Version July 2025
INTRODUCTION —
Macrocytosis describes red blood cell (RBC) size larger than the normal range. It may be caused by abnormalities of RBC production in the bone marrow, altered RBC membrane composition, or increased reticulocytes, which are larger than mature RBCs.
This topic discusses causes of macrocytosis and macrocytic anemia. Additional topics discuss:
●Microcytosis/microcytic anemia – (See "Microcytosis/Microcytic anemia".)
●General anemia evaluation
•Child – (See "Approach to the child with anemia".)
•Adult – (See "Diagnostic approach to anemia in adults".)
●Vitamin B12 and folate deficiency – (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)
●Myelodysplastic syndromes – (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
●Hemolytic anemias – (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
●Alcohol-induced anemia – (See "Hematologic complications of alcohol use".)
DEFINITIONS AND CLASSIFICATION —
Macrocytosis is a morphologic term and does not imply a specific pathophysiology. Macrocytosis can be documented using the mean corpuscular volume (MCV) from an automated hematology instrument, measured in femtoliters (fL; 10-15 liter) or by peripheral blood smear review.
●Increased MCV – The upper limit of normal varies by age (table 1):
•Preterm infants born at ≤25 weeks of gestation – 119±7 fL
•Term newborns (cord blood) – 106±4 fL
•Infants and young children – 90 fL
•Adults – 96 to 100 fL (the higher value may be more appropriate for older adults)
The normal range is defined such that approximately 2.5 percent of the healthy population will have an MCV >96 fL; <0.5 percent will have a MCV >100 fL. High values are flagged, along with other RBC indices (table 2), often without adjustment for age.
●RDW – The RBC distribution width (RDW) measures variation in RBC sizes. A single uniform population of RBCs will have a normal RDW regardless of whether the absolute MCV is normal or abnormal. A population of RBCs with varied sizes or two populations of RBCs (small RBCs plus reticulocytes) will have a large RDW (above approximately 14.5 percent when the coefficient of variation method is used).
RDW is typically increased with disorders that cause macrocytosis and microcytosis (eg, vitamin B12 or folate deficiency plus iron deficiency) [1]. It may be worthwhile to measure all of these nutrients when the RDW is increased.
●Peripheral blood smear – The normal RBC diameter on the peripheral blood smear is 7 to 8 microns, approximately the size of the nucleus of a small lymphocyte (picture 1); RBCs that have a greater diameter are considered macrocytic. (See "Evaluation of the peripheral blood smear".)
Reticulocytes can be recognized on the blood smear as larger RBCs that lack central pallor, are oval to irregular in outline, and have a blue tint (polychromatophilia) (picture 2).
Other findings on the peripheral blood smear may be helpful in determining the cause of macrocytosis. (See 'Clues from the CBC and blood smear' below.)
Megaloblastic anemia (or megaloblastic changes) describes a subset of macrocytic anemias in which the increased size of RBCs is caused by abnormal cell division in RBC precursors in the bone marrow (see 'Pathophysiology' below). The major associated finding on the blood smear is multilobed neutrophils. Bone marrow findings are described separately. (See "Evaluation of bone marrow aspirate smears", section on 'Megaloblastic changes'.)
PATHOPHYSIOLOGY —
Red blood cells (RBCs) leave the bone marrow as reticulocytes, which are larger than mature RBCs. Macrocytic RBCs form as a consequence of inherited or acquired abnormalities in RBC maturation, nucleic acid metabolism, membrane composition, cell water content, or a combination of these factors (table 3) [2-4].
●Increased reticulocytes – Reticulocytes are immature RBCs that have ejected their nuclei but retain some messenger RNA, making them appear slightly bluish/purplish (polychromatophilic) on Wright-Giemsa stain. Reticulocytes in the bone marrow have a volume of 120 to 150 fL. After they enter the circulation, they undergo loss of water and membrane and have a typical mean corpuscular volume (MCV) of approximately 103 to 126 fL, which is averaged into the MCV calculation [4].
In severe anemia, the signal from erythropoietin to increase RBC production may cause developing RBCs to skip cell divisions and reticulocytes to enter the circulation sooner than they otherwise would (eg, "stress" or "shunt" reticulocytes); these circulate for longer periods of time, which may further increase the MCV (figure 1) [5].
