Biochemical Diagnosis Of Pheochromocytoma Research Articles

Epidemiologic Profile and Clinical Outcomes of Patients with Pheochromocytoma in the University of the Philippines Philippine General Hospital (UP-PGH)

Objective. This study aims to describe the epidemiologic profile and determine the clinical outcomes of patients with pheochromocytoma at the University of the Philippines Philippine General Hospital (UP-PGH). Methodology. We reviewed the medical records of 30 patients with histopathology-proven, clinical, and biochemical diagnosis of pheochromocytoma. Demographic, clinical characteristics, and clinical outcomes were collected for each patient. Results. The median age at diagnosis of pheochromocytoma was 37.5 years (IQR 28-55) and the most common metabolic comorbidities were glucose intolerance (60%) and hypertriglyceridemia (23.3%). Majority of the patients were hypertensive (90%). Two third of the patients presented with classic features of pheochromocytoma while the remaining third presented as adrenal incidentaloma. Recurrence was found in 17% of subjects, who were significantly younger (25 years vs 46.5 years P = 0.0229), and had higher rates of bilateral pheochromocytoma (0 vs 75%), p = 0.002). Metastatic pheochromocytoma was found in 10% of the subjects. Conclusion. Our study demonstrated that patients with pheochromocytoma in our setting exhibit great variability in terms of clinical behavior. Although majority of the patients presented with symptoms related to catecholamine excess, almost one-third of the patients were only incidentally discovered. Incidence of pheochromocytoma recurrence and metastasis in our setting are comparable with current available foreign studies.

PSUN28 Factors Associated with False-positive Fractionated Metanephrines in Plasma and Urine

Abstract Context Plasma and 24-hr urine metanephrine (M) and normetanephrine (NM) are the standard of care tests used in the biochemical diagnosis of pheochromocytoma and paraganglioma (PPGL). Considering the rarity of PPGL, false positive (FP) results represent a challenge because they lead to additional investigations, healthcare burden, and uncertainty for the patient. The impact of medications on the rate of FP results is not fully established. Objective We aimed to identify the medications associated with the FP rate of 24-hr urine and plasma M and NM measured by the HPLC-MS/MS method. Methods We conducted a single-center study of patients who had 24-hour urine or plasma M and NM testing between 09/27/2015 and 02/15/2021, and who had a follow-up of at least 6 months. Results were considered FP if M/NM were > upper limit of the normal ranges (ULN) and there was absence of PPGL. Results were considered true negative (TN) when M/NM were within the reference ranges in patients without PPGL. Age- and sex-adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression models. Results Plasma M/NM testing was performed in 3152 patients and 24-hr urine M/NM was performed in 2008 patients. The FP rate for the M fraction (plasma: 0.8%, urine: 1.3%) was much lower than the FP rate for NM (plasma: 16%, urine: 4.4%); thus, the impact of medications on FP rate was examined only for NM. In those with FP NM, the median degrees of elevation were 24% (IQR 10-46) >ULN in plasma and 26% (IQR 11-45) >ULN in urine. When compared to patients with TN results, patients with FP plasma NM were more likely to be treated with opioids (OR=1.29, 95%CI, 1.04-1.60), tricyclic antidepressants (OR=1.61, 95%CI,1.14-2.27), serotonin–norepinephrine reuptake inhibitors (OR=1.85, 95%CI, 1.35-2.53), second generation antipsychotics (OR=2.32, 95%CI, 1.28-4.20), but not first generation antipsychotics (OR=1.23, 95% CI, 0.86-1.75) when compared to the TN group. When compared to patients with TN results, patients with FP urine NM were more likely to be treated with opioids (OR=1.96 95%CI, 1.26-3.06), tricyclic antidepressants (OR=2.61, 95%CI, 1.47-4.65), serotonin–norepinephrine reuptake inhibitors (OR=2.20, 95%CI, 1.20-4.02), and both first (OR=3.06, 95%CI, 1.74-5.38) and second generation antipsychotics (OR=2.51, 95%CI, 1.03-6.13). Conclusion The plasma NM FP rate was 16% and 3-fold higher than the same measurement in urine (4.4%). Several classes of medications had a significant impact on the rate of FP NM. Clinicians should consider use of 24-hr urine M and NM in low suspicion cases of PPGL where the diagnosis simply needs to be excluded. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Granin family peptides and INSM-1 (Insulinoma-associated protein 1) in the biochemical diagnosis of pheochromocytoma

