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Urinary and plasma catecholamines and metanephrines in dogs
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A D V ANCE S
from healthy dogs and dogs with HC. No comparison between urinary and plasma variables has been carried out in dogs.
Objective The aim of this study was to measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, HC, and NAD and to determine the test with the best discrimination for dogs with PC. With regard to the plasma tests, an additional aim was to compare the diagnostic performance of total (free + sulfoconjugated) and free metanephrines.
Procedure
Urinary and Plasma Catecholamines and Metanephrines in Dogs Background Pheochromocytomas (PC) are catecholamine-producing tumors arising from chromaffin cells of the adrenal medulla. Clinical signs result most often from secretion of excessive amounts of catecholamines. Diagnosis of PC in humans is mainly based on biochemical detection of catecholamine-derived secretory products. Commonly used tests are measurement of catecholamines and their O-methoxylated metabolites metanephrines (normetane phrine and metanephrine) in 24-hour urine samples or in plasma. The question of whether urine or plasma is best is still somewhat controversial, but plasma metanephrines are recommended more often as test of choice. In dogs, evaluation of those biomarkers for the diagnosis of PC only started a few years ago; dogs with PC, but also those with nonadrenal (NAD) illness and dogs with hypercortisolism (HC) can have increased catecholamines and metanephrines excretion. Since 24-hour urine sampling is impracticable, measurements of urinary fractionated catecholamines and metanephrines was established in spot urine samples by expressing their concentrations as a ratio to the urinary creatinine concentration. The urinary normetanephrine-to-creatinine ratio was shown to be the parameter which differentiated dogs with PC best
Seven dogs with PC were included. At presentation, dogs showed various clinical signs indicative of PC, including weakness, panting, tachycardia, agitation, trembling, polyuria/polydipsia, abdominal pain, and signs of gastrointestinal disease. Ten dogs with HC were included. Dogs were prospectively enrolled if clinical signs were consistent with HC (e.g., polyuria, polydipsia, polyphagia, panting, skin problems, weakness, and abdominal enlargement), the LDDS test yielded a positive result, and owners were ready to treat and regularly re-evaluate the dog over at least a 6-month period. Fourteen dogs with nonadrenal disease and 10 healthy dogs were included. All dogs were prospectively enrolled in the study according to the study protocol. Urine and plasma samples for the analysis of catecholamines and metanephrines were taken within 30 minutes during work-up in the hospital. Samples were shipped on dry ice to the respective laboratory and thawed immediately before analysis. All samples were evaluated at a reputable laboratory under controlled conditions.
Results Urinary norepinephrine : creatinine and urinary-epinephrine : creatinine did not differ between dogs with PC and dogs with HC. However, urinary norepinephrine : creatinine was significantly higher in dogs with PC than in dogs with NAD and healthy dogs. Urinary normetanephrine : creatinine and urinary metanephrine : creatinine were significantly higher in dogs with PC compared to the dogs in the other 3 groups. There was a marked overlap in plasma epinephrine and plasma norepinephrine among the results of all groups. Plasma
total and free normetanephrine were sig nificantly higher in dogs with PC compared to dogs with HC, NAD, and healthy dogs. Plasma total metanephrine was not different in dogs with PC compared to HC dogs; however, there was a significant difference compared to NAD and healthy dogs. Plasma-free metanephrine was sig nificantly higher in PC dogs compared to dogs of all other groups.
Author Conclusions Determination of normetanephrine seems the best parameter to differentiate between dogs with PC and those with other diseases. So far, no recommendation on whether to test urine or plasma can be made. Until more studies have been performed, the decision should be based on available technical facilities and the availability of dog-specific reference ranges.
Inclusions One figure, 1 table, 33 references.
Editor Annotation A PC is a tumor that arises from the medullary region of the adrenal gland that potentially produces catecholamines. These tumors can result in nonspecific clinical signs including hypertension. In a patient with hypertension and an adrenal mass, one may be suspicious for PC, but these neoplasms are traditionally diagnosed by histology of the adrenal mass. As surgical biopsy is the best diagnostic modality thus far and surgery is the treatment of choice, an antemortem, pre-surgical assay is desirable for the definitive diagnosis of this neoplasm. There is now an assay available for specific catecholamine metabolites, normetanephrine and metanephrine, which have been recognized in plasma and urine. It is ideal to measure these metabolites over a 24-hour period. Since this is not practical in most clinical settings, the values are reported as a ratio of the urinary creatinine concentration. Salesov et al. evaluated urine and plasma metanephrine metabolites. Normetane phrine and metanephrine concentrations in urine and plasma from healthy dogs were compared to patients with PC, hyper cortisolism, and those with non-adrenal disease. Interestingly, they determined that norepinephrine and epinephrine concentrations did not help to diagnose patients with either PC or hypercortisolism. They found that normetanephrine
A D V ANCE S
was the preferred test for diagnosing a catecholamine producing PC and that urine was more reliable than plasma for this assay. Although metanephrine concentrations in patients with adrenal disease were significantly different from those with non-adrenal disease, there was some overlap of urine metanephrine concentrations when patients with PC were compared to patients with hypercortisol ism. These assays are available for veterinary species, but due to the specialized methodology, they are only available at a few reference laboratories. (JR) Salesov E, Boretti FS, et al. Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs. J Vet Intern Med 2015;29:597-602.