Reticulocytosis is a normal physiologic response to anemia of any cause. It will occur unless the bone marrow cannot respond to anemia due to factors such as cytokines in anemia of chronic disease or vitamin or iron deficiency. Increased reticulocytes are a hallmark of hemolytic anemia, bone marrow recovery following a bone marrow insult, or repletion of vitamin B12, folate, or iron. (See "Diagnosis of hemolytic anemia in adults", section on 'High reticulocyte count'.)
●Megaloblastic anemia – Developing RBC precursor cells in the bone marrow divide rapidly and become progressively smaller as they mature (figure 2).
In conditions in which cell division is impaired, such as lack of a nutrient required for DNA synthesis, the synchrony between nuclear and cytoplasmic maturation may be lost, resulting in large, immature nuclei relative to the cytoplasm, along with other megaloblastic changes (eg, binucleate cells). The ultimate basis for production of the megaloblast is inadequate conversion of deoxyuridine to thymidylate (thymidine), which leads to slowing of DNA synthesis and delayed nuclear maturation. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Hematopoiesis'.)
Drugs and nutrient deficiencies that cause megaloblastic anemia will affect all developing blood cells. Similar abnormalities in white blood cell and platelet precursors can be seen in the bone marrow. The peripheral blood smear may show multilobed neutrophils, and the complete blood count (CBC) may show mild pancytopenia. (See 'Clues from the CBC and blood smear' below.)
●Abnormal RBC membrane – The RBC membrane is a complex lipid bilayer with integral membrane proteins attached to an underlying circumferential cytoskeleton that gives it mechanical stability and deformability. Certain inherited and acquired conditions can alter the membrane composition and in some cases increase cell volume. Examples include liver disease with increased membrane cholesterol content and hereditary stomatocytosis with impaired volume regulation. (See 'Causes of macrocytosis/macrocytic anemia' below and "Hematologic complications of alcohol use" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
Macrocytosis, along with the other RBC indices, other CBC findings, and the peripheral blood smear review, can be extremely helpful in evaluating the cause of anemia or the early stage of a condition that may cause anemia if untreated. (See 'Evaluation' below.)
CAUSES OF MACROCYTOSIS/MACROCYTIC ANEMIA
Overview/common causes — The table summarizes causes of macrocytic anemia (table 4).
In two reviews from 2024, the most frequent causes of macrocytosis were [6,7]:
●Vitamin B12 deficiency – 17 to 57 percent
●Folate deficiency – 5 to 17 percent
●Alcohol – 11 to 37 percent
●Medications – 13 percent
●Bone marrow disorders – 10 percent
In a review of 300 consecutive hospitalized adults with macrocytosis from 2000, the following were most common [8]:
●Medications – 37 percent
●Alcohol – 13 percent
●Liver disease – 13 percent
●Reticulocytosis – 8 percent
Mechanisms and additional details include:
●Reticulocytosis
•Hemolytic anemia
•Bone marrow recovery after chemotherapy or hematopoietic stem cell transplantation
•Erythropoiesis following administration of erythropoietin or repletion of iron, vitamin B12, or folate
•Recovery from bleeding
●Megaloblastic anemia
•Vitamin B12 or folate deficiency – (See 'Megaloblastic anemia' below.)
•Medications that interfere with DNA synthesis – (See 'Drug-induced macrocytosis' below.)
•Thiamine-responsive megaloblastic anemia – (See 'Megaloblastic anemia' below.)
●Multifactorial
•Alcohol – (See 'Alcohol/liver disease' below.)
•Liver disease – (See 'Alcohol/liver disease' below.)
•HIV infection (and therapy) – (See "HIV-associated cytopenias".)
•Myelodysplastic syndrome – (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
•Hereditary stomatocytosis – (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
•Congenital dyserythropoietic anemia – (See "Overview of causes of anemia in children due to decreased red blood cell production", section on 'Congenital dyserythropoietic anemia'.)
•Hypothyroidism – (See "Clinical manifestations of hypothyroidism", section on 'Anemia'.)
•Pregnancy – (See "Maternal adaptations to pregnancy: Hematologic changes".)
•Aplastic anemia – (See "Acquired aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis".)
•Multiple myeloma – (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis".)
•Bariatric surgery (or, less commonly, other gastrointestinal surgery) – (See "Bariatric surgery: Postoperative nutritional management".)
•Down syndrome – (See "Down syndrome: Clinical features and diagnosis".)
