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Background: Urine metanephrines are used to screen for phaeochromocytoma or paraganglioma (PPGL). Current reference intervals (RI) derived in healthy individuals are not age or sex-stratified, and lower than in hypertensive patients, leading to high false positive rates. This study aims to determine age and sex-stratified RI from a contingent screening population., Methods: Patients with 24-h deconjugated urine metanephrines from 3/6/2010 to 27/8/2022 were included (2936 males, 5285 females), initially by liquid chromatography-electrochemical detection (LC-ECD) then liquid chromatography-tandem mass spectrometry (LC-MS/MS). Bhattacharya analysis was used after log transformation to determine age and sex-stratified RI for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios., Results: Normetanephrine excretion increases with age (RI: males: 18-<30 years: <3.4 µmol/24 h, 30-<40 years: <3.7 µmol/24 h, 40+ years: <5.3 µmol/24 h; females: 18-<30 years: <2.7 µmol/24 h, 30-<40 years: <3.1 µmol/24 h, 40+ years: <3.7 µmol/24 h), while metanephrine excretion was consistent across adulthood (RI: males: 18+ years: <1.8 µmol/24 h; females: 18+ years: <1.2 µmol/24 h). However, normetanephrine/creatinine and metanephrine/creatinine increase steadily with age after early adulthood, likely due to a decrease in muscle mass, with females having higher normetanephrine/creatinine and metanephrine/creatinine ratios., Conclusions: Age and sex-stratified RI were derived for metanephrine excretion, normetanephrine excretion, metanephrine/creatinine and normetanephrine/creatinine ratios. This is expected to reduce false positives while flagging most PPGL., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: Pheochromocytoma is a tumour arising from the adrenal medulla, which secretes catecholamines. Approximately 20% of pheochromocytomas are cystic and more likely to be asymptomatic. They should be surgically resected as all have a malignant potential and pose cardiovascular risk. Case presentation: We report the case of a 61-year-old female patient admitted electively for laparoscopic adrenalectomy for a large cystic pheochromocytoma detected incidentally. Diagnosis was confirmed preoperatively by elevated 24-h urinary metanephrines. The patient was treated preoperatively with alpha and beta blockade. Surgery was without complication; she had an uneventful postoperative recovery and no evidence of recurrence at one-year follow-up., Conclusion: This case highlights the necessity of investigating for biochemical function in all adrenal lesions by measuring metanephrines, even when entirely cystic on imaging. Given the surgical and anaesthetic risk in resection of pheochromocytoma, attaining a preoperative diagnosis allows for careful preoperative planning and safe surgery.

Catecholamines can be used to evaluate neuroendocrine tumors, stress, and potentially pain, but catecholamines degrade rapidly. Their metabolites normetanephrine (NME) and metanephrine (ME) have better stability in urine. In cats, urine sampling in a home environment would be beneficial to reduce effects of clinical stress and simplify sampling. We evaluated a human urine ELISA for analysis of NME and ME in feline urine, and investigated the effects of acidification, cat tray pellets, and storage time at room temperature up to 8.5 h. In 26 feline urine samples, mean NME concentration was 192 ± 80 ng/mL, mean intra- and inter-assay CV was 6.5% and 4.2%, respectively, and spike recovery was 98-101%, but dilutional recovery was unsatisfactory. For ME, mean intra- and inter-assay CV was 10.2% and 4.1%, respectively. Mean urine ME concentration was 32.1 ± 18.3 ng/mL, close to the kit's lowest standard, and spike recovery was 65-90%; the ELISA could not be validated for ME. The stability study, performed for NME on 12 urine samples, did not identify differences between acidified and non-acidified samples, cat tray pellets, or storage time, and no interaction effects. The ME ELISA was not suitable for feline urine; performance of the NME ELISA was acceptable, except for dilution recovery. For analysis of NME, feline urine can be sampled at home using cat tray pellets and stored at room temperature up to 8.5 h without acidification.

