What is the approach to assessing secondary hypertension, including definition, classification, differential diagnosis, history, physical examination, investigations, empiric treatment, and indications for referral?

Assessment of Secondary Hypertension

Definition

Secondary hypertension is elevated blood pressure caused by an identifiable and potentially correctable underlying condition, affecting 5-10% of all hypertensive patients (increasing to 10-20% in resistant cases). 1, 2, 3

Classification by Etiology

Common Causes (by prevalence):

• Primary aldosteronism: 8-20% of resistant hypertension cases 1, 2
• Renovascular disease: 5-34% in selected populations 1, 4
• Obstructive sleep apnea: 25-50% of resistant hypertension 2
• Renal parenchymal disease: 1-2% of all hypertensive patients 1, 4

Less Common Causes:

• Pheochromocytoma/paraganglioma 1, 3
• Cushing syndrome 3
• Thyroid disorders (hyper/hypothyroidism) 3
• Hyperparathyroidism 3
• Coarctation of the aorta 5, 3
• Drug-induced hypertension 3, 6

Differential Diagnosis Framework

By Age of Onset:

• Age <30 years: Consider coarctation of aorta, fibromuscular dysplasia, renal parenchymal disease, endocrine disorders 1, 5
• Age >50 years: Consider atherosclerotic renovascular disease 5

By Clinical Presentation:

• Resistant hypertension (BP >140/90 mmHg on ≥3 drugs including diuretic): Primary aldosteronism, renovascular disease, obstructive sleep apnea, renal parenchymal disease 1, 2
• Abrupt onset or sudden worsening: Renovascular disease, pheochromocytoma 1, 2
• Hypertensive urgency/emergency: Pheochromocytoma, renovascular disease 2

History Taking

Character of Hypertension:

• Duration and previous BP levels 1
• Response to antihypertensive medications (number and classes used) 1
• Pattern of BP elevation (sustained vs. episodic) 1

Red Flags (Indications for Screening):

• Age of onset <30 years or >50 years 1, 5
• Resistant hypertension (≥3 medications including diuretic) 1, 2
• Abrupt onset or sudden deterioration of previously controlled hypertension 1, 2
• Severe BP elevation (especially with grade III-IV retinopathy) 5
• Target organ damage disproportionate to duration/severity 2
• Hypertensive urgency or emergency 2

Cause-Specific Symptoms:

Renal Parenchymal Disease:

• Urinary tract infections, obstruction, hematuria 1, 4
• Urinary frequency and nocturia 1
• Analgesic abuse history 1
• Family history of polycystic kidney disease 1, 4

Renovascular Disease:

• Flash pulmonary edema 1, 4
• Early-onset hypertension in women (suggests fibromuscular dysplasia) 1

Primary Aldosteronism:

• Muscle cramps or weakness 1, 4
• Family history of early-onset hypertension or stroke at young age 1, 4

Pheochromocytoma:

• Episodic headaches, palpitations, sweating 1
• Labile hypertension 1

Obstructive Sleep Apnea:

• Snoring, witnessed apneas 2
• Daytime sleepiness 2
• Obesity 2

Cushing Syndrome:

• Weight gain, easy bruising 1
• Proximal muscle weakness 1

Risk Factors:

• Medication use: NSAIDs, oral contraceptives, decongestants, stimulants, corticosteroids 1, 3
• Substance use: Alcohol, cocaine, amphetamines 3
• Lifestyle factors: Obesity (especially for sleep apnea), high sodium intake 1
• Family history: Early-onset hypertension, endocrine disorders, polycystic kidney disease 1

Physical Examination (Focused)

Cardiovascular:

• Radio-femoral delay: Coarctation of aorta 2
• Decreased or absent femoral pulses: Coarctation of aorta 5
• Abdominal systolic-diastolic bruit: Renovascular disease 1, 4
• Bruits over carotid/femoral arteries: Atherosclerotic renovascular disease or fibromuscular dysplasia 1
• Arrhythmias (especially atrial fibrillation with hypokalemia): Primary aldosteronism 1, 2

