What investigations are recommended for a patient presenting with secondary hypertension?

Investigations for Secondary Hypertension

When to Investigate for Secondary Causes

Screen for secondary hypertension when patients present with age of onset <30 years or >50 years, resistant hypertension requiring ≥3 medications, sudden onset or deterioration of previously controlled blood pressure, hypertensive urgency/emergency, or target organ damage disproportionate to hypertension duration. 1, 2

Key Clinical Clues Requiring Investigation

• Age-related patterns: Onset before age 30 suggests fibromuscular dysplasia, coarctation, or endocrine disorders; onset after age 50 suggests atherosclerotic renovascular disease 2, 3
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive drugs including a diuretic) is the strongest clinical indicator 1, 2
• Specific symptom clusters: Muscle weakness, tetany, cramps, or arrhythmias suggest primary aldosteronism; episodic sweating, palpitations, and frequent headaches suggest pheochromocytoma 4, 1
• Flash pulmonary edema suggests renal artery stenosis 4, 3
• Snoring and daytime sleepiness with obesity suggest obstructive sleep apnea 4, 5

Essential Basic Laboratory Investigations

First-Line Screening Tests (All Suspected Cases)

• Serum electrolytes (sodium and potassium): Unprovoked hypokalemia strongly suggests primary aldosteronism or renovascular disease 4, 2
• Renal function: Serum creatinine and estimated glomerular filtration rate (eGFR) 4, 1, 2
• Urinalysis and urinary albumin-to-creatinine ratio: Detects proteinuria and kidney damage 4, 1
• Fasting glucose and HbA1c: Screens for diabetes and hyperglycemia associated with Cushing syndrome or pheochromocytoma 4, 6
• Lipid profile: Assesses cardiovascular risk 4, 6
• Thyroid-stimulating hormone (TSH): Screens for thyroid disorders 1, 3
• 12-lead ECG: Detects atrial fibrillation, left ventricular hypertrophy, and ischemic heart disease 4, 1

Critical 2024 Guideline 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 This reflects the high prevalence of primary aldosteronism (8-20% of resistant hypertension cases) 5, 2

Targeted Advanced Investigations Based on Clinical Suspicion

For Primary Aldosteronism

• Aldosterone-to-renin ratio (ARR): High ratio (>20) with elevated aldosterone and suppressed renin suggests primary aldosteronism 1, 2
• Confirmatory testing: Intravenous saline suppression test or oral sodium loading test 1, 2
• Adrenal CT imaging: For localization after biochemical confirmation 4, 1
• Adrenal vein sampling: Distinguishes unilateral from bilateral disease 4

Important caveat: Certain medications affect ARR interpretation—mineralocorticoid receptor antagonists raise aldosterone levels, while beta-blockers and direct renin inhibitors lower renin levels 1

For Renovascular Disease

• Renal ultrasound with Doppler duplex: Initial non-invasive screening test 1, 2
• CT or MR renal angiography: Confirmatory test for precise localization of stenosis 4, 1, 2
• Clinical triggers: Abrupt onset or worsening hypertension, serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB, unilateral smaller kidney or size difference >1.5 cm 3

For Pheochromocytoma

• Plasma free metanephrines or 24-hour urinary catecholamines/metanephrines: First-line biochemical tests 4, 1, 2
• Abdominal/adrenal imaging (CT or MRI): Performed only after biochemical confirmation 1, 2
• Clinical presentation: Episodic symptoms, labile hypertension, sweating, palpitations, headaches 4, 5

For Obstructive Sleep Apnea

• Home sleep apnea testing or polysomnography: Diagnostic test for patients with snoring, daytime sleepiness, obesity, and non-dipping nocturnal BP pattern 1, 5
• Prevalence: Present in 25-50% of resistant hypertension cases 5

For Cushing Syndrome

• Late-night salivary cortisol or other screening tests for cortisol excess 4
• Physical findings: Truncal obesity, purple striae, fatty deposits 4, 7

Additional Imaging Studies

Cardiovascular and Structural Assessment

• Echocardiography: Evaluates left ventricular hypertrophy, systolic/diastolic dysfunction, atrial dilation, and aortic coarctation 4, 1, 2
• Carotid ultrasound: Assesses for plaques and stenosis 4, 2
• Fundoscopy: Recommended if BP >180/110 mmHg to evaluate for hypertensive emergency, retinal changes, hemorrhages, and papilledema 4, 5

Renal and Adrenal Imaging

• Renal ultrasound: Assesses kidney size, echogenicity, and structural abnormalities in suspected renal parenchymal disease 5
• Kidney/renal artery and adrenal imaging: Ultrasound, CT, or MR angiography for renal parenchymal disease, renal artery stenosis, and adrenal lesions 4

Stepwise Diagnostic Algorithm

Follow a stepwise approach: start with basic screening (history, physical examination, basic laboratory tests, ECG), then advance to specialized testing only when clinical clues warrant further investigation. 1, 2

1. Complete medication review FIRST: Identify drug-induced or substance-induced hypertension (oral contraceptives, NSAIDs, decongestants, glucocorticoids, cyclosporine, cocaine, amphetamines) before expensive workup 1, 2
2. Perform basic laboratory screening: Electrolytes, renal function, urinalysis, glucose, lipids, TSH, ECG 4, 1
3. Measure aldosterone-to-renin ratio: Now recommended for all confirmed hypertension 2
4. Proceed with targeted testing: Based on clinical suspicion from initial findings 1, 2
5. Refer to specialized centers: For complex cases requiring expertise in diagnosis and management 1, 8

Critical Pitfalls to Avoid

• Failure to recognize medication-induced hypertension before extensive workup is the most common and costly error 1, 2
• Performing expensive imaging studies before completing basic laboratory screening wastes resources 1
• Combining two RAS blockers (ACE inhibitor and ARB) is not recommended during evaluation 1
• Delayed diagnosis can lead to vascular remodeling and residual hypertension even after treating the underlying cause 5
• Misinterpreting aldosterone-to-renin ratio without considering medication effects 1

Prevalence Context

Secondary hypertension affects 5-10% of all hypertensive patients, but prevalence increases substantially in resistant hypertension populations where specific causes like primary aldosteronism (8-20%) and obstructive sleep apnea (25-50%) are much more common. 5, 2, 8