IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-26 DOI: 10.1016/j.pathol.2025.09.011

Rongjun Mao, Changliang Zhang, Dongbing Li, Si Chen, Rong Rong, Sheng Xiao

引用次数: 0

Interpreting alkaline phosphatase in clinical practice: integrating analytical advances and physiological context 在临床实践中解释碱性磷酸酶：整合分析进展和生理背景。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-23 DOI: 10.1016/j.pathol.2025.11.005

Kenneth Andrew Sikaris , Karen Rankin

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.

准确解释血清碱性磷酸酶（ALP）水平在临床实践中至关重要，需要对分析方法和生理决定因素有细致入微的理解。ALP测定技术的最新进展，特别是IFCC参考方法的采用，导致更高的ALP测量值，需要重新评估参考区间。本综述将分析发展与生理背景结合起来，以指导临床医生解释ALP结果。ALP的水平受年龄、性别、怀孕和绝经等生理状态以及体重指数和骨密度等人体测量因素的影响。国际临床化学和实验室医学联合会（IFCC）方法目前已得到广泛应用，其结果比以前的检测方法高出约10%，影响了参考区间的准确性和临床标记率。ALP升高的临床原因包括肝胆和骨骼疾病、恶性肿瘤、内分泌疾病和良性的一过性高磷酸酶血症，而ALP降低可能是罕见的遗传、肝脏或营养紊乱的信号。使用γ -谷氨酰转移酶作为诊断辅助手段增强了肝源ALP升高的特异性。样品处理和试剂可变性等人为因素仍然是测定一致性的挑战。这篇文章强调了将ALP结果与临床背景、其他实验室结果和更新的参考区间联系起来的重要性。持续的教育和参考间隔的协调对于有效的临床决策和减少不必要的调查是必不可少的，确保ALP仍然是患者评估的宝贵工具。

{"title":"Interpreting alkaline phosphatase in clinical practice: integrating analytical advances and physiological context","authors":"Kenneth Andrew Sikaris , Karen Rankin","doi":"10.1016/j.pathol.2025.11.005","DOIUrl":"10.1016/j.pathol.2025.11.005","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 172-180"},"PeriodicalIF":3.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional reference limit: objectively defining the physiological relationship between serum vitamin D and parathyroid hormone 功能参考限度：客观界定血清维生素D与甲状旁腺激素的生理关系。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-20 DOI: 10.1016/j.pathol.2025.11.006

Tze Ping Loh , Hui Qi Low , Perkin Ming Him Chan , Corey Markus , Chun Yee Lim

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).

功能参考极限被定义为拐点（“断点”），代表两个生物学相关生物标志物之间统计关系的变化。我们用血清25-羟基维生素D（维生素D）和甲状旁腺激素之间的稳态关系作为概念证明，描述了一个统计框架来客观地定义功能参考极限。维生素D（自变量）和甲状旁腺激素（因变量）的测量数据从墨尔本病理学实验室信息系统数据库中提取。首先生成生物标记对的散点图，以直观地评估拐点（断点）的存在。在此之后，测量结果被分组到500、800和1000的固定浓度区间，并进行归一化，以确保两种生物标志物的值范围相同。归一化的数据被分成两个（左和右）帧，两个加权线性回归沿着浓度范围以滑动方式拟合，以寻找两个回归的最佳拟合，由最小的残差均方确定。利用该方法确定了维生素D的最佳功能参考限度，其中甲状旁腺激素的断点为28 nmol/L， 800个固定浓度区间，残差的均方根为0.0022。该方法采用多种统计方法改进加权线性回归的拟合，客观地确定了功能参考极限。这种方法的Excel工具是可用的（补充文件1）。

{"title":"Functional reference limit: objectively defining the physiological relationship between serum vitamin D and parathyroid hormone","authors":"Tze Ping Loh , Hui Qi Low , Perkin Ming Him Chan , Corey Markus , Chun Yee Lim","doi":"10.1016/j.pathol.2025.11.006","DOIUrl":"10.1016/j.pathol.2025.11.006","url":null,"abstract":"<div><div>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).</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 163-166"},"PeriodicalIF":3.0,"publicationDate":"2025-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Screening for multiple myeloma has low yield as part of a secondary osteoporosis screen 作为继发性骨质疏松筛查的一部分，多发性骨髓瘤的筛查率很低。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-19 DOI: 10.1016/j.pathol.2025.11.004

Joanna Y. Gong , Sandra Iuliano , Aye N. Tint , Jas-mine Seah , MaiAnh Nguyen , Cherie Chiang

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.

