Measurement of urinary 5-HIAA: correlation between spot versus 24-h urine collection

Background The 24-h urinary output of 5-hydroxyindoleacetic acid (5-HIAA) is used to monitor disease progression and treatment responses of neuroendocrine neoplasms (NENs). Several conditions are required for 5-HIAA assay, involving urine collection/preservation and food/drug restrictions. Aim To evaluate the correlation between 5-HIAA concentration in a spot urine sample and the output in a 24-h urine collection, and whether spot urine specimens can replace 24-h collection. Methods Patients with NENs or symptoms suggestive of NENs were asked to provide a separate spot urine at the end of the 24-h urine collection for 5-HIAA assessment. The upper reference limit for 24-h urinary 5-HIAA was 40 µmol/24 h. 5-HIAA measurements in spot urine samples were corrected for variation in urine flow rate by expressing results as a ratio to creatinine concentration. Results We included 136 paired urinary samples for 5-HIAA assessment from 111 patients (100 NENs). The correlation between 5-HIAA values measured in 24-h and spot urines was r = +0.863 (P < 0.001) and r = +0.840 (P < 0.001) including only NEN patients. Using the 24-h urinary 5-HIAA as reference method, the AUC on ROC analysis for spot urinary 5-HIAA was 0.948 (95% CI, 0.914–0.983; P < 0.001), attaining a sensitivity of 83% and specificity of 95% using 5.3 mol/mmol as cut-off for the spot urine. The AUC among NEN patients alone was 0.945 (95% CI, 0.904–0.987; P < 0.001). Conclusions The ratio of 5-HIAA to creatinine in a spot urine could replace the measurement of 5-HIAA output in a 24-h urine collection, especially for follow-up of patients with known elevated 5-HIAA levels.

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Neuroblastoma—When are Urinary Catecholamines and Their Metabolites ‘Normal’?

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456328802500604 ◽

1988 ◽

Vol 25 (6) ◽

pp. 620-626 ◽

Cited By ~ 5

Author(s):

D J Worthington ◽

E M Hammond ◽

B B Eldeeb ◽

A Green ◽

G M Addison ◽

...

Keyword(s):

Urinary Excretion ◽

The Other ◽

Published Data ◽

Single Test ◽

Creatinine Concentration ◽

Urinary Catecholamines ◽

Clinical Sensitivity ◽

Reference Limit ◽

Upper Reference Limit ◽

The Individual

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.

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Abstract 14870: Clinical Significance of Troponin Elevation in a Contemporary Hospitalized Population: Endotypes, Morbidity and In-hospital Mortality

Circulation ◽

10.1161/circ.142.suppl_3.14870 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Michael Briscoe ◽

Robert A Sykes ◽

Thomas Krysztofiak ◽

Kenneth Mangion ◽

Oliver H Peck ◽

...

Keyword(s):