Background Plasma-free metanephrines (PFM) or urinary fractionated metanephrines (UFM) are the preferred biochemical tests for the diagnosis of phaeochromocytoma and paraganglioma (PPGL). Borderline increased results should be followed up to either exclude or confirm diagnosis. Methods We extracted all PFM and UFM results reported by our laboratory over a six-month period from the laboratory information system. We categorized patients with borderline increased results according to whether follow-up testing had been performed as suggested in the initial laboratory report. Questionnaires were then sent to all requesting doctors and medical notes reviewed where available. Results Two hundred and four patients with borderline increased PFM or UFM were identified. Sixty-five (38.5%) of 169 patients with borderline increased PFM had a repeat test out of which 36 were normal and 29 did not normalize. Of 35 patients with borderline increased UFM, 17 (48.6%) had subsequent PFM measurement, out of which 15 were normal. Questionnaires were returned to 106 (52%) patients. Of these, the most frequent indication for testing was hypertension ( n = 50); 15 patients had an incidental adrenal mass and two of these patients were diagnosed with a phaeochromocytoma. Conclusion Only 38% of patients with borderline increased PFM had a repeat PFM measurement. This was not significantly higher when compared with the 28% in a previous audit that we reported in 2010 ( P = 0.10). Forty-nine per cent of patients with a borderline increased UFM had a repeat UFM or PFM measurement. There remains a substantial possibility of missed detection of PPGL.

Background Urinary dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid are established tests for diagnosis and monitoring of neuroblastic disease. We compared the diagnostic performance of total urinary 3-methoxytyramine, the O-methylated product of dopamine, to these three established tumour markers. Methods Urinary 3-methoxytyramine, dopamine, homovanillic acid and 4-hydroxy-3-methoxymandelic acid were measured by high-performance liquid chromatography with electrochemical detection on consecutive urine samples from histologically proven neuroblastic patients and controls. Patients with neuroblastic disease were further classified as untreated, advancing, residual or absent disease based on clinical and radiological criteria. Receiver operating characteristic curve analysis was used to compare the diagnostic performance of the four tumour markers. Results Urinary 3-methoxytyramine was well correlated with established tumour markers and its concentration correlated with disease activity. It was the most commonly elevated tumour marker in neuroblastic disease and showed similar sensitivity to dopamine and homovanillic acid. The diagnostic utility of urinary 3-methoxytyramine as measured by area under the receiver operating characteristic curve was similar to dopamine and homovanillic acid. Conclusion Our results support the use of urinary 3-methoxytyramine as a tumour marker in the diagnosis and the monitoring of neuroblastoma disease.

Background After adrenalectomy, urinary fractionated metanephrine concentrations are expected to be reduced. However, there are few studies suggesting cut-offs for adrenalectomy patients. Methods Urinary metanephrine and normetanephrine concentrations in adrenalectomy patients and two controls were compared and hormonal concentrations were evaluated via time intervals after surgery. Results The median urinary metanephrine level after unilateral adrenalectomy was lower than that of the non-pheochromocytoma controls but comparable to healthy controls. Urinary normetanephrine concentrations did not differ between adrenalectomy patients and non-pheochromocytoma controls, although both group had levels higher than those of healthy controls. The median urinary normetanephrine level in the immediate postoperative period was higher than in the later period. Conclusions Urinary metanephrine concentrations were lower after adrenalectomy, but urinary normetanephrine concentrations were not changed compared with the non-pheochromocytoma controls. However, urinary normetanephrine concentrations in the patient group were higher than levels in the heathy controls.

Introduction: Urinary metanephrines are widely used in the diagnosis of catecholamine secreting tumours. Over the past two years we have been using the commercial Recipe(®) ClinRep(®) Complete Kit for Metanephrines in Urine coupled with high-performance liquid chromatography and coulometric detection. It was noticed that the internal standards on the patient chromatograms were sporadically raised due to interference., Methods: The interference had identical chromatographic and electrochemical properties to the Recipe(®) internal standard (undisclosed identity). Inspection of the patient names showed it seemingly had a higher frequency and magnitude in patients of Indian origin. The source of the interference was tracked by dietary observation and intervention to curry leaves, a common component of Indian foods., Results: The interference was chromatographically and electrochemically indistinguishable from the internal standard. The mass spectrum of the pentafluoropropionate derivative of the interference matched the Recipe(®) internal standard and was identified as methoxyhydroxybenzylamine by library match., Conclusion: The component co-elutes exactly with internal standard and artifactually decreases the metanephrine and normetanephrine results. It is surprising that it has not been described previously. Patients being assessed for catecholamine secreting tumours should be advised to withdraw from eating Indian foods at least 24 h prior to commencement of urinary collection.

