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Objective: To determine the optimal clinical strategy utilizing either 1) serum catecholamines, 2) urinary metanephrines, or 3) urinary vanillylmandelic acid measurements in the evaluation of hypertensive patients with suspected pheochromocytoma., Design: Prospective clinical determination of test-operating characteristics., Setting: Tertiary care university medical center., Patients/participants: 415 patients referred for evaluation of suspected pheochromocytoma., Interventions: All subjects had measurements of the three above-mentioned biochemical tests with the diagnosis of pheochromocytoma established by tissue confirmation., Results: All three biochemical tests were similar in sensitivity (0.70-0.75), specificity (0.90-0.95), and receiver operating characteristics. With an estimated disease prevalence of 5.9% in symptomatic hypertensive patients, the predictive value of any single negative test would be 98% in ruling out disease., Conclusions: All three biochemical tests have similar performance characteristics and only a single test need be performed to exclude pheochromocytoma in most symptomatic hypertensive patients in a primary care population.

1. The clonidine suppression of urinary metanephrines as a criterion for the diagnosis of pheochromocytoma is described. Twenty-four patients were divided into 3 groups: Group I, 10 patients with pheochromocytoma (confirmed by tomography and surgery); Group II, 9 patients with suspected pheochromocytoma (clinical evidence plus one mildly elevated value of urinary metanephrines, but with negative tomography); Group III, 5 patients with proven essential hypertension. 2. Urinary metanephrine levels were determined in urine collected before (basal) and 3 h after a single oral dose of clonidine (0.4 or 0.8 mg). 3. Mean basal urinary metanephrine levels were above normal for group I (9.2 +/- 2.2 micrograms/mg creatinine) and group II (2.2 +/- 0.3 micrograms/mg creatinine) but were within the normal range for group III (0.6 +/- 0.1 microgram/mg creatinine). After clonidine administration, urinary metanephrine levels remained elevated for all patients with pheochromocytoma but decreased to within the normal range for all but one patient in group II. The urinary metanephrine levels of group III were not significantly altered by clonidine. 4. These data demonstrate that, when monitored by the clonidine suppression test, urinary metanephrine levels are useful for the diagnosis of pheochromocytoma, permitting the differentiation of affected patients from those exhibiting essential hypertension and increased sympathetic drive.

We examined the effect of an increase of endogenous prostaglandin production, induced by potassium depletion, on the urinary excretion of the norepinephrine metabolites metanephrine, normetanephrine and MHPG. Potassium deficiency caused a significant increase in all three metabolites. Treatment with indomethacin, 10 mg/day for 5 days, partially reversed the increase in the urinary excretion of norepinephrine metabolites. These findings suggest that in the intact organism prostaglandins stimulate, rather than inhibit norepinephrine release. Stimulation of prostaglandin synthesis may lead to an increase in sympathetic nervous system activity by a direct action or via a baroreceptor feedback mechanism.

Data on 24-hour urinary levels of catecholamines and metabolites were determined in 114 depressed patients. For each patient, a D-type score was calculated, using a discriminant function equation that was previously derived using data from an independent group of depressed patients. Of all measures, D-type scores provided the highest sensitivity and specificity for separating bipolar/schizoaffective-depressed patients from all remaining patients or from those patients with unipolar nonendogenous depressions. Using Research Diagnostic Criteria (RDC), bipolar I patients demonstrated significantly lower D-type scores than did all other RDC depressive subtypes, including bipolar II disorders. Similar findings were observed using the Clinical Inventory for the Diagnosis and Classification of Affective Disorders (CIDCAD) system: bipolar/schizoaffective patients demonstrated significantly lower D-type scores than all remaining subtypes, including diagnostically unclassifiable, probable bipolar patients (a category somewhat akin to RDC bipolar II disorder). Data pointed to the heterogeneity of bipolar disorders. Catecholamine and metabolite data in this study were compared with recent studies of others.