Clinical Significance ◽

Myocardial Injury ◽

Troponin I ◽

Coronary Revascularization ◽

High Sensitivity ◽

Hospitalized Patients ◽

Troponin Elevation ◽

Reference Limit ◽

Upper Reference Limit

Introduction: Unplanned hospitalizations are commonly associated with a circulating troponin concentration >99 th percentile upper reference limit (URL). In order to better understand the clinical significance of troponin elevation, we evaluated outcomes in hospitalized patients according to cardiac endotype. Methods: We prospectively screened consecutive hospitalized patients with elevated high-sensitivity troponin-I (hs-TnI) concentrations (Abbott ARCHITECT troponin-I assay; sex-specific URL, 99 th centile: male: >34ng/L; female: >16ng/L) within a regional cardiac care network (population 650,000). A cardiology clinical team adjudicated individual patient records and assigned endotypes by consensus agreement according to the Fourth Universal Definition of Myocardial Infarction (MI). Endotypes were sub-classified into etiological category by inciting event(s). Characteristics and comorbidity were compared and outcomes recorded on virtual follow-up until June 2 nd 2020. Results: A total of 390 consecutive patients with ≥1 hs-TnI value >URL between March 1-April 15, 2020, were evaluated; 44 patients were excluded ( Duplicates: 2; Missing data: 41; Research patient: 1 ). Of 346 who qualified for inclusion, an index diagnosis of Type 1 MI (T1MI), T2MI and myocardial injury were assigned in 115 (33.2%), 79 (22.8%) and 152 (43.9%) patients, respectively. Compared with T1MI, patients with T2MI and myocardial injury had lower peak hs-TnI values (median [IQR]: 86 [250-697] vs 5020 [853-7774]ng/L; p< 0.01), lower estimated 10-year survival (40.2% vs 53.4%; p=0.002), less frequently underwent coronary revascularization (1.4% vs 45.2%; p<0.0005) and had longer inpatient stay (13.0 vs 6.1 days). Inpatient and overall mortality rates from admission to follow-up (median [range]: 71 [0-151] days) were higher among patients with T2MI and myocardial injury (19.9% vs 7.8%; p=0.004; and 26.0% vs 11.3%; Log rank (Mantel-Cox) X 2 = 1.927; p=0.003) independent of similar cardiovascular risk profiles. Conclusions: Despite lower peak circulating troponin concentrations, patients with T2MI and myocardial injury had higher inpatient mortality, lower estimated 10-year survival and longer in-hospital stay compared to those with T1MI.

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Comparison of serum and urinary 5-hydroxyindoleacetic acid as biomarker for neuroendocrine neoplasms

Journal of the Endocrine Society ◽

10.1210/jendso/bvab106 ◽

2021 ◽

Author(s):

Anna Becker ◽

Camilla Schalin-Jäntti ◽

Outi Itkonen

Keyword(s):

Roc Analysis ◽

Solid Phase ◽

Protein Precipitation ◽

University Hospital ◽

Neuroendocrine Neoplasms ◽

Specificity And Sensitivity ◽

Diagnostic Center ◽

Hydroxyindoleacetic Acid ◽

Tandem Mass Spectrometric

Abstract Context Patients with serotonin-secreting neuroendocrine neoplasms (NENs) have increased serum 5-hydroxyindoleacetic acid (5HIAA) concentrations. Serum 5HIAA thus serves as a biomarker in NEN. Objective To evaluate an improved tandem mass spectrometric serum 5HIAA assay for diagnosis and follow-up of NEN in a clinical cohort. Design A retrospective study during 2016 - 2018 at the Diagnostic Center and Department of Endocrinology at Helsinki University Hospital, Finland. Methods Detailed patient data was obtained from 116 patients. Serum 5HIAA was analyzed by two different LC-MS/MS assays with samples prepared either by protein precipitation (PP) or solid phase extraction (SPE). 24-h urine 5HIAA samples (n=33) were analyzed by amperometric LC and the results were compared. Specificity and sensitivity were calculated by receiver operating characteristic (ROC) analysis. Results We achieved 5-10 000 nmol/l linearity and ≤2.5% variation with our new serum 5HIAA assay. In ROC analysis the area under curve (AUC) was 85% by serum assays (URL value 123 nmol/l) and 88% by the 24-h urine 5HIAA assay (URL value of 47.1 µmol), respectively. A difference (p<0.001) between patients with active NEN and patients in remission was found by all 5HIAA assays. Conclusion Serum 5HIAA by LC-MS/MS after protein precipitation performs equally well for the diagnosis of NEN as urinary 5HIAA LC assay. The outcome and sensitivity for serum and 24-h urine assays are convergent. Due to much more reliable and convenient sampling we recommend serum instead of 24-h urine 5HIAA for diagnosis and follow-up of NEN patients.