Background: Medication-related interferences with measurements of catecholamines and their metabolites represent important causes of false-positive results during diagnosis of phaeochromocytomas and paragangliomas (PPGLs). Such interferences are less troublesome with measurements by liquid chromatography with tandem mass-spectrometry (LC-MS/MS) than by other methods, but can still present problems for some drugs. Levodopa, the precursor for dopamine used in the treatment of Parkinson's disease, represents one potentially interfering medication., Methods: Plasma and urine samples, obtained from 20 Parkinsonian patients receiving levodopa, were analysed for concentrations of catecholamines and their O-methylated metabolites by LC-MS/MS. Results were compared with those from a group of 120 age-matched subjects and 18 patients with PPGLs., Results: Plasma and urinary free and deconjugated (free + conjugated) methoxytyramine, as well as urinary dopamine, showed 22- to 148-fold higher (P < 0.0001) concentrations in patients receiving levodopa than in the reference group. In contrast, plasma normetanephrine, urinary noradrenaline and urinary free and deconjugated normetanephrine concentrations were unaffected. Plasma free metanephrine, urinary adrenaline and urinary free and deconjugated metanephrine all showed higher (P < 0.05) concentrations in Parkinsonian patients than the reference group, but this was only a problem for adrenaline. Similar to normetanephrine, plasma and urinary metanephrine remained below the 97.5 percentiles of the reference group in almost all Parkinsonian patients., Conclusions: These data establish that although levodopa treatment confounds identification of PPGLs that produce dopamine, the therapy is not a problem for use of LC-MS/MS measurements of plasma and urinary normetanephrine and metanephrine to diagnose more commonly encountered PPGLs that produce noradrenaline or adrenaline.

Background: Measurement of fractionated plasma or urine metadrenalines is the recommended screening test in the diagnosis of phaeochromocytoma, with clinical cut-offs geared towards diagnostic sensitivity. Current practice at Salford Royal Hospital is to add urine catecholamines onto samples with raised urine metadrenalines, with the aim of adding specificity to a diagnosis of phaeochromocytoma., Methods: This practice was reviewed by identifying a series of patients with raised urine metadrenalines who had catecholamines reflectively added. A total of 358 samples were identified from 242 patients, of which 228 had urine catecholamines measured., Results: A diagnosis of 'phaeochromocytoma' (n = 41) or 'no phaeochromocytoma' (n = 90) was obtained in 131 of 228 patients, giving raised urine metadrenalines a positive predictive value for phaeochromocytoma of 31%. The finding of increased urine catecholamines in samples with raised urine metadrenalines increased specificity for phaeochromocytoma to 70%. However, 95% diagnostic specificity for phaeochromocytoma could be achieved by the introduction of a second cut-off for urine metadrenalines geared towards maximizing specificity., Conclusions: Consideration of the degree of increase in urine metadrenalines is a superior method of determining the likelihood of phaeochromocytoma than measurement of urine catecholamines.

Background: Catecholamine-producing neuroendocrine tumours are found in chromaffin cells of the adrenal medulla (phaeochromocytoma) or extra-adrenal paraganglia (paraganglioma), known collectively as PPGLs. In approximately a quarter or more of cases of PPGL, these rare tumours arise as a result of germline mutations of several tumour susceptibility genes. At the Crosshouse laboratory, urine tests include free metadrenalines (fMAs) (also known as free metanephrines) which demonstrate superior sensitivity over that obtained by urinary vanillyl mandelic acid, catecholamines or plasma catecholamines in the diagnosis of PPGL. This retrospective audit was to determine if urinary fMAs offered discrimination among the hereditary forms of PPGL., Methods: Retrospective biochemical and genetic data were gathered from 1997 to 2011. The identified urine specimens were those obtained at the time of first diagnosis or recurrence of PPGL. Results of catecholamines and metabolites were standardized as multiples of their respective relevant upper reference limits (URLs)., Results: Results were available for 29 affected patients (15 females and 14 males), median age 26 (range 9-63) years, comprising three mutation groups: succinate dehydrogenase subunit B or D ([SDHB/D] 16 patients), multiple endocrine neoplasia type 2 ([MEN 2] 6 patients) and von Hippel-Lindau disease ([VHL] 7 patients). The parent catecholamines exhibited increased values for noradrenaline (NA) and/or adrenaline (AD) for 25/29 (86.2%) patients. Either or both free normetadrenaline (fNMA) and fMA were elevated in 29/29 (100%) patients., Conclusions: The ratio of the multiples of URL for fMA/fNMA displayed a clearer separation of MEN 2 patients from those with SDHB/D or VHL than did the equivalent AD/NA ratio.