•Copper deficiency (although often causes normocytic anemia, and microcytic cells may be seen) – (See "Sideroblastic anemias: Diagnosis and management", section on 'Copper deficiency' and "Overview of dietary trace elements", section on 'Copper'.)
•Sweet syndrome – (See "Sweet syndrome (acute febrile neutrophilic dermatosis): Pathogenesis, clinical manifestations, and diagnosis".)
•VEXAS syndrome – (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)
•Adenosine kinase deficiency (AKD), a rare autosomal recessive inborn error of methionine and adenosine metabolism characterized by psychomotor developmental delay, epilepsy, dysmorphic features, macrocytosis, and liver disease [9].
•Diamond-Blackfan anemia (DBA), a rare congenital disorder characterized by erythroid hypoplasia due to pathogenic variants in genes encoding ribosomal proteins – (See "Diamond-Blackfan anemia".)
•Short telomere syndrome (STS) [10] – (See "Telomere biology disorders, including Dyskeratosis congenita".)
In some conditions, the full mechanism may not be elucidated; there may be a combination of changes in the bone marrow, medication effects, and in some cases mild reticulocytosis.
Reticulocytosis — An increase in the reticulocyte count is associated with a corresponding increase in mean corpuscular volume (MCV). (See 'Pathophysiology' above.)
Reticulocytosis can occur in:
●Any hemolytic anemia – (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
●Repletion of iron, vitamin B12, folic acid, or copper – (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)
●Recovery from bleeding or transient bone marrow aplasia (eg, following parvovirus infection) – (See "Diagnostic approach to anemia in adults".)
●Any condition associated with increased erythropoietin, such as congenital heart disease, erythropoietin-secreting tumors, or "blood doping" – (See "Regulation of erythropoiesis".)
Megaloblastic anemia — Megaloblastic anemia is a form of macrocytic anemia in which nucleic acid metabolism is impaired. (See 'Pathophysiology' above.)
Causes of megaloblastic anemia include deficiency of vitamin B12, folate, or copper, and medications that interfere with DNA synthesis.
●Vitamin B12 deficiency has numerous causes related to its complex absorption (table 5). (See "Treatment of vitamin B12 and folate deficiencies" and "Causes and pathophysiology of vitamin B12 and folate deficiencies".)
●Folate deficiency has become rare in countries in which certain foods are routinely supplemented with folate. It may occur in individuals with severe malnutrition or certain dietary practices (table 6). Folate deficiency was also common in individuals with increased folate requirements such as with chronic eczema (21 of 28 individuals [75 percent] in one series) before routine supplementation was initiated [11]. (See 'Clues from the history and examination' below.)
Relative folate deficiency is common in all hemolytic conditions with reticulocytosis. (See "Warm autoimmune hemolytic anemia (AIHA) in adults", section on 'Folic acid' and "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)
●Thiamine-responsive megaloblastic anemia syndrome (TRMA) is an extremely rare autosomal recessive disorder characterized by anemia, diabetes, and early-onset sensorineural hearing loss and eye and heart findings [12-16]. Details of diagnosis are discussed separately. (See "Overview of water-soluble vitamins", section on 'Vitamin B1 (thiamine)'.)
●Drug-induced megaloblastic anemia has accounted for a larger proportion of megaloblastic anemia in some settings [17]. (See 'Drug-induced macrocytosis' below.)