多发性骨髓瘤（MM）是骨质疏松症的继发原因，建议在脆性骨折后进行普遍筛查。然而，这种方法的纵向产量尚未得到评估。我们的目的是评估2009年6月1日至2014年6月1日期间奥斯汀健康骨折联络服务（FLS）数据库中继发性骨质疏松症筛查的成分率。提取患者人口统计资料、脆性骨折类型、骨密度和病理结果，包括血清蛋白电泳（SPE）、尿Bence Jones蛋白（BJP）和血清游离轻链。SPE结果分为正常、炎症或单克隆[包括意义不明的单克隆γ病（MGUS）或MM]。在5年多的时间里，1589名接受FLS邀请的1592名确诊易碎性骨折患者获得了1026个SPE初步结果。中位年龄为72岁（IQR 62-81）， 26%为男性，24%为髋部或骨盆骨折。骨折后平均7天（IQR 3-35）进行MM筛查，结果显示796例（78%）正常，179例（17%）炎症，51例（5%）单克隆。对121例初始炎性SPE结果的患者进行重复SPE分析，获得另外6个单克隆结果。该单克隆队列的中位随访时间为4.4年（IQR为2.4-7.5）；这导致4.2%的MGUS和0.3%的MM诊断。通用MM筛查的总费用为88,638澳元。骨髓瘤筛查的成功率很低，而且成本很高。所有新的MM病例已被其他常规病理检查标记。

{"title":"Screening for multiple myeloma has low yield as part of a secondary osteoporosis screen","authors":"Joanna Y. Gong , Sandra Iuliano , Aye N. Tint , Jas-mine Seah , MaiAnh Nguyen , Cherie Chiang","doi":"10.1016/j.pathol.2025.11.004","DOIUrl":"10.1016/j.pathol.2025.11.004","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 214-219"},"PeriodicalIF":3.0,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041178","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Bone metabolism in pathology: current practice and future directions 骨代谢病理学：目前的实践和未来的方向。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-18 DOI: 10.1016/j.pathol.2025.12.002

Cherie Chiang , Kay Weng Choy

引用次数: 0

Heritable metabolic bone disorders: a guide to current genetic testing and clinical management for adult endocrinologists 遗传性代谢性骨疾病：成人内分泌学家当前基因检测和临床管理指南。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-18 DOI: 10.1016/j.pathol.2025.12.001

Shejil Kumar , Emma L. Duncan , Lisa Hayes , Yemima Berman , Roderick J. Clifton-Bligh , Sunita M.C. De Sousa

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.

遗传性代谢性骨疾病[包括x连锁低磷血症（XLH）、低磷血症和成骨不全症（OI）]是罕见的骨骼疾病，通常出现在儿童时期，需要终身多学科治疗。在过去的二十年里，成人内分泌学家经常发现自己是医学领域经历巨大变化的护理团队的一部分；无论是诊断上还是治疗上。骨骼发育不良的最佳管理需要深入了解分子病因学、基因检测策略和结果解释；最先进的管理方法，包括解决基本分子机制的新靶向疗法。总之，这些因素正在扩大基因检测进入主流临床实践的范围。这篇综述将讨论三种更常见的遗传性代谢性骨疾病的发病机制和临床负担，概述一种现代的基因检测方法，并讨论当前和未来的治疗前景，根据最近的基因组进展，明确的目的是为执业医生提供一个可行的和最新的方法来治疗XLH、低磷酸酶和成骨不全患者。

{"title":"Heritable metabolic bone disorders: a guide to current genetic testing and clinical management for adult endocrinologists","authors":"Shejil Kumar , Emma L. Duncan , Lisa Hayes , Yemima Berman , Roderick J. Clifton-Bligh , Sunita M.C. De Sousa","doi":"10.1016/j.pathol.2025.12.001","DOIUrl":"10.1016/j.pathol.2025.12.001","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 189-198"},"PeriodicalIF":3.0,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Skeletal health in the precursor stages of multiple myeloma: fracture risk and bone phenotypes in monoclonal gammopathy of undetermined significance and smouldering myeloma 多发性骨髓瘤前体阶段的骨骼健康：未确定意义的单克隆γ病和阴燃骨髓瘤的骨折风险和骨表型

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-16 DOI: 10.1016/j.pathol.2025.11.002

Melissa D. Cantley , Laura J. Trainor , Emma A-J. Cheney , Suzanne M. Watt , Kate Vandyke

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.