A case of new dysautonomia-like disorder in a Japanese infant is reported. The patient showed almost all of the essential criteria for the diagnosis of familial dysautonomia. Results of pharmacologic tests and urinary excretion patterns of catecholamines and their metabolites were also compatible with the disorder. But he lacked some important clinical findings, such as lifelong hypolacrimia, skin blotching, excessive sweating and labile blood pressure. Precise observations of clinical features and literatures on non-Jewish cases of familial dysautonomia lent evidence that this case suffered from a new dysautonomia-like disorder.

The overproduction of catecholamines and their metabolites is a well recognised feature of neuroblastoma. Published data are scarce for their urinary excretion in children with neuroblastoma and in ill children in whom this diagnosis may be considered. We have determined a graphical upper reference limit for total catecholamines, total metadrenalines and HMMA in urine, expressed as a ratio to the creatinine concentration, for a group of 174 children with neuroblastoma and 704 hospitalised children with other disorders. This graph has been determined by examining the overlap region between the results for the two groups of children and avoids the irregularities caused by statistical outliers. The sensitivity and specificity of the individual tests indicate that total catecholamines is marginally the best single test to perform when trying to diagnose neuroblastoma, with the best clinical sensitivity being achieved by examining both total catecholamines and HMMA. Only two of the 174 children with neuroblastoma would not have been detected using these two tests. Total metadrenalines did not appear to add any further information and could be dropped from the repertoire in favour of the other two measurements.

Three biochemical tests for the diagnosis of pheochromocytoma were evaluated in 24 patients with proved tumors and 40 patients whose clinical picture was suspect but who had no evidence of the disease. Measurement of resting, supine plasma catecholamines (by radioenzymatic assay) was more useful than either 24-hour urinary vanillylmandelic acid (VMA) or metanephrines or both. In only one of 23 patients with pheochromocytoma were plasma catecholamines within the range of those in patients without pheochromocytoma, as compared with urinary VMA in 11 of 22, urinary metanephrines in five of 22 and both metabolites in three of 22. These studies reaffirm the value of plasma catecholamines in the diagnosis of pheochromocytoma and indicate that urinary catecholamine metabolites are less useful. The poor correlation between the height of arterial pressure and circulating levels of catecholamines suggests that the regulation of arterial pressure in pheochromocytoma is complex.

Quantitation of the urinary metabolites of catecholamines, including VMA, HVA, and metanephrines, from six normal preschool children was performed during a normal diet, a restricted diet, and a diet with increased amounts of vanilla, vanillin, and phenolic acids. Ingestion of these substances has been suspected of producing elevated values of urinary catecholamines and their metabolites. Urine was collected on the fourth day of each diet in two consecutive 12-hour aliquots, beginning at 8:00 AM. Statistically significant diurnal variation in excretion of all three metabolites and total free catecholamines (epinephrine, norepinephrine, and dopamine) was demonstrated. Diet did not alter exceretion of total free catecholamines or any of the three metabolites. This study suggests that a three-day restricted diet is not necessary prior to screening children for neuroblastoma when using quantitative assay methods and that all screening tests should be performed on a 24-hour urine sample.

1. Plasma noradrenaline concentrations were similar in normotensive and hypertensive outpatients, but were significantly lower in laboratory control subjects. 2. Standing plasma noradrenaline concentrations were similar in all three groups. 3. Urinary vanillyl mandelic acid, catecholamines and metanephrines were also similar in the normotensive and hypertensive groups. 4. Laboratory controls, possibly because of familiarity with the techniques of sphygmomanometry and blood sampling, may attain a 'basal' resting level of sympathetic nervous discharge more readily and rapidly than subjects who are unfamiliar with such procedures. 5. After orthostatic stimulation by standing for 2 min, the activity of the sympathetic nervous system, as determined by pulse rate and plasma noradrenaline concentrations, was similar in the three groups, despite the lower starting values in the laboratory staff. 6. The absence of differences in plasma noradrenaline or urinary catecholamine and metabolite concentrations does not support the hypothesis of excessive sympathetic nervous activity in essential hypertension.

