Simona Ferraro

Hyperuricemia as risk factor for coronary heart disease incidence and mortality in the general population: a systematic review and meta-analysis

Abstract Previous meta-analyses reported no significant or weak association between hyperuricemia (HU) and coronary heart disease (CHD). We updated the literature search, systematically reviewing retrieved papers. The peer-reviewed literature published from 1965 to December 2014 was searched using Medline and Embase. We included prospective cohort studies involving adults (sample size ≥100) with no cardiovascular disease (CVD) and a follow-up of at least 1 year. Studies were excluded if they considered as outcome the CVD incidence/mortality without separately reporting data on CHD, did not adjusted for major confounders and if the 95% confidence interval (CI) for risk ratio (RR) was not available. Relative risk or hazard ratio estimates, with the corresponding CIs, were obtained. For CHD incidence 12 populations were included (457,915 subjects [53.7% males]). For CHD mortality seven populations were included (237,433 subjects [66.3% males]). The overall combined RR were 1.206 (CI 1.066–1.364, p=0.003) for CHD incidence and 1.209 (CI 1.003–1.457, p=0.047) for CHD mortality, respectively. Subgroup analysis showed a marginal (incidence) and not significant (mortality) association between HU and CHD in men, but an increased risk for CHD incidence and mortality in hyperuricemic women (RR 1.446, CI 1.323–1.581, p<0.0001, and RR 1.830, CI 1.066–3.139, p=0.028, respectively). The risk markedly increases for urate concentrations >7.0 mg/dL. HU appears to increase the risk of CHD events in the general population, mainly in adult women. This finding requires, however, further investigation.

Biological variation of neuroendocrine tumor markers chromogranin A and neuron-specific enolase

OBJECTIVES Chromogranin A (CgA) and neuron-specific enolase (NSE) are biomarkers for neuroendocrine tumors. Although the knowledge of their biological variation (BV) is critical, only one study for CgA and no data for NSE are available. We report a definitive assessment of BV components of these biomarkers in the same cohort of subjects by an accurately experimental protocol. DESIGN AND METHODS We collected five blood specimens from each of 22 healthy volunteers (10 men and 12 women, 23-54 years) on the same day every two weeks for two months. Serum specimens were stored at -80 °C until analysis and analyzed in a single run in duplicate. Data were analyzed by ANOVA. RESULTS Serum CgA concentrations were significantly higher for women than for men (P=0.01), whereas no difference was found for NSE. Intra-individual variance was not different between genders for both biomarkers. Within- and between-subject CVs were 16.3% and 33.5% for CgA and 13.6% and 11.5% for NSE, respectively. CgA showed marked individuality, suggesting that the use of population-based reference limits is inadequate for its interpretation. Conversely, the low individuality of NSE allows the use of a single reference interval. Reference change values were 46% for CgA and 39% for NSE. Desirable analytical goals for imprecision, bias, and total error were <8.2%, ±9.3%, and ±22.8% for CgA, and <6.8%, ±4.5%, and ±15.7% for NSE, respectively. CONCLUSION In this study, we defined BV components of serum CgA and NSE and derived indices that may improve the clinical use of these biomarkers.

Revaluating serum ferritin as a marker of body iron stores in the traceability era.

Abstract Serum ferritin is used for diagnosing iron-related disorders. However, most studies validating this application were performed before the introduction of the 2nd and 3rd WHO International Standards (ISs) to harmonize assay results. We revised the available literature to evaluate if consolidated clinical applications of ferritin and recommended cut-offs have been validated using ISs calibrated assays. All Medline retrieved reviews and individual studies performed since ISs availability were selected and analyzed according to predefined criteria. Concerning ferritin and iron deficiency (ID), only one review, including studies published before 1988, met established criteria. Results showed that ferritin can effectively rule out ID anemia in patients with or without inflammatory disease at cut-offs of 70 and 40 μg/L, respectively. From two studies using ISs calibrated assays that met inclusion criteria, no information emerged on which cut-off should be employed to obtain similar sensitivity. Regarding iron overload, even when the framework was restricted to hereditary hemochromatosis, no synthesis of scientific evidence, if any, about diagnostic accuracy of ferritin was available both before and after ISs introduction. Available evidence of the ferritin diagnostic effectiveness is limited to ID conditions. Recommended cut-offs for this application are, however, based on studies published from 1970 to the 1980s using non-harmonized assays.

