Disappearance Rate of Catecholamines, Total Metanephrines, and Neuropeptide Y from the Plasma of Patients after Resection of Pheochromocytoma

Abstract Background: Plasma free metanephrines are a more reliable analyte to measure than catecholamines for the biochemical diagnosis of pheochromocytomas. We hypothesized that the long persistence of total (sulfate-conjugated plus free) metanephrines in the blood might have a significant diagnostic value. Methods: We measured plasma concentrations of catecholamines and total metanephrines (sulfate-conjugated plus free forms) by HPLC with amperometric detection, and neuropeptide Y (NPY) by an amplified ELISA in seven patients before and after removal of their pheochromocytomas. The results for catecholamine, total metanephrines, and NPY in each patient were analyzed for up to 120 min, starting from the time of tumor vessel clamping. The persistence of analytes was quantified as the area under the concentration–time curve over 120 min. Results: On the basis of the upper reference limit for each variable, plasma free norepinephrine (NE) and epinephrine (E) concentrations were increased preoperatively in at least one sample in seven and six patients, respectively. Total normetanephrine (NMN) and metanephrine (MN) were increased in all samples in seven and six patients, respectively. NPY was increased 2- to 465-fold. After removal of the tumor, MN and NMN showed a higher average relative increase above the upper limit of the reference interval than NE and E (P = 0.05), whereas NPY was intermediate. The persistence of increased values was significantly shorter for catecholamines than for metanephrines. The half-life estimated by nonlinear regression was 12.3 ± 7.8 min for NPY. Significant correlations were observed among NE, E, NMN, MN, and NPY concentrations, but parent markers (E and MN or NE and NMN) did not appear significantly intercorrelated. Conclusions: A larger increase and a longer persistence of total metanephrines (reflecting predominantly sulfo-conjugated metanephrines) than catecholamines and NPY in plasma may contribute to their greater diagnostic accuracy in pheochromocytoma.

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Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18168683 ◽

2021 ◽

Vol 18 (16) ◽

pp. 8683

Author(s):

Tatsuya Yoshihara ◽

Masayoshi Zaitsu ◽

Kazuya Ito ◽

Ryuzo Hanada ◽

Eunhee Chung ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Asian Population ◽

Reference Interval ◽

Reference Limit ◽

Neurological Emergencies ◽

Precise Diagnosis ◽

The Mean ◽

Upper Reference Limit ◽

Age Range ◽

Cerebrospinal Fluid Protein

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

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Limited Diagnostic Utility of Chromogranin A Measurements in Workup of Neuroendocrine Tumors

Diagnostics ◽

10.3390/diagnostics10110881 ◽

2020 ◽

Vol 10 (11) ◽

pp. 881

Author(s):

Jonas Baekdal ◽

Jesper Krogh ◽

Marianne Klose ◽

Pernille Holmager ◽

Seppo W. Langer ◽

...

Keyword(s):

Positive Predictive Value ◽

Neuroendocrine Tumors ◽

Predictive Value ◽

Chromogranin A ◽

Plasma Concentrations ◽

Tumor Burden ◽

Reference Limit ◽

Independent Analysis ◽

Net Method ◽

Upper Reference Limit

Background: Plasma chromogranin A (CgA) is related to tumor burden and recommended in the follow-up of patients diagnosed with neuroendocrine tumors (NETs). The use of CgA in the workup of a suspected NET is more questionable. Objective: To assess the positive predictive value (PPV) of CgA plasma concentrations above the upper reference limit (URL) in patients with suspected NET. Method: Patients referred to the NET Centre, Rigshospitalet, Copenhagen from 2015 to 2019 with clinically suspected NET were included if a CgA measurement was performed prior to referral. The utility of CgA was assessed by comparing pre-referral CgA concentrations to the outcome of a thorough workup. In 47 selected cases with continuously unexplained elevated CgA concentrations, a processing-independent analysis (PIA) for CgA was performed. Results: A total of 197 patients were included. NET was ultimately diagnosed in 25 patients. CgA plasma concentrations were above the URL (elevated) in 19/25 patients diagnosed with NET. In total, 167/197 had elevated CgA concentrations at referral. The positive predictive value (PPV) of elevated CgA concentration was 11% (19/167). Proton pump inhibitor (PPI) treatment was identified as the possible cause of CgA elevation in 55/148 patients with falsely elevated CgA. CgA concentration was normal in 28/47 patients when using PIA. Conclusion: Our data do not support using measurement of CgA for screening when NET is suspected since the PPV was rather low. PPI treatment is a common cause of increased CgA concentrations and should always be discontinued before CgA measurement. PIA of CgA could be a way of excluding NET when suspicion is based primarily on elevated CgA.