Recurrent hereditary polyserositis (RHP), also known as familial Mediterranean fever, is a genetically-determined disease characterized by paroxysmal attacks of peritonitis, pleuritis, arthritis or inflammation of other serous membranes. We have previously suggested that the pathogenesis of this disease seems to be related to abnormal catecholamine metabolism. This study compares the plasma and urine catecholamine profile in patients with RHP during different clinical states to that in controls. In RHP there were lower plasma and higher urine dopamine levels in the asymptomatic state and during attacks, while norepinephrine levels remain unchanged. However, plasma epinephrine was significantly lower in the asymptomatic state but markedly higher during attacks. The urine epinephrine values in both situations were similar but significantly lower than in controls, suggesting abnormal renal excretion of epinephrine. The urine metanephrine was markedly elevated in the asymptomatic state compared to controls, but remained unchanged during the attacks, again suggesting defective renal clearance of metanephrine. Metaraminol infusion, which induces attacks in RHP patients, was associated with an increase in plasma dopamine and epinephrine (but not norepinephrine); yet the urinary levels of dopamine, epinephrine and metanephrine remained the same, confirming the dissociation between the plasma and urinary levels of these catecholamines, probably due to abnormalities in the renal clearance mechanism. We postulate that this dissociation leads to retention of these amines in the plasma which may subsequently leak through the serous membranes (the target organs) and incite an acute inflammatory process. Colchicine, the only known drug that protects against disease attacks, reduces the plasma levels of these amines, and thus may act by preventing retention that leads to leakage and subsequent inflammation.

Measurement of the catecholamine's, norepinephrine, epinephrine, metanephrine, normetanephrine, vanilmandelic acid, and 3-methoxy-4-hydroxyphenyl-glycol (MHPG) show certain statistical correlations with three clinical diagnoses. These conditions are as follows: 1) bipolar and schizo-affective depression, 2) unipolar nonendogenous depressions, and 3) schizophrenia related depressions. More specifically MHPG acts to predict which patients will require higher doses of medication, higher plasma levels, and longer treatment periods to respond to treatment.

Vapor phase methodology for quantitative analysis of urine for metanephrine and normetanephrine as the pentafluoropropionyl derivative is described. The use of selected ion monitoring provided sufficient sensitivity and selectivity that milliliter aliquots of urine required only a simple scheme of sample processing; preliminary purification consisted of percolation through a column of XAD-2 followed by solvent extraction. The sample extracts were converted to the pentafluoropropionyl derivatives and analyzed by gas chromatography mass spectrometry with selected ion monitoring. Quantitative analysis was based on alpha[2H2]-beta-[2H1]metanephrine and alpha-[2H2]-beta-[2H1]normetanephrine which were added to the urine sample at the outset. The calibration plots for metanephrine and normetanephrine were linear from 10 ng ml-1 to 2000 ng ml-1 of urine permitting the detection of metanephrine and normetanephrine levels throughout the normal range and well into the subnormal range. Examples of application of the methodology to clinical investigation are described. The overall reproducibility of the sample processing methodology and instrumentation was assessed by replicate analyses of the same urine sample over a period of several weeks; the coefficient of variation was +/- 2.5% (n = 8).

Two patients with "Gaisböck syndrome" (stress polycythemia) were found to have been under chronic "stress" with REM sleep decrease, decreased nocturnal ADH-like activity and consequent nocturnal water loss. The role of REM decrease with chronic "stress" in causing secondary decrease in nocturnal ADH-like activity was emphasized as the means by which "stress" caused the blood volume changes seen with these two patients. Some factors that possibly could play a role in the pathophysiology of this syndrome were ruled out and other factors not studied here were considered for future investigation.

We have modified the procedure for determining total metanephrines in urine described by Gupta, Price and Keane(1) to shorten the time necessary for completion while allowing the technician time to perform other tests. The modification involves the extraction of interfering substances from urine. Instead of having to extract 3 individual tubes for each patient, we have developed an extraction that can be performed in a single tube per sample. This allows the number of tubes handled in the first portion of the procedure to be reduced by 66% and a reduction in analysis time of 25%. Day-to-day precision of the method is 8.7%. The modified procedure was compared to the original procedure by running 38 different patients by each method. The mean for the original and modified method were 1.1 mg/24h and 1.1 mg/24h respectively. The correlation coefficient was 0.9051. The t-test (p = 0.05) indicated that there was no significant difference in the means of the methods and the F-test (p = 0.05) indicated that there was no significant difference in the precision of the methods.