多发性骨髓瘤（MM）是一种血液学恶性肿瘤，主要以骨髓中的克隆浆细胞增殖为特征。高达80%的MM患者患有溶骨性骨病，其特征是病理性骨折的风险增加和显著的骨痛影响生活质量。MM的先兆是意义不明的单克隆γ病（MGUS）和阴燃型多发性骨髓瘤（SMM），这两种疾病通常都是无症状的。尽管患有这些前驱疾病的患者没有出现可检测到的溶骨性骨病，并且通常没有开始任何治疗，但有证据表明骨骼表型发生了改变。多项研究表明，MGUS患者骨折的风险增加，特别是椎体骨折，与骨密度降低有关。然而，在MGUS和SMM中，骨骼参数的普遍变化在整个骨骼中并不常见，局部变化通常归因于浆细胞的接近。组织形态计量学分析显示，与病情稳定的患者相比，进展性MGUS和SMM患者有明显的骨吸收表型，这支持了破骨细胞活性增加在疾病进展之前的概念。降低骨折风险的治疗方法，如双磷酸盐，在MGUS或SMM阶段通常不使用，目前没有临床循证实践或监测骨骼健康的标准护理指南。虽然很明显，快速进展的MGUS和SMM患者具有稳定疾病中未见的独特骨重塑表型，但需要进一步的研究来充分表征这些前体条件下的骨组织形态学变化，并将其与当前的诊断标准相结合，以更好地了解这些表型基础上的特定骨细胞变化。因此，在疾病的前驱阶段考虑这种骨骼表型是很重要的，特别是骨折风险增加的后果，以及与进展相关的骨骼表型。

{"title":"Skeletal health in the precursor stages of multiple myeloma: fracture risk and bone phenotypes in monoclonal gammopathy of undetermined significance and smouldering myeloma","authors":"Melissa D. Cantley , Laura J. Trainor , Emma A-J. Cheney , Suzanne M. Watt , Kate Vandyke","doi":"10.1016/j.pathol.2025.11.002","DOIUrl":"10.1016/j.pathol.2025.11.002","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 199-213"},"PeriodicalIF":3.0,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019180","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genetic, structural, and functional foundations of alkaline phosphatase measurement in clinical diagnostics 临床诊断中碱性磷酸酶测定的遗传、结构和功能基础。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-15 DOI: 10.1016/j.pathol.2025.11.003

Kenneth Andrew Sikaris , Karen Rankin

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.

碱性磷酸酶（ALP）是一种膜结合的外酶，在临床医学中具有重要的诊断意义，特别是在骨骼和肝脏疾病中。本文综述了ALP的遗传、结构和功能基础，强调了其在组织中的分布，如骨、肝、肠、胎盘和中性粒细胞。本文详细介绍了ALP基因家族的进化，包括组织非特异性和组织特异性同工酶，并讨论了遗传变异和翻译后修饰如何影响ALP活性、血清水平和临床解释。同功酶分析，包括电泳和免疫分析技术，能够在ALP升高的情况下区分组织来源，提高对Paget病、肾性骨营养不良和恶性肿瘤等疾病的诊断精度。该综述还探讨了ABO血型对ALP水平的影响，ALP在骨骼矿化和炎症中的功能作用，以及了解分子多样性对准确测量的重要性。ALP异构体的稳定性，清除率和碳水化合物组成被讨论为临床检测的关键决定因素。总的来说，全面了解ALP的遗传和生化多样性对于解释血清ALP测量、区分骨骼和肝脏病理以及为临床决策提供信息至关重要。这些知识增强了ALP作为诊断性生物标志物的效用，并支持其在监测代谢性骨病和其他疾病中的作用。

{"title":"Genetic, structural, and functional foundations of alkaline phosphatase measurement in clinical diagnostics","authors":"Kenneth Andrew Sikaris , Karen Rankin","doi":"10.1016/j.pathol.2025.11.003","DOIUrl":"10.1016/j.pathol.2025.11.003","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 167-171"},"PeriodicalIF":3.0,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proposed common reference intervals for reference bone turnover markers in osteoporosis 提出骨质疏松症参考骨转换标志物的共同参考区间。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-11 DOI: 10.1016/j.pathol.2025.11.001

S.A. Paul Chubb , Samuel D. Vasikaran

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.

