Clinical Chemistry and Laboratory Medicine (CCLM)

Published by De Gruyter

Volume 51 Issue 5 - Highlight: IFCC Scientific Division: An update of the ongoing activities

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)

Contents
Journal Overview

Masthead

Publicly Available May 1, 2013

Masthead

Page range: i-v

Download PDF

Editorial

Publicly Available February 22, 2013

Progress towards standardization: an IFCC Scientific Division Perspective

Philippe Gillery, Ian S. Young

Page range: 915-918

Download PDF

Review

Publicly Available November 23, 2012

Quantitative Clinical Chemistry Proteomics (qCCP) using mass spectrometry: general characteristics and application

Sylvain Lehmann, Andrew Hoofnagle, Denis Hochstrasser, Cato Brede, Matthias Glueckmann, José A. Cocho, Uta Ceglarek, Christof Lenz, Jérôme Vialaret, Alexander Scherl, Christophe Hirtz

Page range: 919-935

More Download PDF

Abstract

Proteomics studies typically aim to exhaustively detect peptides/proteins in a given biological sample. Over the past decade, the number of publications using proteomics methodologies has exploded. This was made possible due to the availability of high-quality genomic data and many technological advances in the fields of microfluidics and mass spectrometry. Proteomics in biomedical research was initially used in ‘functional’ studies for the identification of proteins involved in pathophysiological processes, complexes and networks. Improved sensitivity of instrumentation facilitated the analysis of even more complex sample types, including human biological fluids. It is at that point the field of clinical proteomics was born, and its fundamental aim was the discovery and (ideally) validation of biomarkers for the diagnosis, prognosis, or therapeutic monitoring of disease. Eventually, it was recognized that the technologies used in clinical proteomics studies [particularly liquid chromatography-tandem mass spectrometry (LC-MS/MS)] could represent an alternative to classical immunochemical assays. Prior to deploying MS in the measurement of peptides/proteins in the clinical laboratory, it seems likely that traditional proteomics workflows and data management systems will need to adapt to the clinical environment and meet in vitro diagnostic (IVD) regulatory constraints. This defines a new field, as reviewed in this article, that we have termed quantitative Clinical Chemistry Proteomics (qCCP).

Mini Reviews

Publicly Available October 2, 2012

Analytical goals for the determination of HbA₂

Andrea Mosca, Renata Paleari, Barbara Wild

Page range: 937-941

More Download PDF

Abstract

Background: We present a study aimed to define the analytical goals for the determination of hemoglobin A 2 , a minor hemoglobin present in human blood normally accounting from 2.5% to 3.3% of total hemoglobin, and typically increased up to 6%–7% in subjects carriers of β-thalassemia. Methods: The analytical goals have been derived using two approaches, the first one based on biologic variation, and the second one based on the opinion of experts. Results: The data obtained by studying 17 adult non-carrier healthy subjects, from whom we took blood samples every 2 weeks for 2.0 months, indicated a small intra-individual biologic variation (CV I of 0.7%), with respect to a larger between-subject variation (CV G of 7.7%). The minimum levels for imprecision, bias and total error derived from the analysis of these data were: 0.5%, 2.9% and 4.5%, respectively. The limits derived from the opinion of experts were based on a questionnaire with three clinical cases, which was circulated among two teams of international experts, and on a discussion about the clinical needs. The average total error derived from such surveys ranged between 7.0% and 9.5%. Conclusions: The various methods to derive analytical performance goals gave different limits, thus indicating the need for an increased communication between clinicians and laboratory professionals on this matter.

Publicly Available February 12, 2013

Glucose meters – fit for clinical purpose

Rosy Tirimacco, George Koumantakis, Rajiv Erasmus, Andrea Mosca, Sverre Sandberg, Ian D. Watson, Barbara Goldsmith, Philippe Gillery

Page range: 943-952

More Download PDF

Abstract

Glucose meters have improved considerably since they were first introduced in 1960, but many questions are being asked about their accuracy and reliability in certain clinical situations. These questions have arisen because of the widespread use of these meters into clinical areas they have not been designed for such as critical care. The lack of understanding by some health professionals on factors that affect glucose results, such as sample type, glucose test strip methodologic limitations, calibration to recognized reference methods, and interferences, leads to misleading results that may affect patient care. Much debate continues on the quality specifications for glucose meters. Because there is an extensive use of these meters in different clinical scenarios, the setting of quality specifications will remain a challenge for regulatory and professional organizations. In this article, we have attempted to collect and provide relevant information addressing the limitations above. Pivotal to obtaining the best quality of results is education, particularly for diabetic patients monitoring their glucose. The International Federation of Clinical Chemistry and Laboratory Medicine through its Point-of-Care Testing Task Force and its Working Group on Glucose Point-of-Care Testing is actively working toward improving the quality of glucose results by improving education and working with the industry to improve strip performance and work toward the better standardization of strips.

Opinion Papers

Publicly Available November 12, 2012

Metrological traceability – a concept for standardization in laboratory medicine

Lothar Siekmann

Page range: 953-957

More Download PDF

Abstract

The concept of measurement traceability provides the most important strategy in achieving standardization in laboratory medicine aimed at equivalent measurement results regardless of the principle of measurement, the method, the actual measurement procedure (test kit) and the laboratory where analyses are carried out.

Publicly Available January 4, 2013

Recommendations for clinical laboratory science reports regarding properties, units, and symbols: the NPU format¹⁾

Georges Férard, René Dybkaer

Page range: 959-966

More Download PDF

Abstract

The document describes the Nomenclature for Properties and Units (NPU) format developed by the joint committee on Nomenclature for Properties and Units of the IFCC and IUPAC. Basic concepts, in particular system, component, kind-of-property, and unit are defined. Generalities concerning quantities and units, and terminological rules are recalled. A constant format is structured for reporting clinical laboratory information. It is adapted for examinations, including measurements, performed in the clinical laboratories. The NPU format follows international recommendations. Using this format, more than 16 000 properties examined in the clinical laboratories have been described. A regularly updated version of the descriptions is available from the IFCC. Examples from different disciplines are given to promote the dissemination of the format. The object of the NPU format is the transfer of examination data without loss of accuracy between the laboratory personnel and the clinicians. The format is well-adapted for comparative and epidemiological studies.

