Pathology最新文献

Accurate interpretation of serum alkaline phosphatase (ALP) levels is crucial in clinical practice, requiring a nuanced understanding of both analytical methods and physiological determinants. Recent advancements in ALP assay techniques, particularly the adoption of the IFCC reference method, have led to higher measured ALP values and necessitated a reassessment of reference intervals. This review integrates analytical developments with physiological context to guide clinicians in interpreting ALP results. Levels of ALP are influenced by age, gender, physiological states such as pregnancy and menopause, and anthropometric factors including body mass index and bone density. The International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) method, now widely implemented, yields results that are approximately 10% higher than those from previous assays, impacting reference interval accuracy and clinical flagging rates. Clinical causes of elevated ALP span hepatobiliary and bone disorders, malignancies, endocrine conditions and benign transient hyperphosphatasemia, while reduced ALP may signal rare genetic, hepatic or nutritional disorders. The use of gamma-glutamyl transferase as a diagnostic adjunct enhances specificity for hepatic sources of ALP elevation. Artefacts such as sample handling and reagent variability remain challenges in assay consistency. This article underscores the importance of correlating ALP results with clinical context, other laboratory findings and updated reference intervals. Ongoing education and harmonisation of reference intervals are essential for effective clinical decision-making and minimising unnecessary investigations, ensuring ALP remains a valuable tool in patient assessment.

A functional reference limit is defined as the point of inflection (a 'breakpoint'), representing a change in the statistical relationship, between two biologically related biomarkers. We describe a statistical framework to objectively define functional reference limits using the homoeostatic relationship between serum 25-hydroxy vitamin D (vitamin D) and parathyroid hormone as a proof of concept. Vitamin D (the independent variable) and parathyroid hormone (the dependent variable) measurements were extracted from the Melbourne Pathology laboratory information system database. A scatter plot of the biomarker pair was first generated to visually assess the presence of an inflection point (breakpoint). Following this, the measurements were grouped into fixed concentration intervals of 500, 800 and 1000 and normalised to ensure the range of values were identical for both biomarkers. The normalised data were split into two (left and right) frames, and two weighed linear regressions were fitted in a sliding manner along the concentration range to search for the optimal fit for both regressions, as determined by the smallest mean squared of residual. Using this approach, the optimal functional reference limit for vitamin D, where the breakpoint for parathyroid hormone was found at 28 nmol/L with 800 fixed concentration intervals and a mean squared of residual of 0.0022. This approach uses several statistical procedures to improve the fitting of the weighted linear regressions to objectively identify the functional reference limit. An Excel tool of this approach is available (Supplementary File 1).

Multiple myeloma (MM) is a secondary cause of osteoporosis, and universal screening is recommended post fragility fracture. However, the longitudinal yield of this approach has not been evaluated. We aimed to assess the yield of the secondary osteoporosis screen in the Austin Health Fracture Liaison Service (FLS) database between 1 June, 2009 and 1 June 2014. Patient demographics, fragility fracture type, bone density, and pathology results, including serum protein electrophoresis (SPE), urine Bence Jones protein (BJP), and serum free light chains, were extracted. SPE results were classified as normal, inflammatory, or monoclonal [including monoclonal gammopathy of undetermined significance (MGUS) or MM]. Over 5 years, 1026 initial SPE results were available for 1592 confirmed fragility fractures in 1589 patients who accepted the FLS invitation. The median age was 72 years (IQR 62-81), 26% were men, and 24% sustained a hip or pelvic fracture. Screening for MM was performed a median of 7 days (IQR 3-35) post fracture and revealed 796 (78%) normal, 179 (17%) inflammatory, and 51 (5%) monoclonal results. Repeat SPE for 121 patients with initial inflammatory SPE results yielded an additional six monoclonal results. The monoclonal cohort was followed for a median of 4.4 years (IQR 2.4-7.5); this yielded 4.2% MGUS and 0.3% MM diagnoses. The total cost of universal MM screening was AUD $88,638. The yield of myeloma screening was low and associated with a significant cost. All new MM cases were already flagged by other routine pathology tests.

