What are the possible etiologies in the differential diagnosis of severe acute hypertension?

Differential Diagnosis of Severe Acute Hypertension by Etiology

Primary (Essential) Hypertension

The majority of patients presenting with severe acute hypertension have unrecognized or uncontrolled essential hypertension that has escalated abruptly, rather than a secondary cause. 1, 2

• Medication non-adherence is the single most common trigger, with many patients presenting without having taken any antihypertensive agents 1, 2
• Limited access to healthcare services contributes substantially, particularly among sub-Saharan African migrants and African Americans 1
• Previously stable essential hypertension can suddenly escalate through marked activation of the renin-angiotensin system and pressure-induced natriuresis, creating a self-perpetuating cycle 1

Secondary Causes (20–40% of Malignant Hypertension Cases)

Renal Etiologies

Renal parenchymal disease and renal artery stenosis together represent the most frequent secondary causes of malignant hypertension. 1, 2

• Renal parenchymal disease – chronic kidney disease, glomerulonephritis, polycystic kidney disease, or diabetic nephropathy causing volume overload and renin-angiotensin activation 1, 2
• Renal artery stenosis – atherosclerotic (in older adults with widespread vascular disease) or fibromuscular dysplasia (in younger patients, especially women) 1, 2, 3
• Acute kidney injury – can both precipitate and result from severe hypertension by disrupting renal autoregulation 2

Endocrine Etiologies

Endocrine causes appear rare in malignant hypertension but must be systematically excluded because they are potentially curable. 1

• Pheochromocytoma – presents with sudden severe blood pressure rise accompanied by palpitations, diaphoresis, and headache; screen with plasma metanephrines or 24-hour urine catecholamines 2, 3
• Primary aldosteronism – accounts for a notable proportion of secondary causes; screen with plasma aldosterone-to-renin ratio 2, 3
• Cushing syndrome – suspect with central obesity, striae, proximal muscle weakness, and glucose intolerance 3
• Thyroid disease – both hyperthyroidism and hypothyroidism (especially in adults ≥65 years) can cause secondary hypertension 3

Drug-Induced and Toxicologic Causes

• Sympathomimetic agents – cocaine, methamphetamine, amphetamines trigger acute severe hypertension with risk of end-organ damage 2, 4
• Non-steroidal anti-inflammatory drugs (NSAIDs) – associated with acute blood pressure elevations through sodium retention and prostaglandin inhibition 2, 4
• Systemic corticosteroids – cause sodium retention and volume expansion 2, 4
• Calcineurin inhibitors – cyclosporine and tacrolimus precipitate hypertensive crises through renal vasoconstriction 2, 4
• Anti-angiogenic cancer therapies – VEGF inhibitors cause acute hypertension 2, 4

Vascular Causes

• Acute aortic dissection – commonly presents with severe hypertension and tearing chest/back pain; requires immediate recognition 1, 4
• Coarctation of the aorta – most common in children and young adults; suspect with upper extremity hypertension and diminished femoral pulses 3

Pregnancy-Related Causes

• Severe pre-eclampsia and eclampsia – constitute obstetric hypertensive emergencies; occur during pregnancy or up to 42 days postpartum 1, 4

Neurologic Causes

• Intracranial hemorrhage or acute stroke – can both cause and be caused by acute severe hypertension through disruption of cerebral autoregulation 1, 4
• Increased intracranial pressure – from any cause (tumor, trauma, infection) can trigger severe hypertension via Cushing reflex 5

Obstructive Sleep Apnea

• Obstructive sleep apnea – increasingly recognized as a reversible cause of resistant hypertension through repetitive hypoxemia and sympathetic activation 3

Pathophysiological Mechanisms Sustaining the Crisis

Regardless of the initiating etiology, severe acute hypertension is perpetuated through common final pathways:

• Marked renin-angiotensin system activation – correlates with the degree of microvascular damage and creates a vicious cycle 1, 2
• Pressure-induced natriuresis – leads to intravascular volume contraction, which paradoxically further stimulates renin release 1, 2
• Acute hypertensive microangiopathy – endothelial dysfunction and thrombotic microangiopathy cause renal vasoconstriction and perpetuate the crisis 1, 2
• Autoregulation failure – when compensatory mechanisms are exceeded, breakthrough occurs in the cerebral, renal, and coronary circulations 1, 5

Clinical Approach to Identifying the Etiology

After acute stabilization, systematic screening for secondary causes is mandatory given the 20–40% prevalence of identifiable etiologies. 2, 4

Essential Initial Workup

• Renal function and urinalysis – serum creatinine, urinalysis for protein and sediment to identify renal parenchymal disease 2, 4
• Renal artery imaging – duplex ultrasound or CT/MR angiography if renal artery stenosis suspected (especially with >90% carotid stenosis, unilateral small kidney, or flash pulmonary edema) 2, 3
• Plasma metanephrines – to screen for pheochromocytoma 2
• Plasma aldosterone-to-renin ratio – to identify primary aldosteronism 2
• Thyroid function tests – especially in adults ≥65 years 3
• Medication and substance use history – including NSAIDs, steroids, sympathomimetics, and illicit drugs 2, 4

Red Flags Suggesting Secondary Hypertension

• Age of onset <30 years (especially before puberty) 3
• Severe or resistant hypertension despite three-drug therapy 3
• Acute rise in blood pressure from previously stable readings 3
• Serum creatinine increase ≥50% within one week of starting ACE inhibitor or ARB 3
• Unilateral smaller kidney or kidney size difference >1.5 cm 3
• Recurrent flash pulmonary edema 3

Common Pitfalls to Avoid

• Do not assume "uncontrolled essential hypertension" without excluding secondary causes – 20–40% have identifiable and potentially reversible etiologies 2, 4
• Do not overlook medication non-adherence – the most common trigger that is often missed in the initial assessment 1, 2
• Do not delay secondary cause screening until after discharge – initiate workup during hospitalization to prevent missed diagnoses 2
• Do not forget to assess for widespread atherosclerotic disease – >90% carotid stenosis raises likelihood of concurrent renal artery stenosis 2