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Choice of Statistical Tools for Outlier Removal Causes Substantial Changes in Analyte Reference Intervals in Healthy Populations

Clinical Chemistry ◽

10.1093/clinchem/hvaa208 ◽

2020 ◽

Vol 66 (12) ◽

pp. 1558-1561 ◽

Cited By ~ 1

Author(s):

Peter E Hickman ◽

Gus Koerbin ◽

Julia M Potter ◽

Nicholas Glasgow ◽

Juleen A Cavanaugh ◽

...

Keyword(s):

Statistical Methods ◽

Population Studies ◽

Large Population ◽

Large Body ◽

Reference Interval ◽

Reference Intervals ◽

Outlier Removal ◽

Reference Limit ◽

Statistical Measures ◽

Upper Reference Limit

Abstract Background Reference intervals are an important aid in medical practice as they provide clinicians a guide as to whether a patient is healthy or diseased. Outlier results in population studies are removed by any of a variety of statistical measures. We have compared several methods of outlier removal and applied them to a large body of analytes from a large population of healthy persons. Methods We used the outlier exclusion criteria of Reed-Dixon and Tukey and calculated reference intervals using nonparametric and Harrell-Davis statistical methods and applied them to a total of 36 different analytes. Results Nine of 36 analytes had a greater than 20% difference in the upper reference limit, and for some the difference was 100% or more. Conclusions For some analytes, great importance is attached to the reference interval. We have shown that different statistical methods for outlier removal can cause large changes to reported reference intervals. So that population studies can be readily compared, common statistical methods should be used for outlier removal.

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Rapid determination of serum myoglobin with a routine chemistry analyzer

Clinical Chemistry ◽

10.1093/clinchem/39.4.653 ◽

1993 ◽

Vol 39 (4) ◽

pp. 653-658 ◽

Cited By ~ 6

Author(s):

A J Bakker ◽

D A Boymans ◽

D Dijkstra ◽

J P Gorgels ◽

R Lerk

Keyword(s):

Predictive Value ◽

Rapid Determination ◽

Reference Interval ◽

High Dose ◽

Reference Limit ◽

Hook Effect ◽

Upper Limit ◽

Upper Reference Limit ◽

Serum Myoglobin

Abstract A turbidimetric immunoassay system (Turbitime system, Behringwerke AG) allows rapid determination of myoglobin in serum. We adapted the reagents for this myoglobin assay (Turbiquant myoglobin) for use with a Hitachi 717 analyzer. No high-dose hook effect was observed up to 15,000 micrograms/L. Interassay CVs were 4.6% (mean = 72.0 micrograms/L; n = 9) and 2.5% (mean = 365.6 micrograms/L; n = 11). The calibration curve was stable for at least 1 month. Hemolysis did not interfere, and turbidity from lipemia interfered only when absorbance exceeded 2.0 A. Results of this method (y) correlated well with those by the Turbitime method (y = 1.256x - 44.1 micrograms/L; n = 91; r = 0.991) and by a commercially available radioimmunoassay (Byk-Sangtec; y = 0.739x - 42.2 micrograms/L; n = 94; r = 0.991). The upper limit (95th percentile) of the reference interval for myoglobin was estimated at 57.9 micrograms/L. The positive predictive value for results of myoglobin at admission was 89% with this upper reference limit and 99% with 100 micrograms/L, whereas the negative predictive value was about 60% for both limits.

