What is the diagnostic approach for a patient with suspected secondary hypertension?

Diagnostic Approach to Secondary Hypertension

Begin with targeted screening based on specific clinical clues rather than universal testing, starting with basic laboratory investigations and advancing to specialized imaging and functional tests only when clinical suspicion warrants further evaluation. 1

Clinical Clues That Trigger Evaluation

Screen for secondary hypertension when patients present with:

• Age of onset <30 years or >50 years - younger onset suggests coarctation, fibromuscular dysplasia, or endocrine disorders; older onset suggests atherosclerotic renovascular disease 1, 2
• Resistant hypertension - blood pressure >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications from different classes, including a diuretic 1, 2
• Sudden onset or sudden deterioration of previously controlled hypertension 1, 2
• Hypertensive urgency or emergency 1
• Target organ damage disproportionate to duration or severity of hypertension 1

Symptom-Specific Clinical Clues

For Primary Aldosteronism:

• Muscle weakness, tetany, cramps, arrhythmias (from hypokalemia) 3

For Pheochromocytoma:

• Episodic sweating, palpitations, frequent headaches 3

For Renal Artery Stenosis:

• Flash pulmonary edema 3

For Obstructive Sleep Apnea:

• Snoring, daytime sleepiness, neck circumference >40 cm 3

For Cushing Syndrome:

• Truncal obesity, fatty deposits, colored striae 3

Physical Examination Findings

Cardiovascular examination must include:

• Radio-femoral delay (coarctation of the aorta) 3
• Abdominal bruits (renovascular disease) 3
• Decreased femoral pulses (coarctation) 3

Other systems:

• Enlarged kidneys on palpation (polycystic kidney disease) 3
• Enlarged thyroid (thyroid disease) 3
• Neck circumference >40 cm (obstructive sleep apnea) 3

Basic Laboratory Investigations (All Suspected Cases)

Essential first-line tests:

• Serum sodium and potassium (unprovoked hypokalemia suggests primary aldosteronism or renovascular disease) 3, 2
• Serum creatinine and estimated glomerular filtration rate (eGFR) 3
• Urinalysis and urinary albumin-to-creatinine ratio 3
• Fasting glucose or HbA1c 3
• Lipid profile 3
• Thyroid-stimulating hormone 1
• 12-lead ECG (detect left ventricular hypertrophy, atrial fibrillation) 3

Critical update: The European Society of Cardiology 2024 guidelines now recommend measuring aldosterone-to-renin ratio in all adults with confirmed hypertension (Class IIa recommendation), representing a major departure from traditional selective screening 2

Targeted Advanced Testing Based on Clinical Suspicion

For Primary Aldosteronism (8-20% of resistant hypertension)

Screening:

• Aldosterone-to-renin ratio (ARR) - high ratio (>20) when serum aldosterone is elevated and plasma renin activity is low 1, 2

Confirmatory testing:

• Intravenous saline suppression test or oral sodium loading test 1, 2

Localization:

• Adrenal CT imaging 1
• Adrenal vein sampling for lateralization 1

For Renovascular Disease

Initial screening:

• Renal ultrasound with Doppler duplex 1, 2

Confirmatory imaging:

• CT or MR renal angiography for precise localization of stenosis 1, 2

Specific indications:

• Serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB therapy 4
• Unilateral smaller kidney or kidney size difference >1.5 cm 4
• Recurrent flash pulmonary edema 4

For Pheochromocytoma

Biochemical testing:

• Plasma free metanephrines (preferred) or 24-hour urinary catecholamines/metanephrines 1, 2

Imaging (only after biochemical confirmation):

• Abdominal/adrenal CT or MRI 1, 2

For Obstructive Sleep Apnea (25-50% of resistant hypertension)

Screening:

• Home sleep apnea testing or polysomnography 1

Clinical context:

• Particularly important in patients with obesity, snoring, daytime sleepiness, and non-dipping nocturnal blood pressure pattern 5

For Cushing Syndrome

Screening:

• Late-night salivary cortisol or other screening tests for cortisol excess 3

Additional Imaging When Indicated

Echocardiography for:

• Left ventricular hypertrophy, systolic/diastolic dysfunction, atrial dilation, aortic coarctation 3, 2

Fundoscopy when:

• Blood pressure >180/110 mmHg to evaluate for hypertensive emergency and malignant hypertension 2

Carotid ultrasound:

• Assess for plaques and stenosis 3

Critical Pitfalls to Avoid

Medication-induced hypertension must be excluded first - review for oral contraceptives, NSAIDs, decongestants, glucocorticoids, cyclosporine, cocaine, and amphetamines before pursuing expensive workup 1, 2

Do not perform expensive imaging studies before completing basic laboratory screening 2

Medication effects on aldosterone-renin ratio:

• Mineralocorticoid receptor antagonists raise aldosterone levels 1
• Beta-blockers and direct renin inhibitors lower renin levels 1
• Consider holding these medications before testing when feasible

Do not combine two RAS blockers (ACE inhibitor and ARB) during evaluation 1

Delayed diagnosis consequences:

• Even after treating the underlying cause, some patients require ongoing antihypertensive therapy due to irreversible vascular remodeling 6
• Early detection and treatment are crucial to minimize irreversible changes 6

Referral Considerations

Refer to specialized centers for complex cases requiring adrenal vein sampling, renal angiography, or comprehensive management of confirmed secondary causes 7