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Estimated Daily Urine Volume and Solute Excretion from Spot Urine Samples to Guide the Therapy of Hyponatremia in SIADH

Journal of Clinical Medicine ◽

10.3390/jcm8101511 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1511 ◽

Cited By ~ 3

Author(s):

Decaux ◽

Musch

Keyword(s):

Urine Volume ◽

Urine Osmolality ◽

Urine Collection ◽

Water Restriction ◽

Spot Urine ◽

Inappropriate Secretion ◽

Spot Urine Sample ◽

Daily Urine ◽

Solute Excretion ◽

Normal Controls

Background: In hyponatremia, due to the inappropriate secretion of antidiuretic hormone (SIADH), a high versus low solute intake will affect the urine volume (UV) and, hence, the SNa level. The clinical implication of the fractional solute excretion is presented. Methods: In 35 normal controls and 24 patients with SIADH and urine osmolality higher than serum osmolality, we compared exact solute intake obtained from 24 h urine collection, with the estimated value obtained on a urine morning spot sample by the formula: eGFR (L/min) × Sosm × 1440 × FE.Osm (%) = mmol/24 h. The exact UV was compared with the estimated value given by the formula: eGFR × 1440 × S.Creat/U.Creat (for eGFR the MDRD was used). In 65 patients with chronic SIADH, from which a morning spot urine sample was available, we determined the estimated fluid and solute intake. Results: A good correlation was observed between the measured solute output or urine volume and the estimated values obtained from the controls (r = 0.86) as well as in SIADH (r = 0.91). Conclusion: Patients with low solute intake (FE.Osm <1.4%) and low diuresis (V/eCcr <0.8%) should increase their intake by taking oral urea, for example. Patients with high solute intake (FE.Osm >2.5%) and high diuresis (V/eCcr >1.5%) could usually be treated by mild water restriction (< 1.5–21/24 h).

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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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Comparison of calcium, magnesium, sodium, potassium, zinc, and creatinine concentration in 24-h and spot urine samples in women

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm.2009.039 ◽

2009 ◽

Vol 47 (2) ◽

Cited By ~ 19

Author(s):

Jasminka Z. Ilich ◽

Maja Blanuša ◽

Željka Crnčević Orlić ◽

Tatjana Orct ◽

Krista Kostial

Keyword(s):

Urine Sample ◽

Rank Order ◽

Essential Elements ◽

Urine Samples ◽

Emission Spectrometry ◽

Creatinine Concentration ◽

Spot Urine ◽

Flame Atomic Absorption ◽

Spot Urine Sample ◽

Calcium Magnesium

Abstract: The 24-h urine sample is considered as the most reliable material for testing many but not necessarily all constituents in urine. However, its collection is tedious for both patients and research participants. The aim of this study was to compare concentrations of essential elements calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), and zinc (Zn) in 24-h and spot urine samples.: Urine samples were collected from 143 generally healthy women, aged 30–79 years. Fasting spot urine was collected immediately after the end of the 24-h collection, therefore being of the same content as the first morning urine which ended the 24-h collection. Elements were analyzed by flame atomic absorption/emission spectrometry and expressed as mg/g and/or mmol/mol of creatinine (Cr). Spearman rank order correlations between 24-h and spot urine were carried out for each element. Ratios of elements in 24-h to spot urine samples were calculated to estimate the element-proportion of spot in the 24-h sample.: All coefficients of correlation between 24-h and spot urine of measured elements and Cr were significant (p<0.05): Zn (0.637), Mg (0.623), Ca (0.603), Na (0.452), K (0.396), and Cr (0.217). Ratios of 24-h to spot urine samples for each element (except K) were similar and close to 2, indicating uniform proportion of elements from spot urine sample in the 24-h sample. In addition, a high correlation between various pairs of elements was obtained in both 24-h and spot urine; the highest being between Na/Ca (0.435) and (0.578), respectively. This is in accordance with theoretical presumptions and previous findings regarding those relationships.: Although replacing burdensome 24-h urine collection with spot urine sampling might not provide the solution in all cases, our results show that for the elements analyzed, spot urine could be a reliable alternative.Clin Chem Lab Med 2009;47:216–21.