Endocrine/Metabolic Signs:

• Truncal obesity, purple striae, buffalo hump, moon facies: Cushing syndrome 1, 2, 5
• Exophthalmos: Hyperthyroidism 5
• Skin pallor: Renal parenchymal disease 1
• Skin stigmata of neurofibromatosis: Pheochromocytoma 1

Renal:

• Abdominal mass: Polycystic kidney disease 1, 4
• Enlarged kidneys on palpation: Polycystic kidney disease 1

Ophthalmologic:

• Grade III-IV retinopathy (hemorrhages, exudates, papilledema): Severe hypertension, pheochromocytoma 1, 2

Body Habitus:

• Obesity with large neck circumference: Obstructive sleep apnea 2

Investigations

Basic Screening (All Suspected Cases):

Laboratory Tests:

• Serum electrolytes (sodium, potassium): Hypokalemia suggests primary aldosteronism or renovascular disease 1, 2, 4
• Serum creatinine and eGFR: Elevated in renal parenchymal disease 1, 2, 4
• Urinalysis with dipstick: Proteinuria/hematuria suggests renal parenchymal disease 1, 2
• Urinary albumin-to-creatinine ratio: Assess for albuminuria 2, 4
• Fasting blood glucose or HbA1c: Hyperglycemia in Cushing syndrome, pheochromocytoma 1, 2, 5
• Serum lipids: Cardiovascular risk assessment 2
• Thyroid-stimulating hormone (TSH): Screen for thyroid disorders 2, 4

Imaging:

• 12-lead ECG: Assess for left ventricular hypertrophy, arrhythmias 1, 2

Targeted Investigations (Based on Clinical Suspicion):

Primary Aldosteronism:

• Screening: Plasma aldosterone-to-renin ratio under standardized conditions (correct hypokalemia, withdraw aldosterone antagonists for 4-6 weeks) 1, 2, 4
• Confirmatory: IV saline suppression test or oral sodium loading test with 24-hour urine aldosterone 1, 2
• Localization: Adrenal CT scan 2, 4
• Lateralization: Adrenal vein sampling (for surgical candidates) 2, 4

Renovascular Disease:

• Initial screening: Renal ultrasound with Duplex Doppler 1, 2, 4
• Confirmatory: CT or MR renal angiography 2, 4
• Gold standard: Bilateral selective renal intra-arterial angiography 1, 4

Renal Parenchymal Disease:

• Renal ultrasound: Assess kidney size, echogenicity, masses 1
• Additional tests: Based on suspected etiology of renal disease 1

Pheochromocytoma:

• Screening: 24-hour urinary catecholamines or metanephrines 2
• Imaging: Abdominal/adrenal CT or MRI 2

Obstructive Sleep Apnea:

• Screening: Home sleep apnea testing 2, 4
• Confirmatory: Overnight polysomnography 2, 4

Cushing Syndrome:

• Screening: 24-hour urinary free cortisol, overnight dexamethasone suppression test 1

Coarctation of Aorta:

• Echocardiography: Assess for coarctation, left ventricular hypertrophy 2
• CT or MR angiography: Definitive imaging 7

Advanced Assessments (Selected Cases):

• Echocardiography: Left ventricular hypertrophy, systolic/diastolic dysfunction 2
• Fundoscopy: Retinal changes, hemorrhages, papilledema 2

Expected Findings by Cause:

Primary Aldosteronism:

• Hypokalemia (spontaneous or diuretic-induced) 1, 4
• Elevated aldosterone-to-renin ratio 1, 2
• Suppressed renin 1

Renovascular Disease:

• Elevated serum creatinine (may worsen with ACE inhibitors/ARBs) 1
• Renal artery stenosis on imaging 1, 4

Renal Parenchymal Disease:

• Elevated creatinine, reduced eGFR 1, 4
• Abnormal urinalysis (proteinuria, hematuria) 1