Publicly Available October 6, 2012

“Good samples make good assays” – the problem of sourcing clinical samples for a standardization project

Sofie K. Van Houcke, Linda M. Thienpont

Page range: 967-972

More Download PDF

Abstract

Clinical samples are the cornerstone in all aspects related to in vitro diagnostic testing. They are particularly valuable in the process of establishing/validating metrological traceability, because they eliminate commutability issues potentially associated with artificial calibrators. Therefore, they are essential for IFCC standardization projects. However, sourcing clinical specimens is particularly challenging. It mostly turns out that only dedicated supply sources can accommodate the varying specifications within reasonable timelines. Here we describe the torturous experience in this regard of the IFCC Working Group for Standardization of Thyroid Function tests (since transformed into a Committee). We always focused on obtaining high quality samples in sufficient volume to serve all project participants. We applied a step-up approach: in phase I, we used high volume (200 mL of plasma/serum) single donations from apparently healthy individuals, and switched in phase II and III to medium-sized volume clinical samples (15–30 mL) from well-defined patient categories. In the first two phases we observed for some assays a sample-related discrepant analytical performance for total/free triiodothyronine and thyroid stimulating hormone (TSH), whereas in phase III we faced a severe delay in obtaining the relevant panels for free thyroxine (FT4) and TSH (n=90 and n=100, respectively). Additional experiments only allowed us to exclude hypothesized causes of the observations. We believe that there would be merit in a collaborative effort by chairholders of similar projects to establish a sample procurement infrastructure based on a solid relationship with commercial supply sources with the support of a significant number of committed clinicians.

Publicly Available March 23, 2013

Defining acceptable limits for the metrological traceability of specific measurands

Renze Bais, Dave Armbruster, Rob T. P. Jansen, George Klee, Mauro Panteghini, Joseph Passarelli, Ken A. Sikaris

Page range: 973-979

More Download PDF

Abstract

Although manufacturers are compelled by the European IVD Directive, 98/79/EC, to have traceability of the values assigned to their calibrators if suitable higher order reference materials and/or procedures are available, there is still no equivalence of results for many measurands determined in clinical laboratories. The adoption of assays with metrological traceable results will have a significant impact on laboratory medicine in that results will be equivalent across different laboratories and different analytical platforms. The IFCC WG on Allowable Errors for Traceable Results has been formed to define acceptable limits for metrological traceability chains for specific measurands in order to promote the equivalence of patient results. These limits are being developed based on biological variation for the specific measurands. Preliminary investigations have shown that for some measurands, it is possible for manufacturers to assign values to assay calibrators with a measurement uncertainty that allows the laboratory enough combined uncertainty for their routine measurements. However, for other measurands, e.g., plasma sodium, current assays are too imprecise to fulfil limits based on biological variation. Although an alternative approach based on probability theory is being investigated, the most desirable approach would be for industry to improve measurement methods so that they meet clinical requirements.

Original Articles

Publicly Available December 12, 2012

A reference system for urinary albumin: current status

John C. Lieske, Olga Bondar, W. Greg Miller, Lorin M. Bachmann, Andrew S. Narva, Yoshihisa Itoh, Ingrid Zegers, Heinz Schimmel, Karen Phinney, David M. Bunk

Page range: 981-989

More Download PDF

Abstract

Background: Increased urinary excretion of albumin reflects kidney damage and is a recognized risk factor for progression of renal and cardiovascular disease. Considerable inter-method differences have been reported for both albumin and creatinine measurement results, and therefore the albumin-to-creatinine ratio. Measurement accuracy is unknown and there are no independent reference measurement procedures for albumin and no reference materials for either measurand in urine. Methods: The National Kidney Disease Education Program (NKDEP) Laboratory Working Group and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) have initiated joint projects to facilitate standardization of urinary albumin and creatinine measurement. Results: A candidate LC-MS/MS reference measurement procedure for urinary albumin and candidate reference materials for urinary albumin and creatinine has been developed. The status of validations of these reference system components is reported. Conclusions: The development of certified reference materials and reference measurement procedures for urinary albumin will enable standardization of this important measurand.

Publicly Available December 8, 2012

Toward standardization of carbohydrate-deficient transferrin (CDT) measurements: III. Performance of native serum and serum spiked with disialotransferrin proves that harmonization of CDT assays is possible

Cas Weykamp, Jos P.M. Wielders, Anders Helander, Raymond F. Anton, Vincenza Bianchi, Jan-Olof Jeppsson, Carla Siebelder, John B. Whitfield, François Schellenberg

Page range: 991-996

More Download PDF

Abstract

Carbohydrate-deficient transferrin (CDT) is a generic term that refers to the transferrin glycoforms whose concentration in blood is temporarily increased by sustained alcohol consumption. Due to high clinical specificity, CDT was proposed as a biomarker of heavy alcohol use and has been available for about 20 years. A number of methods have been developed for CDT measurement based on different analytical techniques and principles and without any harmonization or calibration to a reference method. As a consequence, neither the reference limits nor the cut-off values have been similar across assays, hampering understanding of the diagnostic value of CDT and its routine use. This prompted the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) to initiate a Working Group on Standardization of CDT (WG-CDT). This third publication of the WG-CDT is devoted to testing the commutability of native and disialotransferrin-spiked serum panels as candidate secondary reference materials, in order to prove the harmonization potential of commercial CDT methods. The results showed that assay harmonization reduced the inter-laboratory imprecision in a network of reference laboratories running the HPLC candidate reference method. In the seven commercial methods evaluated in this study, the use of multi-level secondary calibrators of human serum origin significantly reduced the between-method imprecision. Thus, harmonization of CDT measurements by different methods can be achieved using this calibration system, opening the way for a full standardization of commercial methods against a reference method by use of certified reference materials.

