{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T13:35:21Z","timestamp":1793712921051,"version":"4.6.1"},"reference-count":34,"publisher":"SAABRON PRESS","issue":"3","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Iron deficiency is the most common micronutrient deficiency worldwide, affecting approximately 2 billion individuals. Iron deficiency without anemia (IDNA), the stage in which iron stores are depleted but hemoglobin remains within the reference range, is estimated to affect approximately 1-2 billion individuals, although the precise prevalence varies by population, ferritin threshold, and inflammatory status. IDNA remains underrecognized because diagnostic evaluation often focuses on hemoglobin concentrations rather than iron stores.<\/jats:p>\n                  <jats:p>A growing body of evidence demonstrates that IDNA is associated with clinically significant fatigue, impaired cognitive function, anxiety, reduced exercise capacity, and diminished quality of life. Randomized controlled trials and meta-analyses of iron repletion in iron-deficient non-anemic cohorts demonstrate clinically meaningful reductions in fatigue.<\/jats:p>\n                  <jats:p>Emerging observational data have also identified an association between iron deficiency and colorectal neoplasia in selected higher-risk populations such as older adults, men, and postmenopausal women. However, the magnitude of this risk and the role of routine endoscopic evaluation in patients with IDNA remain incompletely defined.<\/jats:p>\n                  <jats:p>This narrative review examines the epidemiology, pathophysiology, origins of under-recognition, clinical manifestations, diagnostic approach, treatment, association with colorectal cancer, and future directions for IDNA in adults.<\/jats:p>","DOI":"10.46989\/001c.165952","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:11:51Z","timestamp":1785935511000},"source":"Crossref","is-referenced-by-count":0,"title":["Iron deficiency without anemia: An underrecognized and undertreated clinical condition with special focus on colorectal cancer"],"prefix":"10.46989","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9633-7999","authenticated-orcid":true,"given":"Naga P.","family":"Raja","sequence":"first","affiliation":[{"name":"Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nagapavani","family":"Kandagari","sequence":"additional","affiliation":[{"name":"Oregon Health and Science University, Portland, Oregon, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"26435","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"issue":"17","key":"ref1","doi-asserted-by":"publisher","first-page":"1981","DOI":"10.1182\/blood-2015-05-642223","article-title":"Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women","volume":"126","author":"D. Moretti","year":"2015","journal-title":"Blood"},{"issue":"4","key":"ref2","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1111\/bjh.20030","article-title":"How I treat iron-refractory iron deficiency anaemia-An expert opinion-based treatment guidance for children and adults","volume":"206","author":"V. Hoving","year":"2025","journal-title":"Br J Haematol"},{"issue":"3","key":"ref3","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1002\/ajh.70198","article-title":"Impact of optimizing the lower limit of normal for ferritin on iron deficiency diagnosis and treatment patterns: A pre- and post-intervention study using EHR data","volume":"101","author":"A. Abdelhay","year":"2026","journal-title":"Am J Hematol"},{"issue":"6","key":"ref4","doi-asserted-by":"publisher","first-page":"2637","DOI":"10.1002\/jcsm.13114","article-title":"Systematic review and meta-analysis of intravenous iron therapy for adults with non-anaemic iron deficiency: An abridged Cochrane review","volume":"13","author":"C. Dugan","year":"2022","journal-title":"J Cachexia Sarcopenia Muscle"},{"issue":"10","key":"ref5","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1017\/S0007114517001349","article-title":"Iron deficiency without anaemia is a potential cause of fatigue: Meta-analyses of randomised controlled trials and cross-sectional studies","volume":"117","author":"K. Yokoi","year":"2017","journal-title":"Br J Nutr"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"106372","DOI":"10.1016\/j.neubiorev.2025.106372","article-title":"Psychiatric and cognitive outcomes of iron supplementation in non-anemic children, adolescents, and menstruating adults: A meta-analysis and systematic