Age-related medical decision limits for urinary free (unconjugated) metadrenalines, catecholamines and metabolites in random urine specimens from children

Abstract

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.

Sympathetic Neurotransmitters in Neuroblastoma – Between Physiology and Pathology

“…In contrast, undifferentiated tumors synthesize less NPY, but release it in an uncontrolled manner, which leads to elevated systemic levels of the peptide in neuroblastoma patients, as well as further depletion of the peptide in neuroblastoma tissue. Such an uncontrolled secretion has been already described for catecholamines (Davidson et al, 2011;Itoh & Omori, 1973). The clinical reports associating elevated plasma NPY levels with poor prognosis of neuroblastoma suggested that the peptide can be a growth factor for these tumors.…”

“…The differentiating tumors release a relatively high amount of actual sympathetic neurotransmitters, norepinephrine and epinephrine (Zambrano & Reyes-Mugica, 2002). Paradoxically, however, systemic levels of these catecholamines are rarely elevated in neuroblastoma patients, while concentrations of their metabolites -free normetanephrine and vanillylmandelic acid -are significantly higher than normal (Davidson et al, 2011). This phenomenon is attributed to the fact that poorly differentiated neuroblastomas lack catecholamine storing mechanisms, which leads to an uncontrolled release of norepinephrine and its rapid metabolism (Itoh & Omori, 1973).…”

Clinical validation of urine 3-methoxytyramine as a biomarker of neuroblastoma and comparison with other catecholamine-related biomarkers

“…Urinary free MTY, although theoretically increases clinical sensitivity by the removal of gastro-enteric source of conjugated MTY, is analytically challenging, and evidence for diagnostic utility in the clinical setting is currently limited. 10 Similarly, plasma MTY has been suggested as a promising biomarker in the diagnosis of neuroblastoma; however, the need of blood testing in young children may limit the clinical utility. 21 Our findings support MTY as a biomarker in patients with untreated disease and warrants further comparative studies between total and free MTY in urine and serum.…”

“…Both free and total 3-methoxytyramine (MTY), the O-methylated product of dopamine, have previously been studied as potential markers of neuroblastoma. [10][11][12][13] O-methylated products of epinephrine (metanephrine) and norepinephrine (normetanephrine) have demonstrated diagnostic superiority compared with their catecholamine counterparts in the diagnosis of phaeochromocytoma and paragangliomas; and because of this have been recommended as first line biochemical tests for these tumours. 14,15 Plasma MTY has been demonstrated as the most commonly elevated catecholamine-related tumour marker in patients with head and neck paragangliomas.…”

L-DOPA therapy interferes with urine catecholamine analysis in children with suspected neuroblastoma: a case series

“…18 In a study of 55 patients with neuroblastic tumours, HVA, f3MT, VMA and DA were the most frequently elevated analytes at the time of diagnosis, with HVA elevated in 54/55 and VMA in 45/53 cases. 19 Neuroblastoma has also been demonstrated to be the most common cause of elevated urinary DA in children, however it is a poorer marker than its metabolites in very young patients. 20 Neuroblastomas often exhibit high expression of tyrosine hydroxylase, which catalyses the conversion of tyrosine to DOPA.…”