Background: Neuroblastoma is the most common extracranial solid tumour in childhood (8% of all childhood cancers), the most frequently diagnosed in infancy, and has one of the highest death rates, while chromaffin tumours rarely present in childhood. Both tumour types produce catecholamines and their metabolites. It is difficult to produce reference ranges for tests in children, and currently, no age-related medical decision limits for free metadrenalines (free metanephrines) in random urine specimens exist in the paediatric literature., Methods: Results of vanillylmandelic acid (VMA), 5-hydroxyindoleacetic acid, homovanillic acid (HVA), noradrenaline (NA), adrenaline, dopamine (DA), free normetadrenaline (fNMA), free metadrenaline and free 3-methoxytyramine (f3MT) in 1658 random urines obtained from infants, children and young adults were measured by high performance liquid chromatography with electrochemical detection. Specimens were excluded from consideration if obtained from the following categories, i.e. (a) harbouring neuroblastic, chromaffin, carcinoid or other tumours or malignancies; (b) medical conditions having known association with excess catecholamine excretion; (c) patients administered catecholamine or paracetamol; (d) overly dilute urine; and (e) manifesting outlying values following visual inspection., Results: There remained 872 specimens that were grouped into seven age ranges (<1; 1 or 2; 3 or 4; 5-7; 8-10; 11-13; 14-19 y) for which medical decision limits were determined for each analyte. There was no significant difference between the results for boys or girls. In 55 patients harbouring neuroblastic tumours, HVA (54/55), f3MT (14/16), VMA (45/53) and DA (43/53) were the most frequently elevated analytes at time of diagnosis. In 11 patients presenting in childhood with chromaffin tumours, fNMA (11/11) followed by NA (10/11) were the most frequently elevated. Discussion The likely reasons for outlying or missing values, together with the reasons for variation in the distinctive biochemical patterns of analytes exhibited in individuals harbouring either neuroblastic or chromaffin tumours are discussed.

Introduction: Normetanephrine and metanephrine are intermediate metabolites of noradrenaline and adrenaline metabolism. To assess whether normetanephrine and metanephrine analysis may aid in the diagnosis of Neuroblastoma, a reference interval for these metabolites must first be established., Aim: The overall aim of this study was to establish a paediatric age-related reference interval for the measurement of total fractionated metanephrines., Methods: A total of 267 urine samples were analysed following acid hydrolysis. This releases the metanephrines from their sulphate-bound metabolites. The samples were analysed using reverse phase high-performance liquid chromatography with electro-chemical detection on a Gilson automated sequential trace enrichment of dialysate sample system., Results: Data were analysed using Minitab Release version 14. Outliers were removed using the Dixon/Reed one-third rule. Partitioning of the age groups was achieved using Harris and Boyd's standard normal deviate test. Non-parametric analysis of the data was performed, followed by the establishment of the 2.5th and the 97.5th reference limits., Conclusions: The established reference intervals are described in Table 2.

Background: Measurement of metadrenalines has been recommended in the investigation of phaeochromocytoma. Urinary assays remain the most common; however, drug interference is still one of the main challenges for analytical systems. We have developed a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of total urinary normetadrenaline and total urinary metadrenaline, which does not require extraction procedures prior to analysis., Method: Total urinary normetadrenaline and total urinary metadrenaline were individually quantified by electrospray ionization in the multiple-reaction monitoring mode. Deuterated internal standards were used and an acid hydrolysis step was used to convert conjugated metabolites into free metadrenalines. Chromatographic separation was achieved using a Phenomenex Luna 3 micro PFP column followed by analysis on an API 3200 LC-MS/MS., Results: Linearity was exhibited across the calibration range for both normetadrenaline (r = 1, P < 0.0001) and metadrenaline (r = 1, P < 0.0001) with the limit of quantification of 0.05 and 0.02 micromol/L, respectively. Intra-assay imprecision for both normetadrenaline and metadrenaline was less than 5.5% with % coefficient of variations of less than 4%. Inter-assay imprecision was less than 13%. Neither noradrenaline or adrenaline interfere with the assay as determined by the spiking of samples with high concentrations of noradrenaline or adrenaline (P > 0.05). Acceptable analytical performance was seen with comparison to a high-performance liquid chromatography method and on External Quality Assessment returns., Conclusions: An analytically simple and sensitive method has been developed and evaluated for the analysis of total urinary normetadrenaline and total urinary metadrenaline which is now in routine use.

