[DIAGNOSIS AND TREATMENT OF ELEVATED LIPOPROTEIN(A) IN ISRAEL: CONSENSUS STATEMENT FROM THE ISRAEL SOCIETY FOR RESEARCH, PREVENTION AND TREATMENT OF ATHEROSCLEROSIS AND ISRAEL SOCIETY FOR CLINICAL LABORATORY SCIENCES].

INTRODUCTION: Lipoprotein(a) [Lp(a)] is composed of 2 major protein components, a low-density lipoprotein (LDL) cholesterol-like particle containing apolipoprotein B (apo B) that is covalently bound to apolipoprotein(a). Its level is predominantly genetically determined, and it is estimated that 20% to 25% of the population have Lp(a) levels that are associated with increased cardiovascular risk. Elevated Lp(a) is related to increased vascular inflammation, calcification, atherogenesis and thrombosis, and is considered an independent and potentially causal risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis. Recent data demonstrate that Lp(a) testing has the potential to reclassify patients' risk and improve cardiovascular risk prediction, and therefore could inform clinical decision-making regarding risk management. Statins and ezetimibe are ineffective in lowering Lp(a) levels, whereas proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have a modest effect on Lp(a) reduction. Nevertheless, RNA interference-based therapies with potent Lp(a)-lowering effects are in advanced stages of development, and clinical trials are underway to confirm their benefit in reducing cardiovascular events. This scientific consensus document was developed by a committee that consisted of representatives from the Israeli Society for the Research, Prevention and Treatment of Atherosclerosis, and the Israeli Society for Clinical Laboratory Sciences, in order to create uniformity in Lp(a) measurement methods, indications for testing and reporting of the results, aiming to improve the diagnosis and management of elevated Lp(a) in clinical practice.

A new risk model to predict time to first treatment in chronic lymphocytic leukemia based on heavy chain immunoparesis and summated free light chain.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is frequently accompanied by immune dysregulation. AIMS: In this multicenter prospective study, we investigated whether heavy + light chains (HLC: IgGκ, IgGλ, IgAκ, IgAκ, IgMκ, IgMλ) and IgG subclasses (IgG1, IgG2, IgG3, and IgG4) could be used as novel prognostic markers of immunoparesis in 105 treatment-naïve patients with CLL. RESULTS: Heavy + light chains immunoparesis of ≥1, ≥2, and ≥3 isotypes was evident in 74 (70%), 58 (55%), and 36 (34%) patients, respectively. Severe HLC immunoparesis was identified in 40 (38%) patients. Of the IgG subclasses, IgG1 and IgG2 were most frequently suppressed, affecting 46 (44%) and 36 (34%) patients, respectively; 63 (60%) patients had low levels of at least one IgG subclass. In multivariate analysis, severe HLC immunoparesis (hazard ratio [HR]: 36.5; P = .010) and ΣFLC ≥ 70 mg/L (HR: 13.2; P = .004) were the only factors independently associated with time to first treatment (TTFT). A risk model including these variables identified patients with 0, 1, and 2 risk factors and significantly different TTFT (P < .001). Patients with two factors represented an ultra-high-risk group with a median TTFT of only 1.3 months. CONCLUSION: The above findings demonstrate the potential for the use of HLC immunoparesis, together with sFLC measurements, as future prognostic biomarkers in CLL.

Anemia and estimated glomerular filtration rates.

OBJECTIVE: To determine the relationship between the estimated glomerular filtration rate (eGFR) and the prevalence of anemia that has potential implications for reporting results of the eGFR. METHODS: Serum creatinine and hemoglobin test results from 18,474 outpatients aged 50 years or older were reviewed. We calculated the eGFR using the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) and the Modification of Diet in Renal Disease equation (MDRD) and determined the odds of anemia (according to the World Health Organization definition) at various eGFR levels, adjusted for age and gender. RESULTS: The lowest proportion of anemia was observed in those with an eGFR of 80-89 mL/min per 1.73 m(2) and 90-99 mL/min per 1.73 m(2) (MDRD and CKD-EPI respectively), with an increasing prevalence of anemia in those with either an eGFR of 60-69 mL/min per 1.73 m(2) or 100-109 mL/min per 1.73 m(2) calculated by either equation (p<0.05) with a dose-response effect. CONCLUSIONS: We found a U-shaped relationship between anemia and the eGFR, suggesting that values >60 mL per 1.73 m(2) should be reported. However, the clinical utility and potential side effects of reporting such values need to be determined. Also, these preliminary findings require confirmation by studies in other settings.

Significant, quantifiable differences exist between IgG subclass standards WHO67/97 and ERM-DA470k and can result in different interpretation of results.

OBJECTIVES: Accurate measurement of IgG subclass (IgGSc) levels are essential to aid in the diagnosis of disease states such as primary immunodeficiencies. However, there is no single standardisation of nephelometric and turbidimetric assays for these analytes and two reference materials have been utilised. We expand on previous reports and present data from a multi-site analysis that both identifies and quantitatively defines the differences in calibration resulting from the use of different reference materials. DESIGN AND METHODS: IgGSc antibodies in the serum specimens and reference materials were measured according to the manufacturers' instructions using commercially available IgGSc assays or components. RESULTS: Data from four independent sites showed that in spite of the different commercial suppliers of IgGSc assays calibrating to different reference materials, ERM-DA470k and WHO67 /97, the resulting calibrations were comparable for IgG1 and IgG2. However, for IgG3 and IgG4 the calibrations were significantly different. The use of assay specific normal ranges should compensate for these calibration differences, however, the two manufacturers' assays can give differing clinical classifications. The agreement between the different manufacturers' IgGSc assays was between 85.1% and 95.8% for all IgGSc assays, the discordance of sample classification for IgG1 and IgG2 assays was approximately 12% and 15% respectively, whilst that for IgG3 and IgG4 was 4% and 13% respectively. CONCLUSION: We discuss the similarities and differences between assays that utilise the different reference materials.