Granin family peptides and INSM-1 (Insulinoma-associated protein 1) in the biochemical diagnosis of pheochromocytoma

Plasma or serum, which is the better choice for the measurement of metanephrines?

Background Measurement of metanephrines (MNs: metanephrine [MN] and normetanephrine [NMN]) is recommended for the initial biochemical diagnosis of pheochromocytoma and paraganglioma. Despite some drawbacks, plasma is commonly used for sampling. Here, we determined the feasibility of using serum, as an alternative to plasma, by comparing MNs in plasma and serum and evaluating the stability of MNs in serum. MNs obtained from serum, EDTA plasma, and heparin plasma were measured using LC-MS/MS immediately or after storage at 4 °C for 24 h, 72 h, and 7 days, and at −80 °C for 7 days, after sample collection. The differences between sample stability at given time points were compared using one-way ANOVA and Students’ paired t-test, and the mean percent deviation was compared with total change limit (TCL). No significant difference was observed in MN and NMN between serum and EDTA plasma, and the mean percent deviation of the results obtained from serum compared to that from EDTA plasma was within the TCL. However, the difference of MN between EDTA plasma and heparin plasma exceeded the TCL. Both MNs in EDTA plasma and heparin plasma showed a significant decreasing trend at 4 °C with time (p < .01), while those in serum were relatively stable, with the mean percent deviation not exceeding the TCL at any time point or temperature. In conclusion, MNs measurement did not significantly differ between EDTA plasma and serum when measured immediately after collection, and MNs in serum were more stable than that in plasma.

Biochemical Diagnosis of Pheochromocytoma, a Rediscovered Catecholamine-Metabolizing Tumor.

Featured Article: Lenders JW, Pacak K, Walther MM, Linehan WM, Mannelli M, Friberg P, et al. Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 2002;287:1427–34.4 In our 2002 publication in JAMA about plasma free metanephrines for diagnosis of pheochromocytoma, we established superiority of this test over other tests of catecholamine excess. These findings contributed to a shift in how pheochromocytomas are diagnosed, away from emphasis on catecholamines to their O -methylated metabolites. The concept behind the study followed from a large body of work on catecholamine metabolism carried out by numerous investigators, including the late Irwin J. Kopin (1), former director of the National Institute of Neurological Disorders and Stroke at the National Institutes of Health. By the early 1990s it was established that neuronal metabolism of catecholamines involved deamination and that this occurred mostly after leakage of norepinephrine from vesicular stores into the neuronal cytoplasm. The relative importance of …

Biochemical diagnosis of pheochromocytoma by measurements of overnight excretion levels of catecholamines and metabolites as a simplified alternative to 24-hour collections

Objective: To evaluate differences in day and overnight collections of urinary catecholamines and their free O-methylated metabolites.

Seasonal variation of plasma free normetanephrine concentrations: implications for biochemical diagnosis of pheochromocytoma

