Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma

Abstract

Context: Pheochromocytomas can usually be confirmed or excluded using currently available biochemical tests of catecholamine excess. Follow-up tests are, nevertheless, often required to distinguish false-positive from true-positive results. The glucagon stimulation test represents one such test; its diagnostic utility is, however, unclear.

Objective: The aim of the study was to determine the diagnostic power of the glucagon test to exclude or confirm pheochromocytoma.

Design, setting, and subjects: Glucagon stimulation tests were carried out at three specialist referral centers in 64 patients with pheochromocytoma, 38 patients in whom the tumor was excluded, and in a reference group of 36 healthy volunteers.

Main outcome measures: Plasma concentrations of norepinephrine and epinephrine were measured before and after glucagon administration. Several absolute and relative test criteria were used for calculating diagnostic sensitivity and specificity. Expression of the glucagon receptor was examined in pheochromocytoma tumor tissue from a subset of patients.

Results: Larger than 3-fold increases in plasma norepinephrine after glucagon strongly predicted the presence of a pheochromocytoma (100% specificity and positive predictive value). However, irrespective of the various criteria examined, glucagon-provoked increases in plasma catecholamines revealed the presence of the tumor in less than 50% of affected patients. Diagnostic sensitivity was particularly low in patients with pheochromocytomas due to von Hippel-Lindau syndrome. Tumors from these patients showed no significant expression of the glucagon receptor.

Conclusion: The glucagon stimulation test offers insufficient diagnostic sensitivity for reliable exclusion or confirmation of pheochromocytoma. Because of this and the risk of hypertensive complications, the test should be abandoned in routine clinical practice.

Figure 1

Line graphs showing plasma concentrations of norepinephrine (A) and epinephrine (B) at baseline (BL) and after glucagon (Peak) in individual patients with and without pheochromocytoma, and in the reference group. ***, P < 0.0001 increase compared with baseline; ****, P < 0.00001.

Figure 2

Dot plots showing changes in plasma concentrations of norepinephrine (A and B) and of epinephrine (C and D) in individual patients with and without pheochromocytoma, and in the reference group. Absolute increments (Δ increases) in plasma concentrations of norepinephrine and epinephrine after glucagon (plasma concentrations after glucagon minus baseline plasma concentrations before glucagon) are shown in panels A and C, respectively, whereas relative increments (fold-increases) in plasma norepinephrine and epinephrine levels after glucagon (peak plasma concentrations divided by baseline concentrations) are shown in panels B and D, respectively. *, P < 0.05; ***, P < 0.0001 difference in responses of indicated groups.

Figure 3

Immunohistochemical staining of tyrosine hydroxylase (TH; panels A and C) and of the glucagon receptor (GR; panels B and D) in representative samples of pheochromocytomas from patients with MEN-2 (A and B) and VHL syndrome (C and D).