Society for Endocrinology guidelines for testosterone replacement therapy in male hypogonadism.

Male hypogonadism (MH) is a common endocrine disorder. However, uncertainties and variations in its diagnosis and management exist. There are several current guidelines on testosterone replacement therapy that have been driven predominantly by single disciplines. The Society for Endocrinology commissioned this new guideline to provide all care providers with a multidisciplinary approach to treating patients with MH. This guideline has been compiled using expertise from endocrine (medical and nursing), primary care, clinical biochemistry, urology and reproductive medicine practices. These guidelines also provide a patient perspective to help clinicians best manage MH.

Vitamin D deficiency is an independent predictor of mortality in patients with chronic heart failure.

PURPOSE: Low 25-hydroxyvitamin D (25[OH]D) concentrations have been associated with adverse outcomes in selected populations with established chronic heart failure (CHF). However, it remains unclear whether 25[OH]D deficiency is associated with mortality and hospitalisation in unselected patients receiving contemporary medical and device therapy for CHF. METHODS: We prospectively examined the prevalence and correlates of 25[OH]D deficiency in 1802 ambulatory patients with CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 45%) attending heart failure clinics in the north of England. RESULTS: 73% of patients were deficient in 25[OH]D (< 50 nmol/L). 25[OH]D deficiency was associated with male sex, diabetes, lower serum sodium, higher heart rate, and greater diuretic requirement. During a mean follow-up period of 4 years, each 2.72-fold increment in 25[OH]D concentration (for example from 32 to 87 nmol/L) is associated with 14% lower all-cause mortality (95% confidence interval (CI) 1, 26%; p = 0.04), after accounting for potential confounding factors. CONCLUSIONS: Low 25-hydroxyvitamin D deficiency is associated with increased mortality in patients with chronic heart failure due to left ventricular systolic dysfunction. Whether vitamin D supplementation will improve outcomes is, as yet, unproven.

Cardiovascular magnetic resonance measures of aortic stiffness in asymptomatic patients with type 2 diabetes: association with glycaemic control and clinical outcomes.

BACKGROUND: We aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition. METHODS: Patients with type 2 diabetes (N = 94) and low vascular risk underwent assessment of cardiovascular risk and CMR assessment of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV). Of these patients a subgroup with recent onset microalbuminuria (N = 25) were treated with renin-angiotensin-aldosterone system (RAAS) inhibition and imaging repeated after 1 year. All 94 patients were followed up for 2.4 years for major adverse cardiovascular disease (CVD) events including myocardial infarction detected on late gadolinium enhancement CMR. RESULTS: Ascending aortic distensibility, DAD and PWV all had a significant association with age and 24 h systolic blood pressure but only AAD had a significant association with glycaemic control, measured as HbA1c (Beta - 0.016, P = 0.04). The association between HbA1c and AAD persisted even after correction for age and hypertension. CVD events occurred in 19/94 patients. AAD, but not DAD or PWV, was associated with CVD events (hazard ratio 0.49, 95% confidence interval 0.25-0.95, P = 0.01). On treatment with RAAS inhibition, AAD, but not DAD or PWV, showed significant improvement from 1.51 ± 1.15 to 1.97 ± 1.07 10-3 mmHg-1, P = 0.007. CONCLUSIONS: Ascending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore it may be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents. Clinical trials registration https://clinicaltrials.gov/ct2/show/NCT01970319.

Observational studies on macroprolactin in a routine clinical laboratory.

BACKGROUND: It is now recommended that all samples with raised prolactin should be examined for the presence of macroprolactin. We performed a retrospective review of our experience of macroprolactin to determine the incidence and the natural history of macroprolactin. METHODS: A retrospective study of macroprolactin was made in a large clinical laboratory. Macroprolactin was measured on those samples where it is requested and where the total prolactin is >1000 mIU/L. Prolactin was measured using the Siemens Centaur and macroprolactin was measured following polyethylene glycol (PEG)-precipitation. RESULTS: The incidence of macroprolactin in samples where the total prolactin was >1000 mIU/L was 36/670 (5.4%). During this period, 12,064 samples were received for prolactin analysis. Over the period since 2006, 22 subjects had a sample with an isolated macroprolactin measurement followed by another sample without macroprolactin after a median period of 0.46 years. Twenty-five subjects had multiple consecutive measurements of macroprolactin lasting a median period of 2.1 years. Fourteen subjects had more than six samples which had been subjected to PEG precipitation. In these subjects, the reproducibility of PEG precipitation over a median of 6 years was 1.1% CV (recovery 75% [26-110] (median [range])). CONCLUSIONS: The presence of macroprolactin can change over time and we cannot advise that once a test for macroprolactinemia has been performed that it is not necessary to repeat the investigation if a subsequent sample is hyperprolactinemic; nor can one assume that macroprolactin will not develop even if it has been excluded previously.