Publicly Available January 18, 2013

External Quality Assessment Scheme for reference laboratories – review of 8 years’ experience

Anja Kessler, Lothar Siekmann, Cas Weykamp, Wolf Jochen Geilenkeuser, Orna Dreazen, Jonathan Middle, Gerhard Schumann

Page range: 997-1005

More Download PDF

Abstract

We describe an External Quality Assessment Scheme (EQAS) intended for reference (calibration) laboratories in laboratory medicine and supervised by the Scientific Division of the International Federation of Clinical Chemistry and Laboratory Medicine and the responsible Committee on Traceability in Laboratory Medicine. The official EQAS website, RELA (www.dgkl-rfb.de:81), is open to interested parties. Information on all requirements for participation and results of surveys are published annually. As an additional feature, the identity of every participant in relation to the respective results is disclosed. The results of various groups of measurands (metabolites and substrates, enzymes, electrolytes, glycated hemoglobins, proteins, hormones, thyroid hormones, therapeutic drugs) are discussed in detail. The RELA system supports reference measurement laboratories preparing for accreditation according to ISO 17025 and ISO 15195. Participation in a scheme such as RELA is one of the requirements for listing of the services of a calibration laboratory by the Joint Committee on Traceability in Laboratory Medicine.

Publicly Available May 1, 2013

Utility of a panel of sera for the alignment of test results in the worldwide multicenter study on reference values

Kiyoshi Ichihara, Yesim Ozarda, George Klee, Joely Straseski, Nikola Baumann, Kiyohide Ishikura

Page range: 1007-1025

More Download PDF

Abstract

Background: In a planned International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) worldwide study on reference intervals (RIs), a common panel of serum samples is to be measured by laboratories from different countries, and test results are to be compared through conversion using linear regression analysis. This report presents a validation study that was conducted in collaboration with four laboratories. Methods: A panel composed of 80 sera was prepared from healthy individuals, and 45 commonly tested analytes (general chemistry, tumor markers, and hormones) were measured on two occasions 1 week apart in each laboratory. Reduced major-axis linear regression was used to convert reference limits ( LL and UL ). Precision was expressed as a ratio of the standard error of converted LL or UL to the standard deviation (SD) comprising RI (approx. 1/4 of the RI width corresponding to between-individual SD). The allowable and optimal levels of error for the SD ratio (SDR) were set as ≤0.250 and ≤0.125, respectively, in analogy to the common method of setting limits for analytical bias based on between-individual SD. Results: The values for the calculated SDRs depended upon the distribution patterns of test results: skewness toward higher values makes SDR LL lower and SDR UL higher. However, the CV of the regression line slope, CV( b ), is less affected by skewness. The average of SDR LL and SDR UL (aveSDR) correlates closely with CV ( b ) (r=0.995). The aveSDRs of ≤0.25 and ≤0.125 corresponds approximately to CV ( b ) values of ≤11% and ≤5.5%, respectively. For all results (i.e., n=80), conversion was allowable (optimal) in 98% (89%) of the analytes, as judged by CV ( b ). Resampling studies using random subsets of data with a data size (n) of 70 to 20 revealed that SDRs and CV ( b ) gradually increase with reduction of n, especially with n ≤30. Conclusions: CV ( b ) is a robust estimator for judging the convertibility of reference values among laboratories, even with a skewed distribution. Assuming 40 sera to be a practical size for the panel, reference values of 89% (80%) of analytes examined were made comparable by regression analysis with the allowable (optimal) level of precision.

Publicly Available May 1, 2013

Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values

Yesim Ozarda, Kiyoshi Ichihara, Julian H. Barth, George Klee, and on behalf of the Committee on Reference Intervals and Decision Limits (C-RIDL), International Federation for Clinical Chemistry and Laboratory Medicine

Page range: 1027-1040

More Download PDF

Abstract

The reference intervals (RIs) given in laboratory reports have an important role in aiding clinicians in interpreting test results in reference to values of healthy populations. In this report, we present a proposed protocol and standard operating procedures (SOPs) for common use in conducting multicenter RI studies on a national or international scale. The protocols and consensus on their contents were refined through discussions in recent C-RIDL meetings. The protocol describes in detail (1) the scheme and organization of the study, (2) the target population, inclusion/exclusion criteria, ethnicity, and sample size, (3) health status questionnaire, (4) target analytes, (5) blood collection, (6) sample processing and storage, (7) assays, (8) cross-check testing, (9) ethics, (10) data analyses, and (11) reporting of results. In addition, the protocol proposes the common measurement of a panel of sera when no standard materials exist for harmonization of test results. It also describes the requirements of the central laboratory, including the method of cross-check testing between the central laboratory of each country and local laboratories. This protocol and the SOPs remain largely exploratory and may require a reevaluation from the practical point of view after their implementation in the ongoing worldwide study. The paper is mainly intended to be a basis for discussion in the scientific community.

Guidelines and Recommendations

Publicly Available April 2, 2012

2013 update on the worldwide standardization of the hemoglobin A_1c measurement

Ragnar Hanas, W. Garry John

Page range: 1041-1042

Download PDF

General Clinical Chemistry and Laboratory Medicine

October 19, 2012

Evacuated blood-collection tubes for haematological tests – a quality evaluation prior to their intended use for specimen collection

Nataša Gros

Page range: 1043-1051

Abstract

Background: An inappropriate anticoagulant concentration in a blood sample can cause cell shrinkage and affect the haematocrit and mean corpuscular volume (MCV). In evacuated blood-collection tubes there are two parameters affecting the quality of the product: the anticoagulant amount introduced into the tube during its production and the internal under-pressure at the instant of the blood-specimen collection affecting the draw-volume. No testing procedures that would give an insight into the anticoagulant concentration that can be expected for blood samples after specimen collection have been available up until now. Methods: The methodology suggested here combines the draw-volume test performed with deionised water using a laboratory made measuring device, and a conductivity measurement. The corrections taking into account the air pressure and ambient temperature provide an insight into the anticoagulant concentration that can be expected for blood samples. Results presented in the form of a nomogram facilitate the routine use of the suggested methodology. Results: Our 338-day study confirmed significant differences and variations in the quality and the anticoagulant concentrations of the K 3 EDTA and K 2 EDTA tubes of different producers and identified different examples of non-compliance with the norms during the shelf life of the tubes. Conclusions: The quality evaluation of the evacuated blood-collection tubes prior to their intended use as suggested here can, in everyday laboratory practice, ensure that the tubes are used only if, and only until, their quality is adequate.