2011年，血清I型胶原n端前肽（P1NP）和1型胶原β- c端末端肽（β-CTX）被指定为骨质转换标志物（BTMs）的参考指标，纳入骨质疏松症的临床研究。近年来，骨碱性磷酸酶（BALP）和抗酒石酸酸性磷酸酶5b （TRACP5b）被指定为慢性肾脏疾病相关性骨质疏松症临床研究的参考btm。随着这些发展，有必要为这些btm提供权威的通用参考区间，以便在临床护理环境中使用。本研究的目的是在现有文献的基础上，建立自动化方法测量P1NP、β-CTX、BALP和TRACP5b的候选共同参考区间。对报道成人参考BTM参考区间的出版物进行了系统回顾。对每个BTM、方法、年龄和性别类别、参考区间限值和中心值进行汇总，并用于估计绝经前和绝经后女性和男性的加权平均值和置信限。根据这些信息，开发了临床使用的候选通用参考区间。该系统综述产生了31项研究。罗氏Cobas法检测P1NP和β-CTX的研究有20篇，IDS iSYS法检测P1NP和β-CTX的研究有5篇，自动化检测BALP的方法有10篇。没有研究发现自动测量TRACP5b的方法，但分析了Nittobo酶联免疫吸附试验的数据。有强有力的证据表明，iSYS和Cobas方法可以使用相同的P1NP参考区间。iSYS和Cobas β-CTX检测以及iSYS和Beckman Ostase BALP检测需要不同的参考区间。建议的成人BTMs参考区间将有助于完善现有的通用参考区间，并将研究重点放在需要更多数据的BTMs上。

{"title":"Proposed common reference intervals for reference bone turnover markers in osteoporosis","authors":"S.A. Paul Chubb , Samuel D. Vasikaran","doi":"10.1016/j.pathol.2025.11.001","DOIUrl":"10.1016/j.pathol.2025.11.001","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 181-188"},"PeriodicalIF":3.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146019142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Seeing beyond the surface: bone histomorphometry re-visited—implications for diagnostic pathology 透过表面看：骨组织形态计量学重新审视-诊断病理学的意义。

IF 3 3区医学 Q1 PATHOLOGY

Pathology

Pub Date : 2025-12-05 DOI: 10.1016/j.pathol.2025.10.006

Terrence Diamond , Cherie Chiang , Grahame J. Elder

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.

在20世纪50年代，随着经髂嵴环钻的发展和塑料埋入技术的出现，非钙化骨活检通过允许对矿化骨进行体内评估，彻底改变了骨骼病理学。1969年四环素双标记的加入使骨形成的动态测量成为可能，到20世纪80年代，组织形态计量学命名法已经标准化，为代谢性骨病的定量诊断奠定了基础。尽管取得了这些进展，但非钙化活检的临床应用已经减弱，取而代之的是双能x线吸收仪和血清代谢标志物等替代工具。然而，骨活检仍然是唯一一种同时捕获骨结构、转换动态和矿化状态的方法。虽然脱钙标本仍然是评估骨髓病理、肿瘤和感染的必要条件，但它们会消除矿物相、荧光标记和关键的类骨结构。相比之下，未钙化、荧光标记的切片可以精确量化骨形成率、矿化滞后时间和微结构完整性，为了解骨骼疾病的生理过程提供了直接的窗口。组织形态学已经阐明了疾病的发病机制，包括骨软化症、肾性骨营养不良、动力骨和双磷酸盐诱导的抑制。它还在澄清非典型或治疗抵抗性骨质疏松症的转换状态以及表征骨髓瘤和转移性疾病的骨生物学改变方面发挥核心作用，其中骨破坏通常不仅反映肿瘤侵袭，还反映不耦合或阻止再生。除了标准组织学和组织形态测量学之外，活检芯的显微计算机断层扫描可以对小梁和皮质骨进行三维分析，而傅里叶变换红外光谱、微压痕和电子显微镜等新兴技术为评估骨成分、基质成熟度和纳米级组织提供了新的方法。这篇综述再次介绍了未钙化骨活检作为一种重要的诊断和调查工具。我们概述了其方法，临床适应症，以及在代谢和癌症相关骨骼疾病中的解释价值，并为其实施提供实用指导。

{"title":"Seeing beyond the surface: bone histomorphometry re-visited—implications for diagnostic pathology","authors":"Terrence Diamond , Cherie Chiang , Grahame J. Elder","doi":"10.1016/j.pathol.2025.10.006","DOIUrl":"10.1016/j.pathol.2025.10.006","url":null,"abstract":"<div><div>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 <em>in vivo</em> 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.</div></div>","PeriodicalId":19915,"journal":{"name":"Pathology","volume":"58 2","pages":"Pages 230-242"},"PeriodicalIF":3.0,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146041109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pathology最新文献