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Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma

Acta Endocrinologica ◽

10.1530/eje-09-0996 ◽

2010 ◽

Vol 162 (5) ◽

pp. 951-960 ◽

Cited By ~ 63

Author(s):

Eric Grouzmann ◽

Laurence Drouard-Troalen ◽

Eric Baudin ◽

Pierre-François Plouin ◽

Beat Muller ◽

...

Keyword(s):

Renal Insufficiency ◽

Case Control ◽

University Hospitals ◽

Retrospective Case ◽

Reference Limit ◽

Test Study ◽

Confirmation Test ◽

Upper Reference Limit ◽

Urinary Metanephrines

BackgroundPlasma free and urinary metanephrines are recognized biomarkers for the assessment of pheochromocytoma. Plasma total metanephrines with a long half-life may represent another useful biomarker.ObjectiveThe aim of this study is to evaluate the diagnostic performances of plasma total metanephrines alone or combined with free metanephrines and fractionated 24-h urinary metanephrines.MethodsA retrospective, case–control diagnostic test study was conducted between 1999 and 2007 in two university hospitals in Switzerland and two institutions in France. The patients included 46 cases with histologically proven pheochromocytoma, and 181 controls suspected of tumor with negative investigations and 3-year follow-up. None had renal dysfunction. Sensitivity and specificity were compared after expressing each measurement result as a ratio over its upper reference limit, adding the ratios of normetanephrine and metanephrine, and defining cut-off values of 1 or 2 for this sum.ResultsApplying a cut-off value of 1, plasma free and total metanephrines and urinary fractionated metanephrines had similar sensitivities of 96% (95% confidence interval, 86–99%), 95% (85–99%), and 95% (84–99%) along with similar specificities of 89% (83–94%), 91% (84–95%), and 86% (80–91%). A cut-off of 2 for the sum of ratios over reference limit improves the specificity, and it can be used for a confirmation test based on another biomarker taken among the three biomarkers.ConclusionAll three metanephrine-based tests perform equivalently for diagnosing pheochromocytoma in the absence of renal insufficiency, and can be conveniently associated two by two for confirming/excluding tumor.

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Serum calcitonin negative medullary thyroid carcinoma: a systematic review of the literature

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2015-0058 ◽

2015 ◽

Vol 53 (10) ◽

Cited By ~ 34

Author(s):

Pierpaolo Trimboli ◽

Luca Giovanella

Keyword(s):

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Clinical Approach ◽

Serum Calcitonin ◽

Medullary Thyroid ◽

Reference Limit ◽

Poorly Differentiated ◽

Laboratory Investigations ◽

Upper Reference Limit

AbstractGenerally, calcitonin (CT) values below the upper reference limit rule-out medullary thyroid carcinoma (MTC) with very high accuracy. However, sparse cases of serum-calcitonin-negative MTC (CT-NEG-MTC) have been reported. Here we reviewed CT-NEG-MTC reported in literature, discussed the potential causes and proposed a practical laboratory and clinical approach. A comprehensive literature search was conducted by using the terms “medullary thyroid carcinoma” AND “non-secreting calcitonin” OR “undetectable calcitonin”. The search was updated until December 2014. Original articles that described CT-NEG-MTC were eligible for inclusion. Only MTC cases with preoperative CT below the upper reference limit were included in the present review. Eleven papers with 18 CT-NEG-MTC cases (age 50 years, size 26 mm) were retrieved. Four patients with poorly differentiated MTC died within 3 years. Different CT assays were employed and different reference values were adopted. Preoperative serum CT values were below the institution cut-off levels in all cases, and undetectable in four patients. In some papers negative CT results were confirmed by additional tests. Further laboratory investigations were performed in some of the included studies. In patients with well founded suspicious of MTC and within the reference limits/undetectable CT other laboratory investigations [carcinoembryonic antigen (CEA), procalcitonin, CT stimulation, CT in washout of nodule’s aspiration] have to be performed. Surgical approach to CT-NEG-MTC does not differ from those secreting CT. Postoperative follow-up of these rare cases should include periodical imaging and measurement of all potential markers. Patients with poorly differentiated MTC are at higher risk of disease-related death, and require more aggressive follow-up strategy.

