{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T10:33:54Z","timestamp":1794134034187,"version":"4.8.0"},"reference-count":25,"publisher":"Walter de Gruyter GmbH","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec id=\"j_cclm-2025-1722_abs_001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>Identifying individuals with vitamin B12 (B12) deficiency is challenging due to poor harmonization across total B12 assays. To establish clinically meaningful thresholds for the Roche assay, we characterized B12 concentrations associated with deficiency by comparing individuals with macrocytic anemia and other anemia subtypes or no anemia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1722_abs_002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analysed 10\u00a0years of laboratory data from adults tested for total B12 and folate (Roche Cobas), homocysteine (Abbott Architect), and haematological parameters (Sysmex XE\/XN). Individuals receiving vitamin supplementation or with isolated folate deficiency were excluded. Anemia subtypes (normocytic, microcytic, macrocytic) were classified using red blood cell count, hemoglobin concentration, and mean corpuscular volume relative to reference intervals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1722_abs_003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 5,147 subjects (median age 65\u00a0years; 25th\u201375th percentile: 49\u201377), 36.8\u202f% had anemia. Total B12 concentrations decreased by 2.3\u202fng\/L for each 1\u202f\u03bcmol\/L increase in homocysteine and by 6.8\u202fng\/L per decade of age increase (p&lt;0.0001). Macrocytic anemia (9.4\u202f% of subjects), was associated with a mean reduction of 18.6\u202fng\/L in B12 levels compared with no anemia and microcytic anemia. Mean homocysteine concentrations rose progressively, from 15.9 to 21.5\u202f\u03bcmol\/L and then to 34.9\u202f\u03bcmol\/L, as total B12 concentrations fell in the intervals: 342\u2013447\u202fng\/L, 341\u2013258\u202fng\/L, and 257\u00a0\u2013\u00a0&lt;50\u202fng\/L, respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"j_cclm-2025-1722_abs_004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Among individuals investigated for anemia, macrocytosis, a hallmark of B12 depletion, supports that total B12 concentrations\u00a0\u2264257\u202fng\/L measured using the Roche assay likely reflect severe deficiency. Levels between 258 and 341\u202fng\/L may indicate early depletion and warrant confirmation through elevated homocysteine concentrations.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1515\/cclm-2025-1722","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T13:07:48Z","timestamp":1771247268000},"page":"1117-1123","source":"Crossref","is-referenced-by-count":5,"title":["Optimizing diagnostic thresholds of total vitamin B12 (B12) for identifying cobalamin deficiency in adults with macrocytic anemia"],"prefix":"10.1515","volume":"64","author":[{"given":"Michela","family":"Pelloso","sequence":"first","affiliation":[{"name":"Laboratory Medicine Unit , University-Hospital of Padova , Padova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0980-4008","authenticated-orcid":false,"given":"Bruno Mario","family":"Cesana","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Statistics, Biometry and Epidemiology \u201cG.A. Maccacaro\u201d , University of Milan , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7748-773X","authenticated-orcid":false,"given":"Giulia","family":"Musso","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Unit , University-Hospital of Padova , Padova , Italy"},{"name":"Department of Medicine (DIMED) , University of Padova , Padova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edoardo","family":"Campigotto","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Unit , University-Hospital of Padova , Padova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Tosi","sequence":"additional","affiliation":[{"name":"Department of Health Sciences , University of Milan , Milan , Italy"},{"name":"Department of Pediatrics , Buzzi Children\u2019s Hospital , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lalli","sequence":"additional","affiliation":[{"name":"Unit