Background: Up to 2007 there was no formal external quality assurance programme for plasma free metanephrines. A pilot programme was conceived by the AACB (Australian Association of Clinical Biochemists) Working Party on biogenic amines. With support from the AACB and Royal College of Pathologists of Australasia Quality Assurance programmes, a pilot study was developed. Data from this study are presented for the first time., Methods: Twelve lyophilized plasma samples were distributed to 15 centres. Samples were spiked with metanephrine (metadrenaline), normetanephrine (normetadrenaline) and 3-methoxytyramine, all derived from human urine. Concentrations were arranged in a linear relationship. The analytes were present at six levels and samples were duplicated., Results: High-pressure liquid chromatography and tandem mass spectrometry methods showed acceptable precision but in general enzyme immunoassay displayed a higher degree of imprecision as well as a negative bias., Conclusions: Differences in calibration and matrix effects are likely to have been responsible for the discrepancy between chromatographic and immunoassay methods. These differences need to be further examined although efforts at standardization between different methods have been hampered by the lack of a universal calibrator for plasma metanephrines. Meanwhile, a laboratory's performance characteristics can be monitored and enhanced by participation in suitable external quality assurance programmes.

Background: The measurement of catecholamines and metanephrines in urine is an important diagnostic test in biochemical screening for phaeochromocytoma. Tandem mass spectrometry (MSMS) has the potential to be used in a profiling method for simultaneous assay of these analytes., Methods: Optimal conditions were established for the MSMS detection of catecholamines (noradrenalin, adrenalin and dopamine) and metanephrines (normetanephrine and metanephrine), including commercially available isotopically labelled compounds for use as internal standards. Chromatographic separation of all five polar biogenic amines was achieved under solvent conditions that were compatible with MSMS and multiple reaction monitoring. Several types of solid-phase extraction cartridge were used to investigate clean-up conditions for urine, and acid-hydrolysates of urine, prior to LC-MSMS., Results: Total catecholamines and metanephrines from acid-hydrolysed urines, or free catecholamines and free metanephrines from native urines, were complexed with diphenyl-boronate and recovered in high yield from polymer cartridges after elution with formic acid. Direct injection of eluates into the LC-MSMS system allowed quantitation of catecholamines and metanephrines with a run time of 6 min per sample. Biogenic amine concentrations for patient urines and quality assurance programme samples, and assay imprecision, were similar to values obtained with high-performance liquid chromatography methods, which used electrochemical detection. In normal urines, the ratio of free to total catecholamines was around three-fold higher than the ratio of free to total metanephrines., Conclusion: The assay of urinary catecholamines and metanephrines can be achieved simultaneously using one LC-MSMS method, which is rapid and reduces labour and consumable costs for routine application.

A 41-year-old lady presented with classical symptoms of a phaeochromocytoma and markedly elevated urinary adrenaline concentration. Urinary fractionated metanephrine and normetanephrine concentrations were within the normal reference range. Computed tomography of the abdomen/pelvis and I(123) meta-iodobenzylguanidine scans were negative. Factitious adrenaline use was established as the diagnosis.

Phaeochromocytomas are rare tumours that require consideration among large numbers of patients with hypertension. If not diagnosed, the excessive secretion of catecholamines by these tumours can cause considerable morbidity and mortality. With a wide clinical variability in presentation, diagnosis can be difficult and invariably requires the biochemical confirmation of excessive catecholamine production by the tumour. At the First International Symposium on Phaeochromocytoma in October 2005, a panel of experts recommended that initial biochemical testing for phaeochromocytoma should include measurements of plasma and urinary metadrenalines. The accumulated evidence clearly indicates that measurement of fractionated metadrenalines in urine or plasma provides superior diagnostic sensitivity over plasma or urine measurements of catecholamines and metabolites. The low prevalence of phaeochromocytoma and paraganglioma (PGL) emphasizes the need to use biochemical tests of the highest sensitivity. To achieve this, it is recommended that the initial biochemical testing for phaeochromocytoma and secreting PGL should always include the measurements of metadrenalines in plasma or urine or both.

Background: L-dopa is an important antiparkinsonian drug. It is a precursor of dopamine and the other catecholamines. Potentially, administration of L-dopa could lead to increased urinary excretion of catecholamines and their metabolites to abnormal amounts. The current study aimed to determine these excretions in patients with Parkinson's disease (PD) receiving L-dopa compared with suitable controls. This is the first assessment of the effect of exogenous administration of L-dopa on urinary free metadrenalines., Methods: Using one-way analysis of variance (ANOVA), urine catecholamines and metabolites, expressed as mmol per mole creatinine, were compared in: patients with PD who were receiving L-dopa; patients with PD but not receiving L-dopa; and patients without PD who were being investigated for the presence of phaechromocytoma but were found not to have the disease., Results: Significantly higher values for urinary dopamine, homovanillic acid, free normetadrenaline and free metadrenaline were found in patients with PD receiving L-dopa compared with the other two control groups. In all the patients with PD, these four analytes were significantly correlated with daily dose of L-dopa., Conclusion: L-dopa therapy can result in production of false positives for urinary excretion of dopamine, homovanillic acid, free normetadrenaline or free metadrenaline and thereby decrease the diagnostic value of these measurements in identifying phaeochromocytoma and related tumours.

