Annals of Clinical Biochemistry: International Journal of Laboratory Medicine

Lipoprotein lipase has long been known to hydrolyse triglycerides from triglycerides-rich lipoproteins. More recently, it has been shown to promote the binding of lipoproteins to various lipoprotein receptors. Evidence is also presented regarding the possible atherogenic role of lipoprotein lipase. In theory, lipoprotein lipase deficiency should help to clarify this question. However, the rarity of this condition means that it has not been possible to conduct epidemiological studies. An alternative approach is to investigate the correlation of lipoprotein lipase with onset of cardiovascular disease in prospective studies in large population-based cohorts. Complementary with this approach, animal models have been used to explore the atherogenicity of lipoprotein lipase expressed by macrophages.

Familial hypercholesterolaemia, one of the most common inherited diseases in the general population, is associated with mutations in at least three different genes including the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and protein convertase subtilisin/kexin type 9 (PCSK9) genes. In this report, we describe an unclassified DNA variant (c.1813C>T; p.Leu605Leu) within exon 12 of the LDLR gene in a kindred in which familial hypercholesterolaemia is associated with c.1813C>T heterozygosity. In silico analysis suggested that c.1813C>T might affect splicing of the LDLR gene by creating a cryptic donor splice site, which was confirmed by RT-PCR coupled with cDNA sequencing, to result in the loss of 34 base pairs in the coding sequence. The latter truncated mRNA is predicted to generate a frameshift leading to a premature stop at codon 652 and early termination of the low density lipoprotein receptor polypeptide chain, and thus provides a molecular basis for the hypercholesterolaemic phenotype. This case report highlights the emerging utility of RNA studies for the molecular diagnosis of familial hypercholesterolaemia in patients with potential mRNA splicing variants.

The microbiome is the collective term used to describe the bacteria, viruses, fungi and archaea that reside on and in the human body. The majority of these organisms are found within the large bowel. Mounting evidence suggests that changes in the microbiome may be associated with the development of colorectal cancer, a disease which affects 1.3 million people a year worldwide. Using colorectal cancer as an example, this article presents the inter-specialty collaborative approach to microbiome research and discusses the key role that clinical biochemistry is likely to play.

A small minority of colorectal cancers (CRCs) (≤5%) are caused by a single, inherited faulty gene. These diseases, the Mendelian colorectal cancer (CRC) syndromes, have been central to our understanding of colorectal carcinogenesis in general. Most of the approximately 13 high-penetrance genes that predispose to CRC primarily predispose to colorectal polyps, and each gene is associated with a specific type of polyp, whether conventional adenomas (APC, MUTYH, POLE, POLD1, NTHL1), juvenile polyps (SMAD4, BMPR1A), Peutz-Jeghers hamartomas (LKB1/STK11) and mixed polyps of serrated and juvenile types (GREM1). Lynch syndrome (MSH2, MLH1, MSH6, PMS2), by contrast, is associated primarily with cancer risk. Major functional pathways are consistently inactivated in the Mendelian CRC syndromes: certain types of DNA repair (proofreading of DNA replication errors, mismatch repair and base excision repair) and signalling (bone morphogenetic protein (BMP), Wnt signalling and mTOR). The inheritance of the CRC syndromes also varies: most are dominant but some of the DNA repair deficiencies are recessive. Some of the Mendelian CRC genes are especially important because they play a role through somatic inactivation in sporadic CRC (APC, MLH1, SMAD4, POLE). Additional Mendelian CRC genes may remain to be discovered and searches for these genes are ongoing, especially in patients with multiple adenomas and hyperplastic polyps.

Many health issues that we currently face are related to our lifestyle choices. Educating patients can help them to make better informed health decisions. The internet and smartphones, mobile telephones that perform many of the functions of a computer, are becoming more accessible to the majority of the population. Applications on smartphones and professional health websites can signpost patients to trusted information and allow them to co-produce records. Empowering patients, staff and organizations through enabling access to records and understanding, building a partnership trust and the use of social media can enable people to do more and hopefully improve outcomes. In this article, I describe the steps we have taken to facilitate such interactions within our own primary care practice and the response of patients to these initiatives.

Hypoglycaemia, if it can be proved, may be used as a defence against almost any criminal charge provided it can be established that the perpetrator was in a state of neuroglycopenic (hypoglycaemic) automatism at the time of the offence. Hypoglycaemia produced by exogenous insulin can also be used as a suicidal or homicidal weapon. This paper discusses some of the pitfalls confronting the investigator of suspected insulin misuse including problems arising from the increasing prevalence of insulin analogues and the unreliability of immunoassays for their detection and measurement in the forensic context.

Circadian rhythms, near-24 h oscillations that reflect homeostatic control by an internal timing system rather than the influence of external factors, are an important and sometimes underappreciated aspect of human physiology and biochemistry. Over the past few decades, the pineal gland hormone melatonin has been established both as a robust marker of circadian phase in plasma or saliva and as a chronobiotic drug administered to reset the timing of the circadian oscillator. Recent work by our own and other laboratories has sought to systematically investigate whole categories of molecular components in blood samples in a hypothesis-free fashion by employing metabolomic methodologies to study low molecular weight compounds and transcriptomic methodologies to study gene expression in white blood cells, respectively. A number of components have been pinpointed that show a rhythmic circadian variation or are affected by imposed factors such as sleep deprivation. Although melatonin, a robust and reliable circadian phase marker, will be a hard act to follow, these lines of research suggest numerous potential leads for useful new markers of biological timing.

