What is the recommended workup for secondary hypertension?

Workup for Secondary Hypertension

When to Suspect Secondary Hypertension

Screen for secondary causes when blood pressure remains >140/90 mmHg despite three antihypertensive drugs (including a diuretic), when onset occurs before age 30 or after age 50, when previously controlled hypertension suddenly worsens, or when severe hypertension (>180/110 mmHg) is present. 1, 2

Additional red flags include:

• Target organ damage disproportionate to hypertension duration or severity 1, 2
• Hypertensive emergency or urgency 1
• Serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB 1, 2

Initial Laboratory Screening (Required for All Suspected Cases)

The 2024 ESC guidelines now recommend measuring plasma aldosterone-to-renin ratio (ARR) in all adults with confirmed hypertension (Class IIa), representing a major shift from selective screening. 1, 3, 4 This is because primary aldosteronism accounts for 8-20% of resistant hypertension and is the most common treatable secondary cause. 1, 3

Complete the following baseline panel before pursuing expensive imaging 3:

• Serum electrolytes (sodium, potassium) – spontaneous or diuretic-induced hypokalemia strongly suggests primary aldosteronism 5, 1, 4
• Serum creatinine and eGFR to assess renal function 5, 1, 4
• Urinalysis with microscopy looking for blood, protein, and casts suggesting renal parenchymal disease 5, 4
• Urinary albumin-to-creatinine ratio for early renal damage detection 5, 1, 4
• Fasting glucose or HbA1c 5, 1, 4
• Thyroid-stimulating hormone (TSH) 5, 1, 4
• Fasting lipid panel 5, 1
• 12-lead ECG to assess for left ventricular hypertrophy 5, 1, 4

Physical Examination Clues

Look for these specific findings that direct targeted testing 5, 1:

• Radio-femoral delay → coarctation of the aorta 5, 1
• Abdominal systolic-diastolic bruits → renovascular disease 5, 1
• Central obesity, wide purple striae (>1 cm), easy bruising, proximal muscle weakness, moon facies, buffalo hump → Cushing syndrome 5, 1, 4
• Palpable enlarged kidneys → polycystic kidney disease 5, 1
• Neck circumference >40 cm, snoring, witnessed apneas → obstructive sleep apnea 1

Targeted Confirmatory Testing Based on Clinical Suspicion

Primary Aldosteronism (Most Common)

• If ARR is positive (ratio >20 with elevated aldosterone and suppressed renin), proceed to confirmatory testing with oral sodium loading test (24-hour urine aldosterone) or IV saline infusion test 1, 4
• After biochemical confirmation, obtain adrenal CT scan for localization 1, 4
• Adrenal vein sampling is required when surgical intervention is contemplated to differentiate unilateral from bilateral disease 5, 1

Renovascular Disease

Pursue when patient presents with 1, 4:

• Abrupt onset or sudden worsening of previously controlled hypertension
• Flash pulmonary edema
• Serum creatinine increase ≥50% within one week of starting ACE inhibitor/ARB
• Severe hypertension with unilateral smaller kidney or kidney size difference >1.5 cm
• Abdominal systolic-diastolic bruit on examination

Initial imaging: Renal Duplex Doppler ultrasound 1
Confirmatory imaging: CT or MRI renal angiography 5, 1, 4

Pheochromocytoma

Suspect when patient presents with episodic sweating, palpitations, frequent headaches, and labile or paroxysmal hypertension 1

Biochemical screening: 24-hour urinary metanephrines/normetanephrines OR plasma free metanephrines 1, 4
After biochemical confirmation: Abdominal/adrenal CT or MRI 1

Obstructive Sleep Apnea

Present in 25-50% of resistant hypertension cases 1

Screen when patient has resistant hypertension plus snoring, witnessed apneas, daytime sleepiness, obesity (BMI >30), or non-dipping/reverse-dipping pattern on 24-hour BP monitoring 1, 4

Diagnostic test: Overnight polysomnography (AHI >5 confirms OSA; >30 indicates severe disease) 1

Cushing Syndrome

Screening tests: 24-hour urinary free cortisol OR late-night salivary cortisol OR low-dose dexamethasone suppression test 1

Thyroid Disease

TSH already obtained in initial screening 5, 1
If abnormal, obtain free T4/T3 as indicated 1

Critical Pitfalls to Avoid

• Medication non-adherence accounts for a large share of apparent resistant hypertension; ask explicitly about missed doses, side effects, and cost barriers 1
• Drug-induced hypertension: Review NSAIDs, decongestants, stimulants, oral contraceptives, cyclosporine, erythropoietin, licorice, and ephedra 1
• White-coat hypertension occurs in 20-30% of apparent resistant cases; use ambulatory or home BP monitoring to exclude 1
• Never order expensive imaging (CT, MRI, angiography) before completing basic laboratory screening 3, 4
• ACE inhibitors and ARBs lower aldosterone and raise renin, potentially causing false-negative ARR results; ideally discontinue 2-4 weeks before testing if clinically feasible 1

When to Refer to Specialist

Refer to hypertension specialist or endocrinologist when 1, 3, 4:

• Screening tests are positive and confirmatory testing is required
• Complex procedures (e.g., adrenal vein sampling) are needed
• Surgical intervention is being considered (e.g., unilateral adrenalectomy for primary aldosteronism)
• Blood pressure remains uncontrolled after ≥6 months of optimal medical therapy

Delayed diagnosis leads to vascular remodeling, affecting renal function and resulting in residual hypertension even after treating the underlying cause. 3