Myelodysplastic syndrome — Myelodysplastic syndrome (MDS) is characterized by macrocytic or normocytic anemia. The reticulocyte response is generally inappropriately low. The RDW is often increased. Details are presented separately. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
Drug-induced macrocytosis — Implicated medications may cause megaloblastic anemia and/or hemolytic anemia; these include [17-31]:
●Allopurinol (megaloblastic changes)
●Aminosalicylic acid (reduces folate absorption)
●Antacids (reduce vitamin B12 absorption)
●Ampicillin and other penicillins (reduces folate absorption)
●Azathioprine (megaloblastic changes)
●Capecitabine (megaloblastic changes)
●Chloramphenicol (reduces folate absorption)
●Cladribine (megaloblastic changes)
●CDK 4/6 inhibitors
●Cytosine arabinoside (Ara-C) (megaloblastic changes)
●Dapsone (hemolysis in individuals with G6PD deficiency)
●Erythromycin (reduces folate absorption)
●Estrogens or hormonal contraceptives (reduces folate absorption)
●Fludarabine (megaloblastic changes)
●Fluorouracil (megaloblastic changes)
●Gadolinium (megaloblastic changes)
●Gemcitabine (megaloblastic changes)
●Histamine H2 receptor antagonists (eg, cimetidine, famotidine, nizatidine; reduce vitamin B12 absorption)
●Hydroxyurea (megaloblastic changes)
●Imatinib (unknown; possibly inhibition of c-kit)
●Lamivudine (megaloblastic changes)
●Leflunomide (megaloblastic changes)
●Mercaptopurine (megaloblastic changes)
●Metformin (interferes with folate metabolism)
●Methotrexate (megaloblastic changes)
●Methylene blue (hemolysis in individuals with G6PD deficiency)
●Mycophenolate mofetil (megaloblastic changes)
●Nitrofurantoin (reduces folate absorption, hemolysis in individuals with G6PD deficiency)
●Nitrous oxide (megaloblastic changes)
●Pegloticase (hemolysis in individuals with G6PD deficiency)
●Pentostatin (megaloblastic changes)
●Phenytoin (interferes with folate metabolism)
●Primaquine (hemolysis in individuals with G6PD deficiency)
●Primidone (unknown)
●Proton pump inhibitors (eg, omeprazole, lansoprazole; reduce B12 absorption)
●Rasburicase (hemolysis in individuals with G6PD deficiency)
●Sunitinib (unknown; possibly inhibition of c-kit)
●Teriflunomide (megaloblastic changes)
●Tetracyclines (reduces folate absorption)
●Thioguanine (megaloblastic changes)
●Trimethoprim (megaloblastic changes)
●Zidovudine (megaloblastic changes)
A more extensive discussion of drugs that cause hemolytic anemia is presented separately. (See "Drug-induced hemolytic anemia".)
Alcohol/liver disease — Alcohol is a common cause of macrocytosis and macrocytic anemia. Regular ingestion of 80 grams of alcohol each day (for example, one bottle of wine) is sufficient to cause this effect [2]. Even before anemia appears, chronic alcohol use may cause macrocytosis (typical mean corpuscular volume [MCV] between 100 and 110 fL) [32-34]. (See 'Clues from the history and examination' below.)
Alcohol-induced macrocytosis occurs even in patients who are folate and vitamin B12 replete and do not have liver disease. Abstinence from alcohol results in resolution of macrocytosis within two to four months. (See "Hematologic complications of alcohol use", section on 'Anemia'.)
In a series of 168 individuals with chronic alcohol use from the 1970s, one-half had macrocytosis (mean MCV: 98 fL); in those with concomitant liver disease, 64 percent had macrocytosis (mean MCV: 100 fL) [35]. In a 1990 series of 73 individuals with macrocytosis in a primary care practice, macrocytosis was ascribed to alcohol in 47 (64 percent) [36]. In another primary care series of 300 individuals with macrocytosis, approximately a third of the female participants and four-fifths of the male participants used excess alcohol [37].
The mechanism of alcohol-induced macrocytosis is unknown. Acetaldehyde, a breakdown product of alcohol, can induce membrane changes in red blood cell (RBC) precursors and circulating RBCs, through the in vivo production of acetaldehyde adducts [38]. Acetaldehyde also interferes with cell division and may increase MCV by this mechanism [39]. One study showed a correlation between MCV and aldehyde dehydrogenase genotype in individuals who consumed >300 grams of alcohol per week [40]. (See "Pathogenesis of alcohol-associated liver disease".)
Other forms of liver disease not related to alcohol may cause macrocytosis by effects on RBC membrane lipid composition [2]. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Hematologic abnormalities'.)
Vitamins and trace minerals — Gastric bypass surgery can cause micronutrient malabsorption related to the physical bypass, removal of absorptive cells, reduced dietary intake, and other mechanisms. The risk of nutrient deficiencies is greater with bypass procedures than restrictive procedures such as gastric banding. Patients may develop combined deficiencies of vitamin B12, folate, and iron if they do not receive supplementation. Copper deficiency can also occur. (See "Bariatric surgery: Postoperative nutritional management".)
These deficiencies may also arise in individuals receiving parenteral nutrition without adequate supplementation or infant formulas that lack these constituents [41]. Other malabsorption syndromes or the use of chelating agents may also lead to single or multiple deficiencies. (See "Chronic complications of short bowel syndrome in children", section on 'Nutritional complications' and "Approach to the adult patient with suspected malabsorption" and "Overview of the treatment of malabsorption in adults" and "Parenteral nutrition in infants and children".)