October 19, 2012

Refrigeration is not necessary for measurement of uric acid in patients treated with rasburicase

Neal I. Lindeman, Stacy E.F. Melanson, Anne McDonnell, Daniel J. DeAngelo, Petr Jarolim

Page range: 1053-1057

Abstract

Background: Rasburicase, used for hyperuricemia of tumor lysis syndrome, retains activity at room temperature (RT) in in vitro studies. Cold-temperature handling is recommended for uric acid measurements in patients receiving rasburicase: collection in prechilled tubes, transportation on ice, and 4°C centrifugation. We performed a prospective study of these requirements. Methods: A total of 65 pairs of blood samples were collected from 34 patients, 12–24 h after receiving rasburicase. The effect of temperature on uric acid concentration was tested on paired samples handled either at RT or when cold: centrifugation (18 sample pairs), collection tube (14 pairs), transportation (24 pairs), and nine pairs were retested after 1 h at RT. Results: No significant temperature effect was seen on the uric acid measurements for any of the cold-handling steps: proportional, absolute biases were –1.4%, –0.06 mg/dL (centrifugation), –1.5%, +0.02 mg/dL (tube temperature), and –2.2%, –0.01 mg/dL (transportation). A 20% negative bias was seen in samples retested after 1 h at RT. Conclusions: Cold handling (prechilled tubes, iced transportation, 4°C centrifugation) was equivalent to RT for immediate measurement. An additional 1 h delay at RT led to a 20% decrease in uric acid. The cold handling measures required by the manufacturer are not necessary for uric acid testing of patients receiving rasburicase treatment, if testing is performed without delay.

October 16, 2012

Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis

Silvia Angeletti, Fabrizio Battistoni, Marta Fioravanti, Sergio Bernardini, Giordano Dicuonzo

Page range: 1059-1067

Abstract

Background: The early diagnosis of sepsis plays a central role in patient management. Many mediators to be the cause of sepsis have been proposed. In the present study the combined measurement of procalcitonin (PCT) and mid-regional pro-adrenomedullin (MR-proADM) and their appropriate cut-off values in sepsis patients were evaluated. Methods: PCT and MR-proADM were measured with commercially available immunoluminometric assays (Brahms, Hennigsdorf, Germany) in 200 septic patients, 90 patients with SIRS and 30 healthy individuals. Data were analyzed with ROC curve analysis and likelihood ratios with the MedCalc 11.6.1.0 package. Results: Healthy controls and non-infectious SIRS were clearly distinguished from sepsis patients using the following cut-off values: 0.30 ng/mL for PCT and 1 nmol/L for ADM. In the 200 septic patients the areas under the curve (AUCs) for PCT and MR-proADM were 0.921 and 0.977, respectively, with a statistically significant difference between the two areas of 0.0563 (p=0.0002). Gram-positive, Gram-negative, yeast and polymicrobial sepsis patients showed different geometric means of the two biomarkers: this difference was relevant in Gram-positive sepsis and in yeast sepsis, 0.0819 (p=0.0076) and 0.188 (p=0.0062), respectively. The combined use of PCT and MR-proADM gave a post-test probability of 0.998 in the cohort of all septic patients. By test combination the post-test probability changed from 0.803 to 0.957 in Gram-positive sepsis and from 0.928 to 0.995 in yeast sepsis. Conclusions: In conclusion, data from this study demonstrates that the combined use of PCT and MR-proADM, may substantially improve the early diagnosis of sepsis.

October 6, 2012

Cysteinyl leukotrienes in exhaled breath condensate of smoking asthmatics

Deniz Celik, Sibel Doruk, Handan Inonu Koseoglu, Semsettin Sahin, Serhat Celikel, Unal Erkorkmaz

Page range: 1069-1073

Abstract

Background: Cysteinyl leukotrienes (CysLTs) are among important inflammatory mediators in asthma pathogenesis. In this study, we aimed to determine leukotriene D 4 (LTD 4 ) and leukotriene E 4 (LTE 4 ) levels in exhaled breath condensate (EBC) in asthmatics and to evaluate the effect of smoking upon CysLTs levels and to speculate the importance of adding leukotriene receptor antagonists in smoking asthmatics. Methods: A total of 88 participants were included in the study. Of them, 59 were asthmatics; 30 of the 59 asthmatics were smokers (Group I) and the others were non-smokers (Group II). As a control group (Group III), 29 healthy non-smokers were enrolled. EBC samples were collected (EcoScreen, Jaeger, Hoechberg, Germany) and pulmonary function tests (PFTs) were performed in each case, and an asthma control questionnaire (ACQ) was completed by the asthmatics. LTD 4 and LTE 4 levels in EBC samples were analyzed by using ELISA. Results: LTD 4 levels were found to be higher in Group I than other groups and similar in Group II and Group III. LTE 4 levels were lower in Group III than other groups and similar in Group I and Group II. PFTs were different between Group I and Group III and there was a significant negative correlation between LTE 4 levels and forced expiratory volume in one second and forced vital capacity ratio in Group I. Conclusions: LTD 4 , but not LTE 4 , concentrations in EBC were higher in asthmatic smokers than asthmatic non-smokers. LTE 4 concentrations in EBC were higher in asthmatics than healthy non-smokers. In smoking asthmatics usage of agents that block the effects of LTD 4 can be beneficial; however, new clinical studies are required.

