Andrew C. Don-Wauchope

Bone turnover markers in the management of postmenopausal osteoporosis

Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic.

Laboratory challenges in primary aldosteronism screening and diagnosis.

BACKGROUND AND OBJECTIVE The laboratory has a critical role to play in the screening and diagnosis of primary aldosteronism. This review highlights some of the important analytical considerations and the new developments in the determination of aldosterone and renin. METHODS The review considered the published literature and clinical practice guidelines in the area of primary aldosteronism. RESULTS A brief introduction to primary aldosteronism is provided. A detailed description of the pre-analytical, analytical and post-analytical considerations for the laboratory determination of aldosterone, renin and the aldosterone to renin ratio follows. CONCLUSIONS The lack of internationally accepted standardized methodologies and standard reference material has impeded screening and diagnosis of primary aldosteronism. The development of more accurate and sensitive methods by LC-MS/MS has improved the reliability of aldosterone and renin testing and the availability of commercial chemiluminescent assays may improve the standardization of reporting. Laboratorians need to understand the strengths and weaknesses of their analytical approach and ensure that their interpretative reports are appropriate to their assays.

Acceptable Analytical Variation May Exceed High-Sensitivity Cardiac Troponin I Cutoffs in Early Rule-Out and Rule-In Acute Myocardial Infarction Algorithms.

To the Editor: In patients presenting to the emergency department (ED)1 with symptoms suggestive of acute coronary syndrome (ACS), clinical studies and guidelines have proposed earlier cardiac troponin sampling protocols and, specifically for high-sensitivity cardiac troponin, at 3, 2, or 1 h, depending on the algorithm and high-sensitivity cardiac troponin assay (1). Because of this shorter time interval between high-sensitivity cardiac troponin measurements, there will be smaller changes in concentration (δ) for risk classification. This raises the possibility that the analytical variation of the assay at the low concentration range may possibly exceed the δ for ruling in patients using these shortened algorithms (2). In addition, biological variation should be considered in the evaluation of change, since the frequency of an absolute reference change value ≥2 ng/L in 1 ED study population was observed in nearly half of all patients without ACS (3). The Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) and 2-Hour Accelerated Diagnostic Protocol to Assess Patients with Chest Pain Symptoms Using Contemporary Troponins as the Only Biomarker (ADAPT) study investigators have developed a 2-h protocol for a clinically available (outside US) high-sensitivity cardiac troponin I (hs-cTnI) assay (Abbott Architect) (1). The results show approximately 60% of the patients being ruled out and 15% ruled in (1). However, questions remain around the contribution of analytical and biological variation to the applied cutoffs and deltas. We also questioned whether these …

Evidence based application of BNP/NT-proBNP testing in heart failure

BACKGROUND The B-type natriuretic peptides are now available on many automated clinical analysers. Clinical practice guidelines for heart failure include recommendations for where the B-type natriuretic peptides are possibly useful for clinical practice. A number of systematic reviews considering B-type natriuretic peptides in relation to heart failure patients have been published. METHODS This review will consider the evidence presented in the systematic reviews and how this can be applied to clinical practice. RESULTS Twenty-six systematic reviews are summarised in tables considering applications to diagnostic, prognostic and guiding therapy. Important clinical considerations for these applications are discussed to facilitate appropriate implementation in the clinical laboratory. CONCLUSION Most clinical laboratories should be considering the appropriate implementation of the B-type natriuretic peptide as a diagnostic test to assist in ruling out heart failure. In the application of prognosis and guiding therapy a number of questions remain to be answered.

A systematic review of BNP and NT-proBNP in the management of heart failure: overview and methods

B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are increased in persons with heart failure (HF); low levels of these peptides rule out HF. We systematically reviewed the literature to assess the use of BNP and NT-proBNP in the diagnosis, prognosis, and treatment for HF. We also examined the biological variation of these peptides in persons with and without HF. We searched Medline, Embase, AMED, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and CINAHL for English-language studies published between January 1989 and June 2012. Supplemental searches involved the gray literature and the reference lists of included studies. Trained reviewers used standardized forms to screen articles for inclusion in the review and to extract data from included papers. We examined the risk of bias with QUADAS-2 for diagnosis studies, the Hayden criteria for prognosis studies, and the Jadad scale for treatment studies. We assessed the strength of evidence in four domains (risk of bias, consistency, directness, and precision) for the diagnosis and treatment studies. Results were reported as narrative syntheses. Additional meta-analyses were conducted for the diagnosis studies. Three hundred ten articles passed through screening and were included in the review. One hundred four articles applied to diagnostic accuracy, 190 papers pertained to prognosis, and nine articles addressed BNP- or NT-proBNP-guided treatment. Each individual paper in this series reports, summarizes, and discusses the evidence regarding diagnosis, prognosis, or treatment.

