{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T15:23:24Z","timestamp":1791473004474,"version":"4.3.4"},"reference-count":135,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T00:00:00Z","timestamp":1731628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hyperhomocysteinemia (HHcy) is a medical condition characterized by an abnormally high level of homocysteine (Hcy) in the blood. Homocysteine is a toxic sulfur-containing amino acid that is produced during the metabolism of methionine. Under normal circumstances, Hcy is recycled back to methionine via the remethylation pathway, through the action of various enzymes and vitamins, particularly folic acid (vitamin B9) and B12 used when intracellular methionine levels are low, thus restoring the necessary levels to correctly maintain active protein synthesis. A second pathway, used in cases of intracellular methionine excess, (the trans-sulfuration pathway) is the one that recycles Hcy into cysteine (a precursor of glutathione), first passing through cystathionine (via the enzyme cystathionine beta-synthase), a reaction that requires vitamin B6 in its active form. HHcy has been identified as a risk factor for a variety of disorders, including cardiovascular diseases, multiple sclerosis, diabetes, Alzheimer\u2019s and Parkinson\u2019s diseases, osteoporosis and cancer. However, it remains unclear whether the slightly elevated concentration of Hcy (Hcy 7\u201310 \u03bcmol\/L) is a causative factor or simply a marker of these pathologies. In human plasma, the concentration of Hcy ([Hcy]) is classified as mild (15 to 30 \u03bcmol\/L), moderate (30 to 100 \u03bcmol\/L), and severe (greater than 100 \u03bcmol\/L). Interestingly, many laboratories continue to consider 25 \u03bcmol\/L as normal. This review seeks to examine the controversial literature regarding the normal range of HHcy and emphasizes that even a [Hcy] level of 10 \u03bcmol\/L may contribute to the development of several diseases, aiming to discuss whether it would be appropriate to lower the threshold of HHcy normal values.<\/jats:p>","DOI":"10.3390\/ijms252212295","type":"journal-article","created":{"date-parts":[[2024,11,18]],"date-time":"2024-11-18T04:07:09Z","timestamp":1731902829000},"page":"12295","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Hyperhomocysteinemia and Disease\u2014Is 10 \u03bcmol\/L a Suitable New Threshold Limit?"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6611-8103","authenticated-orcid":false,"given":"Giada","family":"Marroncini","sequence":"first","affiliation":[{"name":"Biomolecular Diagnostic Laboratories, Via N. Porpora, 50144 Florence, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4992-2252","authenticated-orcid":false,"given":"Serena","family":"Martinelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Florence, 50139 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Menchetti","sequence":"additional","affiliation":[{"name":"Biomolecular Diagnostic Laboratories, Via N. Porpora, 50144 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Bombardiere","sequence":"additional","affiliation":[{"name":"Biomolecular Diagnostic Laboratories, Via N. Porpora, 50144 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Saverio","family":"Martelli","sequence":"additional","affiliation":[{"name":"Biomolecular Diagnostic Laboratories, Via N. Porpora, 50144 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.cell.2012.02.045","article-title":"Regulated noise in the epigenetic landscape of development and disease","volume":"148","author":"Pujadas","year":"2012","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nrc1279","article-title":"The history of cancer epigenetics","volume":"4","author":"Feinberg","year":"2004","journal-title":"Nat. Rev. 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