A moderate elevation of the daily excretion of free noradrenaline and adrenalin is observed in chronic circulatory insufficiency, beginning with Stage IIA. The catecholamines metabolism is elevated, as shown by the daily excretion of normethanpherine and methanpherine and of vanillyl-mandelic acid. The activity of renin and angiotensinases was growing along with the progressing cardiac insufficiency. The blood level of angiotensinogen was decreasing, especially in patients with Stage IIB and III of decompensation. The daily excretion of aldosterone was growing along with the development of cardiac insufficiency. The functional state of the glucocorticoid function of the adrenal cortex was of a phased nature in cases of circulatory insufficiency. The study of the functional state of the epiphysis was conducted by way of determining the blood level of melatonine and of its daily excretion. In Stages I and IIA the level of this hormone was clearly elevated, in Stages IIB and III -- decreased as compared with the initial and normal levels. The plasma level of the antidiuretic hormone was distinctly growing, beginning with Stage IIB, reaching its maximal values in Stage III.

Following the removal of a pheochromocytoma in three female patients the daily excretion of catecholamines and their metabolites was still considerably elevated for about one week. The excretion rates declined during this period with half-lives of 1.8 to 10.9 days for catecholamines and 2.1 to 4.7 days for metanephrines, vanilmandelic acid, and vanilglycol. The cumulative urinary excretion of catecholamines and their metabolites following surgical removal of the tumour was nearly as high as the catecholamine content of the pheochromocytomas. This large amount of catecholamines must have been located outside the tumour, most probably within the sympathetic nerve, where it is subject to release following physiological stimuli. Furthermore, this fact may provide an explanation for hypertensive crises in pheochromocytoma patients.

Extra-adrenal pheochromocytomas are more common in children (30%) than in adults (10%). Of the extra-adrenal sites, the intrathoracic site is the most rare. A 15-year-old boy had a pheochromocytoma successfully removed from the left paraspinal region of his chest. Four years before removal, he had radiation therapy of 3,500 rads to the tumor because of its apparent nonresectability. After therapy, there was transient clinical and biochemical improvement. Preoperative angiography and computed tomography helped define the anatomy of the tumor vessels and the relationship to the thoracic aorta of the tumor. These studies also aided in discounting any other site for the pheochromocytoma, either adrenal or extramedullary. A slow-growing pulmonary metastatic lesion was subsequently identified and successfully excised.

1. We have studied endocrine function in nine healthy young men 16 weeks before and immediately after Final degree examinations. Factors other than psychological stress which might have affected hormone levels were excluded. 2. The presence of psychological stress at the time of examinations was confirmed by finding increased values for two self-rating anxiety scales. 3. Urine metadrenaline excretion was increased in all subjects at the time of examination. Serum and early morning urine cortisol as well as pituitary-testicular and pituitary-thyroid function and prolactin levels were unaffected by examination stress. 4. This study questions the popular belief that psychological stress stimulates prolactin secretion and suppresses pituitary-testicular function.

