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Microcytosis/Microcytic anemia

Microcytosis/Microcytic anemia
Authors:
Clara Camaschella, MD
Carlo Brugnara, MD
Section Editor:
Robert T Means, Jr, MD, MACP
Deputy Editor:
Jennifer S Tirnauer, MD
Literature review current through: Jan 2024.
This topic last updated: Apr 22, 2022.

INTRODUCTION — Microcytosis is a descriptive term for red blood cell (RBC) size smaller than the normal range. The causes are numerous, and the evaluation depends on a synthesis of clinical and laboratory information.

This topic discusses causes of microcytosis and microcytic anemia. Additional topics discuss the following:

●Macrocytosis/macrocytic anemia – (See "Macrocytosis/Macrocytic anemia".)

●General anemia evaluation

•Child – (See "Approach to the child with anemia".)

•Adult – (See "Diagnostic approach to anemia in adults".)

•Pregnancy – (See "Anemia in pregnancy".)

●Thalassemias – (See "Diagnosis of thalassemia (adults and children)".)

●Iron deficiency

•Child – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

•Adult – (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

•Pregnancy – (See "Anemia in pregnancy", section on 'Iron deficiency'.)

ASSESSMENT OF RBC SIZE — Red blood cell (RBC) sizes are assessed using an automated hematology instrument. The evaluation of the peripheral blood smear provides additional information. These methods are complementary:

●The automated instrument gives an extremely accurate measure of RBC size (mean corpuscular or mean cell volume [MCV]), averaged over millions of cells, along with the red cell distribution width, which if small indicates a uniform population of RBCs and if large indicates a variety of cell sizes. (See 'MCV (cell volume)' below and 'RDW (size variability)' below.)

●The peripheral blood smear reveals the sizes and shapes of individual RBCs, as well as RBC inclusions and abnormalities of other cell types, all of which may provide important clues to the diagnosis. (See 'Peripheral blood smear review' below.)

MCV (cell volume) — Automated instruments routinely report the MCV (mean cell volume or mean corpuscular volume) (table 1); it is measured in femtoliters (fL; 10-15 L). The MCV provides a measure of the RBC volume averaged over millions of cells. This typically is determined by passing cells one-by-one through a small aperture in an automated instrument that uses light scattering, refraction, or diffraction to estimate size in three dimensions. Additional details about these methodologies are presented separately. (See "Automated complete blood count (CBC)".)

Alternatively, the MCV can be calculated using the measured RBC count (in standard units of million cells/microL, equivalent to 106/microL) and the hematocrit (as a percent).

             MCV (fL) = (10 x hematocrit) ÷ RBC count

As an example, a hematocrit of 40 percent and a RBC count of 5 x 106/microL would give a calculated MCV of 80 fL ([10 x 40]/5 = 80).

The normal range for the MCV is determined from the 95 percent confidence interval from a sampling of healthy individuals. Thus, 5 percent of healthy individuals may have a value outside the normal range (2.5 percent above, 2.5 percent below). Normal ranges also may vary slightly by age, sex, and race, especially in children, and by the specific testing laboratory.

●Adults – 82.5 to 98 fL (table 1); more recent data are summarized in a 2019 publication [1].

●Children – varies by age. Examples are summarized in the table (table 2); more recent and detailed data are available in a 2020 publication [2]. (see "Approach to the child with anemia", section on 'Classification of anemia')

Microcytosis refers to an MCV below the lower limit of normal.

Because MCV is an average, it does not describe the range of RBC sizes in the sample, and a sample with a normal MCV may have significant populations of abnormally small and/or large cells. Variation in RBC size can have important implications for determining the cause of microcytosis [3]. The range and variability of RBC size is determined using the red cell distribution width and/or observation of RBCs on the peripheral blood smear. (See 'RDW (size variability)' below and 'Peripheral blood smear review' below.)

RDW (size variability) — Review of the blood smear is generally more informative than the RBC distribution width (RDW). RDW is a measure of the variation in RBC sizes, based on the width of the MCV histogram (bell-shaped curve around the mean). If there is a single uniform population of cells, the RDW is small because all of the RBC volumes cluster tightly around the mean. If there is a large range of cell sizes, the histogram appears as a broad peak, and if there are two distinct populations, as two narrow peaks, the RDW for both of these non-uniform populations would be increased.

