Pitfalls in the Diagnosis and Management of Hypercortisolism (Cushing Syndrome) in Humans; A Review of the Laboratory Medicine Perspective.

Biochemical confirmation of a diagnosis of hypercortisolism (Cushing syndrome) is vital to direct further investigations, especially given the overlap with non-autonomous conditions, such as pseudo-Cushing, and the morbidity associated with missed diagnoses. A limited narrative review was performed focusing on the laboratory perspective of the pitfalls of making a biochemical diagnosis of hypercortisolism in those presenting with presumed Cushing syndrome. Although analytically less specific, immunoassays remain cheap, quick, and reliable in most situations. Understanding cortisol metabolism can help with patient preparation, specimen selection (e.g., consideration of urine or saliva for those with possible elevations of cortisol binding globulin concentration), and method selection (e.g., mass spectrometry if there is a high risk of abnormal metabolites). Although more specific methods may be less sensitive, this can be managed. The reduction in cost and increasing ease of use makes techniques such as urine steroid profiles and salivary cortisone of interest in future pathway development. In conclusion, the limitations of current assays, particularly if well understood, do not impede diagnosis in most cases. However, in complex or borderline cases, there are other techniques to consider to aid in the confirmation of hypercortisolism.

Bedbugs: how to diagnose and manage cases of infestations.

Bedbugs are on the rise in urban populations across the world, perhaps reflecting the ban on the use of organophosphates in many countries worldwide. They are flat obligate haematophagous insects, preferring humans, and as a consequence the bedbug bites lack toxins and can often go unnoticed for some time. Bites can, however, cause weals, purpura, petechiae, vesicles, pustules, papular urticaria, localized infection and rarely anaphylaxis. Infestations have to be confirmed by finding the bugs, usually around the bed of the person being bitten. Eradication usually requires a combination of physical (for example high temperature, mattresses protectors, traps, cold) and chemical methods (for example chrysanthemic acid derivatives plus potentiators such as geraniol and piperonyl butoxide or acetylcholine esterase inhibitors).

Giant parathyroid tumours in primary hyperparathyroidism: a systematic review.

PURPOSE: Giant parathyroid adenoma (GPA) can present with severe biochemical derangement similar to the clinical presentation of parathyroid carcinoma (PC). This study aims to present the current evidence on surgical management of GPAs in primary hyperparathyroidism. METHODS: A systematic review of the literature on GPAs was conducted following the PRISMA guidelines. Data on clinical, biochemical, preoperative diagnostic, and surgical methods were analysed. RESULTS: Sixty-one eligible studies were included reporting on 65 GPAs in eutopic, ectopic mediastinal, and intrathyroidal locations (61.5%, 30.8%, and 7.7%, respectively). A palpable neck mass was present in 58% of GPAs. A total of 90% of patients had symptoms including fatigue, skeletal pain, pathological fracture, nausea, and abdominal pain. Ninety percent of patients had significant hypercalcaemia (mean 3.51 mmol/L; range: 2.59-5.74 mmol/L) and hyperparathyroidism with PTH levels on average 14 times above the upper limit of the normal reference. There was no correlation between the reported GPA size and PTH nor between GPA weight and PTH (p = 0.892 and p = 0.363, respectively). Twenty-four percent had a concurrent thyroidectomy for suspicious features, intrathyroidal location of GPA, or large goitre. Immunohistochemistry such as Ki-67, parafibromin, and galectin-3 was used in 18.5% of cases with equivocal histology. Ninety-five percent of GPAs were benign with 5% reported as atypical adenomas. CONCLUSION: The reported data on GPAs are sparse and heterogeneous. In GPAs with suspicious features for malignancy, en bloc resection with concurrent thyroidectomy may be considered. In the presence of equivocal histological features, ancillary immunohistochemistry is advocated to differentiate GPAs from atypical adenomas and PCs.

Real-world experience of SARS-CoV-2 antibody assays in UK healthcare workers.

BACKGROUND: The seroprevalence of antibodies to SARS-CoV-2 in healthcare workers is variable throughout the world. This study compares the use of two antibody assays among large cohorts of healthcare workers in southern England. METHODS: This cohort study includes data obtained from staff at Western Sussex Hospitals NHS Foundation Trust (WSHT) and Brighton and Sussex University Hospitals (BSUH) during voluntary antibody testing, using Abbott and Roche SARS-CoV-2 antibody assays at each Trust respectively. RESULTS: The observed seroprevalence level was 7.9% for the WSHT/Abbott cohort versus 13% for the BSUH/Roche cohort. Based on a previous positive PCR, we find that the false-negative rate of the Abbott and Roche assays were 60.2% and 19% respectively, implying sensitivity levels of 39.8% and 81%. Within these cohorts, seropositivity was most strongly associated with those of South Asian ethnicity, allied health professionals and male sex (p<0.0001). CONCLUSIONS: In this real-world study, neither antibody test performed to the specification level stated by the manufacturer. More rigorous testing of these and other assays in target populations is recommended prior to widespread usage if they are to provide data that might be useful to control the pandemic.

HbA1c: a review of non-glycaemic variables.

