What are the secondary causes of hypertension?

Secondary Causes of Hypertension

Screen for secondary hypertension when patients present with resistant hypertension, early-onset hypertension (<30 years), abrupt onset or worsening of blood pressure control, or specific clinical clues suggesting an underlying cause. 1, 2

Common Secondary Causes

Renal Parenchymal Disease (1-2% prevalence)

• Look for history of urinary tract infections, obstruction, hematuria, urinary frequency, nocturia, analgesic abuse, or family history of polycystic kidney disease 1
• Physical examination may reveal abdominal mass (polycystic kidney disease) or skin pallor 1
• Screen with renal ultrasound and check for elevated serum creatinine and abnormal urinalysis 1

Renovascular Disease (5-34% prevalence depending on clinical context)

• Suspect in patients with resistant hypertension, abrupt onset or worsening hypertension, flash pulmonary edema (atherosclerotic), or early-onset hypertension especially in women (fibromuscular dysplasia) 1, 2
• Listen for abdominal systolic-diastolic bruit or bruits over carotid and femoral arteries 1
• Screen with renal Duplex Doppler; confirm with bilateral selective renal intra-arterial angiography, MRA, or abdominal CT 1
• Consider renovascular disease if serum creatinine increases ≥50% within one week of starting ACE inhibitor or ARB therapy 3

Primary Aldosteronism (8-20% prevalence in resistant hypertension)

• This is one of the most frequent and important secondary causes because aldosterone excess causes greater target organ damage than primary hypertension, including 3.7-fold increase in heart failure, 4.2-fold increase in stroke, 6.5-fold increase in MI, and 12.1-fold increase in atrial fibrillation 1, 2
• Suspect in patients with resistant hypertension, spontaneous or diuretic-induced hypokalemia, muscle cramps or weakness, incidentally discovered adrenal mass, obstructive sleep apnea, or family history of early-onset hypertension or stroke 1, 2
• Screen with plasma aldosterone/renin ratio under standardized conditions (correct hypokalemia and withdraw aldosterone antagonists for 4-6 weeks) 1
• Confirm with oral sodium loading test or IV saline infusion test, followed by adrenal CT scan and adrenal vein sampling 1, 2

Obstructive Sleep Apnea (25-50% prevalence in resistant hypertension)

• This is the most common condition associated with resistant hypertension when systematically evaluated 4
• Look for snoring, fitful sleep, breathing pauses during sleep, daytime sleepiness, obesity, Mallampati class III-IV, and loss of normal nocturnal BP fall 1, 2
• Age >50 years, neck circumference ≥41 cm for women and ≥43 cm for men, and presence of snoring are strong predictors 4
• Screen with Berlin Questionnaire, Epworth Sleepiness Score, or overnight oximetry; confirm with polysomnography 1, 2

Drug-Induced Hypertension

• Review all medications including NSAIDs, oral contraceptives, decongestants, stimulants, and herbal supplements before pursuing expensive workup 1, 2

Uncommon Secondary Causes

Pheochromocytoma/Paraganglioma

• Presents with episodic symptoms (headache, palpitations, sweating), labile hypertension, and pallor 1, 2
• Screen with 24-hour urinary catecholamines or metanephrines 2

Cushing Syndrome

• Look for weight gain, moon facies, buffalo hump, purple striae, proximal muscle weakness 1
• Screen with 24-hour urinary free cortisol or overnight dexamethasone suppression test 1

Thyroid Disorders

• Hyperthyroidism causes isolated systolic hypertension; hypothyroidism causes diastolic hypertension 1, 3
• Screen with thyroid-stimulating hormone 2

Aortic Coarctation

• Suspect in young patients (<30 years) with hypertension 1
• Blood pressure is higher in upper extremities than lower extremities, absent femoral pulses, continuous murmur over back/chest/abdomen 1
• Measure thigh BP in patients ≤30 years with elevated brachial BP 5
• Confirm with echocardiogram or thoracic/abdominal CT angiogram or MRA 1

Primary Hyperparathyroidism

• Presents with hypercalcemia 1
• Screen with serum calcium; confirm with serum parathyroid hormone 1

Clinical Indications for Screening

Screen for secondary hypertension when any of the following are present: 1, 2, 5

• Age of onset <30 years (especially before puberty)
• Resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 drugs including a diuretic)
• Severe or accelerated/malignant hypertension with grade III-IV retinopathy
• Abrupt onset or sudden deterioration of previously controlled hypertension
• Hypertensive urgency or emergency
• Target organ damage disproportionate to duration or severity of hypertension
• Unprovoked hypokalemia

Diagnostic Approach

Initial Screening for All Suspected Cases

• Thorough history focusing on duration and previous BP levels, symptoms suggesting secondary causes, medication use (especially NSAIDs, oral contraceptives, decongestants), lifestyle factors, and family history 2
• Physical examination including features of Cushing syndrome, skin stigmata of neurofibromatosis, palpation for enlarged kidneys, auscultation for abdominal murmurs, assessment of femoral pulses 2
• Basic blood biochemistry: fasting blood glucose and HbA1c, serum lipids, sodium, potassium, creatinine with eGFR 2
• Urinalysis and urinary albumin-to-creatinine ratio 2
• Thyroid-stimulating hormone 2
• 12-lead ECG 2

Targeted Screening Based on Clinical Suspicion

• Plasma aldosterone-to-renin ratio for primary aldosteronism 2
• Renal ultrasound with Doppler for renovascular disease 2
• Polysomnography for obstructive sleep apnea 2
• 24-hour urinary catecholamines or metanephrines for pheochromocytoma 2

Management Principles

Treat the underlying cause whenever possible, as this can lead to cure or dramatic improvement and reduce cardiovascular risk. 1, 2

• Unilateral laparoscopic adrenalectomy for unilateral primary aldosteronism or mineralocorticoid receptor antagonists (spironolactone or eplerenone) for bilateral disease 1, 2
• Medical therapy for atherosclerotic renovascular disease 2
• Percutaneous transluminal renal angioplasty without stenting for fibromuscular dysplasia 2
• CPAP therapy for moderate-severe obstructive sleep apnea 2
• Optimize antihypertensive therapy while addressing the underlying cause 2

Critical Pitfalls to Avoid

• Secondary hypertension affects approximately 10% of all hypertensive patients but is often underrecognized 6, 3
• Do not perform expensive imaging studies before completing basic laboratory screening 2
• Do not overlook medication-induced hypertension before pursuing extensive workup 2
• Delayed diagnosis can lead to irreversible vascular remodeling, resulting in residual hypertension even after treating the underlying cause 2
• Consider referral to specialist centers with expertise in diagnosing and managing secondary hypertension for complex cases 1, 2