{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T02:34:51Z","timestamp":1781922891471,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Patient Blood Management Academy, 25.11.2021, F\u00f6rderprogramm 2021, Alexandra R\u00fcger"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Iron deficiency anemia (IDA) is common in critically ill patients treated in the intensive care unit (ICU), and it can lead to severe consequences. Precise and immediate diagnostics are not available, but they are inevitably needed to administer adequate therapy. Serological parameters such as serum ferritin and transferrin saturation (TSAT) are heavily influenced by simultaneous inflammation reactions, resulting in the need for more suitable parameters. Reticulocyte biomarkers such as reticulocyte hemoglobin content (RET-He) and Delta-hemoglobin equivalent (Delta-He) determined by fluorescence flowcytometry are more specific for the diagnosis of IDA-based anemia and should be investigated for this purpose. Methods: In a prospective cohort single-center study, serum ferritin and transferrin saturation (TSAT) were collected and compared to RET-He and Delta-He by performing a receiver operating curve (ROC) analysis. The sensitivity and specificity of a single variable or the combination of two variables, as well as cutoff values, for the diagnosis of IDA were calculated. A group comparison for IDA patients without IDA was performed for a control group. Results: A total of 314 patients were enrolled from an interdisciplinary ICU. RET-He (area under the curve (AUC) 0.847) and Delta-He (AUC 0.807) did indicate iron-deficient anemia that was more specific and sensitive in comparison to serum ferritin (AUC 0.678) and TSAT (AUC 0.754). The detection of functional iron deficiency (FID) occurred in 28.3% of cases with anemia. Conclusions: Determination of RET-He and Delta-He allows for the increased precision and sensitivity of iron-deficient anemia in the ICU.<\/jats:p>","DOI":"10.3390\/cells12010140","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:14:28Z","timestamp":1672370068000},"page":"140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Improved Diagnosis of Iron Deficiency Anemia in the Critically Ill via Fluorescence Flowcytometric Hemoglobin Biomarkers"],"prefix":"10.3390","volume":"12","author":[{"given":"Mascha","family":"Zuther","sequence":"first","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie, Operative Intensivmedizin und Schmerztherapie, Universit\u00e4tsklinikum M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Luise","family":"R\u00fcbsam","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie, Intensiv-, Notfall- und Schmerzmedizin, Universit\u00e4tsmedizin Greifswald, 17475 Greifswald, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Zimmermann","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Labormedizin K\u00f6penick, DRK Kliniken Berlin, 12559 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Zarbock","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie, Operative Intensivmedizin und Schmerztherapie, Universit\u00e4tsklinikum M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9658-253X","authenticated-orcid":false,"given":"Christian","family":"H\u00f6nemann","sequence":"additional","affiliation":[{"name":"Klinik f\u00fcr An\u00e4sthesiologie, Operative Intensivmedizin und Schmerztherapie, Universit\u00e4tsklinikum M\u00fcnster, 48149 M\u00fcnster, Germany"},{"name":"Abteilung f\u00fcr An\u00e4sthesiologie und Operative Intensivmedizin, St. Marienhospital Vechta, 49337 Vechta, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.21608\/mjcu.2020.125162","article-title":"Anemia in Critically Ill Patients; Prevalence and Prognostic Implications","volume":"88","author":"Manal","year":"2020","journal-title":"Med. J. Cairo Univ."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lanser, L., Fuchs, D., Kurz, K., and Weiss, G. (2021). Physiology and Inflammation Driven Pathophysiology of Iron Homeostasis-Mechanistic Insights into Anemia of Inflammation and Its Treatment. Nutrients, 13.","DOI":"10.3390\/nu13113732"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1056\/NEJMra1804281","article-title":"Anemia of Inflammation","volume":"381","author":"Ganz","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1111\/joim.13004","article-title":"Iron Deficiency Anaemia Revisited","volume":"287","author":"Cappellini","year":"2020","journal-title":"J. Intern. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMra041809","article-title":"Anemia of Chronic Disease","volume":"352","author":"Weiss","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"566","DOI":"10.5603\/AHP.2021.0091","article-title":"Ferritin and Transferrin Saturation Cannot Be Used to Diagnose Iron-Deficiency Anemia in Critically Ill Patients","volume":"52","author":"Czempik","year":"2021","journal-title":"Acta Haematol. Pol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1258\/acb.2007.007167","article-title":"Interpreting Indicators of Iron Status during an Acute Phase Response-Lessons from Malaria and Human Immunodeficiency Virus","volume":"45","year":"2008","journal-title":"Ann. Clin. Biochem."