Pheochromocytoma:

• Elevated urinary catecholamines/metanephrines 2
• Adrenal mass on imaging 2

Empiric Treatment

General Principles:

Treat the underlying cause while optimizing blood pressure control with appropriate antihypertensive agents. 2

Cause-Specific Treatment:

Primary Aldosteronism:

• Unilateral disease: Adrenalectomy (curative) 2, 4
• Bilateral disease: Mineralocorticoid receptor antagonists (spironolactone 50-100 mg daily or eplerenone) 2, 4

Renovascular Disease:

• Atherosclerotic: Medical therapy (ACE inhibitors/ARBs, statins, antiplatelet agents) 2
• Fibromuscular dysplasia: Percutaneous transluminal renal angioplasty without stenting 2

Renal Parenchymal Disease:

• Address underlying renal disease with specific treatments 2
• ACE inhibitors or ARBs (monitor renal function carefully) 2

Obstructive Sleep Apnea:

• CPAP therapy for moderate-severe cases 2
• Weight loss 1, 2

Resistant Hypertension (After Excluding Secondary Causes):

• Optimize lifestyle modifications (sodium restriction, weight loss, limit alcohol) 1, 2
• Use thiazide-like diuretics (not classic thiazides) 2
• Consider loop diuretics if eGFR <30 ml/min/1.73m² 2
• Add spironolactone as fourth-line agent (if K+ <4.5 mmol/L and eGFR >45 ml/min/1.73m²) 2, 4

Indications to Refer

Refer to Specialist Centers:

• Positive screening for secondary hypertension requiring diagnostic confirmation 1
• Complex cases requiring specialized expertise (especially endocrine hypertension) 1, 4
• Consideration for surgical intervention (adrenalectomy, renal angioplasty) 2
• Resistant hypertension uncontrolled despite optimal medical therapy 2
• Need for specialized procedures (adrenal vein sampling, renal angiography) 2, 4

Specific Referrals:

• Nephrology: Renal parenchymal disease, renovascular disease 8
• Endocrinology: Primary aldosteronism, Cushing syndrome, pheochromocytoma, thyroid/parathyroid disorders 1, 8
• Sleep medicine: Obstructive sleep apnea 2
• Cardiology/cardiac surgery: Coarctation of aorta 7
• Interventional radiology: Renal angioplasty 2

Critical Pitfalls

Diagnostic Pitfalls:

• Underrecognition of secondary hypertension despite affecting 5-10% of all hypertensive patients (10-20% in resistant cases) 2, 4, 6
• Performing expensive imaging studies before completing basic laboratory screening 2
• Failing to consider medication-induced hypertension (NSAIDs, oral contraceptives, decongestants) before extensive workup 2
• Not correcting hypokalemia or withdrawing aldosterone antagonists before testing for primary aldosteronism (leads to false-negative results) 1
• Missing the diagnosis in young patients (<30 years) or new-onset hypertension in older patients (>50 years) 1, 5

Treatment Pitfalls:

• Delayed diagnosis leads to vascular remodeling, affecting renal function and resulting in residual hypertension even after treating the underlying cause 2, 4
• Combining two RAS blockers (ACE inhibitor and ARB) is not recommended 2
• Starting ACE inhibitors/ARBs in bilateral renal artery stenosis without careful monitoring can precipitate acute kidney injury 2
• Assuming hypertension will resolve after treating the underlying cause—some patients require ongoing antihypertensive therapy 2
• Using classic thiazides instead of thiazide-like diuretics in resistant hypertension (thiazide-like are more effective) 2
• Adding spironolactone without checking potassium and renal function (risk of hyperkalemia if K+ >4.5 mmol/L or eGFR <45 ml/min/1.73m²) 2, 4

Management Pitfalls:

• Not referring complex cases to specialized centers with appropriate expertise for comprehensive evaluation and management 1, 4, 8
• Inadequate follow-up monitoring of blood pressure, renal function, and electrolytes after initiating treatment 2