Identification of the correlation between HbA1c and diabetic complications has yielded one of the most clinically useful biomarkers. HbA1c has revolutionised the diagnosis and monitoring of diabetes mellitus. However, with widespread adoption of HbA1c has come increasing recognition that non-glycaemic variables can also affect HbA1c, with varying clinical significance. Furthermore, the identification of a discrepancy between predicted and measured HbA1c in some individuals, the so-called 'glycation gap', may be clinically significant. We aimed to review the current body of evidence relating to non-glycaemic variables to quantify any significance and provide subsequent suggestions. A PubMed-based literature search was performed, using a variety of search terms, to retrieve articles detailing the non-glycaemic variables suggested to affect HbA1c. Articles were reviewed to assess the relevance of any findings in clinical practice and where possible guidance is given. A range of non-glycaemic variables have statistically significant effects on HbA1c. While the clinical implications are generally irrelevant, a small number of non-glycaemic variables do have clinically significant effects and alternative biomarkers should be considered instead of, or in addition to, HbA1c. There are a small number of non-glycaemic variables which have a clinically significant effect on HbA1c, However, the vast majority of non-glycaemic variables have no clinical relevance. While clinicians should have an awareness of those non-glycaemic variables with clinical significance, in the vast majority of clinical scenarios HbA1c should continue to be used with confidence.

Development of fracture liaison services: What have we learned?

Due to dramatic improvements in life expectancy we are seeing a rapidly growing population of older people. Increasing frailty and susceptibility to fragility fractures are becoming pressing issues for both the individuals that suffer them as well as society, through pressures on health and social care budgets. The success of fracture liaison services, co-ordinated programmes enhancing the management of the fracture, osteoporosis, frailty and falls risk, is undisputed. To achieve optimal outcomes, however, it is important to have a standardisation of design, scope and structure of the service. Experience has taught us that by delegating responsibility for the holistic care of the patient to a trained and adequately resourced professional/team (fracture prevention practitioner) with clear standards against which benchmarking occurs, is the optimal model of delivery. Future challenges include how best to measure the success of services in imparting a reduction in fractures at a local population level as well as how to detect those patients with unmet need who do not uniformly present to health care services, such as those with vertebral fractures. The implementation of fracture liaison services however, is a clear demonstration of how collaboration between health care, social care and charity organisations, among others, has materially improved the health and well-being of the population.

Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.

BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia. METHODS: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands. RESULTS: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004]. CONCLUSIONS: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

Use of fibrates in the metabolic syndrome: A review.

The use of fibrates in the treatment of dyslipidaemia has changed significantly over recent years. Their role appeared clear at the start of this century. The Helsinki Heart Study and Veterans Affairs High-Density Cholesterol Intervention Trial suggested significant benefit, especially in patients with atherogenic dyslipidaemia. However, this clarity disintegrated following the negative outcomes reported by the Bezafibrate Infarction Prevention, Fenofibrate Intervention and Event Lowering in Diabetes and Action to Control Cardiovascular Risk in Diabetes randomised controlled trials. In this review we discuss these and other relevant trials and consider patient subgroups such as those with the metabolic syndrome and those needing treatment to prevent the microvascular complications associated with diabetes in whom fibrates may be useful. We also discuss observations from our group that may provide some explanation for the varying outcomes reported in large trials. The actions of fibrates in patients who are also on statins are interesting and appear to differ from those in patients not on statins. Understanding this is key as statins are the primary lipid lowering agents and likely to occupy that position for the foreseeable future. We also present other features of fibrate treatment we have observed in our clinical practice; changes in creatinine, liver function tests and the paradoxical high density lipoprotein reduction. Our purpose is to provide enough data for the reader to make objective decisions in their own clinical practice regarding fibrate use.

A Novel 'Dilute-and-Shoot' Liquid Chromatography-Tandem Mass Spectrometry Method for the Screening of Antihypertensive Drugs in Urine.

Arterial hypertension is one of the most preventable causes of premature morbidity and mortality with resistant hypertension reported to be present in 5-30% of the total hypertensive population. Despite the poor prognosis, as many as 53% of those with resistant hypertension are reported to be nonadherent to their prescribed medication. An objective test of adherence, which is easy to administer, quick, inexpensive and reliable, is therefore needed to identify patients with true resistance to antihypertensive drugs to optimize their treatment. We have developed a novel LC-MS-MS method for the detection of 23 commonly prescribed antihypertensive medications in urine. The validated method was subsequently applied to the analysis of urine from a cohort of 49 individuals who were taking at least one antihypertensive agent in the screening profile to determine their adherence. The screening method was found to be reproducible, sensitive and specific with the limit of detection ranging from 0.1 to 1.0 µg/L. Sample preparation is rapid (30 s) and simple, with a total analysis time of 11 min. The assay successfully identified the majority of drugs our cohort had admitted to taking (88%) with drugs not detected in urine, potentially indicating nonadherence to prescribed medication. The performance of this simple, robust LC-MS-MS procedure is suitable for screening urine for the presence of commonly prescribed antihypertensive medications. The assay, which can easily be implemented in other laboratories, has the potential to significantly improve investigation and management of resistant hypertension.

Metabolic syndrome: A review of the role of vitamin D in mediating susceptibility and outcome.

Despite the well-recognised role of vitamin D in a wide range of physiological processes, hypovitaminosis is common worldwide (prevalence 30%-50%) presumably arising from inadequate exposure to ultraviolet radiation and insufficient consumption. While generally not at the very low levels associated with rickets, hypovitaminosis D has been implicated in various very different, pathophysiological processes. These include putative effects on the pathogenesis of neoplastic change, inflammatory and demyelinating conditions, cardiovascular disease (CVD) and diabetes. This review focuses on the association between hypovitaminosis D and the metabolic syndrome as well as its component characteristics which are central obesity, glucose homeostasis, insulin resistance, hypertension and atherogenic dyslipidaemia. We also consider the effects of hypovitaminosis D on outcomes associated with the metabolic syndrome such as CVD, diabetes and non-alcoholic fatty liver disease. We structure this review into 3 distinct sections; the metabolic syndrome, vitamin D biochemistry and the putative association between hypovitaminosis D, the metabolic syndrome and cardiovascular risk.