The Diagnosis of Pheochromocytoma by Determination of Urinary 3-Methoxy,4-Hydroxymandelic Acid*†

Gitlow, Stanley E.; Mendlowitz, Milton; Khassis, S; Cohen, Gerald; Sha, Joanne

doi:10.1172/jci104022

Cited by 118 publications

(19 citation statements)

References 18 publications

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“…Although most patients with pheochromocytoma exhibit a diagnostic increase in their urinary excretion of free catecholamines and all metabolites, occasional patients have an increase in free catecholamine excretion in the presence of a normal excretion of VMA (5), whereas others are reported to show an increase in VMA excretion in the presence of normal or near normal values for free urinary NE and E (19,26). It is important to recognize that both situations may occur and that the diagnostic value of a given assay (e.g., free catecholamines versus VMA excretion), particularly in a patient with a minimal increase in total catecholamine production, may depend upon the degree of in situ metabolism and upon the secretion rate of the tumor at the time of the urine collection.…”

Section: Resultsmentioning

confidence: 99%

Turnover and Metabolism of Catecholamines in Patients with Pheochromocytoma*

Crout¹,

Sjoerdsma²

1964

J. Clin. Invest.

188

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When norepinephrine (NE) or epinephrine (E) is infused into a human subject, all but about 4% of the amine is metabolized to urinary 0-methylated and deaminated metabolites (1-4).The percentage excreted as each metabolite is fairly constant even in different individuals (1)(2)(3). This is in distinct contrast to the situation in patients with pheochromocytoma. In this disease patients with similar excretion values for free catecholamines may show up to tenfold differences in their excretion rates of metabolites (5). This implies that a pheochromocytoma may not be simply an endogenous source of circulating NE and E; catecholamine metabolism in these patients is more complex than traditional views would suggest. This paper describes a) the urinary excretion rates of NE and E and of their two major metabolites in 24 patients with pheochromocytoma, b) the NE and E content of the tumors of 23 of these patients, and c) the normetanephrine (NMN) plus metanephrine (MN) content of 9 tumors. An analysis of these data reveals certain correlations, not previously emphasized, between the size of the tumor, the rate of turnover of catecholamines within the tumor, and the pattern of catecholamine metabolites in the urine. We concluded that in some pheochromocytomas much of the catecholamine synthesized is degraded directly in the tumor before it ever reaches the circulation. This process may partially "protect" the patient from the cardiovascular effects of his tumor and thereby modify the clinical course of the disease.Materials and Methods Twenty-four hour urine specimens were collected in glass bottles containing 10 to 15 ml 6 N hydrochloric acid and were stored at -200 C or at 00 C. Portions of tumor were frozen on removal and stored at -200 C until the time of assay. Urine specimens and tumor samples shipped from outside hospitals were kept frozen on dry ice en route. Free urinary NE and E were determined fluorimetrically by a modification of the trihydroxyindole method (6). The mean recovery of NE plus E was 87%o; the results were not corrected for this small loss. Total NMN plus MN was determined by a modification of Pisano's method (5); no correction was made for an average recovery of 84%. This method measures the combined total of free and conjugated NMN plus MN but does not distinguish between these two 0-methylated amines. Urinary 3-methoxy-4-hydroxymandelic acid (vanilmandelic acid, VMA) was measured by the method of Pisano, Crout, and Abraham (7) ; the recovery in this procedure is quantitative.Tumors were assayed for NE and E by homogenizing 0.5 to 1.0 g of tissue in 10 ml cold 5% trichloroacetic acid, centrifuging to obtain a clear supernatant solution, and assaying this extract fluorimetrically. The tumor content of NMN plus MN was determined by preparing a 5% trichloroacetic acid extract as described above, adjusting its pH to 8.4 with 2 N ammonium hydroxide, and passing it over a 1.2-X 6-cm column of alumina to remove catecholamines. The effluent was then brought to pH 6.0 with 1 N acetic acid and carried th...