Background: Higher plasma concentrations of catecholamines in winter than in summer are established; whether this impacts plasma concentrations of metanephrines used for the diagnosis of pheochromocytoma is unknown. Objective: In this study, we examined seasonal variations in plasma concentrations of metanephrines, the impact of this on diagnostic test performance and the influences of forearm warming (‘arterialization’ of venous blood) on blood flow and measured concentrations. Methods: Measurements of plasma concentrations of metanephrines were recorded from 4052 patients tested for pheochromocytoma at two clinical centers. Among these patients, 107 had tumors. An additional 26 volunteers were enrolled for measurements of plasma metanephrines and forearm blood flow before and after forearm warming. Results: There was no seasonal variation in the plasma concentrations of metanephrines among patients with pheochromocytoma, whereas among those without tumors, plasma concentrations of normetanephrine were higher (P!0.0001) in winter than in summer. Lowest concentrations of normetanephrine were measured in July, with those recorded from December to April being more than 21% higher (P!0.0001). These differences resulted in a twofold higher (PZ0.0012) prevalence of false-positive elevations of normetanephrine concentrations in winter than in summer, associated with a drop in overall diagnostic specificity from 96% in summer to 92% in winter (PZ0.0010). Forearm warming increased blood flow and lowered (PZ0.0020) plasma normetanephrine concentrations. Conclusions: Plasma concentrations of normetanephrine are subject to seasonal variation with a resulting higher prevalence of false-positive results in winter than in summer. Lowered plasma concentrations of normetanephrine with forearm warming suggest an effect of temperature. These results have implications for considerations of temperature to minimize false-positive results.

Dexmedetomidine induced catecholamine suppression in pheochromocytoma

Pheochromocytoma is a neuroendocrine tumour of chromaffin cells, though rare but a known cause of paroxysmal hypertension with a triad of headache, diaphoresis and palpitation. The biochemical diagnosis of pheochromocytoma is based on estimation of plasma nor-adrenaline, adrenaline and their metabolites in plasma or urine. Clonidine suppression test is performed to differentiate the raised catecholamine level due to pheochromocytoma or other than heochromocytoma especially in cases where plasma nor-adrenaline levels are less than 2000 pg/ml. Clonidine is stated to be unable to suppress catecholamine level in cases of pheochromocytoma, therefore we tested the other α2-agonist Dexmedetomidine intravenous in a case of Pheochromocytoma with remarkably raised nor- adrenaline (25,183 pg/ml) and found 49.42% suppression.

Modern biochemical methods for the diagnostics of pheochromocytoma

The objective of the present work was to estimate the possibility of using the ELISA technique for the quantitative analysis of the metanephrine and normetanephrine levels in urine and to determine the cross-off points for the discrimination between their normal and pathological values for the purpose of diagnostics of pheochromocytoma. Methylated derivatives of adrenaline and noradrenaline were measured in 3,234 urine sample obtained from the patients presenting with elevated arterial pressure, resistance to therapy, and adrenal mass lesions who had visited the inpatient and outpatient departments of the Endocrinological Research Centre during the past 4 years. The measurement of total metanephrine and normetanephrine (free plus deconjugated fractions) was performed using commercial ELISA kits (IBL, Hambutg, Germany). The content of normetanephrine over 612 mcg in daily urine samples was shown to be the borderline between the normal values and those suggesting diagnosis of pheochromocytoma. The sensitivity of this assay was 97,5% (95% CI 91,1-99,6%), specificity 100% (95% CI 93,8-100%). For metanephrine, the level of more than 550 mcg/24 hours was the borderline between the normal values and those suggesting diagnosis of pheochromocytoma. The sensitivity of the method was 100% (95% CI 88-100%), specificity - 96% (95% CI 86-99,4%). The biochemical diagnosis of pheochromocytoma was confirmed by the reference pathomorphological method in 99% of the cases. The incidence of pheochromocytoma predicted by the biochemical analysis of the urine samples delivered to the laboratory during 4 years from the patients with the tentative diagnosis of this pathology (based on the elevated arterial pressure and the presence of adrenal mass lesions) was 4% on the average. It is concluded that the application of ELISA in a "manual" mode provides high sensitivity and specificity of quantitative determination of metanephrines in daily urine comparable to those achieved with the widely used but more expensive high performance liquid chromatography.

The diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma

The diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma

Laboratory diagnostics of pheochromocytoma

Biochemical diagnosis of pheochromocytoma is based on the measurement of altered levels of normetanephrine and metanephrine in plasma or 24-hour urine samples. Plasma normetanephrine and metanephrine levels four times the upper limit of the normal value or metanephrine and normetanephrine excretion in urine above 700 and 1500 mcg/24 hours respectively makes further testing unnecessary and subsequent examination must be focused on the determination of tumour localization. In patients presenting with the above parameters elevated within the "grey zone", effect of medicinal products needs to be excluded and the diagnosis confirmed in the clonidine test or by the measurement of chromogranin A level.

The Utility of Metaiodobenzylguanidine (MIBG) Scintigraphy in Patients with Pheochromocytoma

Radiolabeled metaiodobenzylguanidine scintigraphy (MIBG) can be used to image pheochromocytomas. While cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) usually localize the tumor, MIBG is often obtained to rule out multifocal and metastatic disease, and to corroborate anatomic imaging with functional data. We questioned the utility of MIBG in the diagnosis and management of pheochromocytoma. All patients who received MIBG at one academic center from 1999 to 2004 were identified. For the subset of patients who received MIBG in the work-up of possible pheochromocytoma, the following data were reviewed: demographics, symptoms, results of biochemical and imaging studies, histopathological diagnosis, and management. A total of 60 patients received MIBG, including 27 patients for the evaluation of a possible pheochromocytoma. Biochemical testing was performed in all patients. Fourteen patients received MIBG despite normal biochemistry and an absence of risk factors such as a hereditary syndrome or prior history of pheochromocytoma. None of these 14 low-risk patients with negative biochemistry had a final diagnosis of pheochromocytoma. In the ten patients with pheochromocytoma, all tumors were localized by CT and/or MRI. Importantly, MIBG did not identify any foci of disease not seen on cross sectional imaging, and MIBG did not alter the surgical management of any patient in this series. In patients with clinical findings suggestive of pheochromocytoma, biochemical testing should be used to confirm the diagnosis, and cross-sectional imaging is sufficient for tumor localization. In the absence of hereditary disease or a past history of pheochromocytoma, MIBG does not alter the treatment plan and therefore should not be routinely performed. Instead, MIBG should be used selectively, such as for the rare patient with a biochemical diagnosis of pheochromocytoma and no tumor seen on exhaustive anatomical imaging.

A systematic review of the literature examining the diagnostic efficacy of measurement of fractionated plasma free metanephrines in the biochemical diagnosis of pheochromocytoma.

BackgroundFractionated plasma metanephrine measurements are commonly used in biochemical testing in search of pheochromocytoma.MethodsWe aimed to critically appraise the diagnostic efficacy of fractionated plasma free metanephrine measurements in detecting pheochromocytoma. Nine electronic databases, meeting abstracts, and the Science Citation Index were searched and supplemented with previously unpublished data. Methodologic and reporting quality was independently assessed by two endocrinologists using a checklist developed by the Standards for Reporting of Diagnostic Studies Accuracy Group and data were independently abstracted.ResultsLimitations in methodologic quality were noted in all studies. In all subjects (including those with genetic predisposition): the sensitivities for detection of pheochromocytoma were 96%–100% (95% CI ranged from 82% to 100%), whereas the specificities were 85%–100% (95% CI ranged from 78% to 100%). Statistical heterogeneity was noted upon pooling positive likelihood ratios when those with predisposition to disease were included (p < 0.001). However, upon pooling the positive or negative likelihood ratios for patients with sporadic pheochromocytoma (n = 191) or those at risk for sporadic pheochromocytoma (n = 718), no statistical heterogeneity was noted (p = 0.4). For sporadic subjects, the pooled positive likelihood ratio was 5.77 (95% CI = 4.90, 6.81) and the pooled negative likelihood ratio was 0.02 (95% CI = 0.01, 0.07).ConclusionNegative plasma fractionated free metanephrine measurements are effective in ruling out pheochromocytoma. However, a positive test result only moderately increases suspicion of disease, particularly when screening for sporadic pheochromocytoma.

Biochemical diagnosis of pheochromocytoma: how to distinguish true- from false-positive test results.

