{"doi":"10.1002/ajh.27489","title":"Three‐generation female cohort with macrocytic anemia and iron overload","abstract":"A 16-year-old female (P-IIIA) with a past medical history of asthma presented to the hematology clinic with mild macrocytic anemia (hemoglobin 10 g/dL, red blood cells [RBC] 3.19 × 106/μL, mean corpuscular volume [MCV] 103 femtoliters [fL], and red cell distribution width [RDW] of 12.9%). Platelet and white blood cell counts were normal. Two complete blood counts (CBC) tested within the previous 3 years on two occasions, once for a syncopal episode and the other for abdominal pain, had demonstrated similar findings. She was referred to hematology after her macrocytic anemia was noted during an attempted blood donation. At the hematology clinic, along with the CBC results noted above, she was found to have a negative direct antiglobulin test, a mildly elevated ferritin (158 ng/mL), with normal renal function, iron, total iron binding capacity (TIBC, 322 μg/dL), and iron saturation (30%). She reported mild occasional fatigue and intermittent thoracic back pain but was otherwise asymptomatic. She denied bleeding symptoms. Her examination was unremarkable, and she did not have evidence of splenomegaly. At the time of evaluation, she had transitioned to a pescatarian diet for 7 months, eating also vegetables and dairy. Her grandmother (P-I), mother (P-II), and younger sister (P-IIIB) were also noted to have mild macrocytic anemia, while P-II had also been found to have elevated ferritin of unclear etiology (reaching 646 ng/mL, but improved after phlebotomy every 6 weeks for a year). Macrocytosis is defined as an MCV above the upper limit of normal for age, which varies from infants to adults. Increased MCV in an automatic complete blood count (CBC) may be artifactual, such as with a marked compensatory reticulocytosis in response to anemia; reticulocytes are normally larger than mature circulating red cells (up to 126 fL for healthy adults), while they can be even larger in conditions of stress erythropoiesis, raising the perceived MCV of the total erythrocytes (mature and non-mature) in automated CBC measurements.1 Cold agglutinins may also cause spurious macrocytosis due to cell counting errors of red cell aggregates.2 Obtaining the reticulocyte count and evaluating the blood smear are always valuable first steps to confirm a true macrocytosis and start the diagnostic evaluation. True macrocytosis, typically associated with anemia, can have numerous causes based on clinical context, encompassing both acquired and congenital disorders. The most common pathophysiologic mechanisms involved are (1) impaired DNA synthesis in the erythroblast nuclei during terminal erythropoiesis causing megaloblastic bone marrow changes because of nuclear-cytoplasmic asynchrony, (2) altered red cell hydration increasing cell volume, or (3) altered composition of the lipid bilayer of the RBC membrane. Impaired DNA synthesis in megaloblastic anemia is caused by vitamin B12 or folate deficiency, both critical components in the thymidine synthesis pathway. Deficiency of folate and/or vitamin B12 occurs either due to dietary restrictions, malabsorption syndromes like short-gut syndrome, or in autoimmune disorders associated with loss of intrinsic factor production (atrophic gastritis) or anti-intrinsic factor antibodies, which would prevent vitamin B12 absorption. Rare genetic disorders of vitamin B12 or folate transport and metabolism also exist, leading to syndromes that may present not only with megaloblastic anemia, but also with failure to thrive, other cytopenias, neurodevelopmental disorders, and/or thromboembolic events.3, 4 Medications, such as methotrexate (a folate antimetabolite), antiretrovirals, and chemotherapeutic nucleoside analogs, all of which interfere with DNA synthesis, may also cause macrocytosis with or without anemia. Notably, a very rare cause of macrocytosis is copper deficiency which also causes neutropenia and neurological manifestations like B12 deficiency. Genetic disorders causing altered RBC hydration and hereditary hemolyt","journal":"American Journal of Hematology","year":2024,"id":477625,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1315871,"name":"Vanessa Dayton","orcid":"0000-0001-5611-0477","position":1,"is_corresponding":false},{"id":996640,"name":"Annaliisa R. Pratt","orcid":null,"position":2,"is_corresponding":false},{"id":453411,"name":"Nicolas Nassar","orcid":"0000-0003-0481-4784","position":3,"is_corresponding":false},{"id":1316257,"name":"Yasmin Elgammal","orcid":null,"position":4,"is_corresponding":false},{"id":479397,"name":"Theodosia A. Kalfa","orcid":"0000-0002-0426-9686","position":5,"is_corresponding":false},{"id":1315870,"name":"Alexander A. Boucher","orcid":"0009-0004-8212-453X","position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:06:37.812633Z","pmid":"39329459","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}