Medication effects on biochemical diagnosis of pheochromocytoma

A colleague asked me about a case of suspected recurrent pheochromocytoma. The patient is already on doxazosin and propranolol. The question we had: Would these medications affect results of biochemical testing?

There are many factors that can affect results of biochemical testing of pheochromocytoma. False-positives can occur due to a variety of reasons. Plasma metanephrines may be slightly elevated due to withdrawal from benzodiazepines, alcohol and clonidine. Certain anesthetics, cocaine and cardiac antiarrhythmics such as lidocaine can elevate plasma metanephrines.

Catecholamines increase in response to acute stress or discomfort. Caffeine and nicotine elevate catecholamines for a short time after consuming them. In addition to the causes of increased plasma metanephrines listed above, tricyclic antidepressants, vasodilating drugs, diuretics and desmopressin acetate tablets (DDAVP, Sanofi Aventis) can also affect catecholamine levels. In the past, interfering substances caused problems with the assays used. This does not appear to be as much of a problem with newer high-pressure liquid chromatography-based assays.

Phenoxybenzamine (Dibenzyline, WellSpring Pharmaceuticals) certainly causes false-positive results. In a study by Eisenhofer et al, phenoxybenzamine and tricyclic antidepressants together resulted in up to 45% of elevated plasma normetanephrine and norepinephrine in patients who did not have pheochromocytoma. Plasma or urinary normetanephrine and norepinephrine were elevated by 1.9 to 2.6 times compared with patients receiving other drugs or no medications.

Unlike phenoxybenzamine, selective alpha 1-adrenoceptor-blocking drugs such as doxazosin do not markedly increase plasma norepinephrine or normetanephrine. However, they can cause false-positive elevation of urinary norepinephrine.

Eisenhofer et al did not find that beta-blockers increased frequency of false-positive elevations of plasma normetanephrine, norepinephrine or epinephrine. However, they were associated with a higher frequency of falsely elevated plasma metanephrines (12.5% vs. 1.6%; P<.001) compared with patients not on beta-blockers. Beta-blockers were also associated with higher frequency of false-positive urine normetanephrine, metanephrine, norepinephrine and epinephrine.

Calcium channel blockers caused false-positive plasma norepinephrine, but not plasma normetanephrine, epinephrine or metanephrine. Calcium channel blockers resulted in false-positive urinary norepinephrine and epinephrine but did not affect urinary normetanephrine and metanephrine.

However, my colleague’s patient was already on doxazosin and propranolol. Ideally, testing should be performed off of all potential interfering substances. Phenoxybenzamine should certainly be avoided. However, some patients must remain on anti-hypertensives for blood pressure control during biochemical testing. Calcium channel blockers, alpha 1 blockers and beta-blockers may be continued as long as potential effects upon results are understood. A negative plasma metanephrine strongly argues against the presence of pheochromocytoma while a marked elevation suggests the diagnosis. Only mild elevation or equivocal testing requires that medications be withheld.

Eisenhofer G. J Clin Endocrinol Metab. 2003;88:2656-2666.