Impact of Variation between Assays and Reference Intervals in the Diagnosis of Endocrine Disorders

Method-related variations in the measurement of hormones and the reference intervals used in the clinical laboratory can have a significant, but often under-appreciated, impact on the diagnosis and management of endocrine disorders. This variation in laboratory practice has the potential to lead to an errant approach to patient care and thus could cause harm. It may also be the source of confusion or result in excessive or inadequate investigation. It is important that laboratory professionals and clinicians know about these impacts, their sources, and how to detect and mitigate them when they do arise. In this review article, we describe the historical and scientific context from which inconsistency in the clinical laboratory arises. Examples from the published literature of the impact of the method, reference interval, and clinical decision threshold-related discordances on the assessment and monitoring of various endocrine disorders are discussed to illustrate the sources, causes, and effects of this variability. Its potential impact on the evaluation of growth hormone deficiency and excess, thyroid and parathyroid disorders, hyperandrogenism, hypogonadism, glucocorticoid excess and deficiency, and diabetes mellitus is elaborated. Strategies for assessment and mitigation of the discordance are discussed. The clinical laboratory has a responsibility to recognise and address these issues, and although a lot has been accomplished in this area already, there remains more to be done

Hypophosphatasia.

Hypophosphatasia (HPP) is a group of inherited disorders characterised by the impaired mineralisation of bones and/or teeth and low serum alkaline phosphatase (ALP) activity. It is caused by a mutation in the ALPL gene encoding the tissue-non-specific isoenzyme of ALP (TNSALP) resulting in a loss of function. The disease is highly heterogenous in its clinical expression ranging from stillbirth without mineralised bone to the mild form of late adult onset with symptoms and signs such as musculoskeletal pain, arthropathy, lower-extremity fractures, premature loss of teeth or an incidental finding of reduced serum ALP activity. A classification based on the age at diagnosis and the presence or absence of bone symptoms was historically used: perinatal, prenatal benign, infantile, childhood, adult and odontohypophosphatasia. These subtypes are known to have overlapping signs and complications. Three forms of HPP distinguishable by their genetic characteristics have been described: severe, moderate and mild. Severe forms of HPP (perinatal and infantile severe) are recessively inherited, whereas moderate HPP may be dominantly or recessively inherited. The biochemical hallmark of HPP is persistently low serum ALP for age and increase in natural substrates of TNSALP, pyridoxal 5'-phosphate and phosphoethanolamine supported by radiological findings. The diagnosis is confirmed by ALPL sequencing. A multidisciplinary team of experts is essential for the effective management. Calcium restriction is recommended in infants/children to manage hypercalcaemia. A targeted enzyme replacement therapy for HPP has become available and correct diagnosis is crucial to allow early treatment

Clinical characteristics do not reliably identify non-adherence in patients with uncontrolled hypertension

Purpose Chemical adherence testing is a reliable method to assess adherence to antihypertensive drugs. However, it is expensive and has limited availability in clinical practice. To reduce the number and costs of chemical adherence tests, we aimed to develop and validate a clinical screening tool to identify patients with a low probability of non-adherence in patients with uncontrolled hypertension. Materials and Methods In 495 patients with uncontrolled hypertension referred to the University Medical Centre Utrecht (UMCU), the Netherlands, a penalised logistic regression model including seven pre-specified easy-to-measure clinical variables was derived to estimate the probability of non-adherence. Non-adherence was defined as not detecting at least one of the prescribed antihypertensive drugs in plasma or urine. Model performance and test characteristics were evaluated in 240 patients with uncontrolled hypertension referred to the Heartlands Hospital, United Kingdom. Results Prevalence of non-adherence to antihypertensive drugs was 19% in the UMCU and 44% in the Heartlands Hospital population. After recalibration of the model’s intercept, predicted probabilities agreed well with observed frequencies. The c-statistic of the model was 0.63 (95%CI 0.53–0.72). Predicted probability cut-off values of 15%–22.5% prevented testing in 5%–15% of the patients, carrying sensitivities between 97% (64–100) and 90% (80–95), and negative predictive values between 74% (10–99) and 70% (50–85). Conclusion The combination of seven clinical variables is not sufficient to reliably discriminate adherent from non-adherent individuals to safely reduce the number of chemical adherence tests. This emphasises the complex nature of non-adherence behaviour and thus the need for objective chemical adherence tests in patients with uncontrolled hypertension