October 18, 2012

Helicobacter pylori serology in autoimmune diseases – fact or fiction?

Maya Ram, Ori Barzilai, Yinon Shapira, Juan-Manuel Anaya, Angela Tincani, Ljudmila Stojanovich, Stefano Bombardieri, Nicola Bizzaro, Shaye Kivity, Nancy Agmon Levin, Yehuda Shoenfeld

Page range: 1075-1082

Abstract

Background: The pathogenesis of autoimmunity is presumed to be a complex process including genetic predisposition, hormonal balance and environmental factors such as infectious agents . Helicobacter pylori , a common bacterial infectious agent has been associated with a variety of autoimmune disorders. However, this bacteria is also thought to play a protective role in the development of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and inflammatory bowel disease (IBD). We tested various links between anti- H. pylori (anti-HP) antibodies and a wide profile of autoimmune diseases and autoantibodies. Methods: A total of 1290 patients diagnosed with 14 different autoimmune diseases from two geographical areas (Europe and Latin America) and two groups of healthy matching controls (n=385) were screened for the presence of H. pylori IgG antibodies by “pylori detect” kit. In parallel, a large profile belonging to three groups of autoantibodies was tested in all sera (anti-nuclear antibodies, autoantibodies associated with thrombophilia and gastrointestinal diseases). Results: Our data demonstrate associations between anti-HP antibodies and anti-phospholipid syndrome, giant cell arteritis, systemic sclerosis and primary biliary cirrhosis. Our data also support a previously known negative association between the prevalence of anti-HP antibodies and IBD. Additionally, links were made between seropositivity to H. pylori and the presence of anti-nuclear antibodies, dsDNA, anti-Ro and some thrombophilia-associated antibodies, as well as negative associations with gastrointestinal-associated antibodies. Conclusions: Whether these links are epiphenomenal or H. pylori does play a causative role in the autoimmune diseases remains uncertain. The negative associations could possibly support the notion that in susceptible individuals infections may protect from the development of autoimmune diseases.

November 23, 2012

Serum DNase I activity in systemic lupus erythematosus: correlation with immunoserological markers, the disease activity and organ involvement

Dusan Skiljevic, Ivica Jeremic, Milos Nikolic, Sladjana Andrejevic, Mirjana Sefik-Bukilica, Biljana Stojimirovic, Branka Bonaci-Nikolic

Page range: 1083-1091

Abstract

Background : Decreased activity of serum desoxyribonuclease I (DNase I) in systemic lupus erythematosus (SLE) has been reported, but its role as a biomarker in SLE is still unelucidated. Methods : Seventy-seven SLE patients (aged 39.6±13.1 years) were studied for serum DNase I activity, levels of antinuclear (ANA), anti-dsDNA [high-avidity ELISA, conventional ELISA and indirect immunofluorescence (IIF)], anti-nucleosome, anti-histone antibodies, complement components C3 and C4. SLE disease activity was evaluated by disease activity index (SLEDAI-2K). Thirty-five patients were serologically and clinically followed for 3–12 months (mean 5.6±2.8). Thirty-seven healthy blood donors were the control group. Results : DNase I activity in SLE patients was lower than in healthy controls (p<0.01). DNase I activity was in positive correlation with SLEDAI-2K (p<0.01), levels of ANA, anti-dsDNA, anti-nucleosome and anti-histone antibodies (p<0.01) and in negative correlation with C3 concentration (p<0.05). The highest correlation was found between DNase I activity and anti-dsDNA concentrations determined by high-avidity ELISA (r=0.624), followed by IIF (r=0.541) and conventional ELISA (r=0.405). In the follow-up study, DNase I activity also correlated with SLEDAI-2K (p<0.01). SLE patients with low DNase I activity more frequently had SLE-specific cutaneous lesions (p<0.05). Conclusions : Monitoring of DNase I activity simultaneously with SLEDAI-2K might be a useful tool in the follow-up of SLE. An increase of DNase I activity characterized relapse in most SLE patients, although it did not reach the levels of healthy individuals. A decrease of DNase I activity in SLE flare-ups might be a functional biomarker of a subset of patients with specific dysfunction of apoptotic chromatin degradation.

November 23, 2012

Antibodies against Nε-homocysteinylated proteins in patients on different methods of renal replacement therapy

Marek Kolarz, Jolanta Małyszko, Tomasz Stompór, Alicja Całka, Anetta Undas, Michał Myśliwiec

Page range: 1093-1099

Abstract

Background: High levels of antibodies against Nε-homocysteinylated (Nε-Hcy) proteins have been observed in patients on long-term hemodialysis (HD). We sought to investigate whether these antibodies are present in patients on peritoneal dialysis (PD) in comparable titers and to characterize the factors that determine levels of those antibodies in both patient groups. Methods: The study involved 80 patients on HD and age- and sex-matched 75 subjects on PD. Serum IgG antibodies against Nε-Hcy-albumin and -hemoglobin were determined using in-house enzyme-linked immunosorbent assays. Total homocysteine (tHcy), folate, 8-isoprostaglandin F 2α (8-iso-PGF 2α ) and paraoxonase-1 (PON-1) activity were also measured. Results: Patients on PD and those on HD had similar levels of anti-Nε-Hcy-albumin [absorbancy at 490 nm: 0.571 (0.519–0.609) vs. 0.583 (0.523–0.625), p=0.41, respectively] and anti-Nε-Hcy-hemoglobin antibodies [0.659 (0.597–0.705) vs. 0.664 (0.597–0.722), p=0.60, respectively]. In both groups levels of the antibodies correlated with tHcy (r from 0.54 to 0.77, p<0.0001), 8-iso-PGF 2α (r from 0.57 to 0.77, p<0.0001), and folate (r from −0.59 to −0.74, p<0.0001) levels, but not with the cause of renal disease, dialysis vintage, a history of coronary artery disease or PON-1 activity. In the multivariate logistic regression, after adjustment for potential confounders, plasma tHcy was the independent predictor of antibodies against Nε-Hcy-proteins irrespective of the method of dialysis. Conclusions: Levels of antibodies against Nε-Hcy-proteins are similar in patients on long-term PD and HD. The level of tHcy is the only independent predictor of both antibodies irrespective of the dialysis method.