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Sensitive Assays for Urinary Retinol-Binding Protein and β-2-Glycoprotein-1 Based on Commercially Available Standards

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456329803500116 ◽

1998 ◽

Vol 35 (1) ◽

pp. 115-119 ◽

Cited By ~ 14

Author(s):

M Lapsley ◽

K Akers ◽

A G W Norden

Keyword(s):

Reference Range ◽

Binding Protein ◽

Healthy Adults ◽

Retinol Binding Protein ◽

Healthy Children ◽

Creatinine Concentration ◽

Reference Limit ◽

Renal Tubular ◽

Upper Reference Limit

Measurements of urinary retinol-binding protein (RBP) and β-2-glycoprotein-1 (β2G1) provide sensitive indicators of proximal renal tubular malfunction. β2G1 is very stable in urine but RBP, which is much less stable, has been more extensively studied. We have designed two similar immunoassays allowing measurement of both proteins from one urine dilution. The assays both use widely available commercial standards and permit accurate measurement throughout most of the reference range. We measured both proteins in the urine of 70 healthy adults and 80 healthy children aged between three and 16 years, expressing the results as a ratio to creatinine concentration. Using the 98th centile as the upper reference limit, adults excreted up to 17 μg/mmol RBP (median 8) and up to 30 μg/mmol β2G1 (median 15) with no difference between the sexes. Children had different ranges to adults with excretion of up to 22 μg/mmol RBP (median 10) and up to 80 μg/mmol β2G1 (median 24).

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A high rate of modestly elevated plasma normetanephrine in a population referred for suspected PPGL when measured in a seated position

Acta Endocrinologica ◽

10.1530/eje-19-0176 ◽

2019 ◽

Vol 181 (3) ◽

pp. 301-309 ◽

Cited By ~ 5

Author(s):

Jessica Boyd ◽

Alexander A Leung ◽

Hossein SM Sadrzadeh ◽

Christina Pamporaki ◽

Karel Pacak ◽

...

Keyword(s):

High Plasma ◽

False Positives ◽

High Rate ◽

Reference Laboratory ◽

Reference Limit ◽

Additional Testing ◽

Abnormal Rate ◽

Medical Population ◽

Upper Reference Limit

Objective Determine rate of high plasma normetanephrine or metanephrine (PNM-PMN) in a large sample of patients according to PNM-PMN posture and age-adjusted references. Design Retrospective re-analysis of PNM-PMN from a Canadian reference laboratory (n = 5452), 2011–2015; most were in seated position (n = 5112) rather than supine (n = 340). An international PPGL database demonstrated expected distribution of supine PNM-PMN in PPGL patients. Methods All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2× upper reference limit (URL) was considered likely true PPGL. Results 1–2× URL were uncertain, requiring additional testing/follow-up despite most being false positive given the rarity of PPGL. The rate of results in the 1–2× URL category were calculated for each group according to collection posture and differing published URL: seated, supine or supine age adjusted. Results When collected and interpreted by seated URL, 19.6% of PNM required additional testing; only 4.6% being >2× URL. For patients over age 50 years, the abnormal rate was 24.9%. When collected supine, interpreted by supine age-adjusted URL, only 5.3% of PNM were mildly elevated. Possible false positives may be even lower when considering PMN or plasma methoxytyramine which were commonly high in true PPGL despite mild PNM elevations. Conclusions In a general medical population, seated PNM has a high rate of abnormal results, far exceeding expected prevalence. Supine measurement with supine, age-adjusted interpretation is strongly preferred prior to costly or invasive PPGL investigations. Summary Review of 5452 plasma normetanephrine measurements showed 20% to be high, likely false positives for most. Supine, age-adjusted measures were half as likely to be elevated.

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