Indirect methods for reference interval determination - review and recommendations.

Reference intervals are a vital part of the information supplied by clinical laboratories to support interpretation of numerical pathology results such as are produced in clinical chemistry and hematology laboratories. The traditional method for establishing reference intervals, known as the direct approach, is based on collecting samples from members of a preselected reference population, making the measurements and then determining the intervals. An alternative approach is to perform analysis of results generated as part of routine pathology testing and using appropriate statistical techniques to determine reference intervals. This is known as the indirect approach. This paper from a working group of the International Federation of Clinical Chemistry (IFCC) Committee on Reference Intervals and Decision Limits (C-RIDL) aims to summarize current thinking on indirect approaches to reference intervals. The indirect approach has some major potential advantages compared with direct methods. The processes are faster, cheaper and do not involve patient inconvenience, discomfort or the risks associated with generating new patient health information. Indirect methods also use the same preanalytical and analytical techniques used for patient management and can provide very large numbers for assessment. Limitations to the indirect methods include possible effects of diseased subpopulations on the derived interval. The IFCC C-RIDL aims to encourage the use of indirect methods to establish and verify reference intervals, to promote publication of such intervals with clear explanation of the process used and also to support the development of improved statistical techniques for these studies.

Could accreditation bodies facilitate the implementation of medical guidelines in laboratories?

Several studies have shown that recommendations related to how laboratory testing should be performed and results interpreted are limited in medical guidelines and that the uptake and implementation of the recommendations that are available need improvement. The EFLM/UEMS Working Group on Guidelines conducted a survey amongst the national societies for clinical chemistry in Europe regarding development of laboratory-related guidelines. The results showed that most countries have guidelines that are specifically related to laboratory testing; however, not all countries have a formal procedure for accepting such guidelines and few countries have guideline committees. Based on this, the EFLM/UEMS Working Group on Guidelines conclude that there is still room for improvement regarding these processes in Europe and raise the question if the accreditation bodies could be a facilitator for an improvement.

Analytical performance of 17 general chemistry analytes across countries and across manufacturers in the INPUtS project of EQA organizers in Italy, the Netherlands, Portugal, United Kingdom and Spain.

BACKGROUND: Optimum patient care in relation to laboratory medicine is achieved when results of laboratory tests are equivalent, irrespective of the analytical platform used or the country where the laboratory is located. Standardization and harmonization minimize differences and the success of efforts to achieve this can be monitored with international category 1 external quality assessment (EQA) programs. METHODS: An EQA project with commutable samples, targeted with reference measurement procedures (RMPs) was organized by EQA institutes in Italy, the Netherlands, Portugal, UK, and Spain. Results of 17 general chemistry analytes were evaluated across countries and across manufacturers according to performance specifications derived from biological variation (BV). RESULTS: For K, uric acid, glucose, cholesterol and high-density density (HDL) cholesterol, the minimum performance specification was met in all countries and by all manufacturers. For Na, Cl, and Ca, the minimum performance specifications were met by none of the countries and manufacturers. For enzymes, the situation was complicated, as standardization of results of enzymes toward RMPs was still not achieved in 20% of the laboratories and questionable in the remaining 80%. CONCLUSIONS: The overall performance of the measurement of 17 general chemistry analytes in European medical laboratories met the minimum performance specifications. In this general picture, there were no significant differences per country and no significant differences per manufacturer. There were major differences between the analytes. There were six analytes for which the minimum quality specifications were not met and manufacturers should improve their performance for these analytes. Standardization of results of enzymes requires ongoing efforts.

Obesity services: how best to develop a coherent way forward.

