hypertension with unilateral smaller kidney or kidney size difference >1.5 cm, or abdominal systolic-diastolic bruit on examination. 2, 4

Initial imaging: Renal ultrasound with Duplex Doppler. 2, 4

Confirmatory imaging: CT or MR renal angiography. 2, 4

Obstructive Sleep Apnea (Present in 25-50% of Resistant Hypertension)

Clinical clues: Resistant hypertension, snoring, witnessed apneas, daytime sleepiness, obesity (BMI >30) with Mallampati class III-IV airway, neck circumference >40 cm, or non-dipping nocturnal blood pressure pattern on ambulatory monitoring. 2, 4

Diagnostic test: Overnight polysomnography (apnea-hypopnea index >5 confirms OSA; >30 indicates severe disease). 4

Pheochromocytoma

Clinical clues: Episodic sweating, palpitations, and frequent headaches (classic triad); labile or paroxysmal hypertension; hypertensive crisis during anesthesia or surgery; or family history of pheochromocytoma or multiple endocrine neoplasia. 2, 4

Screening: 24-hour urinary metanephrines/normetanephrines or plasma free metanephrines. 2, 4

Imaging: Abdominal/adrenal CT or MRI after biochemical confirmation. 4

Cushing Syndrome

Clinical clues: Central obesity with thin extremities, purple striae (>1 cm wide), easy bruising, proximal muscle weakness, moon facies, buffalo hump, or supraclavicular fat pads. 1, 2, 4

Screening: 24-hour urinary free cortisol or late-night salivary cortisol. 4

Confirmatory test: Low-dose dexamethasone suppression test. 4

Thyroid Disease

Hypothyroidism clues: Dry skin, cold intolerance, constipation, hoarseness, weight gain, delayed ankle reflexes, periorbital puffiness, coarse skin, slow movement, or goiter. 1

Hyperthyroidism clues: Warm moist skin, heat intolerance, nervousness, tremulousness, insomnia, weight loss, diarrhea, proximal muscle weakness, lid lag, fine tremor of outstretched hands. 1

Screening: TSH with free T4 and T3 as indicated. 1

Coarctation of the Aorta

Clinical clues: Radio-femoral delay, blood pressure in thigh >10 mmHg lower than arm blood pressure while supine (in patients <30 years of age). 1, 4

Imaging: CT angiography or MRI if clinical suspicion exists. 1

Physical Examination Findings by Etiology

Perform a targeted examination looking for: 1, 4

• Radio-femoral delay → coarctation of the aorta
• Abdominal systolic-diastolic bruits → renovascular disease
• Jugular venous distension and peripheral edema → flash pulmonary edema from renovascular disease
• Colored striae and fatty deposits → Cushing syndrome
• Enlarged thyroid → thyroid dysfunction
• Palpable enlarged kidneys → renal parenchymal disease (polycystic kidney disease)
• Acral enlargement (large hands/feet) → acromegaly

Common Pitfalls to Avoid

Do not order expensive imaging (CT, MRI, angiography) before completing basic laboratory screening. 2, 4

Do not assume medication adherence without diplomatic inquiry. Poor adherence accounts for a significant proportion of apparent treatment resistance. Ask specifically about missed doses per week, adverse effects affecting adherence, and financial barriers to medication access. 1

Do not overlook medication-induced hypertension. Review all prescription and over-the-counter medications, including NSAIDs, decongestants, stimulants, oral contraceptives, cyclosporine, erythropoietin, natural licorice, and herbal compounds containing ephedra. 1

Do not diagnose resistant hypertension without confirming elevated blood pressure outside the office setting. Use ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring to exclude white-coat effect, which occurs in 20-30% of patients with apparent resistant hypertension. 1

Do not combine two renin-angiotensin system blockers (ACE inhibitor + ARB). This combination increases the risk of hyperkalemia, hypotension, and acute kidney injury without additional benefit. 2

When to Refer to a Specialist

Refer to a hypertension specialist or appropriate subspecialist when: 1, 4

• Screening tests are positive and require confirmatory testing
• Complex procedures (such as adrenal vein sampling) are contemplated
• Surgical intervention is being considered (such as unilateral adrenalectomy for primary aldosteronism)
• Blood pressure remains uncontrolled despite 6 months of optimal medical therapy
• A specific secondary cause is suspected but diagnosis remains uncertain