Measurements of plasma normetanephrine and metanephrine provide a highly sensitive test for diagnosis of pheochromocytoma, but false-positive results remain a problem. We therefore assessed medication-associated false-positive results and use of supplementary tests, including plasma normetanephrine responses to clonidine, to distinguish true- from false-positive results. The study included 208 patients with pheochromocytoma and 648 patients in whom pheochromocytoma was excluded. Clonidine-suppression tests were carried out in 48 patients with and 49 patients without the tumor. Tricyclic antidepressants and phenoxybenzamine accounted for 41% of false-positive elevations of plasma normetanephrine and 44-45% those of plasma and urinary norepinephrine. High plasma normetanephrine to norepinephrine or metanephrine to epinephrine ratios were strongly predictive of pheochromocytoma. Lack of decrease and elevated plasma levels of norepinephrine or normetanephrine after clonidine also confirmed pheochromocytoma with high specificity. However, 16 of 48 patients with pheochromocytoma had normal levels or decreases of norepinephrine after clonidine. In contrast, plasma normetanephrine remained elevated in all but 2 patients, indicating more reliable diagnosis using normetanephrine than norepinephrine responses to clonidine. Thus, in patients with suspected pheochromocytoma and positive biochemical results, false-positive elevations due to medications should first be eliminated. Patterns of biochemical test results and responses of plasma normetanephrine to clonidine can then help distinguish true- from false-positive results.

Choice of biochemical test for diagnosis of pheochromocytoma: validation of plasma metanephrines.

Pheochromocytomas, although a rare cause of hypertension, are dangerous tumors that require consideration among large numbers of patients. The subsequent low prevalence of the tumor among those tested and inadequacies of commonly used biochemical tests make excluding or confirming the tumor an often difficult and time consuming task. Recognition that catecholamines are metabolized to free metanephrines within pheochromocytoma tumor cells, and that this process is independent of catecholamine release, provides a rationale for use of these metabolites in the biochemical diagnosis of pheochromocytoma. Measurements of plasma concentrations of free metanephrines thereby promise more reliable and efficient diagnosis of pheochromocytoma than offered by conventional biochemical tests.

A kindred with multiple endocrine neoplasia type 2A associated with pruritic skin lesions.

A kindred affected by multiple endocrine neoplasia type 2A (MEN 2A), associated with symmetric, bilateral, scapular pruritic skin lesions (PSL), is reported. There were 21 members, including the propositus, in four generations. Screening of 10 family members showed a palpable thyroid tumor in 1 and positive results for a pentagastrin test in 7 others. Two of these patients had surgically confirmed pheochromocytoma. Two others had a biochemical diagnosis of pheochromocytoma but did not have surgery. Medullary thyroid carcinoma was confirmed in five patients and nodular C-cell hyperplasia in another. In five affected adults, PSL were observed in the interscapular region, crossing the midline in some. These lesions were characterized by hyperkeratosis and hyperpigmentation. In all the patients, the pruritus had been present long before the clinical or biochemical diagnosis. Skin biopsies were performed in two of these patients. No amyloid deposits were found (Congo red stain and electron microscopic examination were used). Two children (14 and 6 years old) in the fourth generation complained of scapular pruritus, although skin lesions were not apparent. Localized PSL must be sought when screening for MEN 2A.

Biochemical Diagnosis of Pheochromocytoma by Simultaneous Measurement of Urinary Excretion of Epinephrine and Norepinephrine

The utility of specific assay of urinary catechols in pheochromocytoma diagnosis was examined by reviewing our data on the investigation of pheochromocytoma in a population of 2476 patients investigated over a six-year period. We used specific gas-chromatographic/mass-spectrometric (GC/MS) analysis for the simultaneous measurement of norepinephrine, dopamine, and the neuronal metabolites 3,4-dihydroxyphenylglycol (DHPG) and 3,4-dihydroxyphenylacetic acid (DOPAC) in all samples; the last two years of data collection (from 1101 patients) also included the specific GC/MS assay of epinephrine. The importance of assaying epinephrine as well as norepinephrine was shown by these latter data. During this latter period, 19 of 1101 patients were found to have pheochromocytoma; of these, nine had tumors that exclusively secreted norepinephrine, six had tumors that exclusively secreted epinephrine, and four exhibited excess production of both norepinephrine and epinephrine. Neither dopamine nor DOPAC was useful in the diagnosis of pheochromocytoma. A substantial proportion of patients may have uniquely epinephrine-secreting pheochromocytomas, previously considered a rarity. Thus we recommend that the biochemical testing for pheochromocytoma include the specific measurement of both norepinephrine and epinephrine.

