Clinical Biochemist Reviews最新文献

Autoimmune glycaemic dysregulation and hyperinsulinaemic hypoglycaemia mediated by insulin autoantibodies is an increasingly recognised but controversial phenomenon described in both exogenous insulin naïve (insulin autoimmune syndrome) and exposed (exogenous insulin antibody syndrome) individuals. There has been a significant proliferation of case reports, clinical studies and reviews in the medical literature in recent years which have collectively highlighted the discrepancy between experts in the field with regard to the nomenclature, definition, proposed pathophysiology, as well as the clinical and biochemical diagnostic criteria associated with the condition. The essential characteristics of the condition are glycaemic dysregulation manifesting as episodes of hyperglycaemia and unpredictable hyperinsulinaemic hypoglycaemia associated with high titres of endogenous antibodies to insulin. Although the hypoglycaemia is often life-threatening and initiation of targeted therapies critical, the diagnosis is often delayed and attributable to various factors including: the fact that existence of the condition is not universally accepted; the need to exclude surreptitious causes of hypoglycaemia; the diverse and often complex nature of the glycaemic dysregulation; and the challenge of diagnostic confirmation. Once confirmed, the available therapeutic options are expansive and the reported responses to these therapies have been variable. This review will focus on our evolving understanding, and the associated diagnostic challenges - both clinical and laboratory - of this complex condition.

The goal of screening programs for inborn errors of metabolism (IEM) is early detection and timely intervention to significantly reduce morbidity, mortality and associated disabilities. Phenylketonuria exemplifies their success as neonates are identified at birth and then promptly treated allowing normal neurological development. Lysosomal diseases comprise about 50 IEM arising from a deficiency in a protein required for proper lysosomal function. Typically, these defects are in lysosomal enzymes with the concomitant accumulation of the enzyme's substrate as the cardinal feature. None of the lysosomal diseases are screened at birth in Australia and in the absence of a family history, traditional laboratory diagnosis of the majority, involves demonstrating a deficiency of the requisite enzyme. Diagnostic confusion can arise from interpretation of the degree of residual enzyme activity causative of disease and is impractical when the disorder is not due to an enzyme deficiency per se. Advances in mass spectrometry technologies has enabled simultaneous measurement of the enzymes' substrates and their metabolites which facilitates the efficiency of diagnosis. Employing urine chemistry as a reflection of multisystemic disease, individual lysosomal diseases can be identified by a characteristic substrate pattern complicit with the enzyme deficiency. Determination of lipids in plasma allows the diagnosis of a further class of lysosomal disorders, the sphingolipids. The ideal goal would be to measure biomarkers for each specific lysosomal disorder in the one mass spectrometry-based platform to achieve a diagnosis. Confirmation of the diagnosis is usually by identifying pathogenic variants in the underlying gene, and although molecular genetic technologies can provide the initial diagnosis, the biochemistry will remain important for interpreting molecular variants of uncertain significance.

Establishing paediatric reference intervals (RIs) is a challenging task due to difficulties in subject recruitment, collection of adequate blood volume, and the inherent physiological changes of many biomarkers with age. Despite these challenges, several national and international initiatives have demonstrated: (a) the feasibility of prospectively designed paediatric RI studies; (b) the development of continuous RIs; and (c) the comparison of reference values across analyser types to harmonise paediatric RIs. Whilst these studies have improved the interpretation of paediatric test results and compliance with international accreditation (ISO15189) requirements, several gaps and challenges in translating current paediatric RIs into routine laboratory practice remain. Future priorities for paediatric RI studies include: (a) determination of the impact of discrete versus continuous RIs, analyser-specific versus harmonised RIs, and prospective collection versus data mining on the proportion of results outside the RIs; (b) understanding the clinical implications of analyser-to-analyser variation in reference values and use of evidence-based paediatric harmonised RIs where applicable; (c) adaptation of laboratory information systems to incorporate continuous RIs; (d) further understanding of the biological variation in paediatric biomarkers; (e) studies to address the paucity of accurate data for neonatal RI development; (f) periodic demonstration of RIs being clinically 'fit-for purpose'; and (g) agreement and policy updates for use of modern, best practice statistical methods in estimation of paediatric RIs. Furthermore, in vitro diagnostic manufacturers may require incentivised paediatric RI studies and publications through co-ordinated grants and collaboration at end-user sites to reduce the burden on sole users.

Fibrosis prediction is an essential part of the assessment and management of patients with chronic liver disease. Traditionally the gold standard for assessment of fibrosis is liver biopsy, but it suffers from various limitations including risk of patient injury and sampling error. As a result, noninvasive tests of hepatic fibrosis have been used in patients with chronic liver disease due to conditions such as hepatitis B and C, and alcoholic and non-alcoholic fatty liver disease. With the advent of new direct-acting antivirals, hepatic fibrosis staging is an important component of treatment decisions in the care of patients with chronic hepatitis C virus infection. Current limitations of the noninvasive biomarker models include a significant indeterminate range, and a predictive ability that is limited to only a few stages of fibrosis. However newer technologies and novel proteins identified by proteomics and genomics offer the possibility for further refinement and individualisation of biomarker fibrosis models in the future.