},{"key":"ref_8","unstructured":"Joint World Health Organization\/Centers for Disease Control and Prevention Technical Consultation on the Assessment of Iron Status at the Population Level (2004). Assessing the Iron Status of Populations: Including Literature Reviews: Report of a Joint World Health Organization\/Centers for Disease Control and Prevention Technical Consultation on the Assessment of Iron Status at the Population Level, World Health Organization."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Shander, A., and Corwin, H.L. (2018). Anemia in the Critically Ill. Hematologic Challenges in the Critically Ill, Springer International Publishing.","DOI":"10.1007\/978-3-319-93572-0"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Petzer, V., Theurl, I., and Weiss, G. (2018). Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases. Pharmaceuticals (Basel), 11.","DOI":"10.3390\/ph11040135"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1515\/cclm-2022-0094","article-title":"Reference Intervals for Sysmex XN Hematological Parameters as Assessed in the Dutch Lifelines Cohort","volume":"60","author":"Klatte","year":"2022","journal-title":"Clin. Chem. Lab. Med. (CCLM)"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5937\/jomb0-31435","article-title":"The Effect of Reticulocyte Hemoglobin Content on the Diagnosis of Iron Deficiency Anemia: A Meta-Analysis Study","volume":"41","author":"Serteser","year":"2022","journal-title":"J. Med. Biochem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/vox.12700","article-title":"Applying Newer Parameter Ret-He (Reticulocyte Haemoglobin Equivalent) to Assess Latent Iron Deficiency (LID) in Blood Donors-Study at a Tertiary Care Hospital in India","volume":"113","author":"Tiwari","year":"2018","journal-title":"Vox Sang"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"667","DOI":"10.7754\/Clin.Lab.2015.150830","article-title":"Delta-He, Ret-He and a New Diagnostic Plot for Differential Diagnosis and Therapy Monitoring of Patients Suffering from Various Disease-Specific Types of Anemia","volume":"62","author":"Weimann","year":"2016","journal-title":"Clin. Lab."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e23225","DOI":"10.1002\/jcla.23225","article-title":"Diagnostic Performance of Reticulocyte Hemoglobin Equivalent in Assessing the Iron Status","volume":"34","author":"Chinudomwong","year":"2020","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1111\/j.1365-2257.2006.00812.x","article-title":"Reticulocyte Hemoglobin Equivalent (Ret He) and Assessment of Iron-Deficient States","volume":"28","author":"Brugnara","year":"2006","journal-title":"Clin. Lab. Haematol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"496","DOI":"10.2478\/jomb-2018-0052","article-title":"The Importance of RET-He in the Diagnosis of Iron Deficiency and Iron Deficiency Anemia and the Evaluation of Response to Oral Iron Therapy","volume":"38","author":"Falay","year":"2019","journal-title":"J. Med. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1093\/ckj\/sfu038","article-title":"Delta-He: A Novel Marker of Inflammation Predicting Mortality and ESA Response in Peritoneal Dialysis Patients","volume":"7","author":"Danielson","year":"2014","journal-title":"Clin. Kidney J."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zimmermann, M., Y\u00fcrek, S., Konzack, R., Walter, M., Schober, P., Luedi, M.M., and H\u00f6nemann, C. (2021). Delta-Hemoglobin Equivalent and Granularity Index as Cell-Derived Biomarkers for the Detection of Bacterial Infections. Clin. Lab., 67.","DOI":"10.7754\/Clin.Lab.2021.210104"},{"key":"ref_20","unstructured":"World Health Organization (2011). Haemoglobin Concentrations for the Diagnosis of Anaemia and Assessment of Severity. Vitamin and Mineral Nutrition Information System, World Health Organization."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1182\/blood-2018-05-815944","article-title":"Iron Deficiency","volume":"133","author":"Camaschella","year":"2019","journal-title":"Blood"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1093\/ecco-jcc\/jju009","article-title":"European Consensus on the Diagnosis and Management of Iron Deficiency and Anaemia in Inflammatory Bowel Diseases","volume":"9","author":"Dignass","year":"2015","journal-title":"J. Crohn\u2019s Colitis"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5.1.1","DOI":"10.1002\/cpim.40","article-title":"Flow Cytometry: An Overview","volume":"120","author":"McKinnon","year":"2018","journal-title":"Curr. Protoc. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1093\/clinchem\/39.4.561","article-title":"Receiver-Operating Characteristic (ROC) Plots: A Fundamental Evaluation Tool in Clinical Medicine","volume":"39","author":"Zweig","year":"1993","journal-title":"Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2307\/2531595","article-title":"Comparing the Areas under Two or More Correlated Receiver Operating Characteristic Curves: A Nonparametric Approach","volume":"44","author":"DeLong","year":"1988","journal-title":"Biometrics"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1037\/0033-2909.112.1.155","article-title":"A Power Primer","volume":"112","author":"Cohen","year":"1992","journal-title":"Psychol. Bull."