Obesity now affects 25% of the UK population. This volume of patients cannot be managed by current NHS services. It really needs a public health approach which encourages an environment where it is easier for the public to take healthy rather than unhealthy actions. However, there remain substantial numbers of patients who will benefit from medical intervention. This needs a joined-up service which extends from a healthy environment, linking gyms, weight loss groups, community cooking lessons, etc. with pathways connecting primary and secondary healthcare. To date, the National Health Service has not managed to develop a coherent policy that addresses obesity as a major cause of health and social care expenditure. The most important step in primary care is probably to identify the presence of obesity. The medical steps should be in the identification and management of comorbidities. The purpose of treating obesity is not weight loss alone but improving health, so the narrative needs to change from weight to blood pressure, glucose tolerance, physical fitness, etc. Many physicians believe that weight loss is an unwinnable battle but there are several well conducted studies in which primary care, supported by specialists, can deliver successful clinical weight loss. Specialist medical and surgical care for obesity will be required for complex cases and is essential for overseeing long-term postsurgical follow-up to prevent and treat nutritional and metabolic complications. Obesity management suffers from a lack of coherent national public health policies, fragmentation of care and a lack of knowledge of what successful treatment entails. Health benefits do not require a return to a healthy BMI.

Nutritional follow-up of patients after obesity surgery: best practice.

Obesity surgery is an appropriate treatment option for patients with severe and complex obesity and helps in the improvement of comorbidities. In the first 2 years following surgery, follow-up is provided by the obesity surgery centre. Ongoing care is then usually returned to the general practitioner. Patients need access to ongoing support and monitoring otherwise may be at risk of developing nutritional deficiencies such as anaemia or protein malnutrition. The British Obesity and Metabolic Surgery Society have developed guidelines on nutritional monitoring and nutritional supplements to support both bariatric centres and general practitioners. The Royal College of General Practitioners and BOMSS have worked collaboratively to develop Ten Top Tips for the management of obesity surgery patients to aid with the long-term management in primary care. Women, planning to get pregnant, need access to preconception advice and additional monitoring during pregnancy. It is essential that long-term data are collected and inputted into the National Bariatric Surgery Register. Obesity surgery improves comorbidities; however, patients must have access to long-term nutritional monitoring.

Why are clinical practice guidelines not followed?

Clinical practice guidelines (CPG) are written with the aim of collating the most up to date information into a single document that will aid clinicians in providing the best practice for their patients. There is evidence to suggest that those clinicians who adhere to CPG deliver better outcomes for their patients. Why, therefore, are clinicians so poor at adhering to CPG? The main barriers include awareness, familiarity and agreement with the contents. Secondly, clinicians must feel that they have the skills and are therefore able to deliver on the CPG. Clinicians also need to be able to overcome the inertia of "normal practice" and understand the need for change. Thirdly, the goals of clinicians and patients are not always the same as each other (or the guidelines). Finally, there are a multitude of external barriers including equipment, space, educational materials, time, staff, and financial resource. In view of the considerable energy that has been placed on guidelines, there has been extensive research into their uptake. Laboratory medicine specialists are not immune from these barriers. Most CPG that include laboratory tests do not have sufficient detail for laboratories to provide any added value. However, where appropriate recommendations are made, then it appears that laboratory specialist express the same difficulties in compliance as front-line clinicians.

Evaluation of standardization capability of current cardiac troponin I assays by a correlation study: results of an IFCC pilot project.

BACKGROUND: As a part of an International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) project to prepare a commutable reference material for cardiac troponin I (cTnI), a pilot study evaluated current cTnI assays for measurement equivalence and their standardization capability. METHODS: cTnI-positive samples collected from 90 patients with suspected acute myocardial infarction were assessed for method comparison by 16 cTnI commercial assays according to predefined testing protocols. Seven serum pools prepared from these samples were also assessed. RESULTS: Each assay was assessed against median cTnI concentrations measured by 16 cTnI assays using Passing-Bablok regression analysis of 79 patient samples with values above each assay's declared detection limit. We observed a 10-fold difference in cTnI concentrations for lowest to highest measurement results. After mathematical recalibration of assays, the between-assay variation for patient samples reduced on average from 40% to 22% at low cTnI concentration, 37%-20% at medium concentration, and 29%-14% at high concentration. The average reduction for pools was larger at 16%, 13% and 7% for low, medium and high cTnI concentrations, respectively. Overall, assays demonstrated negligible bias after recalibration (y-intercept: -1.4 to 0.3 ng/L); however, a few samples showed substantial positive and/or negative differences for individual cTnI assays. CONCLUSIONS: All of the 16 commercial cTnI assays evaluated in the study demonstrated a significantly higher degree of measurement equivalence after mathematical recalibration, indicating that measurement harmonization or standardization would be effective at reducing inter-assay bias. Pooled sera behaved similarly to individual samples in most assays.

Management of severe in-patient hyponatraemia: an audit in two teaching hospitals in Yorkshire, UK.

