What disease presents with episodic severe hypertension accompanied by flushing, headache, palpitations, and sweating?

Pheochromocytoma: The Disease of Episodic Severe Hypertension with Flushing

The disease you are describing is pheochromocytoma (or paraganglioma when extra-adrenal), a rare catecholamine-producing tumor that causes episodic severe hypertension accompanied by the classic triad of headache, palpitations, and sweating. 1

Clinical Presentation

The classic triad of headache, palpitations, and sweating in a hypertensive patient has 93.8% specificity and 90.9% sensitivity for pheochromocytoma, with a 99.9% exclusion value when absent. 1 This presentation mandates immediate biochemical testing before attributing symptoms to other causes. 1

Key Clinical Features:

• Episodic (paroxysmal) or sustained hypertension with blood pressure spikes that can be extreme 2, 3
• Headaches (severe, throbbing) 4, 2
• Palpitations and tachycardia 4, 2
• Diaphoresis (profuse sweating, often described as "cold sweat") 5, 2
• Pallor or flushing during episodes 5
• Weight loss and hyperglycemia may also occur 6

Life-Threatening Complications if Undiagnosed:

Pheochromocytoma can cause syncope, cardiac arrest, myocardial infarction, cardiomyopathy, hypertensive crisis, stroke, or sudden death if left untreated. 1, 5 The diagnosis is often delayed by 3 years on average. 5

Diagnostic Approach

First-Line Biochemical Testing:

Plasma free metanephrines are the screening test of choice, with 96-100% sensitivity and 89-98% specificity. 7, 1 Ideally, collect from an indwelling venous catheter after the patient has been lying supine for 30 minutes to minimize false positives. 7, 1

Alternative acceptable test: 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) if plasma testing is unavailable. 7, 1

Interpretation Algorithm:

• ≥4 times upper limit of normal: Proceed immediately to imaging (MRI preferred over CT due to risk of hypertensive crisis with IV contrast) 7, 1
• 2-4 times upper limit of normal: Repeat testing in 2 months and consider genetic testing 7, 5
• 1-2 times upper limit of normal: Repeat testing in 6 months using proper collection technique, or consider clonidine suppression test (100% specificity, 96% sensitivity) 1, 5

Critical Preanalytical Factors:

Avoid false positives by ensuring patient rest, discontinuing tricyclic antidepressants, avoiding acetaminophen, and considering obesity and obstructive sleep apnea as confounders. 7, 5

Imaging and Localization

High-resolution CT of the abdomen is first-line anatomical imaging after biochemical confirmation. 7 MRI is preferred if metastatic disease is suspected, patient is pregnant or young, or extra-adrenal paraganglioma is suspected. 7

Functional imaging with ¹²³I-MIBG scintigraphy is useful for confirming functionality and detecting metastatic disease. 7

Genetic Considerations

Up to 35% of pheochromocytomas are hereditary, making genetic testing mandatory in all cases. 4, 6 Key hereditary syndromes include:

• SDHB mutations: Associated with higher malignancy risk (20-50% for paragangliomas), extra-adrenal tumors, and require lifelong intensive surveillance 4, 5
• Multiple endocrine neoplasia type 2 (MEN2) 2, 6
• von Hippel-Lindau disease 4, 6
• Neurofibromatosis type 1 6

Critical Management Pitfalls to Avoid

Never Perform These Actions Before Excluding Pheochromocytoma:

• Never biopsy an adrenal mass suspected to be pheochromocytoma—this can precipitate fatal hypertensive crisis 7, 1
• Never initiate beta-blockers alone before alpha-blockade—this causes unopposed alpha-stimulation and paradoxical severe hypertension 7, 1
• Avoid contrast-enhanced CT until biochemically excluded—use MRI preferentially 1

Preoperative Management:

All patients with biochemically confirmed pheochromocytoma require alpha-adrenergic blockade 7-14 days before any surgical intervention to prevent hypertensive crisis. 7, 5 Start with phenoxybenzamine, then add beta-blocker only after adequate alpha-blockade is achieved. 7

Definitive Treatment

Laparoscopic adrenalectomy is the definitive curative treatment for confirmed pheochromocytoma once adequate preoperative blockade is achieved. 7 This is preferred for most adrenal pheochromocytomas <6 cm without local invasion. 7

Post-Surgical Follow-Up:

All patients require long-term surveillance due to risk of malignant recurrence, particularly those with SDHB mutations, extra-adrenal tumors, or tumors >5 cm. 5 Repeat biochemical testing 14 days post-surgery to confirm complete resection. 5