Catecholamines (DA, NE, E), methoxyamines (MT, NMN, MN), DOPA and DOPAC were studied in urine of term small for gestational age infants (SGA) and preterm with appropriate birthweights for gestational age (PT) during the first ten days of life. Results were compared to values obtained for full term infants (FT). As a whole no deficit in urine catecholamines was observed in either group of SGA and PT neonates suggesting that capacities to synthesize catecholamines are already developed at birth. Furthermore, in SGA infants, adrenergic function seems to be enhanced during the first four days of life; however, SGA infants with low blood glucose levels excreted amounts of epinephrine similar to those of FT neonates, but much lower than those obtained in normoglycemic SGA neonates. These data suggest that enhanced release of catecholamines is required in SGA infants to maintain the glycemic homeostasis. In premature infants, the adrenergic pattern was highly altered only in younger preterm neonates (31 weeks of gestational age) who excreted more catecholamines than older preterm babies (33 to 36 weeks) or full term neonates; this catecholamine increase in urine of young preterm infants might be related to immaturity of storage vesicles and/or to thermoregulatory or respiratory events. On the other hand, a striking deficit in excretion of DOPAC was observed in small for gestational age infants and in young preterm neonates during the first ten days of life. DOPAC excretion was even lower in SGA than in young preterm neonates. These findings suggest that the maturation of dopaminergic neurons occurs late in gestational age and is greatly dependent on nutritional factors.

We have investigated hypotheses that link the stiff-man syndrome to an imbalance of neurotransmitter systems. No evidence was found to support the concept of defective synaptic transmission at either cholinergic input to Renshaw inhibitory elements or at glycinergic inhibitory input to motoneurons from spinal interneurons, since neither physostigmine nor glycine altered symptomatology. Urinary excretion of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenyl glycol showed a high correlation with clinical status. This suggests the involvement in the stiff-man syndrome of a central norepinephrine neuronal system that has net excitatory effects upon motoneurons, a system whose activity can be increased slightly by levodopa and decreased markedly by diazepam, with corresponding changes in stiffness.

Three patients with rapidly progressive, disseminated malignant pheochromocytoma were treated with a combination chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and dacarbazine in repeated 21- to 28-day cycles. All three patients had a marked decrease in blood pressure and an improvement in performance status within the first few cycles of treatment. At a follow-up of 6 to 13 months all patients continue to receive chemotherapy with further regression of tumor in two and stable disease in one. Their blood pressure is normal with minimal or no antiadrenergic therapy. Therapy has been well tolerated; moderate reversible granulocytopenia, neurotoxicity, and one episode of pneumonitis have been the major toxicities encountered. Thus, combination chemotherapy appears to be effective for symptomatic malignant pheochromocytoma.

Thirty-four normal male subjects were tested to determine the relationships between physical fitness condition (Ismail criterion), levels of self-reported depression (MMPI) and anxiety (Welsh criterion), and the urinary concentrations of 3-methoxy-4-hydroxyphenylglycol (MHPG), normetanephrine (NM), and metanephrine (M). Urinary samples were collected after sleep and during occupational activities to ascertain the effects of different psychosocial stimuli on the relationships among the variables. Univariately, urinary MHPG did not relate to physical fitness and was moderately related to depression (p less than or equal to 0.10) during the occupational period. Multivariate canonical correlational results revealed a significant (p less than or equal to 0.04) relationship between the biochemical and personality sets of variables during the occupational settings. MHPG was the most sensitive catecholamine metabolite for reflecting depressive conditions. The results suggest a biochemical reactivity syndrome involving MHPG that may relate to depressive personality characteristics.

Spectrophotometric assays for urinary metanephrines are still widely used because of the simple equipment needed. These methods, however, have the major drawback of being very susceptible to interference. Using the original Pisano technique (Pisano, J. J. (1960) Clin. Chim. Acta 5, 406-414) we have often observed overestimation of the metanephrine concentration. By measuring absorbances at three different wavelengths we were able to considerably reduce this positive bias. With many patients this resulted in a significant downward adjustment of the values found for the total metanephrine excretion.

A special urine chemistry survey was implemented by the College of American Pathologists during the year 1981. Ten analytes are included in this survey, including aldosterone, free catecholamines, total catecholamines, estriol, 5-hydroxyindole acetic acid, 17-ketogenic steroids, 17-ketosteroids, vanillylmandelic acid, cortisol, and metanephrines. Data obtained from 1981 and 1982 was derived from 398 subscriptions. Inadequacies in quantitative analytic methods for aldosterone, 5-hydroxyindole acetic acid, 17-ketogenic steroids, and urinary free cortisol were demonstrated. Some screening methods for 5-hydroxyindole acetic acid yielded false results.