The normal range for the RDW is 11.5 to 14.5 percent. There is no condition that regularly yields a RDW less than normal. Thus, in practice, the RDW is either normal or elevated.

An RDW in the normal range indicates that the size distribution of RBCs has the normal degree of variation (ie, a relatively homogenous population of cells). However, a normal RDW is relatively insensitive for eliminating the possibility of RBC abnormalities because there may be a uniform population of abnormally small or abnormally large cells (ie, a normal RDW centered around an abnormal cell size).

An increased RDW suggests greater-than-normal variation in RBC size; however, it is not highly specific or sensitive for making or excluding any diagnoses. As an example, the RDW is frequently increased in anemias caused by vitamin or mineral deficiencies (eg, folate, vitamin B12, iron). One study evaluated the RDW in 26 patients with untreated vitamin B12 deficiency from pernicious anemia and found that one-third of the individuals had a normal RDW [4]. An increased RDW may also be seen with two homogenous populations of cells (eg, a population of microcytic cells from hemolysis plus a population of reticulocytes, which are larger than normal RBCs) or following RBC transfusion, when patient RBCs and transfused RBCs are averaged together. We believe the use of RDW to suggest a specific hematologic diagnosis may be misleading and cannot take the place of peripheral blood smear review by an experienced clinician, despite attempts to derive pattern analysis algorithms based on RDW and other RBC parameters [5-10]. (See 'Peripheral blood smear review' below.)

Numerous observational studies have correlated a high RDW with adverse outcomes, including mortality. However, the RDW may be merely a marker of other adverse prognostic factors such as age, comorbidities, or physiologic stress [11-17]. Examples include the following:

●Overall mortality [18-23]

●Cardiovascular/cerebrovascular events [11,24-33]

●Venous thromboembolism [34,35]

●Chronic kidney disease [36-38]

●Liver disease [39]

The morphologic term that corresponds to an increased RDW is "anisocytosis" (RBCs of differing sizes); however, most hematologists prefer to use other more descriptive terms for specific RBC morphologies as anisocytosis is nonspecific and does not imply any particular diagnosis. (See "Evaluation of the peripheral blood smear", section on 'Red blood cells'.)

Additional information about the criteria for determining RDW (eg, standard deviation versus coefficient of variation) is discussed separately. (See "Automated complete blood count (CBC)", section on 'RBC indices'.)

Peripheral blood smear review — Microcytosis can be estimated from the peripheral 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. RBCs that have a diameter less than that of the nucleus of a small lymphocyte on a peripheral smear are considered microcytic (picture 1). (See "Evaluation of the peripheral blood smear".)

●Other RBC findings on the peripheral blood smear that may be helpful in a patient with microcytosis include:

•A population of large, slightly bluish/purplish cells suggests reticulocytosis, which implies that the bone marrow production of RBCs is increased, as seen in hemolysis, but not in iron deficiency, lead poisoning, sideroblastic anemias, or anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Overview of hemolytic anemias in children" and "Diagnosis of hemolytic anemia in adults".)

•A large variation in RBC morphologies (and size), including target cells and teardrop cells, is characteristic of thalassemia. In thalassemia trait, especially in alpha-thalassemia, microcytosis is present without anemia. (See "Diagnosis of thalassemia (adults and children)".)

•A large variation in RBC size may also be seen in iron deficiency; however, many patients with iron deficiency have normal-appearing RBCs, especially in the early stages of deficiency. Some patients with iron deficiency may have mild microcytosis without anemia. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

•In the majority of cases of ACD/AI, RBCs are normal in size and shape; a subset may have smaller than average RBCs. (See "Anemia of chronic disease/anemia of inflammation".)