of Translational Immunology , IRCCS Foundation National Cancer Institute , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianvicenzo","family":"Zuccotti","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Buzzi Children\u2019s Hospital , Milan , Italy"},{"name":"Department of Biomedical and Clinical Science , University of Milan , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Montagnana","sequence":"additional","affiliation":[{"name":"Laboratory Medicine Unit , University-Hospital of Padova , Padova , Italy"},{"name":"Department of Medicine (DIMED) , University of Padova , Padova , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0270-1711","authenticated-orcid":false,"given":"Mario","family":"Plebani","sequence":"additional","affiliation":[{"name":"Honorary Professor of Clinical Chemistry and Clinical Molecular Biology , University of Padova , Padua , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Ferraro","sequence":"additional","affiliation":[{"name":"Department of Pediatrics , Buzzi Children\u2019s Hospital , Milan , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"374","published-online":{"date-parts":[[2026,2,13]]},"reference":[{"key":"2026033013262447084_j_cclm-2025-1722_ref_001","doi-asserted-by":"crossref","unstructured":"Moore, E, Mander, A, Ames, D, Carne, R, Sanders, K, Watters, D. Cognitive impairment and vitamin B12: a review. Int Psychogeriatr 2012;24:541\u201356. https:\/\/doi.org\/10.1017\/s1041610211002511.","DOI":"10.1017\/S1041610211002511"},{"key":"2026033013262447084_j_cclm-2025-1722_ref_002","unstructured":"Vitamin B12 deficiency in over 16s: diagnosis and management [C] Evidence review for diagnostic tests NICE guideline NG239. Evidence\u00a0reviews underpinning recommendations 1.3.1 to 1.3.16\u00a0and\u00a0recommendations for research in the NICE guideline March\u00a02024. PMID: 38713783. Bookshelf ID: NBK603366. https:\/\/pubmed.ncbi.nlm.nih.gov\/38713783\/# [Accessed Dec 2024]."},{"key":"2026033013262447084_j_cclm-2025-1722_ref_003","doi-asserted-by":"crossref","unstructured":"Ferraro, S, Mozzi, R, Panteghini, M. Tracing a roadmap for vitamin B12 testing using the health technology assessment approach. 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J\u00a0Nutr 2018;148:738\u201345. https:\/\/doi.org\/10.1093\/jn\/nxy028.","DOI":"10.1093\/jn\/nxy028"},{"key":"2026033013262447084_j_cclm-2025-1722_ref_018","doi-asserted-by":"crossref","unstructured":"Acharya, U, Gau, JT, Horvath, W, Ventura, P, Hsueh, CT, Carlsen, W. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J\u00a0Hematol Oncol 2008;1:26. https:\/\/doi.org\/10.1186\/1756-8722-1-26.","DOI":"10.1186\/1756-8722-1-26"},{"key":"2026033013262447084_j_cclm-2025-1722_ref_019","doi-asserted-by":"crossref","unstructured":"Fenech, M. Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity. Mutat Res 2012;733:21\u201333. https:\/\/doi.org\/10.1016\/j.mrfmmm.2011.11.003.","DOI":"10.1016\/j.mrfmmm.2011.11.003"},{"key":"2026033013262447084_j_cclm-2025-1722_ref_020","doi-asserted-by":"crossref","unstructured":"Wolffenbuttel, BH, Owen, PJ, Ward, M, Green, R. 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Vitam Horm 2022;119:325\u201353. https:\/\/doi.org\/10.1016\/bs.vh.2022.01.011.","DOI":"10.1016\/bs.vh.2022.01.011"}],"container-title":["Clinical Chemistry and Laboratory Medicine (CCLM)"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2025-1722\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2025-1722\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,30]],"date-time":"2026-03-30T13:27:50Z","timestamp":1774877270000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.degruyterbrill.com\/document\/doi\/10.1515\/cclm-2025-1722\/html"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,13]]},"references-count":25,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,12,15]]},"published-print":{"date-parts":[[2026,4,24]]}},"alternative-id":["10.1515\/cclm-2025-1722"],"URL":"https:\/\/doi.org\/10.1515\/cclm-2025-1722","relation":{},"ISSN":["1434-6621","1437-4331"],"issn-type":[{"value":"1434-6621","type":"print"},{"value":"1437-4331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,13]]}}}