Prognostic value of cystatin C in acute coronary syndromes: enhancer of atherosclerosis and promising therapeutic target.

Abstract Background: Cystatin C (CC) has been proposed to play a role in atherosclerosis. We aimed to review the prognostic value of CC serum/plasma levels in patients with acute coronary syndromes (ACS). Methods: Fifteen observational longitudinal studies were selected by Medline. Results: Increased CC over threshold values ranging from 0.93 to 1.3 mg/L were prognostic for death (hazard ratio; HR: 2.04–3.6) and for the occurrence of any fatal and non-fatal cardiovascular events (HR: 1.7–9.6) for patients with either ACS only or coronary heart disease and prevalent ACS. Only one study showed an increased risk for future myocardial infarction (MI) in patients with marker levels higher than 1.0 mg/L. Three studies reported the risk associated with a change of one unit of CC for long-term death (HR ranging from 1.9 to 6.3) and for the composite end point of 1 year MI and death (HR 2.15). Some studies showed the additional prognostic value contributed from CC measurements to other markers and to conventional risk scores. Conclusion: Despite low to moderate evidence, there is a general agreement on the significant prognostic value of CC in ACS that might encourage further research focused on risk assessment for patients with MI.

Laboratory medicine in the new healthcare environment

Abstract The 21st century challenge is to redesign healthcare systems to be safe, efficient, effective, timely, equitable and patient-centred. Although laboratory medicine is integral to many of these objectives involving prevention, diagnosis, treatment, and managing disease of patients, it suffers from poor visibility as a medical discipline and as a profession and fewer rewards for educational efforts when compared to other medical disciplines. Laboratory scientists are often perceived as managing machinery and equipment, but conversely they need to take a position of shared clinical leadership, showing the role of laboratory tests to guarantee optimal care for patients. This is however challenging because of some reluctance by laboratory professionals to involve themselves in test structuring and requesting and in the inspection of work as it arrives because it is assumed that all requests are clinically necessary; there is a poor communication and integration between clinical wards and laboratory; and, importantly, there is the need for an excellent cultural and scientific background of laboratory professionals for implementing outcome research and to act as knowledge managers and skilled clinical consultants. By combining the unique talent of performing quality laboratory assays with knowledge of the pathophysiologic rationale behind the tests, laboratory professionals have the expertise to advise their clinical colleagues in regard to the appropriate test selection and interpretation of laboratory results, thereby creating opportunities to define the added value and the pivotal role of laboratory medicine on healthcare delivery.

Human epididymis protein 4: factors of variation.

BACKGROUND Amongst the newly proposed biomarkers for ovarian cancer, serum human epididymis protein 4 (HE4) shows the greatest potential for clinical use. However, systematic appraisals of its biological characteristics are not available. This study sought to critically revise the available literature on biological and lifestyle factors affecting HE4 concentrations in serum to understand their possible influence on the marker interpretation. METHODS A literature search was undertaken on electronic databases and references from retrieved articles. Article results were analyzed by evaluating study design, sample size, statistical approach, employed assay and, when available, by collecting similar information for carbohydrate antigen 125 (CA-125). RESULTS Several factors may influence serum HE4 concentrations. In contrast to CA-125, higher HE4 concentrations are reported in the elderly. Although no variations in HE4 concentrations can be clearly associated to menopausal status, a strong difference in biomarker biological intra-individual variation according to the fertility status is reported. Smoking and renal function can also significantly influence HE4 results. CONCLUSION The knowledge of factors influencing HE4 concentrations is relevant to promote more adequate interpretative criteria for use of this biomarker in the clinical setting.