Multiple Endocrine Neoplasia Type IIB Identified by Magnetic Resonance Imaging

Ectopic, epinephrine-secreting pheochromocytomas are rare and difficult to diagnose. In our case, MRI was able to show the lesion, which could not be clearly identified by CT. The histologic specificity provided by T2-weighted images confirmed the biochemical diagnosis of pheochromocytoma. MRI should be considered as an alternative to CT in the diagnosis of familial pheochromocytomas.

Biochemical diagnosis of pheochromocytoma by determining normetanephrine and metanephrine concentrations in single voided urine

Diagnosis of pheochromocytoma has been made by the determination of urinary noradrenaline and adrenaline excretion for 24 hours. The assay procedure and the collection of urine for 24 hrs. are intricate. In the present study, we have ascertained the clinical significance of urinary normetanephrine (NM) and metanephrine (M), chemically stable metabolites of catecholamines, in single voided urine for a diagnosis of pheochromocytoma. Urine and plasma samples were collected from 361 normal subjects, 59 patients with essential hypertension, 22 patients with chronic renal failure and 22 patients with pheochromocytoma. Urinary NM and M concentrations were determined by radioimmunoassay with prior hydrolysis by acidification with 1N HCl. Plasma NM and M concentrations in normal subjects were 71.8 +/- 30.7 pg/ml and 41.5 +/- 8.61 pg/ml, respectively. Plasma NM was increased in 8 and plasma M was increased in 20 of 21 patients with pheochromocytoma, although many of these overlapped with those patients with chronic renal failure (NM, 285.9 +/- 175.1 pg/ml; M, 206.3 +/- 186.7 pg/ml) and essential hypertension (NM, 107.7 +/- 90.7 pg/ml; M, 46.7 +/- 20.2 pg/ml). Urinary NM and M concentrations did not show specific diurnal variation and there was significant correlations between the values in single voided urine and those in the 24 hour urine. Urinary NM and M concentrations in normal controls were 197.5 +/- 46.7 ng/mg Cr. and 125.3 +/- 37.1 ng/mg Cr., respectively. Urinary NM concentration was increased in 14 and urinary M concentration was increased in all of 17 patients with pheochromocytoma. In addition, urinary M concentration was higher in most of the 17 patients with pheochromocytoma than that in the patients with chronic renal failure and essential hypertension. However, the values in three patients with Sipple's syndrome with a small adrenal tumor or recurrent cases overlapped with those in other diseases. Relationships between urinary concentrations of NM and/or M and tumor size showed positive correlations. Urinary NM and M concentrations showed significant decreases after surgical removal of the tumors. These results suggest that NM and/or M concentrations in single voided urine could be a sensitive and specific diagnostic tool for pheochromocytoma.

Intracaval Extension of Pheochromocytoma Simulating Pulmonary Embolism

Pheochromocytoma, a chromaffin tumor of the sympathoadrenal nervous system, rarely exhibits direct extension into the inferior vena cava. We report a patient with a right adrenal pheochromocytoma that caused symptoms of recurrent pulmonary emboli. Intracaval extension of the tumor was detected during investigations for the source of the emboli by abdominal CT scan, ultrasonography, and venacavography. The biochemical diagnosis of pheochromocytoma was confirmed by sharply elevated catecholamine, metanephrine, and VMA urinary levels, which returned to normal upon resection of the tumor. The patient had no evidence of metastatic disease.