BACKGROUND: Hyponatraemia, the commonest electrolyte abnormality amongst in-patients, is associated with increased mortality. Until recently, there has been a lack of international consensus management of patients with severe hyponatraemia. AIM: We performed a retrospective study in two teaching hospitals in Yorkshire, UK, to evaluate the management of patients with severe hyponatraemia (serum Na ≤ 110 mmol/L) and to assess the frequency of complications observed in this group, in particular central pontine myelinolysis (CPM) and death. METHODS: Retrospective data collection was performed on all of patients admitted with severe hyponatraemia in a calendar year in two teaching hospitals in Yorkshire. A detailed case note evaluation was conducted to determine the patient clinical characteristics, aetiology, investigations performed, treatment, complications and outcome of patients. RESULTS: We identified 39 patients in total at both sites over a calendar year. There was a notable female predominance (n = 27), with the median (range) age being 65 (45-92) years and median sodium concentration 107 (94-110) mmol/L. Hyponatraemia was classified as acute (onset < 48 h) in six patients, chronic (onset > 48 h) in 20 patients and of unknown duration in 13 patients. Iatrogenic hyponatraemia secondary to drugs, especially thiazides was the most commonly observed aetiology. The mortality rate was 48.7% (n = 19) at the end of one year after admission episode and CPM was seen in 7.6% (n = 3) of patients. CONCLUSIONS: Severe hyponatraemia is associated with significant morbidity and mortality. Drug-induced hyponatraemia was the most common aetiology observed in our group of patients.

Harmonization of quality indicators in laboratory medicine. A preliminary consensus.

Quality indicators (QIs) are fundamental tools for enabling users to quantify the quality of all operational processes by comparing it against a defined criterion. QIs data should be collected over time to identify, correct, and continuously monitor defects and improve performance and patient safety by identifying and implementing effective interventions. According to the international standard for medical laboratories accreditation, the laboratory shall establish and periodically review QIs to monitor and evaluate performance throughout critical aspects of pre-, intra-, and post-analytical processes. However, while some interesting programs on indicators in the total testing process have been developed in some countries, there is no consensus for the production of joint recommendations focusing on the adoption of universal QIs and common terminology in the total testing process. A preliminary agreement has been achieved in a Consensus Conference organized in Padua in 2013, after revising the model of quality indicators (MQI) developed by the Working Group on "Laboratory Errors and Patient Safety" of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The consensually accepted list of QIs, which takes into consideration both their importance and applicability, should be tested by all potentially interested clinical laboratories to identify further steps in the harmonization project.

Glycemic control in the 12 months following a change to SI hemoglobin A1c reporting units.

BACKGROUND: Many countries have implemented, or are considering, a change in hemoglobin A1c (Hb A1c) units from traditional percentage values [Diabetes Control and Complications Trial (DCCT)] to the new Système International d'Unités (SI) unit in millimoles per mole. Concern exists that such a large alteration in numeric values might lead, through confusion, to a deterioration in patients' glycemia. This study has assessed Hb A1c in the year before and after the change of units in a UK diabetes population. METHODS: The Hb A1c in the 12 months immediately before the unit change (October 2010 to September 2011) was compared with the 12 months after (October 2011 to September 2012). Also, the subsequent change in Hb A1c in patients who had poor glycemic control [Hb A1c >8% (64 mmol/mol)], either before or after the unit change, was compared. RESULTS: Over the 2 years, 44 721 Hb A1c measurements were requested on 13,197 (7247 male, 5950 female) known diabetes patients. The population Hb A1c was no different between years, with a median [interquartile range (IQR)] value of 7.5% (6.6%-8.7%) after the change and 7.5% (6.5-8.7) before (P = 0.34). The subsequent change in Hb A1c following a raised (>8%) result was the same regardless of whether the initial value reported was in DCCT or SI units [median (IQR) change in Hb A1c -0.2% (-0.9% to 0.3%), n = 4316, following a DCCT result, vs -0.2% (-0.8% to 0.3%), n = 4396, following SI; P = 0.44]. CONCLUSIONS: In this UK diabetes population, a move to SI Hb A1c reporting did not lead to any marked short-term deterioration in glycemia or a different Hb A1c outcome in patients with initial poor glucose control.

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

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.

Can current analytical quality performance of UK clinical laboratories support evidence-based guidelines for diabetes and ischaemic heart disease?--A pilot study and a proposal.