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.hrtlng.2009.07.002","article-title":"Anemia and Blood Transfusion Practices in the Critically Ill: A Prospective Cohort Review","volume":"39","author":"Thomas","year":"2010","journal-title":"Heart Lung"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Bellmann-Weiler, R., Lanser, L., Barket, R., Rangger, L., Schapfl, A., Schaber, M., Fritsche, G., W\u00f6ll, E., and Weiss, G. (2020). Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection. J. Clin. Med., 9.","DOI":"10.3390\/jcm9082429"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/0049475516678478","article-title":"Correlation between Serum Ferritin and Bone Marrow Iron Stores","volume":"47","author":"Anupama","year":"2017","journal-title":"Trop. Doct."},{"key":"ref_30","unstructured":"World Health Organization (2011). Serum Ferritin Concentrations for the Assessment of Iron Status and Iron Deficiency in Populations. Vitamin and Mineral Nutrition Information System, World Health Organization."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1002\/ajh.24820","article-title":"Iron Deficiency across Chronic Inflammatory Conditions: International Expert Opinion on Definition, Diagnosis, and Management","volume":"92","author":"Cappellini","year":"2017","journal-title":"Am. J. Hematol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1056\/NEJMra1401038","article-title":"Iron-Deficiency Anemia","volume":"372","author":"Camaschella","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_33","first-page":"9394060","article-title":"Limitations of Serum Ferritin in Diagnosing Iron Deficiency in Inflammatory Conditions","volume":"2018","author":"Dignass","year":"2018","journal-title":"Int. J. Chronic. Dis."},{"key":"ref_34","first-page":"431","article-title":"Blood Transfusion Therapy","volume":"101","author":"Goodnough","year":"2017","journal-title":"Med. Clin."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1097\/PTS.0000000000000142","article-title":"From Bad to Worse: Anemia on Admission and Hospital-Acquired Anemia","volume":"13","author":"Koch","year":"2017","journal-title":"J. Patient Saf."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1001\/jama.2019.0554","article-title":"Patient Blood Management: Recommendations From the 2018 Frankfurt Consensus Conference","volume":"321","author":"Mueller","year":"2019","journal-title":"JAMA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.bpa.2013.02.002","article-title":"The Three-Pillar Matrix of Patient Blood Management--an Overview","volume":"27","author":"Isbister","year":"2015","journal-title":"Best Pract. Res. Clin. Anaesthesiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1046\/j.1523-1755.2001.00077.x","article-title":"A Randomized Trial of Iron Deficiency Testing Strategies in Hemodialysis Patients","volume":"60","author":"Fishbane","year":"2001","journal-title":"Kidney Int."},{"key":"ref_39","first-page":"919","article-title":"Reticulocyte hemoglobin equivalent as a diagnostic marker for the current iron deficiency: Old wine in new bottles","volume":"69","author":"Hagemann","year":"2020","journal-title":"Anaesthesist"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Hoenemann, C., Ostendorf, N., Zarbock, A., Doll, D., Hagemann, O., Zimmermann, M., and Luedi, M. (2021). Reticulocyte and Erythrocyte Hemoglobin Parameters for Iron Deficiency and Anemia Diagnostics in Patient Blood Management. A Narrative Review. J. Clin. Med., 10.","DOI":"10.3390\/jcm10184250"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e108","DOI":"10.1213\/ANE.0000000000005491","article-title":"Potential Role of Reticulocyte Hemoglobin in Facilitating Patient Blood Management","volume":"132","author":"Doll","year":"2021","journal-title":"Anesth. Analg."},{"key":"ref_42","first-page":"38","article-title":"Reticulocyte Hemoglobin Vis-a-Vis Serum Ferritin as a Marker of Bone Marrow Iron Store in Iron Deficiency Anemia","volume":"64","author":"Mehta","year":"2016","journal-title":"J. Assoc. Physicians India"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1510","DOI":"10.1016\/j.mayocp.2020.10.042","article-title":"Using Reticulocyte Hemoglobin Equivalent as a Marker for Iron Deficiency and Responsiveness to Iron Therapy","volume":"96","author":"Auerbach","year":"2021","journal-title":"Mayo Clin. Proc."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Almashjary, M.N., Barefah, A.S., Bahashwan, S., Ashankyty, I., ElFayoumi, R., Alzahrani, M., Assaqaf, D.M., Aljabri, R.S., Aljohani, A.Y., and Muslim, R. (2022). Reticulocyte Hemoglobin-Equivalent Potentially Detects, Diagnoses and Discriminates between Stages of Iron Deficiency with High Sensitivity and Specificity. J. Clin. Med., 11.","DOI":"10.3390\/jcm11195675"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1093\/ajcp\/aqac103","article-title":"Implementing Reticulocyte Hemoglobin Into Current Hematology Algorithms","volume":"158","author":"Lundgren","year":"2022","journal-title":"Am. J. Clin. Pathol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/140\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:55:30Z","timestamp":1760147730000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/1\/140"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,29]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cells12010140"],"URL":"https:\/\/doi.org\/10.3390\/cells12010140","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,29]]}}}