Reference Values and Biological Variations

November 23, 2012

Reference values for urinary neutrophil gelatinase-associated lipocalin (NGAL) in pediatric age measured with a fully automated chemiluminescent platform

Giuliana Cangemi, Simona Storti, Massimiliano Cantinotti, Antonio Fortunato, Michele Emdin, Matteo Bruschettini, Daniela Bugnone, Giovanni Melioli, Aldo Clerico

Page range: 1101-1105

Abstract

Background: Neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as the most promising biomarker of acute kidney injury. However, there are no reliable data on analytical sensitivity and reference limits of urinary NGAL (uNGAL) assay in pediatric age. The aim of the present study is to evaluate the analytical sensitivity and the reference range of uNGAL measured in urine specimens of pediatric age with the fully automated platform ARCHITECT ® i1000. Methods: A total of 333 urine samples were collected from 25 healthy newborns (16 males and 9 females; age 1–4 days) and 308 children (150 males and 147 females; mean age 80.7 months, range 0.63–248 months) and assayed for uNGAL by two different Italian centers (Department of Laboratory Medicine of the Fondazione Toscana G. Monasterio of Pisa and Massa and the Clinical Pathology Laboratory Unit of Istituto Giannina Gaslini of Genova). Results: The calculated limits of blank (LOB) and detection (LOD) values were 0.5 ng/mL and 0.95 ng/mL, respectively. The distribution of uNGAL values approximated a log-normal distribution (median 5.2 ng/mL, interquartile range 2.5–12.8 ng/mL, 99th percentile 117.6 ng/mL). uNGAL values of the 25 neonates were significantly higher than those of 308 children (neonates: mean 44.2 ng/mL, median 30.3 ng/mL, range 5.2–137.4 ng/mL; children: mean 10.2 ng/mL, median 4.6 ng/mL, range 0.2–146.7 ng/mL; p<0.0001). Conclusions: uNGAL assay shows a good analytical sensitivity and imprecision, which allows the measurement of uNGAL values around the cut-off value (i.e., 117.6 ng/mL) with an imprecision <5 CV%. The distribution of uNGAL values in pediatric age approximates a log-normal distribution, with values which are higher in neonates compared to children.

November 8, 2012

High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis

Enrico Rossi, Leon A. Adams, Helena L. Ching, Max Bulsara, Gerry C. MacQuillan, Gary P. Jeffrey

Page range: 1107-1114

Abstract

Background: Serum hyaluronic acid and biochemical models which require hyaluronic acid analysis are commonly used as predictors of liver fibrosis in patients with chronic liver disease, however biological variation data for hyaluronic acid are deficient. Methods: Four serial serum samples were obtained at weekly intervals from healthy volunteers and patients with chronic hepatitis B, chronic hepatitis C and non- alcoholic fatty liver disease (NAFLD; 20 in each group). The within-individual week-to-week variation (CV I ) and reference change values for hyaluronic acid, α 2 -macroglobulin and Hepascore were obtained. Hepascore is calculated from hyaluronic acid, α 2 -macroglobulin, bilirubin and γ-glutamyltransferase activity. Results: Hyaluronic acid displayed large within-individual variation, the CV I values were 62% in healthy subjects, 38% in hepatitis C, 37% in hepatitis B and 36% in NAFLD patients. Hepascore CV I s were 43% in healthy subjects, 24% in hepatitis C, 28% in hepatitis B and 39% in NAFLD patients. α 2 -Macroglobulin was much less variable with CV I s ranging from 4.4% to 7.6%. Bland-Altman plots of week-to-week variations showed rates of significant disagreement for samples collected in any 2 successive weeks varied from 5% in NAFLD patients to 8.3% in healthy subjects. Conclusions: When using non-fasting serum samples, hyaluronic acid and to a lesser extent, the Hepascore model display large within-individual variations in both health and chronic liver disease. This information is critical for interpreting the significance of both single measurements and changes in serial measurements.

Cardiovascular Diseases

September 19, 2012

Circulating matrix Gla protein: a potential tool to identify minor carotid stenosis with calcification in a risk population

Ciprian N. Silaghi, Daniela Fodor, Alexandra M. Crăciun

Page range: 1115-1123

Abstract

Background: Carotid calcification is an independent marker for future ischemic events, which are more frequently encountered in postmenopausal women as the prevalence of type 2 diabetes mellitus (T2DM) and hypertension (HT) increases. Matrix Gla protein (MGP) is a major inhibitor of vascular calcification. Here, we report on the prospect of serum MGP to become an identifying tool for minor carotid stenosis (minCAS) with calcification in a risk population. Methods: Based on carotid ultrasound examination, out of 72 enrolled postmenopausal women, 33 had minCAS with carotid calcification (minCAS group) and 39 were without minCAS and carotid calcification (non-minCAS group). Serum total MGP, high-sensitivity C-reactive protein (hs-CRP), bone mineral density (BMD) and carotid intima-media thickness (CIMT) were determined. Results: We found significantly elevated serum MGP levels in the minCAS compared to the non-minCAS group (p<0.05). MGP was independently associated with hs-CRP (unstandardized β-regression coefficient=2.6; 95% CI 0.007–5.3; p=0.049) and CIMT (β=–611.3; 95% CI –1172.6––49.9; p=0.034) within the minCAS group, but not with BMD. Furthermore, significantly higher MGP levels were determined in two minCAS subgroups (one with HT or T2DM and second with both diseases) compared to a non-minCAS subgroup with HT or T2DM (p<0.05 and p<0.01, respectively). A threshold of 87.9 μg/L serum MGP (area under the receiver operating characteristic=0.72±0.06; 95% CI 0.60–0.84; p=0.001) may identify minCAS with calcification in postmenopausal women with 63% precision. Conclusions: Higher circulating MGP levels could help identify minCAS with calcification in a relatively homogenous risk population (i.e., postmenopausal women), regardless of underlying cardiovascular risk factors.