review","volume":"178","author":"D. Fiani","year":"2025","journal-title":"Neurosci Biobehav Rev"},{"issue":"6","key":"ref7","doi-asserted-by":"publisher","first-page":"e2515642","DOI":"10.1001\/jamanetworkopen.2025.15642","article-title":"Brain structure and functional connectivity in adolescents with nonanemic iron deficiency","volume":"8","author":"J. Zheng","year":"2025","journal-title":"JAMA Netw Open"},{"issue":"3","key":"ref8","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1053\/j.gastro.2020.06.046","article-title":"AGA clinical practice guidelines on the gastrointestinal evaluation of iron deficiency anemia","volume":"159","author":"C. W. Ko","year":"2020","journal-title":"Gastroenterology"},{"issue":"2","key":"ref9","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1111\/ejh.14229","article-title":"Serum ferritin and risk of colonic neoplasia: Implications for the workup and treatment of iron deficiency","volume":"113","author":"A. L. Urback","year":"2024","journal-title":"Eur J Haematol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"100865","DOI":"10.1016\/j.mam.2020.100865","article-title":"Oral iron supplementation in iron-deficient women: How much and how often?","volume":"75","author":"N. U. Stoffel","year":"2020","journal-title":"Mol Aspects Med"},{"issue":"20","key":"ref11","doi-asserted-by":"publisher","first-page":"1813","DOI":"10.1001\/jama.2025.0452","article-title":"Iron deficiency in adults: A review","volume":"333","author":"M. Auerbach","year":"2025","journal-title":"JAMA"},{"issue":"2","key":"ref12","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1111\/ejh.13892","article-title":"The role of oral iron in the treatment of adults with iron deficiency","volume":"110","author":"J. O. Lo","year":"2023","journal-title":"Eur J Haematol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1007\/978-3-031-92033-2_24","article-title":"Oral and intravenous iron therapy","volume":"1480","author":"A. U. Steinbicker","year":"2025","journal-title":"Adv Exp Med Biol"},{"issue":"5","key":"ref14","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1001\/jama.2019.22450","article-title":"Effects of iron isomaltoside vs ferric carboxymaltose on hypophosphatemia in iron-deficiency anemia: two randomized clinical trials","volume":"323","author":"M. Wolf","year":"2020","journal-title":"JAMA"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"CD013084","DOI":"10.1002\/14651858.CD013084.pub2","article-title":"Intravenous iron therapy for non-anaemic, iron-deficient adults","volume":"12","author":"L. F. Miles","year":"2019","journal-title":"Cochrane Database Syst Rev"},{"issue":"9","key":"ref16","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1111\/jgh.16215","article-title":"Prevalence of gastrointestinal malignancy in non-anemic iron deficiency and significance for endoscopic screening: A Western Australian multicenter cohort study","volume":"38","author":"S. Hodges","year":"2023","journal-title":"J Gastroenterol Hepatol"},{"issue":"8","key":"ref17","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1136\/gutjnl-2020-321849","article-title":"Young-onset colorectal cancer risk among individuals with iron-deficiency anaemia and haematochezia","volume":"70","author":"J. Demb","year":"2021","journal-title":"Gut"},{"issue":"11","key":"ref18","doi-asserted-by":"publisher","first-page":"e78850","DOI":"10.1371\/journal.pone.0078850","article-title":"Dietary iron enhances colonic inflammation and IL-6\/IL-11-Stat3 signaling promoting colonic tumor development in mice","volume":"8","author":"A.C. Chua","year":"2013","journal-title":"PLoS One"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1098501","DOI":"10.3389\/fonc.2023.1098501","article-title":"Iron metabolism in colorectal cancer","volume":"13","author":"L. Huang","year":"2023","journal-title":"Front Oncol"},{"issue":"1","key":"ref20","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1093\/nutrit\/nuaa040","article-title":"Iron deficiency, immunology, and colorectal cancer","volume":"79","author":"O. Phipps","year":"2021","journal-title":"Nutr Rev"},{"issue":"24","key":"ref21","doi-asserted-by":"publisher","first-page":"4156","DOI":"10.3390\/cancers16244156","article-title":"The impact of iron on cancer-related immune functions in oncology: Molecular mechanisms and clinical evidence","volume":"16","author":"O. Badran","year":"2024","journal-title":"Cancers (Basel)"},{"issue":"1","key":"ref22","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1182\/hematology.2019000034","article-title":"Management of iron