Excessive zinc ingestion may cause copper deficiency, including zinc used in denture adhesives. (See "Copper deficiency myeloneuropathy", section on 'Causes of acquired copper deficiency'.)
Nitrous oxide can cause vitamin B12 deficiency. (See 'Drug-induced macrocytosis' above.)
Rare genetic conditions affecting vitamin and mineral metabolism may cause macrocytic anemia. (See "Treatment of vitamin B12 and folate deficiencies" and "Copper deficiency myeloneuropathy".)
Hypothyroidism — Macrocytosis can occur in hypothyroidism. The mechanism is unclear and may be multifactorial.
In a series of 202 patients with hypothyroidism from 1976, 53 (26 percent) had anemia [1]. Among 53 individuals with macrocytosis who were analyzed in more detail, vitamin B12, folate, and iron stores were normal. Treatment with thryroxine resulted in resolution of anemia in 13 (25 percent). Autoimmune hypothyroidism may cause vitamin B12 deficiency due to autoantibodies to gastric parietal cells. In the series of 202 patients, 10 of 118 (8.5 percent) had pernicious anemia.
The typical MCV in hypothyroidism is mildly increased (90 to 100 fL).
Macrocytosis with mild or no anemia — Macrocytosis may be seen in newborns (the upper limit of normal for the MCV is age-adjusted), during pregnancy, and in some older adults.
A full evaluation as discussed below often reveals no abnormalities, and the peripheral blood smear shows only macrocytic RBCs (See 'Evaluation' below.)
A concern is that this may be a harbinger of myelodysplastic syndrome (MDS). Some consultants perform a bone marrow examination with MDS-specific testing, while others prefer to watch and follow. Studies to clarify the benefits of each approach are needed. (See 'Patient age' below.)
EVALUATION
Initial considerations — Before embarking on an extensive evaluation, confirm that macrocytosis is real. Causes of spurious macrocytosis include clumping of red blood cells (RBCs) by cold agglutinins, osmotic swelling of RBCs with severe hyperglycemia (blood glucose >625 mg/dL [>35 mmol/L]) or prolonged storage, or high concentrations of certain forms of EDTA in the blood collection tube (EDTA can also cause microcytosis) [42-47]. (See "Automated complete blood count (CBC)", section on 'Sample collection and processing'.)
These possibilities can generally be eliminated by repeating the complete blood count (CBC) and reviewing the peripheral blood smear. If cold agglutinins are suspected, the sample can be warmed prior to analysis.
While the mean value for the MCV in adults is 88 fL, several studies of non-anemic ambulatory adults >65 years have reported mean values ranging from 91 to 93 fL, with up to 10 percent having a MCV >96 fL, and 2 to 6 percent having a MCV >100 fL [48-51]. We generally do not initiate an intensive evaluation of older adults for an MCV between 96 and 100 fL unless the patient is anemic or the MCV value represents a meaningful change from baseline. (See 'Macrocytosis with mild or no anemia' above.)
Clues from the history and examination — Patient age, medical history, alcohol use, and medications are especially important in the evaluation of macrocytosis (algorithm 1).
Patient age
●Neonates – Normal values for the MCV are higher in neonates (especially those born preterm) and infants; age-appropriate values should be consulted (table 1) [52-54]. (See "Approach to the child with anemia", section on 'Red blood cell indices'.)
●Children – Common causes of macrocytosis/macrocytic anemia include medications and conditions present from birth. A 1992 retrospective series of 146 children with macrocytosis identified the following as common causes [54]:
•Medications (anticonvulsants, zidovudine, immunosuppressive agents) – 51 (35 percent)
•Congenital heart disease – 20 (14 percent)
•Down syndrome – 12 (8 percent)
•Reticulocytosis – 11 (8 percent)
•Bone marrow failure/dysplasia – 6 (4 percent)
Rare causes of macrocytosis in children include inherited disorders or vitamin B12 or thiamine metabolism. (See 'Megaloblastic anemia' above.)