BACKGROUND: The implementation of national and international guidelines is beginning to standardise clinical practice. However, since many guidelines have decision limits based on laboratory tests, there is an urgent need to ensure that different laboratories obtain the same analytical result on any sample. A scientifically-based quality control process will be a pre-requisite to provide this level of analytical performance which will support evidence-based guidelines and movement of patients across boundaries while maintaining standardised outcomes. We discuss the finding of a pilot study performed to assess UK clinical laboratories readiness to work to a higher grade quality specifications such as biological variation-based quality specifications. METHODS: Internal quality control (IQC) data for HbA1c, glucose, creatinine, cholesterol and high density lipoprotein (HDL)-cholesterol were collected from UK laboratories participating in the Bio-Rad Unity QC programme. The median of the coefficient of variation (CV%) of the participating laboratories was evaluated against the CV% based on biological variation. RESULTS: Except creatinine, the other four analytes had a variable degree of compliance with the biological variation-based quality specifications. More than 75% of the laboratories met the biological variation-based quality specifications for glucose, cholesterol and HDL-cholesterol. Slightly over 50% of the laboratories met the analytical goal for HBA1c. Only one analyte (cholesterol) had a performance achieving the higher quality specifications consistent with 5σ. CONCLUSIONS: Our data from IQC do not consistently demonstrate that the results from clinical laboratories meet evidence-based quality specifications. Therefore, we propose that a graded scale of quality specifications may be needed at this stage.

Critical review of laboratory investigations in clinical practice guidelines: proposals for the description of investigation.

BACKGROUND: Correct information provided by guidelines may reduce laboratory test related errors during the pre-analytical, analytical and post-analytical phase and increase the quality of laboratory results. METHODS: Twelve clinical practice guidelines were reviewed regarding inclusion of important laboratory investigations. Based on the results and the authors' experience, two checklists were developed: one comprehensive list including topics that authors of guidelines may consider and one consisting of minimal standards that should be covered for all laboratory tests recommended in clinical practice guidelines. The number of topics addressed by the guidelines was related to involvement of laboratory medicine specialists in the guideline development process. RESULTS: The comprehensive list suggests 33 pre- analytical, 37 analytical and 10 post-analytical items. The mean percentage of topics dealt with by the guidelines was 33% (median 30%, range 17%-55%) and inclusion of a laboratory medicine specialist in the guideline committee significantly increased the number of topics addressed. Information about patient status, biological and analytical interferences and sample handling were scarce in most guidelines even if the inclusion of a laboratory medicine specialist in the development process seemingly led to increased focus on, e.g., sample type, sample handling and analytical variation. Examples underlining the importance of including laboratory items are given. CONCLUSIONS: Inclusion of laboratory medicine specialist in the guideline development process may increase the focus on important laboratory related items even if this information is usually limited. Two checklists are suggested to help guideline developers to cover all important topics related to laboratory testing.

Clinical and analytical evaluation of an immunoturbidimetric heart-type fatty acid-binding protein assay.

BACKGROUND: Heart-type fatty acid-binding protein (H-FABP) is a low molecular weight protein involved in the intracellular uptake and buffering of long chain fatty acids in the myocardium. It is an early marker for ACS. We have evaluated the Randox Laboratories immunoturbidimetric assay on a Siemens Advia 1800 analyzer. The assay employs latex particles coated with mouse monoclonal anti-HFABP antibodies to generate turbidity. METHODS: We used redundant patient samples and pools to assess precision, functional sensitivity, limit of detection, linearity, recovery of recombinant H-FABP and interference. We evaluated the 99th centile values and compared H-FABP with troponin in samples routinely received from chest pain patient samples. RESULTS: Precision was typically < 10% and 12.5% at all concentrations for within and between batches. The functional sensitivity was 2.4 µg/L. The assay was linear on dilution over the range 2.76-115 µg/L. Recovery of recombinant H-FABP was approximately 20-25%. No interference was seen with haemoglobin concentrations <1.5 g/L, bilirubin < 250 µg/L and triacylglycerol < 5 mmol/L or rheumatoid factor. The 99th centile value in a reference population with eGFR > 60mL/min/1.73m(2) was 9.1 µg/L with no significant gender difference. H-FABP was measured in routine clinical samples (N = 1310) received for troponin I measurement. Using Siemens TnI > 50 ng/L as an indicator of myocardial damage, the ROC area under curve for H-FABP was 0.82. CONCLUSIONS: The immunoturbidimetric H-FABP assay is robustly designed and shows good analytical performance. It is therefore well suited for use in a routine clinical laboratory.