Laboratory defined critical value limits: how do hospital physicians perceive laboratory based critical values?

OBJECTIVES To assess whether our critical values were viewed as appropriate by our physicians and to assess their understanding of critical values. METHODS A web-based survey was prepared. The critical value levels were taken from our current values and select values based on a review of the literature. One of the options in the response for each analyte probed the understanding of the concept of critical value. RESULTS There were 115 respondents from a range of disciplines. The results indicated that some (4/11) of our critical values were appropriate however, many required review (7/11). Most respondents (79%) did not fully appreciate the concept of critical value. CONCLUSIONS This survey specifically considers physician input for the establishment of critical values. The data enabled our laboratory to better identify critical values and has highlighted the need for physician education in the concept of critical values.

Performance of BNP and NT-proBNP for diagnosis of heart failure in primary care patients: a systematic review

National and international guidelines have been published recommending the use of natriuretic peptides as an aid to the diagnosis of heart failure (HF) in acute settings; however, few specific recommendations exist for governing the use of these peptides in primary care populations. To summarize the available data relevant to the diagnosis of HF in primary care patient population, we systematically reviewed the literature to identify original articles that investigated the diagnostic accuracy of B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) in primary care settings. The search yielded 25,864 articles in total: 12 investigating BNP and 20 investigating NT-proBNP were relevant to our objective and included in the review. QUADAS-2 and GRADE were used to assess the quality of the included articles. Diagnostic data were pooled based on three cutpoints: lowest and optimal, as chosen by study authors, and manufacturers’ suggested. The effect of various determinants (e.g., age, gender, BMI, and renal function) on diagnostic performance was also investigated. Pooled sensitivity and specificity of BNP and NT-proBNP using the lowest [0.85 (sensitivity) and 0.54 (specificity)], optimal (0.80 and 0.61), and manufacturers’ (0.74 and 0.67) cutpoints showed good performance for diagnosing HF. Similar performance was seen for NT-proBNP: lowest (0.90 and 0.50), optimal (0.86 and 0.58), and manufacturers’ (0.82 and 0.58) cutpoints. Overall, we rated the strength of evidence as high because further studies will be unlikely to change the estimates diagnostic performance.

Adverse metabolic effects of a hypercaloric, high-fat diet in rodents precede observable changes in body weight

Although a high-fat diet (HFD) is recognized as an important contributor to obesity, human research is limited by confounders such as income, whereas animal research has typically examined diet during specific developmental periods rather than throughout the lifespan. We hypothesized that the use of an HFD in short-term studies as has been commonly done in animals does not adequately reflect the lifelong dietary patterns seen frequently in humans with consequent metabolic disturbances. We examined the impact of HFD from weaning until 39 weeks (middle age) on the metabolism of male rats. At 7, 26, and 39 weeks, glucose tolerance tests were performed, a subset of animals was euthanized, and serum and tissues were collected. After 4 weeks, preceding increased body weight, HFD animals had increased intra-abdominal fat, triglycerides, and hyperglycemia. Hyperinsulinemia was insufficient to maintain normoglycemia, and beta cell mass and glucagon-like peptide 1 decreased over time in HFD and control animals. Despite lacking significant lipid abnormalities, nonalcoholic fatty liver disease was evident by 39 weeks. Our HFD model demonstrated that significant metabolic abnormalities may go undetected by current standard screening such as weighing and biochemistry.

Missed follow-up opportunities using a two-step screening approach for gestational diabetes

A 1-step approach for gestational diabetes (GDM) screening using a 75 g-oral glucose tolerance test (75 g-OGTT) has been recommended. We undertook an audit (January 2007-June 2010) to assess adherence to an existing 2-step approach (50 g-glucose challenge test followed by a 75 g-OGTT). Adherence was sub-optimal. Overall follow-up was missed in 14.5% of those screened. Only 36% of those who met dysglycemia criteria for a follow-up 75 g-OGTT received the test as per step 2 of the protocol.

Pediatric critical values: laboratory-pediatrician discourse.

OBJECTIVES To review pediatric critical values after consultation with departmental pediatricians. METHODS An electronic survey with the critical value list of 26 high or low abnormal chemistry laboratory values of 12 analytes was circulated to pediatricians. The survey results were presented to a focus group of 3 pediatricians for comments and review. RESULTS Thirty-one of 125 pediatricians affiliated with the Department of Pediatrics responded. Sixteen of 26 (61.5%) current values met the agreement criteria. The procedures for calling high glucose levels in neonates and children, and the low magnesium and low ionized calcium critical values were revised after discussion with the focus group. CONCLUSIONS This survey among the hospitals pediatricians resulted not only in a revised list of critical values, but also the procedure for calling the user. The use of unique critical values for different areas of clinical practice within the childrens hospital was identified as an area for future development.