•In the majority of cases of myelodysplastic syndrome (MDS), RBCs are normal or slightly larger than average in size. An extremely small subset may have microcytosis if they have concomitant acquired thalassemia [40]. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

●The most common causes of microcytosis, such as thalassemia and iron deficiency, are not associated with abnormalities of white blood cells or platelets, with the possible exception of increased platelet number in the setting of iron deficiency. Abnormalities of other cell types implies a bone marrow disorder or other process affecting blood cells such as infection.

CAUSES OF MICROCYTOSIS

Overview — Microcytosis (mean corpuscular volume [MCV] <80 fL) usually reflects a decreased hemoglobin content within the red blood cell (RBC), and is often associated with a parallel reduction in mean corpuscular hemoglobin (MCH), producing a hypochromic appearance on blood smear (picture 1).

There are three common causes of microcytosis or microcytic anemia (table 3):

●Iron deficiency – Iron deficiency may be seen in parts of the world where nutrition is inadequate, or in individuals with chronic blood loss, including menstruating women and individuals with gastrointestinal bleeding or in people with reduced intestinal iron absorption. (See 'Iron deficiency anemia' below.)

●ACD/AI – Anemia of chronic disease/anemia of inflammation (ACD/AI) may be associated with microcytosis and anemia, although normal RBC size is more frequently seen; however, the overall high prevalence of this condition, especially in the developed world, makes it a common cause of microcytosis even though microcytosis is not the most common manifestation. (See 'Anemia of chronic disease/anemia of inflammation' below.)

●Thalassemia – Thalassemia major and thalassemia intermedia are more common in certain parts of the world, but thalassemia trait may be identified as an incidental finding. Iron deficiency and thalassemia are both characterized by decreased hemoglobin production, due to insufficient availability of heme or globin, respectively. (See 'Thalassemia' below.)

Rare causes of microcytosis include inherited syndromes of defective iron metabolism, some forms of drug-induced anemia and lead poisoning, and copper or zinc deficiency (See 'Rare causes' below.)

Iron deficiency anemia — Iron deficiency and iron deficiency anemia (IDA) may be seen in individuals of any age but are especially common in children and menstruating females.

●In children, iron deficiency is due to increased iron needs for growth and more commonly to reduced iron intake than to blood loss, especially in resource-poor settings. The exclusive use of cow's milk (without breastfeeding or iron-supplemented formula) may also cause iron deficiency in infants. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

●In adults, iron deficiency is more frequently due to blood loss that exceeds iron intake. In females with heavy menstrual periods or pregnancy, the cause is obvious [41]. In others, the source of blood loss may not be immediately apparent. A search for the source of blood loss is almost always indicated, especially in individuals over 50 years of age with new onset iron deficiency, for whom colorectal cancer is not an uncommon underlying cause of blood loss. Another cause is reduced iron absorption as in H. Pylori and celiac disease. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Anemia in pregnancy", section on 'Iron deficiency'.)

Individuals with suspected iron deficiency should have laboratory testing that is stratified for their age and possible related conditions. All individuals should have iron parameters measured (serum ferritin, total iron binding capacity [TIBC], and serum iron).

Iron deficiency is associated with microcytosis, low serum ferritin, and increased TIBC; in early stages the hemoglobin level may be only mildly reduced or within the normal range. IDA is characterized by an inappropriately low reticulocyte count (unless a dose of iron was recently administered), low serum ferritin, increased TIBC, and low serum iron. Patients with IDA have parallel decreases in hemoglobin, hematocrit, and RBC count. The degree of hypochromia and microcytosis can be quite variable from cell to cell, leading to the presence of an elevated RBC distribution width (RDW). The severity of iron deficiency correlates somewhat with the degree of microcytosis (individuals with severe iron deficiency may have dramatically reduced MCV), but the MCV is neither sensitive nor specific for making the diagnosis [42].