November 23, 2012

Midregional pro-atrial natriuretic peptide in the general population/Insights from the Gutenberg Health Study

Stergios Tzikas, Till Keller, Philipp S. Wild, Andreas Schulz, Isabella Zwiener, Tanja Zeller, Renate B. Schnabel, Christoph Sinning, Edith Lubos, Jan Kunde, Thomas Münzel, Karl J. Lackner, Stefan Blankenberg

Page range: 1125-1133

Abstract

Background: The use of biomarkers is firmly established for the assessment of cardiovascular disease. Emerging biomarkers such as midregional pro-atrial natriuretic peptide (MR-proANP) challenge established markers regarding risk prediction and stratification ability. The aim of the present study was to describe the distribution of a contemporary MR-proANP assay in a large population-representative sample and to evaluate the association with prevalent cardiac diseases and cardiovascular risk factors. Methods: MR-proANP was determined by the use of a contemporary commercially available assay (BRAHMS GmbH, Hennigsdorf, Germany) in a representative sample of 5000 participants from the large population-based Gutenberg Health Study. N-terminal pro B-type natriuretic peptide (NT-proBNP) was used as a comparator. Results: Mean age was 55.5±10.9 years. Coronary artery disease (CAD) was documented in 4.6%, heart failure (HF) in 1.5% of the study participants. We observed a moderate to strong correlation of the biomarkers with age, diabetes, hypertension, smoking, renal function, prevalence of CAD and HF. Males showed lower MR-proANP concentrations than females. MR-proANP showed no relevant correlation with BMI (ρ=−0.030) and CRP (ρ=0.039). Reference limits for MR-proANP representing the 95th/97.5th/99th percentile were determined for healthy individuals with 116/132/169 pmol/mL. Conclusions: The current analysis in a large population-based sample elucidates the correlations and distribution of MR-proANP. Its concentration in healthy individuals depends on prevalent cardiovascular diseases and classical risk factors. The reported population-based reference values might be useful for distinguishing between healthy and diseased individuals, thus improving risk stratification and triaging in various clinical settings.

Letters to the Editor

December 25, 2012

Relationship between Helicobacter pylori infection and autoimmune disorders

Jannis Kountouras, Christos Zavos, Stergios A. Polyzos, Stavros Michael, Elena Tsiaousi, Elizabeth Vardaka, Panagiotis Katsinelos, George Kouklakis, Dimitrios Paikos, Emmanuel Gavalas, Georgia Deretzi, Evangelia Giartza-Taxidou, Efimia Loli

Page range: e73-e74

September 22, 2012

Rapid simultaneous genotyping of polymorphisms in ADH1B and ALDH2 using high resolution melting assay

Xiao-Wen Yuan, Wan-Jun Zhou, Xuan Shang, Liang Li, Yan-Hui Liu, Xiang-Min Xu

Page range: e75-e77

December 6, 2012

Comparison of biological specimens and DNA collection methods for PCR amplification and microarray analysis

Jasmine A. Rethmeyer, Xiaoyu Tan, Ann Manzardo, Stephen R. Schroeder, Merlin G. Butler

Page range: e79-e83

November 9, 2012

Transferrin/log(ferritin) ratio: a self-fulfilling prophecy when iron deficiency is defined by serum ferritin concentration

Changqing Ma, Ann M. Gronowski, Mitchell G. Scott

Page range: e85-e86

March 2, 2013

Response to: Transferrin/log(ferritin) ratio: a self-fulfilling prophecy when iron deficiency is defined by serum ferritin concentration

Rob Castel, Paul B. Berendes

Page range: e87-e88

November 9, 2012

Determinants of homocysteine concentrations in mother and neonatal girl pairs

Yui Sekitani, Naomi Hayashida, Toshiyuki Ikeoka, Atsushi Yoshida, Mio Nakazato, Mitsuhiro Wada, Akira Fujita, Atsushi Matsuo, Tsunetake Miyamura, Masahiko Obama, Kenichiro Nakashima, Takahiro Maeda, Hideaki Masuzaki, Noboru Takamura

Page range: e89-e92

October 12, 2012

Cysteine analog breaks cryoprecipitate associated with chronic hepatitis C

Toshio Okazaki, Kaoru Yamazaki, Tetsumi Iwasaki, Yoshifumi Kurosaki, Tetsuroh Okano, Mikio Taniguchi, Takahiro Fujioka

Page range: e93-e94

September 18, 2012

Cut-off values of serum growth hormone (GH) in pharmacological stimulation tests (PhT) evaluated in short-statured children using a chemiluminescent immunometric assay (ICMA) calibrated with the International Recombinant Human GH Standard 98/574

Eduardo Adrian Chaler, Gabriela Ballerini, Juan M. Lazzati, Mercedes Maceiras, Mauro Frusti, Ignacio Bergada, Marco A. Rivarola, Alicia Belgorosky, Gabriela Ropelato

Page range: e95-e97

December 6, 2012

Normalized MEDx chart as a useful tool for evaluation of analytical quality achievements. A picture is worth a thousand words

Vesna Supak Smolcic, Lidija Bilic-Zulle

Page range: e99-e101

November 12, 2012

Harmonization of immunoassays to the all-procedure trimmed mean – proof of concept by use of data from the insulin standardization project

Sofie K. Van Houcke, Stefan Van Aelst, Katleen Van Uytfanghe, Linda M. Thienpont

Page range: e103-e105

Congress Abstracts

Publicly Available May 1, 2013

Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias & International Meeting of Porphyria Patients: Personalized Medicine and Rare Diseases

Lucerne, May 16-18, 2013

Page range: eA1-eA64

Download PDF

About this journal

Objective
Clinical Chemistry and Laboratory Medicine (CCLM) publishes articles on novel teaching and training methods applicable to laboratory medicine. It is focused on basic and applied research and cutting-edge clinical laboratory medicine. CCLM is one of the leading journals in the field, with an impact factor over 8. All contributions submitted for publication in CCLM are single-blind peer reviewed by at least two experts in the field. CCLM is led by a multi-institutional editorial board. It is issued monthly, both in print and electronically. Letters to the Editor and Congress Abstracts are published online only.