●Adults – Common causes of macrocytosis/macrocytic anemia include alcohol use or abuse, liver disease, thyroid disease, and megaloblastic anemias [27,55]. Hemolytic anemias with reticulocytosis and bone marrow failure states including myelodysplastic syndromes (MDS), aplastic anemia, and paroxysmal nocturnal hemoglobinuria (PNH) are also seen. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
●Older adults – Macrocytosis is a common presenting feature of MDS [56]. In one series of bone marrow examinations that included mostly older adults, a score including unexplained macrocytosis, abnormal RBC distribution width (RDW), and elevated lactate dehydrogenase (LDH) identified 114 of 313 (36 percent) as having MDS [48]. Many did not have an ultimate diagnosis even after bone marrow evaluation. There are not good data suggesting that an extensive evaluation for MDS improves outcomes in this setting. (See 'Macrocytosis with mild or no anemia' above.)
Medications — Typically, medications that cause megaloblastic anemia will be obvious from the medical history. These include hydroxyurea, certain chemotherapy agents, and combination antiretroviral therapy (ART) for HIV infection. (See 'Drug-induced macrocytosis' above.)
Other medications that may be less obvious include:
●Oxidant agents in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency
●Over-the-counter antacids or medications to reduce gastric acid production, which may reduce vitamin B12 absorption
●Certain antibiotics
Nitrous oxide anesthesia (or as a recreational drug) can cause macrocytic anemia by inducing transient vitamin B12 deficiency. (See "Causes and pathophysiology of vitamin B12 and folate deficiencies", section on 'Nitrous oxide'.)
Alcohol — Alcohol use is considered to be under-reported and should be specifically queried in the context of macrocytosis. (See 'Alcohol/liver disease' above.)
Diet — The dietary history may be helpful in identifying the use of an infant formula or formula substitute that may lack sufficient nutrients, strict vegetarians who do not take supplemental vitamin B12, poor nutritional intake, or other unusual dietary practices. Excessive intake of zinc can cause copper deficiency. (See 'Vitamins and trace minerals' above.)
Clues from the CBC and blood smear — The severity of macrocytosis, other cytopenias, and specific RBC morphologies may be useful in narrowing the possible causes of macrocytosis and in guiding the evaluation (algorithm 1).
●Severe macrocytosis (MCV >110 to 115 fL) is associated almost exclusively with megaloblastic anemias. This was illustrated in a 2014 series of 109 individuals with MCV >130 fL [57]. Over 90 percent were due to one of the following: HIV treatment, hydroxyurea, or vitamin B12 or folate deficiency. An extremely high MCV may also be a clue to an artifactually high MCV caused by RBC agglutination. (See 'Evaluation' above.)
●Anemia plus one or more additional cytopenias (leukopenia and/or thrombocytopenia) suggests a primary bone marrow problem (megaloblastic anemia, myelodysplasia). If a drug-induced cause or a vitamin B12, folate, or copper deficiency is not diagnosed, bone marrow evaluation usually is indicated. (See 'Bone marrow/hematologist referral' below.)
●The following findings on the blood smear may be helpful, although none are pathognomonic for a specific condition:
•Target cells (picture 3) suggest liver disease.
•Macro-ovalocytes (picture 1) suggest a megaloblastic process such as vitamin B12, folate, or copper deficiency; or drug-induced megaloblastic anemia; or membrane disorders such as hereditary stomatocytosis (HSt). (See "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)
•Spherocytes in autoimmune hemolytic anemia. (See "Hereditary spherocytosis" and "Warm autoimmune hemolytic anemia (AIHA) in adults".)
•RBC agglutination in cold agglutinin disease (CAD). (See "Cold agglutinin disease".)
•Neutrophils with more than five distinct lobes (picture 4) (multilobed or hypersegmented neutrophils) are suggestive of a megaloblastic process.
•Neutrophils with fewer than three distinct lobes (referred to as hypolobulated neutrophils or pseudo-Pelger-Huet cells) and/or reduced number of cytoplasmic granules (hypogranular neutrophils) suggest myelodysplasia (picture 5).
Initial testing — Review the complete blood count (CBC) including RBC indices and other cell lines. Individuals for whom the history does not point to a clear diagnosis should have one or more of the following tests:
●Reticulocyte count
●Serum vitamin B12 and folate level
●Thyroid-stimulating hormone (TSH)
●Liver function tests
●Copper level, especially after gastric bypass surgery
Whether these are done simultaneously or sequentially depends on other clinical features, the degree of suspicion of one or more of the likely causes of macrocytosis, and the acuity and severity of anemia.