deficiency","volume":"2019","author":"S. Ning","year":"2019","journal-title":"Hematology Am Soc Hematol Educ Program"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"635899","DOI":"10.3389\/fimmu.2021.635899","article-title":"Flipside of the coin: Iron deficiency and colorectal cancer","volume":"12","author":"A. Aksan","year":"2021","journal-title":"Front Immunol"},{"issue":"10","key":"ref24","doi-asserted-by":"publisher","first-page":"1166","DOI":"10.3390\/genes16101166","article-title":"Crossroads of iron metabolism and inflammation in colorectal carcinogenesis: Molecular mechanisms and therapeutic perspectives","volume":"16","author":"N. Ahmadi","year":"2025","journal-title":"Genes (Basel)"},{"issue":"3","key":"ref25","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.cmet.2016.07.015","article-title":"Iron uptake via DMT1 integrates cell cycle with JAK-STAT3 signaling to promote colorectal tumorigenesis","volume":"24","author":"X. Xue","year":"2016","journal-title":"Cell Metab"},{"key":"ref26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2026.04.020","article-title":"Iron-addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death","author":"C. Jain","year":"2026","journal-title":"Cell Metab"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"104439","DOI":"10.1016\/j.critrevonc.2024.104439","article-title":"Faecal immunochemical tests can improve colonoscopy triage in patients with iron deficiency: A systematic review and meta-analysis","volume":"201","author":"J. Pham","year":"2024","journal-title":"Crit Rev Oncol Hematol"},{"issue":"3","key":"ref28","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1111\/hae.70227","article-title":"National Bleeding Disorder Foundation clinical practice recommendations for laboratory screening of iron deficiency with and without anemia in the inherited bleeding disorders population","volume":"32","author":"G. Batsuli","year":"2026","journal-title":"Haemophilia"},{"issue":"5","key":"ref29","doi-asserted-by":"publisher","first-page":"e376","DOI":"10.1016\/S2352-3026(25)00038-9","article-title":"Management of iron deficiency in children, adults, and pregnant individuals: Evidence-based and expert consensus recommendations","volume":"12","author":"A. E. Benson","year":"2025","journal-title":"Lancet Haematol"},{"issue":"4","key":"ref30","doi-asserted-by":"publisher","first-page":"e019240","DOI":"10.1136\/bmjopen-2017-019240","article-title":"Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: A systematic review of randomised controlled trials","volume":"8","author":"B. L. Houston","year":"2018","journal-title":"BMJ Open"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.ejim.2019.12.015","article-title":"Prevalence of gastrointestinal malignancy in iron deficiency without anaemia: A systematic review and meta-analysis","volume":"72","author":"L. Alexandre","year":"2020","journal-title":"Eur J Intern Med"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"20497","DOI":"10.1038\/s41598-026-51533-8","article-title":"Gastrointestinal malignancy in iron deficiency without anemia: A retrospective study from Jordan","volume":"16","author":"S. Haj Ali","year":"2026","journal-title":"Sci Rep"},{"issue":"8","key":"ref33","doi-asserted-by":"publisher","first-page":"e2425692","DOI":"10.1001\/jamanetworkopen.2024.25692","article-title":"Ferritin cutoffs and diagnosis of iron deficiency in primary care","volume":"7","author":"L. Jaeger","year":"2024","journal-title":"JAMA Netw Open"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"CD011817","DOI":"10.1002\/14651858.CD011817.pub2","article-title":"Serum or plasma ferritin concentration as an index of iron deficiency and overload","volume":"5","author":"M. N. Garcia-Casal","year":"2021","journal-title":"Cochrane Database Syst Rev"}],"container-title":["Clinical Hematology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chi.scholasticahq.com\/article\/165952-iron-deficiency-without-anemia-an-underrecognized-and-undertreated-clinical-condition-with-special-focus-on-colorectal-cancer","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T13:05:06Z","timestamp":1793711106000},"score":1,"resource":{"primary":{"URL":"https:\/\/chi.scholasticahq.com\/article\/165952-iron-deficiency-without-anemia-an-underrecognized-and-undertreated-clinical-condition-with-special-focus-on-colorectal-cancer"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.46989\/001c.165952","relation":{},"ISSN":["2590-0048"],"issn-type":[{"value":"2590-0048","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}