Please submit your manuscript here

Topics

clinical biochemistry
clinical genomics and molecular biology
clinical haematology and coagulation
clinical immunology and autoimmunity
clinical microbiology
drug monitoring and analysis
evaluation of diagnostic biomarkers
disease-oriented topics (cardiovascular disease, cancer diagnostics, diabetes)
new reagents, instrumentation and technologies
new methodologies
reference materials and methods
reference values and decision limits
quality and safety in laboratory medicine
translational laboratory medicine
clinical metrology

Article formats
Research Articles, Reviews, Mini Reviews and Opinion Papers on all aspects of clinical chemistry and laboratory medicine, Guidelines and Recommendations, Point/Counterpoint Articles, Letters to the Editor, Editorials

For EFLM Academy Members

To take advantage of all the opportunities offered to members of the EFLM Academy, please access your personal area in the EFLM Academy at the link https://academy.eflm.eu/secretariat/login (if you do not remember your login details, you can use the option FORGOT PASSWORD). Click on the section “International Journals” on the left-hand side where you find CCLM as the first listed journal.

Volume 51 Issue 5 - Highlight: IFCC Scientific Division: An update of the ongoing activities

Issue of Clinical Chemistry and Laboratory Medicine (CCLM)

Masthead

Progress towards standardization: an IFCC Scientific Division Perspective

Quantitative Clinical Chemistry Proteomics (qCCP) using mass spectrometry: general characteristics and application

Abstract

Analytical goals for the determination of HbA2

Abstract

Glucose meters – fit for clinical purpose

Abstract

Metrological traceability – a concept for standardization in laboratory medicine

Abstract

Recommendations for clinical laboratory science reports regarding properties, units, and symbols: the NPU format1)

Abstract

“Good samples make good assays” – the problem of sourcing clinical samples for a standardization project

Abstract

Defining acceptable limits for the metrological traceability of specific measurands

Abstract

A reference system for urinary albumin: current status

Abstract

Toward standardization of carbohydrate-deficient transferrin (CDT) measurements: III. Performance of native serum and serum spiked with disialotransferrin proves that harmonization of CDT assays is possible

Abstract

External Quality Assessment Scheme for reference laboratories – review of 8 years’ experience

Abstract

Utility of a panel of sera for the alignment of test results in the worldwide multicenter study on reference values

Abstract

Protocol and standard operating procedures for common use in a worldwide multicenter study on reference values

Abstract

2013 update on the worldwide standardization of the hemoglobin A1c measurement

Evacuated blood-collection tubes for haematological tests – a quality evaluation prior to their intended use for specimen collection

Abstract

Refrigeration is not necessary for measurement of uric acid in patients treated with rasburicase

Abstract

Procalcitonin and mid-regional pro-adrenomedullin test combination in sepsis diagnosis

Abstract

Cysteinyl leukotrienes in exhaled breath condensate of smoking asthmatics

Abstract

Helicobacter pylori serology in autoimmune diseases – fact or fiction?

Abstract

Serum DNase I activity in systemic lupus erythematosus: correlation with immunoserological markers, the disease activity and organ involvement

Abstract

Antibodies against Nε-homocysteinylated proteins in patients on different methods of renal replacement therapy

Abstract

Reference values for urinary neutrophil gelatinase-associated lipocalin (NGAL) in pediatric age measured with a fully automated chemiluminescent platform

Abstract

High biological variation of serum hyaluronic acid and Hepascore, a biochemical marker model for the prediction of liver fibrosis

Abstract

Circulating matrix Gla protein: a potential tool to identify minor carotid stenosis with calcification in a risk population

Abstract

Midregional pro-atrial natriuretic peptide in the general population/Insights from the Gutenberg Health Study

Abstract

Relationship between Helicobacter pylori infection and autoimmune disorders

Rapid simultaneous genotyping of polymorphisms in ADH1B and ALDH2 using high resolution melting assay

Comparison of biological specimens and DNA collection methods for PCR amplification and microarray analysis

Transferrin/log(ferritin) ratio: a self-fulfilling prophecy when iron deficiency is defined by serum ferritin concentration

Response to: Transferrin/log(ferritin) ratio: a self-fulfilling prophecy when iron deficiency is defined by serum ferritin concentration

Determinants of homocysteine concentrations in mother and neonatal girl pairs

Cysteine analog breaks cryoprecipitate associated with chronic hepatitis C

Cut-off values of serum growth hormone (GH) in pharmacological stimulation tests (PhT) evaluated in short-statured children using a chemiluminescent immunometric assay (ICMA) calibrated with the International Recombinant Human GH Standard 98/574

Normalized MEDx chart as a useful tool for evaluation of analytical quality achievements. A picture is worth a thousand words

Harmonization of immunoassays to the all-procedure trimmed mean – proof of concept by use of data from the insulin standardization project

Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias & International Meeting of Porphyria Patients: Personalized Medicine and Rare Diseases

Lucerne, May 16-18, 2013

Analytical goals for the determination of HbA₂

Recommendations for clinical laboratory science reports regarding properties, units, and symbols: the NPU format¹⁾

2013 update on the worldwide standardization of the hemoglobin A_1c measurement