It is also worth noting that a reduction in MCV due to iron deficiency may be blunted by concomitant conditions that lead to macrocytic anemia, such as liver disease or vitamin B12 deficiency. The gold standard for assessing iron deficiency has been bone marrow evaluation and staining of macrophages and RBC precursors for iron using Prussian blue staining. In practice this may be helpful if bone marrow evaluation is done for other reasons but is rarely required to diagnose iron deficiency. Decreased levels of serum ferritin are instead used as surrogates for iron deficiency. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

Patients with IDA without an obvious source of blood loss should have stool tested for blood. However, adults >50 years of age with new onset IDA should have a gastrointestinal evaluation for a bleeding lesion regardless of the results of stool occult blood testing, because gastrointestinal lesions can bleed intermittently. Other causes of iron loss may include gastrointestinal telangiectasias, exercise-induced hemolysis and urinary blood loss, and bariatric surgery, especially surgery involving the duodenum (site of iron absorption) as in some bariatric surgery procedures [41].

A response to iron administration may be sufficient in some infants with anemia and suspected iron deficiency; however, a trial of iron administration is not appropriate for individuals with complex medical illnesses, possible other causes for anemia, and adults, because this fails to identify and address other possible illnesses. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

Celiac disease is a chronic inflammatory disease of the small intestine. Iron deficiency anemia that is unresponsive to oral iron administration is often seen, especially in adults [43]. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in children" and "Diagnosis of celiac disease in adults" and "Diagnosis of celiac disease in children".)

In some iron-replete individuals, iron is not accessible for RBC production due to decreased levels of erythropoietin (as in chronic kidney disease [CKD]) and/or increased levels of inflammatory cytokines that increase the production of the iron hormone hepcidin and cause a block in iron utilization with iron sequestration in stores (functional iron deficiency); however, some cases have concomitant true iron deficiency and require iron treatment. Rarely, toxicity of heavy metals such as lead may interfere with iron utilization.

Anemia of chronic disease/anemia of inflammation — Anemia of chronic disease/anemia of inflammation (ACD/AI) is a diagnosis made in individuals with a medical illness that can cause chronic inflammation, in whom other causes of anemia have been eliminated; it is a diagnosis of exclusion [41]. Direct testing of cytokines or of the iron regulatory protein hepcidin are not available for routine clinical practice, although hepcidin testing is being developed and may turn out to be useful. (See "Anemia of chronic disease/anemia of inflammation" and "Regulation of iron balance", section on 'Hepcidin'.)

The MCV is not especially helpful in making the diagnosis of ACD/AI. However, an MCV <70 fL is unlikely to be due to ACD/AI alone and suggests concomitant iron deficiency. The hallmarks of ACD/AI are low serum iron, low TIBC, and normal to increased serum ferritin. However, serum ferritin is an acute phase reactant and may be normal or elevated due to inflammation rather than adequate iron stores. Additionally, some individuals with ACD/AI may also have (or develop) iron deficiency.

Inflammatory conditions responsible for ACD/AI are diverse and numerous and include chronic infections (pulmonary tuberculosis), inflammation (active rheumatoid arthritis), malignancies, and others (See "Anemia of chronic disease/anemia of inflammation".)

Thalassemia — Thalassemias are inherited conditions characterized by variants in the alpha or beta globin genes that reduce the levels of globin chains used to make hemoglobin. Alpha thalassemia is due to reduced alpha globin and beta thalassemia is due to reduced beta globin. For each, the severity of the disease correlates with the magnitude of the reduction in globin levels. Thalassemias are most prevalent in Northern Africa, Mediterranean regions, and Southeast Asia [41]. However, heterozygosity for thalassemia mutations is seen worldwide, and heterozygous individuals (thalassemia minor or thalassemia trait) may be diagnosed incidentally in childhood or adulthood. Physical examination may reveal mild splenomegaly.

Individuals with thalassemia minor or thalassemia trait, especially alpha thalassemia trait, may not be anemic (or may have only mild anemia). A typical hemoglobin is 10 to 13 g/dL in beta thalassemia minor, with an MCV of approximately 65 to 75 fL [41]. The peripheral blood smear may show hypochromia, microcytosis, target cells (picture 2), teardrop forms, and basophilic stippling.

Unlike iron deficiency anemia, the RBC count in thalassemia may be normal or increased (as the bone marrow generates large numbers of small cells). Iron stores are also normal or increased (as ineffective erythropoiesis leads to increased intestinal iron absorption). The RDW is normal in some patients with thalassemia minor. In others, it may be elevated, but the elevation is not usually to the levels seen in iron deficiency anemia [44]. (See "Diagnosis of thalassemia (adults and children)".)