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Routine α-Amylase Assay Using Protected 4-Nitrophenyl-1,4-α-d-maltoheptaoside and a Novel α-Glucosidase

Clinical Chemistry ◽

10.1093/clinchem/46.5.644 ◽

2000 ◽

Vol 46 (5) ◽

pp. 644-649 ◽

Cited By ~ 14

Author(s):

Klaus Lorentz

Keyword(s):

Amylase Activity ◽

Reference Method ◽

Reference Interval ◽

Lag Phase ◽

Reference Limit ◽

Independent Constant ◽

Increased Sensitivity ◽

Upper Reference Limit ◽

Manual Performance ◽

Age And Sex

Abstract Background: In contrast to numerous methods for measuring α-amylase activity, the approved IFCC reference method offers an invariable time-independent constant product pattern, thus avoiding possibly changing stoichiometric calculations. However, reference methods do not lend themselves to routine use, so that such methods need to be modified. Methods: Ethylidene-blocked 4-nitrophenylmaltoheptaoside (EPS-G7) is degraded to glucose and 4-nitrophenol in a coupled assay with a bacterial α-glucosidase under the following measurement conditions: 3.5 mmol/L EPS-G7, 7.1 kU/L α-glucosidase, 70 mmol/L sodium chloride, 1 mmol/L calcium chloride, 50 mmol/L HEPES, pH 7.15, at 37 °C. The increase of absorbance is continuously monitored for 3 min at 405 nm after a lag phase of 2 min. Results: Catalytic concentrations up to 15-fold higher than the upper reference limit can be determined without dilution. Precision studies in manual performance show CVs of 1.4–2.6% (within-run) and 1.9–2.8% (day-to-day). There was no interference from 100 mmol/L glucose, 30 mmol/L triacylglycerols, 610 μmol/L bilirubin, and 2.95 g/L hemoglobin. The method closely correlates with other chromogenic assays. The preliminary 0.95 reference interval for adults, not dependent on age and sex, is 33.6–96.2 U/L. Conclusion: The procedure is a robust adaptation of the reference method to routine use at 37 °C with increased sensitivity, fewer interferences, and reduced cost.

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Albumin and calcium reference interval using healthy individuals and a data-mining approach

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/0004563220944204 ◽

2020 ◽

Vol 57 (5) ◽

pp. 373-381 ◽

Cited By ~ 2

Author(s):

N Jassam ◽

A Luvai ◽

D Narayanan ◽

D Turnock ◽

G Lee ◽

...

Keyword(s):

Metrological Traceability ◽

Reference Interval ◽

Reference Population ◽

Reference Intervals ◽

Healthy Individuals ◽

Reference Limit ◽

Common Reference ◽

Age Related ◽

Upper Reference Limit ◽

Analytical Platforms

Background Harmonization of reference intervals for analytes that have a sound calibration and metrological traceability is a widely recommended practice. The UK Pathology Harmony has recently harmonized reference intervals for calcium and albumin. In this study, we have determined the reference intervals for calcium and albumin on the UK’s most commonly used analytical platforms. Method A prospective reference population of healthy individuals was recruited according to the IFCC CRIDL criteria. A second indirect population was collected from 14 primary care setting and measured in laboratories using various analytical platforms and methods (Roche, Abbott, Beckman and Siemens analytical platforms). Results In total, 299 subjects were recruited; the central 95th centile values for calcium for three out of four analytical platforms were in a close agreement with UK Pathology Harmony reference intervals of 2.2–2.6 mmol/L. Reference intervals of BCG methods from both cohorts and irrespective of analytical platforms were higher for both lower and upper reference limits than those for BCP. In comparison, the indirect study showed an age-related variation. The younger population reference intervals varied by up to 5.7% at the lower reference limit and up to 12% at the upper reference limit compared with Pathology Harmony reference intervals, and the older population showed a variation of up to 14% at both limits. Conclusion While calcium reference intervals can be a subject for harmonization, albumin reference intervals studied showed large variation which is unsupportive of embracing a common reference interval for albumin.