In a patient without anemia, reticulocytes make up 1 to 2 percent of RBCs. Hemolytic anemia typically raises the reticulocyte percentage above 4 to 5 percent provided bone marrow function is adequate and vitamin B12, folate, and iron are available. Hemolysis testing such as haptoglobin and lactate dehydrogenase (LDH) is reasonable if the reticulocyte count is not dramatically increased but hemolysis is suspected. Interpretation of the absolute reticulocyte count and evaluation for the cause of hemolysis is presented separately. (See "Diagnosis of hemolytic anemia in adults".)
If the vitamin B12 or folate level is borderline, additional testing for methylmalonic acid and homocysteine levels may be indicated. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Additional testing for selected individuals'.)
A small percentage of individuals with multiple myeloma have macrocytosis, either due to vitamin B12 deficiency or from an unknown mechanism. Patients with suggestive findings (back pain, hypercalcemia, kidney disease) should have a serum protein electrophoresis (SPEP). (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Anemia'.)
Response to therapy as confirmation — Macrocytosis or macrocytic anemia should resolve with appropriate treatment. If macrocytosis or anemia persists despite correction of an underlying abnormality, investigation for additional causes of anemia is appropriate.
Bone marrow/hematologist referral — When the cause of macrocytosis is not obvious from preliminary laboratory testing, hematologist referral is appropriate to evaluate the possibility of less-common causes of chronic hemolytic anemia and bone marrow disorders such as myelodysplasia. (See "Diagnosis of hemolytic anemia in adults".)
Bone marrow evaluation for dysplasia, hematologic malignancy, or abnormal RBC maturation is appropriate if there is pancytopenia or if the initial testing listed above does not provide a diagnosis. (See 'Initial testing' above.)
Bone marrow testing for MDS and other hematologic disorders is discussed separately. (See "Myelodysplastic syndromes/neoplasms (MDS): Overview of diagnosis and management".)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)
SUMMARY AND RECOMMENDATIONS
●Definitions – Macrocytosis refers to mean corpuscular volume (MCV) above the upper limit of normal, which is typically >96 to 100 femtoliters (fL) in adults. Neonates, infants, and young children have a higher upper limit of normal. (See 'Definitions and classification' above.)
●Mechanisms – RBCs leave the bone marrow as reticulocytes, which are larger than mature red blood cells (RBCs). Macrocytic RBCs form as a consequence of inherited or acquired abnormalities in RBC maturation, nucleic acid metabolism, membrane composition, cell water content, or a combination of these. (See 'Pathophysiology' above.)
●Causes – Causes of macrocytic anemia include reticulocytosis due to hemolytic anemia, bone marrow recovery, or erythropoietin; megaloblastic anemia from vitamin B12, folate, or copper deficiency; drugs that interfere with nucleic acid metabolism or cell division; myelodysplasia; multifactorial processes such as alcohol, liver disease, hypothyroidism; and others listed above (table 4). (See 'Causes of macrocytosis/macrocytic anemia' above.)
●Evaluation – Patient age, medical history, alcohol use, and medications are especially important in the evaluation of macrocytosis (algorithm 1). Age-appropriate normal ranges for the MCV should be consulted for neonates and infants. Medications should be checked, alcohol use discussed, and dietary practices reviewed. (See 'Clues from the history and examination' above.)
●CBC and blood smear review – The severity of macrocytosis, other cytopenias on the complete blood count (CBC), and specific RBC morphologies on the peripheral blood smear may help narrow the possible causes and guide the evaluation (algorithm 1). Severe macrocytosis (MCV >110 to 115 fL) is associated almost exclusively with megaloblastic anemias. Anemia plus other cytopenias (leukopenia and/or thrombocytopenia) suggests a bone marrow problem (megaloblastic anemia, myelodysplastic syndrome [MDS]). (See 'Clues from the CBC and blood smear' above.)
●Additional testing – If the history does not suggest a clear diagnosis, testing should include reticulocyte count; serum vitamin B12, folate, and copper levels; thyroid-stimulating hormone (TSH); and liver function tests. Serum protein electrophoresis (SPEP) may be appropriate if the other tests are normal or there are clinical features of multiple myeloma. (See 'Initial testing' above.)
●Hematologist input and bone marrow – If the preliminary evaluation is negative or there is severe pancytopenia, referral to a hematologist and bone marrow evaluation with MDS testing are appropriate. (See 'Bone marrow/hematologist referral' above and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
ACKNOWLEDGMENTS —
UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic review and was a founding Editor-in-Chief for UpToDate in Hematology.
The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.