Osteoporosis (OP) is a condition where there is low bone density and microarchitectural deterioration which can predispose to fragility fractures. There is a wealth of literature on OP from the developed countries, but less so from Asia. This review will explore the field of OP research in South-East Asia with regard to the epidemiology, the diagnosis of OP and the role of laboratory tests in the management of OP, with emphasis on 25-dihydroxyvitamin D and bone turnover markers.

The pressure on healthcare budgets including laboratory medicine is relentless and the focus on activities and costs remains the dominant funding model of laboratory medicine everywhere. The limitations of this model are well documented and for a decade or more laboratory professions worldwide have started looking at alternative models where the value of laboratory medicine and its impact on patient outcomes are the predominant driving force. There are multiple ways to determine the value of a medical test, particularly if one takes into consideration its impact upon the complete clinical pathway. Thus various approaches to value determination are being explored by a number of international organisations. These organisations will be reviewed below, including one which uses the concept of a value proposition that describes in detail how a test should be implemented by measuring its clinical, operational and economic impact. All approaches for determination of value require professional leadership. There is a need for research of varying types including that related to translating global evidence into local practice, a key challenge facing laboratory medicine and healthcare generally. Another challenge is to think and act beyond the silo of the laboratory to achieve greater collaboration with those colleagues more directly involved in patient care.

Hypophosphatasia (HPP) is a rare inherited systemic metabolic disease caused by mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. TNSALP is expressed in the liver, kidney and bone, and its substrates include TNSALP inorganic pyrophosphate, pyridoxal-5'-phosphate (PLP)/vitamin B6 and phosphoethanolamine (PEA). Autosomal recessive and dominant forms of the disease result in a range of clinical entities. Major hallmarks are low alkaline phosphatase (ALP) and elevated PLP and PEA levels. Very severe infantile forms of HPP cause premature death as a result of respiratory insufficiency and also present with hypo-mineralisation leading to deformed limbs with, in some cases, the near-absence of bones and skull altogether. Respiratory failure, rib fractures and seizures due to vitamin B6 deficiency are indicative of a poor prognosis. Craniosynostosis is frequent. HPP leads to an unusual presentation of rickets with high levels of calcium and phosphorus, resulting in hypercalciuria, nephrocalcinosis and low ALP levels. Hypercalcaemic crisis, failure to thrive and growth retardation are concerns in infants. Fractures are common in both infantile and adult forms of the disease, concomitantly occurring with unexplained chronic pain and fatigue. Dental clinical presentations, which include the premature loss of teeth, are also commonly found in HPP and specifically manifest as odontohypophosphatasia. A novel enzyme therapy for human HPP, asfotase alfa, which is specifically targeted to mineralised tissues, has been developed in the past decades. While this treatment seems very promising, especially for infantile HPP, many questions regarding its long-term effects, the management of treatment, and any potential secondary adverse effects remain unresolved.

Carbohydrate intolerance is one of several syndromes and diseases which together are known as malabsorption syndromes. These include small intestinal bacterial overgrowth (SIBO), coeliac disease, intestinal lymphangiectasia, short bowel syndrome, tropical sprue and some inherited metabolic disorders such as galactosaemia and pyruvate kinase deficiency. Specifically, the malabsorption of sugars affects morbidity for millions of sufferers across the world. Disaccharidase measurement is used in the investigation of disorders of the gastrointestinal tract. Diagnosis is by endoscopic small bowel biopsy of the duodenum or jejunum with subsequent biochemical and histopathological analysis. The diagnosis of bowel disorders presents several challenges with numerous overlapping presentations and symptoms such as bloating, diarrhoea, constipation, flatulence, borborygmus, weight loss and severe discomfort.

Genetic testing has an increasingly important role in the diagnosis and management of cardiac disorders, where it confirms the diagnosis, aids prognostication and risk stratification and guides treatment. A genetic diagnosis in the proband also enables clarification of the risk for family members by cascade testing. Genetics in cardiac disorders is complex where epigenetic and environmental factors might come into interplay. Incomplete penetrance and variable expressivity is also common. Genetic results in cardiac conditions are mostly probabilistic and should be interpreted with all available clinical information. With this complexity in cardiac genetics, testing is only indicated in patients with a strong suspicion of an inheritable cardiac disorder after a full clinical evaluation. In this review we discuss the genetics underlying the major cardiomyopathies and channelopathies, and the practical aspects of diagnosing these conditions in the laboratory.