What are the causes of secondary hypertension and how are they investigated?

Secondary Hypertension: Causes and Investigation

When to Suspect Secondary Hypertension

Screen for secondary hypertension in patients with early-onset hypertension (<30 years), resistant hypertension, sudden deterioration in BP control, hypertensive urgency/emergency, or strong clinical clues suggesting specific causes. 1

Key clinical scenarios warranting investigation include:

• Age-related patterns: Onset before age 30 (especially without obesity, metabolic syndrome, or family history) or new-onset after age 50 suggests renovascular disease 1, 2
• Resistant hypertension: BP >140/90 mmHg despite optimal doses of three antihypertensive drugs including a diuretic 1, 3
• Severe hypertension: Markedly elevated BP with grade III-IV retinopathy 2
• Biochemical clues: Spontaneous or diuretic-induced hypokalemia, elevated creatinine, abnormal urinalysis 1

Common Causes of Secondary Hypertension

Secondary hypertension affects 5-10% of hypertensive patients, though this increases to 10-20% in resistant cases 1, 4, 5

Most Common Causes in Adults:

Renal Parenchymal Disease (1-2% prevalence) 1

• History of urinary tract infections, obstruction, hematuria, urinary frequency, nocturia, analgesic abuse 1, 3
• Family history of polycystic kidney disease 1, 3
• Physical exam: Abdominal mass (polycystic kidneys), skin pallor 1

Renovascular Disease (5-34% in selected populations) 1

• Abrupt onset or worsening hypertension, flash pulmonary edema (atherosclerotic) 1, 3
• Early-onset hypertension in women suggests fibromuscular dysplasia 1, 3
• Physical exam: Abdominal systolic-diastolic bruit, bruits over carotid or femoral arteries 1
• Serum creatinine increase ≥50% within one week of starting ACE inhibitor/ARB 5

Primary Aldosteronism (8-20% of resistant hypertension) 1, 3

• Resistant hypertension with spontaneous or diuretic-induced hypokalemia 1, 3
• Muscle cramps or weakness 1, 3
• Family history of early-onset hypertension or stroke at young age (<40 years) 1, 3
• Physical exam: Arrhythmias, especially atrial fibrillation 1

Obstructive Sleep Apnea (25-50% of resistant hypertension) 1, 3

• Snoring, fitful sleep, breathing pauses during sleep, daytime sleepiness 1, 3
• Physical exam: Obesity, Mallampati class III-IV, loss of normal nocturnal BP fall 1, 3

Drug/Substance-Induced Hypertension 1

• NSAIDs, oral contraceptives, sympathomimetics, corticosteroids, alcohol 1, 3

Less Common Causes:

• Pheochromocytoma: Episodic symptoms, labile hypertension, headaches, palpitations, sweating 3, 2
• Cushing's Syndrome: Truncal obesity, purple striae, hyperglycemia 2, 6
• Thyroid/Parathyroid Disease: Hyperthyroidism (exophthalmos), hypothyroidism, hypercalcemia 2, 5
• Coarctation of Aorta: Decreased femoral pulses, upper extremity hypertension 2, 5

Diagnostic Approach

Step 1: Exclude Pseudoresistance and Drug-Induced Hypertension

Before extensive workup, confirm true resistant hypertension and review all medications, supplements, and substances that may elevate BP. 1, 3

Step 2: Basic Screening (All Suspected Cases)

Perform thorough history focusing on duration of hypertension, symptoms suggesting secondary causes, medication use, lifestyle factors, and family history 1, 3

Physical examination should assess for:

• Cushing's features (truncal obesity, striae) 3, 2
• Enlarged kidneys (polycystic disease) 1, 3
• Abdominal bruits (renovascular disease) 1, 3
• Femoral pulse delay/diminution (coarctation) 3, 2
• Neurofibromatosis stigmata (pheochromocytoma) 3

Basic laboratory screening includes: 1, 3

• Serum sodium, potassium, creatinine, eGFR 1, 3
• Thyroid-stimulating hormone (TSH) 1, 3
• Fasting blood glucose or HbA1c 3
• Urinalysis with dipstick for blood and protein 1, 3
• Urinary albumin-to-creatinine ratio 3
• 12-lead ECG 3

Step 3: Targeted Investigations Based on Clinical Suspicion

Choose further investigations carefully based on findings from history, physical examination, and basic screening. 1

For Primary Aldosteronism: 1, 3

• Plasma aldosterone-to-renin ratio (correct hypokalemia first, withdraw aldosterone antagonists 4-6 weeks prior) 1, 3
• Confirmatory testing: IV saline suppression test or oral sodium loading test 1
• Adrenal CT scan 1
• Adrenal vein sampling (to distinguish unilateral from bilateral disease) 1

For Renovascular Disease: 1, 3

• Renal ultrasound with Duplex Doppler 1, 3
• CT or MR renal angiography (depending on renal function) 1, 3
• Bilateral selective renal intra-arterial angiography (confirmatory) 1

For Obstructive Sleep Apnea: 1, 3

• Home sleep apnea testing (level 3 sleep study) 1, 3
• Overnight polysomnography 1, 3

For Pheochromocytoma: 3

• 24-hour urinary free catecholamines or metanephrines 3
• Abdominal/pelvic CT or MRI 1, 3

For Cushing's Syndrome: 1

• Dexamethasone suppression tests 1
• 24-hour urinary free cortisol 1
• Abdominal/pituitary imaging 1

For Renal Parenchymal Disease: 1

• Renal ultrasound 1
• Tests to evaluate specific cause of renal disease 1

Critical Pitfalls to Avoid

• Do not perform expensive imaging before completing basic laboratory screening 3
• Medication-induced hypertension must be excluded before extensive workup 3
• Hypokalemia is absent in the majority of primary aldosteronism cases and has low negative predictive value 1
• Delayed diagnosis leads to vascular remodeling and residual hypertension even after treating the underlying cause 3
• Secondary hypertension is often underrecognized despite affecting 5-10% of all hypertensive patients 1, 7

Referral Considerations

Refer patients with suspected secondary hypertension to specialist centers with appropriate expertise and resources for complex diagnostic testing and treatment. 1

Specific referrals include:

• Hypertension specialist or endocrinologist for positive primary aldosteronism screening 1
• Specialist centers for resistant hypertension management 1
• Centers with access to specialized testing (adrenal vein sampling, renal angiography) 1