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Section: Resultsmentioning

confidence: 99%

Turnover and Metabolism of Catecholamines in Patients with Pheochromocytoma*

Crout¹,

Sjoerdsma²

1964

J. Clin. Invest.

188

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“…A dose of reserpine known to interfere with sympathetic activity but failing to elicit a change in excretion of endogenous catecholamine catabolites, nonetheless resulted in a marked abnormality in the metabolic handling of labeled norepinephrine. It is anticipated that such studies may not only be of value in measuring sympathetic activity in the intact human INTRODUCTION Although evaluation of human adrenergic activity was considerably advanced by the discovery and measurement of norepinephrine (NE)1 and its catabolites in human plasma or urine, these biochemical techniques often lacked the sensitivity to elucidate subtle physiologic changes, pathologic variations, or abnormalities resulting from drug administration (1)(2)(3)(4). By 1959, it was apparent that injected, labeled catecholamines were only degraded and excreted in part, and that a significant fraction was stored intact (5,6).…”

mentioning

confidence: 99%

Human norepinephrine metabolism

Gitlow¹,

Mendlowitz²,

Bertani³

et al. 1971

J. Clin. Invest.

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A B S T R A C T It has become increasingly apparent that evaluation of human norepinephrine metabolism simply by assay of catecholamines in urine is inadequate for differentiation of many physiological or pathological states. In an attempt to examine norepinepherine metabolism in the human subject, tritium-labeled dl-norepinephrine was administered to 11 normal adults and the definitive turnover rates and relative specific activities of norepinephrine and its major catabolites, vanillylmandelic acid, 3-methoxy-4-hydroxyphenylethyleneglycol, and normetanephrine, as well as the cumulative 24 hr isotope excretion were determined. The major endogenous norepinephrine catabolites were also quantitatively assayed. In order to verify the reliability of the isotope label, parallel studies were carried out in two patients to whom norepinephrine--"C was administered. Metabolic studies were repeated after the administration of reserpine to gain further insight into the distribution of the label.All studies demonstrated a consistent difference between the relative specific activities of the amines and their deaminated congeners, thereby indicating an uneven distribution of the labeled material. The marked decrease in the relative specific activities of the deaminated catabolites after the administration of reserpine showed that the present experimental technique succeeded in labeling, though to a limited extent, the storage or reserpine-releasable pool. A dose of reserpine known to interfere with sympathetic activity but failing to elicit a change in excretion of endogenous catecholamine catabolites, nonetheless resulted in a marked abnormality in the metabolic handling of labeled norepinephrine. It is anticipated that such studies may not only be of value in measuring sympathetic activity in the intact human

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“…Gitlow et al 17 proposed hypothetically that a deficiency of O-methyl transferase in the vascular wall might delay the decomposition of catecholamine in the arterial wall.…”

Section: Discussionmentioning

confidence: 99%

Urinary Excretion of Catecholamine Derivatives in Essential Hypertension

Inoue

Takahashi

Adachi

et al. 1968

Tohoku J. Exp. Med.

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Urinary excretion of norepinephrine (NE), epinephrine (E), normetanephrine (NMN), metanephrine (MN) and vanillyl mandelic acid (VMA) were measured in 10 hypertensive and 10 normotensive subjects at walking and in sleep. No difference in urinary excretion of each of NE, E, NMN, MN and VMA was observed in sleep between the hypertensive and normotensive subjects. Urinary excretions of NE, E, NMN, MN and VMA at walking were 3 to 6 times higher than those in sleep in both groups. The rate of increase in catecholamine excretion at walking was higher in the hypertensive subjects. At walking, urinary excretion of VMA in the hypertensive group was significantly higher. The ratio of VMA to total catecholamine was lower at walking.Elevated urinary catecholamine excretion in the hypertensive suggests that the substance plays a role as a causative factor of hypertension.Studies of hypertension induced by endogenous substances have been carried out with special attention to the adrenal medulla. However, the results of urinary excretion of catecholamines and their metabolites in essential hypertension have been controversial.It is well established that excretion of catecholamines is increased under various conditions such as upright posture,1 exercise2 and emotional tension.3 Consequently, a proper comparison is possible only when the effects of such conditions are minimized at the measurement.The present study was made to determine whether or not there are any dif ferences in excretion of catecholamines between patients with essential hyperten sion and normal subjects by measuring the urinary output of norepinephrine (NE), epinephrine (E), normetanephrine (NMN), metanephrine (MN) and vanillyl mandelic acid (VMA) in sleep and at walking. MATERIALS AND METHODSUrinary excretion of NE and E, conjugated NMN and MN, and VMA at walk ing and in sleep was measured in 10 hypertensive subjects aged 20 to 47 years (averaging 37 years) with systolic blood pressure over 150mm Hg and/or diastolic

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The Diagnosis of Pheochromocytoma by Determination of Urinary 3-Methoxy,4-Hydroxymandelic Acid*†

Cited by 118 publications

References 18 publications

Turnover and Metabolism of Catecholamines in Patients with Pheochromocytoma*

Turnover and Metabolism of Catecholamines in Patients with Pheochromocytoma*

Human norepinephrine metabolism

Urinary Excretion of Catecholamine Derivatives in Essential Hypertension

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