Heritable metabolic bone disorders [including X-linked hypophosphataemia (XLH), hypophosphatasia and osteogenesis imperfecta (OI)] are rare skeletal conditions often presenting in childhood and requiring lifelong multidisciplinary care. Adult endocrinologists frequently find themselves as part of the caring team in an area of medicine experiencing dramatic changes over the past two decades; both diagnostically and therapeutically. Optimal management of skeletal dysplasia requires in-depth understanding of molecular aetiology, genetic testing strategies, and result interpretation; and state-of-the-art management approaches including newer targeted therapies that address fundamental molecular mechanisms. Together, these factors are expanding the reach of genetic testing into mainstream clinical practice. This review will discuss the aetiopathogenesis and clinical burden across the lifespan of three of the more common heritable metabolic bone disorders, outline a modern approach to genetic testing, and discuss current and future therapeutic landscapes informed by recent genomic progress-with the explicit aim of providing practising physicians with a workable and up-to-date approach to the care of individuals with XLH, hypophosphatasia, and OI.

Multiple myeloma (MM) is a haematological malignancy characterised by clonal plasma cell proliferation principally in the bone marrow. Up to 80% of individuals with MM experience osteolytic bone disease, characterised by an increased risk of pathological fractures and significant bone pain impacting quality of life. MM is preceded by monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM), both of which are usually asymptomatic. Although patients with these precursor conditions do not present with detectable osteolytic bone disease and generally are not commenced on any treatment, there is evidence to suggest an altered skeletal phenotype. Multiple studies have revealed that MGUS patients have an increased risk of fractures, particularly vertebral fractures, associated with a reduced bone mineral density. Ubiquitous changes to bone parameters throughout the skeleton are nevertheless uncommon in MGUS and SMM, with local changes often attributed to plasma cell proximity. Histomorphometric analyses have revealed a distinct bone resorption phenotype in patients with progressing MGUS and SMM compared with those who remain stable, supporting the concept that increased osteoclastic activity precedes disease progression. Therapeutics to reduce bone fracture risk, such as bisphosphonates, are not commonly administered during the MGUS or SMM stages, and there are currently no clinical evidence-based practice or standard-of-care guidelines for monitoring skeletal health. While it is clear that patients with rapidly progressing MGUS and SMM possess a unique bone remodelling phenotype not seen in stable disease, further studies are required to fully characterise the bone histomorphometric changes in these precursor conditions and align them with current diagnostic criteria, to better inform specific bone cell changes that underlie these phenotypes. It is therefore important to consider this skeletal phenotype in the precursor disease stages, particularly the consequences of an increased fracture risk, as well as the skeletal phenotype associated with progression.

Alkaline phosphatase (ALP) is a membrane-bound ectoenzyme with critical diagnostic relevance in clinical medicine, particularly for bone and liver diseases. This review examines the genetic, structural, and functional foundations of ALP, highlighting its distribution across tissues such as bone, liver, intestine, placenta, and neutrophils. The article details the evolution of the ALP gene family, including tissue-non-specific and tissue-specific isoenzymes, and discusses how genetic variation and post-translational modifications influence ALP activity, serum levels, and clinical interpretation. Isoenzyme analysis, including electrophoretic and immunoassay techniques, enables differentiation of tissue origins in cases of elevated ALP, improving diagnostic precision for conditions such as Paget's disease, renal osteodystrophy, and malignancy. The review also explores the impact of ABO blood group on ALP levels, the functional roles of ALP in skeletal mineralisation and inflammation, and the importance of understanding molecular diversity for accurate measurement. The stability, clearance, and carbohydrate composition of ALP isoforms are discussed as key determinants in clinical assays. Overall, a comprehensive understanding of ALP's genetic and biochemical diversity is essential for interpreting serum ALP measurements, distinguishing between bone and liver pathology, and informing clinical decision-making. This knowledge enhances the utility of ALP as a diagnostic biomarker and supports its role in monitoring metabolic bone disease and other disorders.