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A D V ANCE S
from healthy dogs and dogs with HC. No comparison between urinary and plasma variables has been carried out in dogs.
Objective The aim of this study was to measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, HC, and NAD and to determine the test with the best discrimination for dogs with PC. With regard to the plasma tests, an additional aim was to compare the diagnostic performance of total (free + sulfoconjugated) and free metanephrines.
Procedure
Urinary and Plasma Catecholamines and Metanephrines in Dogs Background Pheochromocytomas (PC) are catecholamine-producing tumors arising from chromaffin cells of the adrenal medulla. Clinical signs result most often from secretion of excessive amounts of catecholamines. Diagnosis of PC in humans is mainly based on biochemical detection of catecholamine-derived secretory products. Commonly used tests are measurement of catecholamines and their O-methoxylated metabolites metanephrines (normetane phrine and metanephrine) in 24-hour urine samples or in plasma. The question of whether urine or plasma is best is still somewhat controversial, but plasma metanephrines are recommended more often as test of choice. In dogs, evaluation of those biomarkers for the diagnosis of PC only started a few years ago; dogs with PC, but also those with nonadrenal (NAD) illness and dogs with hypercortisolism (HC) can have increased catecholamines and metanephrines excretion. Since 24-hour urine sampling is impracticable, measurements of urinary fractionated catecholamines and metanephrines was established in spot urine samples by expressing their concentrations as a ratio to the urinary creatinine concentration. The urinary normetanephrine-to-creatinine ratio was shown to be the parameter which differentiated dogs with PC best
Seven dogs with PC were included. At presentation, dogs showed various clinical signs indicative of PC, including weakness, panting, tachycardia, agitation, trembling, polyuria/polydipsia, abdominal pain, and signs of gastrointestinal disease. Ten dogs with HC were included. Dogs were prospectively enrolled if clinical signs were consistent with HC (e.g., polyuria, polydipsia, polyphagia, panting, skin problems, weakness, and abdominal enlargement), the LDDS test yielded a positive result, and owners were ready to treat and regularly re-evaluate the dog over at least a 6-month period. Fourteen dogs with nonadrenal disease and 10 healthy dogs were included. All dogs were prospectively enrolled in the study according to the study protocol. Urine and plasma samples for the analysis of catecholamines and metanephrines were taken within 30 minutes during work-up in the hospital. Samples were shipped on dry ice to the respective laboratory and thawed immediately before analysis. All samples were evaluated at a reputable laboratory under controlled conditions.
Results Urinary norepinephrine : creatinine and urinary-epinephrine : creatinine did not differ between dogs with PC and dogs with HC. However, urinary norepinephrine : creatinine was significantly higher in dogs with PC than in dogs with NAD and healthy dogs. Urinary normetanephrine : creatinine and urinary metanephrine : creatinine were significantly higher in dogs with PC compared to the dogs in the other 3 groups. There was a marked overlap in plasma epinephrine and plasma norepinephrine among the results of all groups. Plasma
total and free normetanephrine were sig nificantly higher in dogs with PC compared to dogs with HC, NAD, and healthy dogs. Plasma total metanephrine was not different in dogs with PC compared to HC dogs; however, there was a significant difference compared to NAD and healthy dogs. Plasma-free metanephrine was sig nificantly higher in PC dogs compared to dogs of all other groups.
Author Conclusions Determination of normetanephrine seems the best parameter to differentiate between dogs with PC and those with other diseases. So far, no recommendation on whether to test urine or plasma can be made. Until more studies have been performed, the decision should be based on available technical facilities and the availability of dog-specific reference ranges.
Inclusions One figure, 1 table, 33 references.
Editor Annotation A PC is a tumor that arises from the medullary region of the adrenal gland that potentially produces catecholamines. These tumors can result in nonspecific clinical signs including hypertension. In a patient with hypertension and an adrenal mass, one may be suspicious for PC, but these neoplasms are traditionally diagnosed by histology of the adrenal mass. As surgical biopsy is the best diagnostic modality thus far and surgery is the treatment of choice, an antemortem, pre-surgical assay is desirable for the definitive diagnosis of this neoplasm. There is now an assay available for specific catecholamine metabolites, normetanephrine and metanephrine, which have been recognized in plasma and urine. It is ideal to measure these metabolites over a 24-hour period. Since this is not practical in most clinical settings, the values are reported as a ratio of the urinary creatinine concentration. Salesov et al. evaluated urine and plasma metanephrine metabolites. Normetane phrine and metanephrine concentrations in urine and plasma from healthy dogs were compared to patients with PC, hyper cortisolism, and those with non-adrenal disease. Interestingly, they determined that norepinephrine and epinephrine concentrations did not help to diagnose patients with either PC or hypercortisolism. They found that normetanephrine
A D V ANCE S
was the preferred test for diagnosing a catecholamine producing PC and that urine was more reliable than plasma for this assay. Although metanephrine concentrations in patients with adrenal disease were significantly different from those with non-adrenal disease, there was some overlap of urine metanephrine concentrations when patients with PC were compared to patients with hypercortisol ism. These assays are available for veterinary species, but due to the specialized methodology, they are only available at a few reference laboratories. (JR) Salesov E, Boretti FS, et al. Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs. J Vet Intern Med 2015;29:597-602.
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