What is the role of metanephrines (metanephrines) in the diagnosis and management of hypertension (hypertension)?

Role of Metanephrines in the Diagnosis of Hypertension

Plasma free metanephrines or urinary fractionated metanephrines are the screening tests of choice for pheochromocytoma, a rare but important secondary cause of hypertension with high morbidity and mortality if left undiagnosed. 1

Pheochromocytoma as a Cause of Hypertension

• Pheochromocytoma is a rare cause of hypertension with a prevalence of 0.01% to 0.2% in the general hypertensive population, but may be present in up to 4% of patients with resistant hypertension 1
• These tumors cause hypertension through excessive catecholamine production, which can present as paroxysmal hypertension (episodic) or sustained hypertension (in up to 50% of cases with high norepinephrine production) 1
• Classic symptoms include headache, palpitations, pallor, and sweating ("cold sweat"), which when occurring together have a 90% diagnostic specificity 1
• There is typically a 3-year delay in diagnosis, and approximately one-third of cases are inherited, making early detection crucial 1

Diagnostic Value of Metanephrines

• Metanephrines are metabolites of catecholamines produced by the enzyme catechol-O-methyl transferase within pheochromocytoma tumor cells 1
• Two main testing options exist:
  • Plasma free metanephrines: highest sensitivity (96%-100%) and specificity (89%-98%) 1, 2
  • Urinary fractionated metanephrines: high sensitivity (86%-97%) and specificity (86%-95%) 1
• Plasma free metanephrines are superior to plasma catecholamines, urine catecholamines, and other metabolites for diagnosing pheochromocytoma 2
• In patients with normal renal function, plasma metanephrines above a threshold value of 50 nmol/L provide 100% sensitivity and 94% specificity 3

Interpretation of Results and Potential False Positives

• Hypertensive patients may have elevated catecholamine metabolites, especially with:
  • Obesity
  • Obstructive sleep apnea
  • Use of tricyclic antidepressants 1
• False positive elevations are usually <4 times the upper limit of normal 1
• Common antihypertensive medications (β-blockers, diuretics, ACE inhibitors) do not affect plasma free metanephrine measurements when using LC-MS/MS analysis 4
• In cases of equivocal results with strong clinical suspicion, clonidine suppression testing can be used (100% specificity, 96% sensitivity) 1, 5

Diagnostic Algorithm for Suspected Pheochromocytoma

1. Initial screening: Measure plasma free metanephrines or urinary fractionated metanephrines in patients with:

   • Early-onset hypertension (<30 years) 1
   • Resistant hypertension 1
   • Paroxysmal hypertension with classic symptoms 1
   • Significant blood pressure variability 1, 6
   • Family history of pheochromocytoma 1

2. If results are positive:

   • If levels are >4 times upper limit of normal: proceed to imaging 1
   • If levels are moderately elevated (1-4 times upper limit): repeat testing and consider clonidine suppression test 1, 5

3. Imaging (only after biochemical confirmation):

   • Start with CT or MRI of abdomen 1, 5
   • MRI is preferred to avoid contrast-induced hypertensive crisis 5
   • For suspected metastatic disease, consider metaiodobenzylguanidine (MIBG) scanning 1

Clinical Pearls and Pitfalls

• Imaging should only be pursued after biochemical evidence of pheochromocytoma has been obtained 1
• Urinary tests may be more reliable than plasma tests in patients with intermittent hypertension 7
• Renal failure can cause false positive elevations in plasma metanephrines 3
• 24-hour blood pressure monitoring showing high variability and absence of nocturnal dipping may suggest pheochromocytoma 6
• Genetic testing should be considered in all confirmed cases of pheochromocytoma, especially in patients under 50 years of age 6

Importance in Resistant Hypertension

• Secondary causes should be considered in resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic) 1
• Screening for pheochromocytoma is recommended after excluding pseudoresistance and substance-induced hypertension 1
• Early diagnosis and treatment can significantly reduce morbidity and mortality associated with pheochromocytoma 1