The importance of individual biology in the clinical use of serum biomarkers for ovarian cancer

Abstract Background: An increased focus on the biological behaviour of serum biomarkers for ovarian cancer, i.e., carbohydrate antigen 125 (CA-125) and human epididymis protein 4 (HE4), has been advocated to improve their clinical use. Due to the paucity and poor design of available studies evaluating biological variation (BV) of CA-125 and the lack of BV data for HE4, in this study we evaluated BV of both biomarkers. Methods: Monthly we obtained serum samples from 14 pre- (PreM) and 14 post-menopausal (PostM) healthy women for 4 consecutive months. Once all samples were available, they were analysed in a single run in duplicate for CA-125 and HE4 on Roche Modular system. Data were analysed by ANOVA. Results: For both biomarkers no difference in median concentrations was found between PreM and PostM. For CA-125 the intra-individual CV (CVI) was not different between groups (9.1% in both). For HE4 CVI was higher in PreM (12.1%) than in PostM (6.5%) (p<0.001). Between-subject CVs were 10.6% for CA-125 and 16.4% for HE4, with no influence by the fertility status. Both biomarkers showed high individuality meaning that the use of population-based reference limits may have limited value for their interpretation. Reference change values were 26% for CA-125 (all), 34% for HE4 PreM and 18% for HE4 PostM. Conclusions: Monitoring longitudinal changes in serum concentrations of ovarian cancer biomarkers over time is probably better than using single threshold rules. According to differences in BV due to the hormonal status, one should differently interpret HE4 changes in PreM and PostM.

Inside ST-elevation myocardial infarction by monitoring concentrations of cardiovascular risk biomarkers in blood.

BACKGROUND No information is available on the optimal sampling time to catch the highest increase for biomarkers whose elevation after ST-elevation myocardial infarction (STEMI) is prognostic for adverse events. This study aimed to investigate release kinetics and peak times of cardiac troponin I (cTnI), C-reactive protein (CRP), B-type natriuretic peptide (BNP), chromogranin A (CgA) and cystatin C (CyC) in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). METHODS Blood concentrations of cTnI, CRP, BNP, CgA and CyC were measured before and 6 h, 24 h, and 48 h after PPCI in 84 STEMI patients. The averaged trajectory of marker kinetics was estimated by multivariable regression models adjusted for patient characteristics and orthogonal polynomials were used to describe related releases. RESULTS From the estimated kinetics cTnI peaked at 10 h from symptoms, BNP at 28 h and CRP within 30 h. CyC concentrations did not change, whereas CgA concentrations increased from 6 to 48 h after PPCI. The amount of BNP release was found to be affected by the interaction between gender and age: females<75 years had BNP concentrations fourfold higher than males. CONCLUSIONS According to different release kinetics a single blood sampling for measuring all biomarkers is not recommended.

Is serum human epididymis protein 4 ready for prime time

The National Institute for Health and Clinical Excellence (NICE) guidelines have sparked hot debate regarding the role of carbohydrate antigen 125 (CA-125) for ovarian cancer (OC) detection. Recent literature and evidence calls into question the use of CA-125 in diagnostic algorithms, given the better performance of human epididymis protein 4 (HE4) vs. CA-125 to rule OC. This is an important consideration since combined measurements are not cost-effective. The quality of this evidence is, however, threatened by important gaps related to study design, enrolled populations and analytical issues. For instance, despite the clinical need to prioritize the evaluation of biomarker performance in early stage tumours, sound evidence on this cannot be provided. In addition, results should be cautiously interpreted due to wide differences in the type of employed assays and in adopted diagnostic thresholds for HE4. Comparability among results obtained by different commercially available HE4 assays, together with an objective establishment of analytical goals is essential for the optimal clinical application of this marker.

The role of laboratory in ensuring appropriate test requests

This review highlights the role of laboratory professionals and the strategies to be promoted in strict cooperation with clinicians for auditing, monitoring and improving the appropriateness of test request. The introduction of local pathways and care maps in agreement with international and national guidelines as well as the implementation of reflex testing and algorithms have a central role in guiding test request and in correcting the overuse/misuse of tests. Furthermore, removing obsolete tests from laboratory menu and vetting of restricted tests is recommended to increase cost-effectiveness. This saves costs and permits to introduce new biomarkers with increased diagnostic accuracy with a better impact on patient outcome. An additional issue is concerning the periodicity of (re)testing, accounting that only a minority of tests may be ordered as often as necessary. In the majority of cases, a minimum retesting interval should be introduced. The availability of effective computerised order entry systems is relevant in ensuring appropriate test requests and in providing an aid by automated rules that may stop inappropriate requests before they reach the laboratory.