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Reference values of fecal calgranulin C (S100A12) in school aged children and adolescents

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2017-0152 ◽

2017 ◽

Vol 56 (1) ◽

Cited By ~ 5

Author(s):

Anke Heida ◽

Anneke C. Muller Kobold ◽

Lucie Wagenmakers ◽

Koos van de Belt ◽

Patrick F. van Rheenen

Keyword(s):

Characteristic Curve ◽

Reference Value ◽

Reference Interval ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Children ◽

Healthy Controls ◽

Reference Limit ◽

School Aged Children ◽

Activated Neutrophils ◽

Upper Reference Limit

AbstractBackground:Calgranulin C (S100A12) is an emerging marker of inflammation. It is exclusively released by activated neutrophils which makes this marker potentially more specific for inflammatory bowel disease (IBD) compared to established stool markers including calprotectin and lactoferrin. We aimed to establish a reference value for S100A12 in healthy children and investigated whether S100A12 levels can discriminate children with IBD from healthy controls.Methods:In a prospective community-based reference interval study we collected 122 stool samples from healthy children aged 5–19 years. Additionally, feces samples of 41 children with suspected IBD (who were later confirmed by endoscopy to have IBD) were collected. Levels of S100A12 were measured with a sandwich enzyme-linked immunosorbent assay (ELISA) (InflamarkResults:The upper reference limit in healthy children was 0.75 μg/g (90% confidence interval: 0.30–1.40). Median S100A12 levels were significantly higher in patients with IBD (8.00 μg/g [interquartile range (IQR) 2.5–11.6] compared to healthy controls [0.22 μg/g (IQR<0.22); p<0.001]). The best cutoff point based on receiver operating characteristic curve was 0.33 μg/g (sensitivity 93%; specificity 97%).Conclusions:Children and teenagers with newly diagnosed IBD have significantly higher S100A12 results compared to healthy individuals. We demonstrate that fecal S100A12 shows diagnostic promise under ideal testing conditions. Future studies need to address whether S100A12 can discriminate children with IBD from non-organic disease in a prospective cohort with chronic gastrointestinal complaints, and how S100A12 performs in comparison with established stool markers.

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Immunoassay for Quantifying Squamous Cell Carcinoma Antigen in Serum

Clinical Chemistry ◽

10.1373/clinchem.2010.143156 ◽

2010 ◽

Vol 56 (9) ◽

pp. 1496-1499 ◽

Cited By ~ 28

Author(s):

J Alan Erickson ◽

Jun Lu ◽

Jeffery J Smith ◽

Joshua A Bornhorst ◽

David G Grenache ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Reference Interval ◽

Microtiter Plate ◽

Squamous Cell Carcinoma Antigen ◽

Reference Limit ◽

Automated Assay ◽

The Us ◽

Upper Reference Limit

BACKGROUND Although the benefits of quantifying serum squamous cell carcinoma antigen (SCCa) have been reported, SCCa reagents were no longer available in the US by the late 1990s. Because SCCa quantification still has demonstrated clinical utility, we developed and validated a microtiter plate–based ELISA for measuring SCCa in serum. METHODS We coated microtiter strips overnight with capture anti-SCCa monoclonal antibody, washed the wells, added blocking buffer, and lyophilized the strips. For detection, we used a biotinylated anti-SCCa detection antibody, streptavidin/horseradish peroxidase conjugate, and tetramethylbenzidine/H2O2 substrate. A novel blocking reagent against human antimouse antibodies (HAMA) was evaluated. A reference interval was established with sera from healthy individuals and was confirmed in smokers. RESULTS The assay was linear to 40 μg/L SCCa (slope, 1.00; y intercept, 0.695; R2, 0.996) with a detection limit of 0.3 μg/L. The intraassay imprecision results [mean (CV)] were 2.5 μg/L (3.4%), 18.0 μg/L (3.0%), and 30.7 μg/L (2.4%); interassay imprecision results were 2.0 μg/L (9.9%), 20.0 μg/L (7.6%), and 36.3 μg/L (3.5%). A correlation analysis against an established automated assay generated a slope of 0.976 and a y intercept of −0.193 μg/L (r2 = 0.916). An upper reference limit of 2.1 μg/L SCCa was established at 95% confidence level, with no difference observed in smokers. No correlation between SCCa concentration and age was observed (r2 = 0.0003). At a blocking reagent concentration of 5 mg/L, HAMA interference was eliminated in 3 samples known to produce falsely increased SCCa results. CONCLUSIONS This SCCa ELISA demonstrates acceptable performance characteristics for quantifying serum SCCa and is effective in eliminating HAMA interference.