The diagnosis typically is made by hemoglobin analysis for beta thalassemia (high performance liquid chromatography [HPLC], hemoglobin electrophoresis) or DNA analysis for alpha thalassemia, details of which are discussed separately. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

Rare causes — Rare causes of microcytosis and microcytic anemia include a number of conditions that interfere with hemoglobin synthesis or that cause hemolysis (table 3).

These diagnoses generally are not considered unless the initial evaluation is negative for one of the more common conditions discussed above. Exceptions may include an individual with a known family history of a rare sideroblastic anemia, an individual with suspected environmental exposure to lead, or unusual dietary practices that might lead to copper or zinc deficiency.

●Rare inherited microcytic anemias include those due to gene variants affecting iron absorption, transport, utilization, or recycling [43,45-47]; these are discussed in more detail separately:

•X-linked and other types of inherited sideroblastic anemia – (See "Sideroblastic anemias: Diagnosis and management".)

•Hereditary hypotransferrinemia – (See "Regulation of iron balance", section on 'Transferrin'.)

•Hereditary aceruloplasminemia – (See "Bradykinetic movement disorders in children", section on 'Neurodegeneration with brain iron accumulation'.)

•Erythropoietic protoporphyria – (See "Erythropoietic protoporphyria and X-linked protoporphyria".)

•Iron-refractory iron deficiency anemia – (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Inherited disorders/IRIDA'.)

•Other thalassemic mutations such as hemoglobin E and Hb Lepore disease – (See "Hemoglobin variants including Hb C, Hb D, and Hb E", section on 'Hb E' and "Molecular genetics of the thalassemia syndromes", section on 'Hb Lepore'.)

●Acquired causes of rare microcytic anemia include:

•Lead poisoning – (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure, toxicity, and poisoning in adults".)

•Zinc deficiency – (See "Zinc deficiency and supplementation in children" and "Vitamin and mineral deficiencies in inflammatory bowel disease".)

•Copper deficiency (which may be due to zinc toxicity) – (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Copper deficiency'.)

•Alcohol and certain drugs – (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Alcohol' and "Causes and pathophysiology of the sideroblastic anemias", section on 'Medications'.)

In many of these conditions, the blood smear can show marked hypochromia, microcytosis, and anisocytosis (picture 3). Specific laboratory testing for lead levels, levels of micronutrients, or DNA analysis may be required. Input from a specialist may be required if routine testing proves unhelpful.

APPROACH TO THE EVALUATION — The evaluation of a patient with unexplained microcytosis or microcytic anemia must take into account the patient age, nutritional status, ethnic background, family history, and review of the complete blood count, other red blood cell (RBC) indices, and other routine laboratory testing [41,43].

Confirm microcytosis/microcytic anemia — Before embarking on an extensive evaluation, confirm that the mean corpuscular volume (MCV) is low and determine if the patient is anemic.

Possible causes of spurious microcytosis include in vitro RBC fragmentation due to collection in a sample tube containing an inappropriate fluid or debris, inadvertent heating of the sample (eg, during transport), or an especially long delay between sample collection and analysis. Rarely, extremely large platelets or white blood cell fragments may be counted as RBCs. These artifactual effects and machine error can be addressed by repeating the sample and/or reviewing the peripheral blood smear. These issues are becoming less of a problem as technology for automated hematology instruments continues to advance. (See "Automated complete blood count (CBC)".)

Exclude iron deficiency and thalassemia — For most patients, it is appropriate for the initial evaluation to focus on distinguishing between iron deficiency and thalassemia. If the RBC count is low (suggestive of iron deficiency), we obtain iron studies. If the ethnicity or family history is suggestive of thalassemia, we may perform hemoglobin analysis, especially if the RBC count is normal or increased. If the patient has an acute illness such as an infection, it may be appropriate to repeat iron studies after the illness resolves.

Approaches to the evaluation for iron deficiency and thalassemia are presented separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Diagnosis of thalassemia (adults and children)".)