Background: Some high-performance liquid chromatography techniques with electrochemical detection for urinary catecholamines and their metabolites can be subject to interference from drugs and their metabolites. Prime amongst these interferences are those due to paracetamol ingestion., Methods: The prevalence of paracetamol contamination was determined by measuring the drug in all patient specimens submitted for catecholamine analysis over a 2-month period. These findings were then related to the proportion of unreportable results at each range of specimen paracetamol concentration. The apparent results from a small representative sample of the paracetamol-positive specimens are illustrated., Results: Approximately one-third of urine specimens were found to contain paracetamol. Low-level contamination can produce apparent patterns of results which may easily be confused with those found in predominantly adrenaline-, or metadrenaline-secreting phaeochromocytomas., Conclusion: Despite the fact that significantly less than 5% of an oral dose of paracetamol is excreted as the free drug, its analysis provides a good surrogate marker for the likelihood of spurious results. It is useful to know prior to urinary free metadrenaline or catecholamine analysis which urine specimens are likely to contain potentially interfering paracetamol metabolites.

Adrenal incidentalomas are tumors that are serendipitously found by radiological examination. The incidence of adrenal incidentalomas in patients undergoing abdominal CT approaches 1 %. The evaluation of a patient with an adrenal incidentaloma requires, in addition to a clinical history and physical examination, a focused biochemical evaluation to investigate if there is excess secretion of catecholamines, glucocorticoids, or aldosterone. Some tumors have specific features on imaging that identify them as benign or malignant. The recommendations for management of adrenal incidentalomas include resection of all functioning tumors regardless of size, preferably by the laparoscopic approach. Large, non-functional tumors should also be removed. Biochemical and radiological surveillance is recommended for at least one year, if a tumor is left in place.

Background: Normal urine catecholamine values in patients with phaeochromocytoma is an occasional finding and may lead to a missed diagnosis. Additional urinary free metadrenaline analysis may be of value in this situation., Methods: In addition to vanillylmandelic acid, homovanillic acid and the catecholamines, urinary free normetadrenaline (fNMA) and free metadrenaline (fMA) were measured. This report describes six confirmed cases of phaeochromocytoma showing normal urinary catecholamine output and compares fMA results and tumour size with other confirmed cases where the urine catecholamines were increased., Results: Urine catecholamines in these patients with, on average, smaller tumours, were all normal. Urinary fNMA and fMA were available on five patients, and were increased in three. The data suggest that, unlike the catecholamines, urinary fNMA and fMA could be a useful predictor of tumour size., Conclusion: The inclusion of fNMA and fMA in the test profile is likely to be of additional benefit in tumour detection, particularly when catecholamines or other metabolites are normal.

A method for the determination of metanephrine (MN; also known as metadrenaline), normetanephrine (NMN; also known as normetadrenaline) and 3-methoxytyramine (3-MT) in human urine using high-performance liquid chromatography followed by electrochemical detection (ECD) was validated primarily by comparing the results with those obtained by a gas chromatography mass spectrometry (GC-MS) reference method. Correlation coefficients of 0.93, 0.94 and 0.91 were obtained for MN, NMN and 3-MT, respectively, in a group of healthy controls consisting of 30 women and 30 men. A systematic difference was detected only for 3-MT (-16%). Further tests of accuracy (linearity and recovery) and precision demonstrated that the described method must be considered to be a reliable approach to assess urinary metanephrines in the diagnosis of phaeochromocytoma. At lower concentrations (MN, 248 nmol/L; NMN, 434 nmol/L; 3-MT, 402 nmol/L), within-assay coefficients of variation were close to 5% or less (5.3, 4.6 and 2.2%, respectively) and between-assay coefficients of variation were 8.9, 11.2 and 12.3%, respectively, for the same low levels. This raises the possibility that this method can also be applied to assess urinary free, unconjugated metanephrines. Sex differences were detected for MN and NMN excretion when expressed in nmol per 24h and nmol/mmol creatinine, respectively, by both ECD and GC-MS methods.

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.