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Occurrence of hyperhomocysteinaemia in cardiovascular, haematology and nephrology patients: contribution of folate

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1258/0004563001899447 ◽

2000 ◽

Vol 37 (3) ◽

pp. 304-312

Author(s):

James G D Onnelly ◽

Phillip A Isotalo

Keyword(s):

Reference Interval ◽

Folate Deficiency ◽

Control Group ◽

Uraemic Patient ◽

Folate Supplementation ◽

Reference Limit ◽

Plasma Folate ◽

Metabolic Marker ◽

Patient Groups ◽

Upper Reference Limit

We investigated the contribution of plasma folate deficiency to hyperhomocysteinaemia in selected patient groups. Based on our observations, we have determined a lower folate reference interval cut-off using homocysteine as a metabolic marker of folate deficiency. Four hundred and twenty-five consecutive plasma specimens from cardiology ( n=120), haematology ( n=190) and nephrology ( n=115) patients were analysed for homocysteine and plasma folate concentrations. Healthy volunteers were used as controls ( n=117). We observed elevated homocysteine values above our upper reference limit of 13 µmol/L in 20·1%, 28·4% and 74·8% of the cardiology, haematology and nephrology patients, respectively. All but 1·9% of the patients had plasma folate values greater than the lower reference interval limit (3·4 nmol/L) for our folate assay. The percentage of patients from cardiology and haematology clinics who were hyperhomocysteinaemic and had folate values > 15 nmol/L was 5·0% and 4·2% , respectively. In contrast, 58% of our nephrology patients with folate values > 15 nmol/L were hyperhomocysteinaemic. In all three groups, an inverse relationship was found between folate and homocysteine. The folate/homocysteine ratios in the patient groups were approximately one-third of the values observed in our control group. Folate deficiency appears to be the primary cause of hyperhomocysteinaemia in our cardiology and thrombosis patients. However, severe folate deficiency appears to be uncommon. The majority of our nephrology patients are hyperhomocysteinaemic without an apparent folate deficiency. We conclude that raising the lower reference interval cut-off for folate to 15 nmol/L would help to identify individuals at risk for hyperhomocysteinaemia in our non-uraemic patient population. Increasing folate supplementation to maintain a plasma concentration above 15 nmol/L in cardiac, thrombosis and renal patients would greatly reduce the occurrence of hyperhomocysteinaemia in these patients.

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Evaluation of plasma N-terminal pro-B-type natriuretic peptide levels in healthy North American Salukis with normal echocardiographic measurements.

10.1101/2021.11.03.467139 ◽

2021 ◽

Author(s):

Tamilselvam Gunasekaran ◽

Christopher Brennan ◽

Robert Sanders

Keyword(s):

Body Weight ◽

Heart Disease ◽

Natriuretic Peptide ◽

Plasma Concentrations ◽

Clinical Use ◽

Reference Limit ◽

Cardiac Health ◽

Percentile Method ◽

Reference Limits ◽

Upper Reference Limit

Measurement of N‐terminal pro‐B‐type natriuretic peptide (NT-proBNP) levels has been shown to have clinical significance for diagnosis and management of heart disease in dogs. Evaluation of current reference limits for specific breeds is necessary to ensure the test can accurately distinguish between healthy and diseased animals. The objective of this study is to evaluate the adequacy of currently established NT-proBNP reference limits for clinical use in healthy Salukis. Cardiac health of 33 clinically healthy Salukis was evaluated via echocardiography using available breed standards. Plasma concentrations of NT-proBNP were measured using a commercially available assay. A one-sided 97.5% upper reference limit for the NT-proBNP concentrations was calculated using non-parametric percentile method. The 97.5% upper reference limit was 769 pmol/L (90% CI, 547-1214 pmol/L) for the study dogs. This upper reference limit was within the currently established non-breed specific NT-proBNP upper reference limit of 900 pmol/L. No relationship between sex, age, or body weight on plasma levels of NT-proBNP was noted. Results of this study supports the use of currently available non-breed specific NT-proBNP cut-off values for clinical evaluation of healthy Salukis.

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