Assess the likelihood of ACD/AI — If initial studies are negative and we believe the serum ferritin is not elevated due to an acute illness, we determine the likelihood of anemia of chronic disease/anemia of inflammation (ACD/AI) versus a more unusual cause of anemia. For a patient with a chronic inflammatory state such as diabetes, it may be appropriate to focus on treating that condition without performing extensive additional evaluations. The typical clinical and laboratory features of the ACD/AI are discussed in more detail separately. The complexity of the differential diagnosis of concomitant iron deficiency and ACD/AI are also included in this discussion. (See "Anemia of chronic disease/anemia of inflammation".)

For an otherwise healthy young person, it may be appropriate to evaluate for less common inherited conditions. Even if these do not require specific therapy, there may be value in avoiding extensive evaluations for other causes of anemia at subsequent clinical encounters. (See 'Rare causes' above.)

Additional evaluations — For those who require additional evaluations, testing is individualized based on the RBC morphology and other clinical features. (See "Evaluation of the peripheral blood smear".)

As noted above, it is important to consider the possibility that the patient has more than one cause of anemia that may alter the expected findings on the complete blood count and peripheral blood smear. Evaluation of complex and multifactorial anemias is presented separately. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults".)

A bone marrow evaluation is rarely needed in the evaluation of isolated microcytic anemia. Possible uses of the bone marrow may include evaluation for myelodysplastic syndrome based on findings on the peripheral blood smear, or for Perls' staining in unexplained sideroblastic anemia. (See "Bone marrow aspiration and biopsy: Indications and technique" and "Evaluation of bone marrow aspirate smears".)

Besides the classic erythrocyte indexes such as MCV, MCH, and RBC distribution width (RDW), hematology analyzers provide additional parameters to assess cellular hypochromia and microcytosis in both reticulocytes and mature RBCs [48].

●Percentage of hypochromic RBC

●Reticulocyte Hb content (ret-He, CHr) (See "Automated complete blood count (CBC)" and "Anemia of chronic disease/anemia of inflammation", section on 'Tests in development'.)

Although not used in routine clinical practice, these parameters may become useful in special conditions to assess the development of iron deficiency after erythropoiesis stimulating agent (ESA) treatment in CKD [48].

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

●Definition – Microcytosis can be documented from the complete blood count (CBC) and mean cell volume (MCV) on an automated hematology instrument (MCV <80 femtoliters [fL] for adults or below the age-appropriate value for children) (table 2) or from the peripheral blood smear. (See 'Assessment of RBC size' above.)

●Causes – Causes of microcytic anemia are listed in the table (table 3). (See 'Causes of microcytosis' above.)

•Common – The three most common are:

-Iron deficiency (picture 1) (see 'Iron deficiency anemia' above)

-Thalassemia (picture 2) (see 'Thalassemia' above)

-Anemia of chronic disease/anemia of inflammation (ACD/AI) (see 'Anemia of chronic disease/anemia of inflammation' above)

Features that can help in the distinction among these, and the importance of testing to find the cause of iron deficiency, is presented above and in separate topic reviews. (See 'Causes of microcytosis' above and "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Diagnosis of thalassemia (adults and children)".)

•Rare – Rare causes include (see 'Rare causes' above):

-Lead poisoning (picture 3)

-Copper or zinc deficiency

-Some forms of drug-induced anemia

-Inherited syndromes of defective iron metabolism

-Myelodysplastic syndrome (MDS) with acquired thalassemia

Evaluation – The evaluation of unexplained microcytosis or microcytic anemia takes into account patient age, nutritional status, ethnic background, family history, and review of the CBC, other RBC indices, and other laboratory testing. For most patients, it is appropriate to focus initially on distinguishing between iron deficiency and thalassemia. A bone marrow evaluation is rarely needed. (See 'Approach to the evaluation' above.)

●General approach to anemia – Overviews of the general diagnostic approach to anemia, RBC indices, and evaluation of blood smear are presented separately. (See "Approach to the child with anemia" and "Diagnostic approach to anemia in adults" and "Automated complete blood count (CBC)" and "Evaluation of the peripheral blood smear".)