In 2011, serum pro-collagen type I N-terminal propeptide (P1NP) and β-C-terminal telopeptide of type 1 collagen (β-CTX) were designated as reference bone turnover markers (BTMs) for inclusion in clinical studies of osteoporosis. Recently, bone alkaline phosphatase (BALP) and tartrate-resistant acid phosphatase 5b (TRACP5b) were designated as reference BTMs for clinical studies in chronic kidney disease-associated osteoporosis. Following these developments, there is a requirement for authoritative common reference intervals for these BTMs for use in clinical care settings. The aim of this study was to develop candidate common reference intervals for P1NP, β-CTX, BALP and TRACP5b measured by automated methods, based on current literature. A systematic review of publications that reported reference intervals for the reference BTM in adults was conducted. For each BTM, method, age and sex category, reference interval limits and central values were pooled and used to estimate weighted means and confidence limits for pre- and post-menopausal females, and males. From this information, candidate common reference intervals for clinical use were developed. The systematic review yielded 31 studies. There were 20 studies for the Roche Cobas methods for P1NP and β-CTX, five for the IDS iSYS methods for P1NP and β-CTX and 10 for automated methods for BALP. No studies were found for automated methods of measuring TRACP5b, but data for the Nittobo enzyme-linked immunosorbent assay were analysed. There was strong evidence that the same reference intervals for P1NP by both iSYS and Cobas methods could be used. Different reference intervals are needed for iSYS and Cobas β-CTX assays, as well as for iSYS and Beckman Ostase BALP assays. The proposed reference intervals for BTMs in adults will contribute to the refinement of existing common reference intervals and focus research effort on those BTMs where more data are required.

First introduced in the 1950s following the development of the transiliac crest trephine and the advent of plastic embedding techniques, undecalcified bone biopsy revolutionised skeletal pathology by allowing in vivo assessment of mineralised bone. The addition of tetracycline double-labelling in 1969 enabled dynamic measurement of bone formation, and by the 1980s, histomorphometric nomenclature had been standardised, laying the foundation for quantitative diagnosis of metabolic bone disease. Despite these advances, the clinical use of undecalcified biopsy has waned, supplanted by surrogate tools such as dual-energy X-ray absorptiometry and serum markers of turnover. Yet bone biopsy remains the only method that simultaneously captures bone architecture, turnover dynamics, and mineralisation status. While decalcified specimens remain essential for evaluating marrow pathology, neoplasia, and infection, they obliterate the mineral phase, fluorochrome labels, and critical osteoid structures. In contrast, undecalcified, fluorochrome-labelled sections permit precise quantification of bone formation rates, mineralisation lag time, and micro-architectural integrity, offering a direct window into the physiological processes underlying skeletal disease. Histomorphometry has elucidated the pathogenesis of disorders, including osteomalacia, renal osteodystrophy, adynamic bone, and bisphosphonate-induced suppression. It also plays a central role in clarifying turnover status in atypical or treatment-resistant osteoporosis ​and in characterising the altered bone biology of myeloma and metastatic disease, where bone destruction often reflects not only tumour invasion but also uncoupled or arrested regeneration. Beyond standard histology and histomorphometry, microcomputed tomography of biopsy cores enables three-dimensional analysis of trabecular and cortical bone, while emerging techniques, such as Fourier-transform infrared spectroscopy, micro-indentation, and electron microscopy, offer new ways to evaluate bone composition, matrix maturity, and nanoscale organisation. This review re-introduces undecalcified bone biopsy as a vital diagnostic and investigative tool. We outline its methodology, clinical indications, and interpretive value across metabolic and cancer-related bone disorders ​and provide practical guidance for its implementation.