Cardiac biomarker measurement currently addresses two key questions in patient management: the differential diagnosis of chest pain and the differential diagnosis of the patient with breathlessness. There are currently three major themes in the strategies for the differential diagnosis of chest pain. The first is to undertake troponin measurement in patients selected to be at lower risk, hence to have a low prior probability of disease. The second is the introduction of high-sensitivity cardiac troponin (hs cTn) assays into routine clinical use with measurement at 0 and 3 h from admission. Two other approaches that utilize the diagnostic characteristics of these assays have also been suggested. The first is to use the limit of detection or limit of blank of the assay as the diagnostic discriminant. The second approach is to use the low imprecision of the assay within the reference interval and combine a discriminant value with an absolute rate of change (delta value). The third is the use of additional biomarkers to allow early discharge from the emergency department. The concept is to measure high-sensitivity cardiac troponin plus the extra marker on admission. The role of measurement of B-type natriuretic peptide or its N-terminal prohormone, N-terminal pro-B-type natriuretic peptide, has been accepted and incorporated into guidelines for chronic heart failure for some time. More recently, guidelines for acute heart failure can also recommend a single measurement of B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide in people presenting with new suspected acute heart failure.

Adequate iodine intake is important during pregnancy as it is a component of the thyroid hormones that are crucial for fetal brain and neurological development. While randomized controlled trials in severe iodine deficiency have shown that iodine deficiency in pregnancy causes impaired offspring cognition, less is known of the effects in regions of mild/mild-to-moderate deficiency. The United Kingdom is now classified as mildly iodine deficient by the World Health Organization, based on a 2011 national study of 14–15-year-old schoolgirls. As pregnancy is the most critical time for brain development, we evaluated iodine status in pregnant women in Surrey (n = 100) and Oxford (n = 230). The median urinary iodine concentration was 85.3 μg/L in Surrey women, considerably lower than the WHO/United Nations Children’s Fund/International Council for the Control of Iodine Deficiency Disorders cut-off of 150 μg/L. Oxford women had similarly low status. We investigated whether that level of iodine deficiency was associated with adverse child cognitive effects using stored samples and data from the Avon Longitudinal Study of Parents and Children cohort. In adjusted analyses, we found a significant association between low maternal iodine status in early pregnancy (urinary iodine-to-creatinine ratio <150 μg/g) such that children had an approximately 60% greater risk of being in the bottom quartile of scores for verbal intelligence quotient, reading accuracy and comprehension. UK women who might become pregnant should ensure they have adequate iodine status to avoid compromising their children’s brain development.

Cystatin C is a 13-kDa cysteine protease inhibitor that satisfies many of the criteria required of a marker of glomerular filtration rate. It can be readily measured in laboratories using automated, standardised immunoassays. Hitherto there has been reluctance to adopt cystatin C measurement in the assessment of kidney function, despite demonstrated superiority compared to the current standard of practice, serum creatinine. This may be due to increased direct reagent costs. Recent strong evidence has confirmed the superior ability of cystatin C compared to creatinine to predict risk of a range of poor outcomes (including kidney failure, cardiovascular events and mortality) among patients with chronic kidney disease. On the back of this, national and international guidelines including those of the National Institute for Health and Clinical Excellence have recommended the use of cystatin C to risk stratify individuals with mild to moderately reduced glomerular filtration rate and no albuminuria. Cystatin C presents an opportunity for laboratories to engage with their users in developing clinical pathways which will usefully focus chronic kidney disease management on those most likely to benefit while reassuring patients at low risk.

The International Standard, ISO 15189 which specifies requirements for quality and competence in medical laboratories was written by medical laboratory professionals. Since its first publication in 2003, it has raised awareness of the importance of medical laboratories with governments throughout the world and provided a tool with which laboratories may develop their quality management systems and assess their own competence. This paper examines the use of the Standard in the context of self-assessment, accreditation and regulation of medical laboratories.

Hard evidence of the specific contribution made by laboratory testing to patient outcomes and the delivery of health care is not easy to obtain. An understanding of the value of laboratory medicine, how that value can be measured and the various factors that influence it is vital to ensuring that laboratory services are provided and used optimally to improve patient care. To maximise the value of laboratory medicine, work is required to improve the utilisation of existing and new biomarkers, develop standard protocols for prospective patient-centred studies of biomarker clinical effectiveness or extra-analytical process effectiveness, benchmark existing and new tests in specified clinical situations with commonly accepted effectiveness measures, and define new roles for laboratory professionals that are focussed on optimising patient outcomes by adding value throughout the total testing process. This requires effective collaboration with clinical staff and a determination to accept patient outcome and patient experience as the primary measure of laboratory performance.