The diagnostic problem of pheochromocytomas raises two questions: should all hypertensives be routinely investigated for this condition, and what is the best diagnostic method? As this is a rare condition, systematic screening gives a low return; considering the large number of hypertensive patients, it is also costly. On the other hand, as systematic autopsy studies have shown, the missed diagnosis can be serious (especially during pregnancy or surgery). Screening for this condition is proposed when the clinical features are suggestive, in pregnancy, when surgery is undertaken in a hypertensive patient and in all cases of method is still a matter of controversy: urinary hormonal levels (especially metanephrine levels) are supported by some workers, whilst serum catecholamine levels are supported by others. In any case, pharmacodynamic tests should only be used when these two methods are inconclusive. The long term prognosis of operated pheochromocytoma is less favourable then used to be thought: a certain number have persistent benign hypertension which may require treatment and which may become malignant at a later date. Adrenal medullary hyperplasia is a clinical entity which should be recognised.

The biochemical diagnosis of pheochromocytoma is essentially based on the plasma and urinary levels of catecholamines and their derivatives, the metanephrines and vanyl-mandelic acid. The advantages and disadvantages of these investigations are reviewed, especially as regards the specificity and sensitivity of each test. The measurement of urinary metanephrine is the best test as its excretion is relatively higher, and it is rarely normal. The measurement of plasma catecholamines is more difficult but gives satisfactory results, but experience so far is limited.

Investigations in 13 hospitalized patients with pheochromocytomata showed peculiar characteristics of heart rate variation at rest, when compared with normals. All patients were given alpha- and beta-sympatholytic drugs. In one case alpha-methyl-Tyrosine caused I-II degree AV blocks and a stable high frequency sinus rate without physiological variations. Resting heart rate in pheochromocytoma varied interindividually from 55-105/min, in the absence of clinical attacks of the underlying disease. The frequency profile was characterized in 12 patients by sudden and inadequate rises of heart rate (200%) of short duration, which were often recorded within 20 seconds of the onset of muscular activity. A similar but less pronounced heart rate modulation was found 1-2 weeks after operation in 3 cases. Our observations indicate that the heart rate profile described may be a sensitive parameter of dysfunction of the autonomous nervous system in pheochromocytoma. Whether the heart rate characteristics are of diagnostic value has to be assessed by further studies.

In 20 normal persons and in 57 patients with heart diseases with functional class I-IV (according to the classification of the New York Heart Association) the 24 hour urinary excretion of the catecholamines adrenaline, noradrenaline and dopamine and of the O2-methylated degradation products metanephrine and normetanephrine was determined. The 3 catecholamines and the 2 O-methylated derivatives were measured simultaneously using chromatographic extraction and purification (Bio-Rex 70) and selective flurometric determination. The following results could be obtained: 1. The urinary excretion of noradrenaline increased with increasing severity of the heart disease. 2. In patients with severe congestive heart failure (functional class IV) in addition the adrenaline excretion in addition the adrenaline excretion increased significantly. 3. There was no relationship between the urinary excretion of dopamine and the severity of the heart disease. 4. The ratio of noradrenaline excretion to dopamine excretion increased with increasing severity of the heart disease, indicating an increased activity of dopamine-mu-hydroxylation in patients with congestive heart failure. 5. The excretion of the O-methylated degradation products metanephrine and normetanephrine in normal persons and in patients with heart diseases paralleled the excretion of the corresponding catecholamines adrenaline and noradrenaline. This indicates, that increased excretion of noradrenaline and adrenaline (Class IV) in patients with heart failure was not due to impaired catecholamine-degradation but indead to increased catecholamine-release indicating increased sympatho-adrenergic activity. These results show in addition that also in patients with heart failure O-methylation represents still the main degradation step for the inactivation of the circulating catecholamines. 6. The relationship of toal excretion of 0-methylated derivates to total excretion of adrenaline and noradrenaline, however, decreased with increasing severity of heart disease, indicating a relative impairment of O-methylation under the condition of severe congestive heart failure.