Incidental findings of variant hemoglobin during hemoglobin A(1c) testing.

A variant hemoglobin fraction may be an incidental finding during HbA(1c) analysis using the G8 Tosoh HPLC analyzer, but it is unclear if the retention times and fraction patterns can reliably predict the findings of a high-performance liquid chromatography (HPLC) ß-thalassemia program (Bio Rad Variant II analyzer). We chose 100 samples sent for HbA(1c) determinations (G8 Tosoh) with an incidental finding of variant hemoglobin and did a reflex test using the Bio Rad Variant II analyzer (ß-thalassemia program). Two observers attempted to predict the results with that analyzer from fraction patterns and retention times of the hemoglobin variants detected with the G8. They independently identified all hemoglobin variants (HbS, Hb Setif, HbC, and HbD) by their patterns and retention times. We conclude that HPLC confirmation of certain variant hemoglobin fractions found incidentally during HbA(1c) testing on the G8 Tosoh is not necessary.

A novel algorithm for the diagnosis of celiac disease and a comprehensive review of celiac disease diagnostics.

There is an urgent clinical need for a better laboratory celiac disease diagnosis with both less false positive results and minimal underdetection. The aim of the present study was to evaluate the performance and diagnostic accuracy of different assays in an outpatient population setting for the diagnosis for celiac disease (CD) in order to design an optimal algorithm. We used 15 different ELISA assays to assess 47 blood samples of newly diagnosed children (positive biopsy results) and 52 samples from age- and sex-matched children with negative biopsy results for CD. Scoring criteria were established for grading the assays performance and characteristics. The combined gliadin and tTG assays exhibited the best sensitivity (100%). The addition of other assays to the CeliCheck neo-epitopes assay improved specificity so that the final algorithm had 100% sensitivity, 96.2% specificity, and 98.1% accuracy. The clinical demand for both maximal sensitivity and maximal specificity cannot be achieved with a single test. Using a combination of a sensitive assay together with specific assays improved celiac disease detection rates, with an acceptable number of false positive results. This model, however, needs to be confirmed prospectively in both children and adults.

A new algorithm for the diagnosis of celiac disease.

Celiac disease (CD) affects at least 1% of the Western population but remains largely unrecognized. In our laboratory, we utilize a novel algorithm to diagnose pediatric CD that offers both high sensitivity and high specificity for diagnosis in an outpatient setting. The aim of the present study was to challenge this algorithm and to test its performance in children and adults suspected of having CD. Using a three-assay algorithm, screening with the most sensitive tissue transglutaminase (tTG) complexed with deamidated gliadin peptide neoepitope immunoglobulin A (IgA)+IgG assay and confirming with the two specific tTG IgA and tTG IgA+IgG assays, we examined the serological results from 112 children aged 0-17 years old and 60 adults in comparison to their respective biopsy results. The algorithm performance was calculated by statistical analysis. The use of the new algorithm enabled us to diagnose CD with 98% sensitivity, 93% specificity and 95% accuracy in the pediatric group and 94% sensitivity, 92% specificity and 93% accuracy in the total population studied. The false-negative cases in the adult group were attributed to previous adherence to a gluten-free diet, and the single false-negative result in a young child became a true positive after 6 months. We have also monitored three celiac patients before and after diagnosis and found that the algorithm may be suitable for disease monitoring. The newly proposed three-assay algorithm for celiac detection is very reliable in both children and adults. Due to the high performance of this assay, the further need for confirmatory intestinal biopsies will be reassessed.

Is the association between Helicobacter pylori infection and anemia age dependent?

BACKGROUND: The relationship between H. pylori infection and anemia in childhood is still unclear. The aim of the study was to examine the association between H. pylori infection and anemia or iron deficiency in school-age children and in infants. MATERIALS AND METHODS: Six- to 9-year-old Israeli Arab children (N = 202) and infants (N = 197) were examined for hemoglobin and ferritin levels. ELISA was used to detect H. pylori antigens in stool specimens collected from the participants. Household characteristics were obtained through personal interviews with the mothers. RESULTS: The prevalence of anemia was 15.5 versus 5.5% in H. pylori-positive and -negative school-age children, respectively and 34.5 versus 29.8% in H. pylori-positive and -negative infants, respectively. The Mantel-Haenszel age-adjusted prevalence ratio (PR) and 95% confidence intervals (CIs) were 1.6 (95%CI 1.0, 2.6). In multivariate analysis controlling for socioeconomic variables, H. pylori infection was associated with 2.8 higher prevalence of anemia only in school-age children: adjusted PR 2.8 (95% CI 0.9, 9.3). The adjusted mean difference in hemoglobin levels between H. pylori infected school-age children and uninfected ones was -0.372 gr/dL (95% CI -0.704, -0.039) (p = .04). The respective mean ferritin difference was -6.74 µg/L (95% CI -13.38, -.011) (p = .04). Such differences were not found in infants. CONCLUSIONS: H. pylori infection is associated with higher prevalence of anemia in school-age children independently of socioeconomic variables. Such association was not observed in infants. These findings are of clinical and public health importance.