ACKNOWLEDGMENTS — UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who contributed as Section Editor on earlier versions of this topic 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.

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  26. Poludasu S, Marmur JD, Weedon J, et al. Red cell distribution width (RDW) as a predictor of long-term mortality in patients undergoing percutaneous coronary intervention. Thromb Haemost 2009; 102:581.
  27. Kurt M, Tanboga IH, Buyukkaya E, et al. Relation of red cell distribution width with CHA2DS2-VASc score in patients with nonvalvular atrial fibrillation. Clin Appl Thromb Hemost 2014; 20:687.
  28. Güngör B, Özcan KS, Erdinler İ, et al. Elevated levels of RDW is associated with non-valvular atrial fibrillation. J Thromb Thrombolysis 2014; 37:404.
  29. Adamsson Eryd S, Borné Y, Melander O, et al. Red blood cell distribution width is associated with incidence of atrial fibrillation. J Intern Med 2014; 275:84.
  30. Providência R, Ferreira MJ, Gonçalves L, et al. Mean corpuscular volume and red cell distribution width as predictors of left atrial stasis in patients with non-valvular atrial fibrillation. Am J Cardiovasc Dis 2013; 3:91.
  31. Saliba W, Barnett-Griness O, Elias M, Rennert G. The association between red cell distribution width and stroke in patients with atrial fibrillation. Am J Med 2015; 128:192.e11.
  32. Kim J, Kim YD, Song TJ, et al. Red blood cell distribution width is associated with poor clinical outcome in acute cerebral infarction. Thromb Haemost 2012; 108:349.
  33. Aung N, Dworakowski R, Byrne J, et al. Progressive rise in red cell distribution width is associated with poor outcome after transcatheter aortic valve implantation. Heart 2013; 99:1261.
  34. Rezende SM, Lijfering WM, Rosendaal FR, Cannegieter SC. Hematologic variables and venous thrombosis: red cell distribution width and blood monocyte count are associated with an increased risk. Haematologica 2014; 99:194.
  35. Bucciarelli P, Maino A, Felicetta I, et al. Association between red cell distribution width and risk of venous thromboembolism. Thromb Res 2015; 136:590.
  36. Solak Y, Yilmaz MI, Saglam M, et al. Red cell distribution width is independently related to endothelial dysfunction in patients with chronic kidney disease. Am J Med Sci 2014; 347:118.
  37. Ujszaszi A, Molnar MZ, Czira ME, et al. Renal function is independently associated with red cell distribution width in kidney transplant recipients: a potential new auxiliary parameter for the clinical evaluation of patients with chronic kidney disease. Br J Haematol 2013; 161:715.
  38. Afonso L, Zalawadiya SK, Veeranna V, et al. Relationship between red cell distribution width and microalbuminuria: a population-based study of multiethnic representative US adults. Nephron Clin Pract 2011; 119:c277.
  39. Kim HM, Kim BS, Cho YK, et al. Elevated red cell distribution width is associated with advanced fibrosis in NAFLD. Clin Mol Hepatol 2013; 19:258.
  40. Wykretowicz J, Song Y, McKnight B, et al. A diagnosis of discernment: Identifying a novel ATRX mutation in myelodysplastic syndrome with acquired α-thalassemia. Cancer Genet 2019; 231-232:36.
  41. DeLoughery TG. Microcytic anemia. N Engl J Med 2014; 371:1324.
  42. Archer NM, Brugnara C. Diagnosis of iron-deficient states. Crit Rev Clin Lab Sci 2015; 52:256.
  43. Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood 2014; 123:326.
  44. Marsh WL Jr, Bishop JW, Darcy TP. Evaluation of red cell volume distribution width (RDW). Hematol Pathol 1987; 1:117.
  45. Camaschella C. How I manage patients with atypical microcytic anaemia. Br J Haematol 2013; 160:12.
  46. Athiyarath R, Arora N, Fuster F, et al. Two novel missense mutations in iron transport protein transferrin causing hypochromic microcytic anaemia and haemosiderosis: molecular characterization and structural implications. Br J Haematol 2013; 163:404.
  47. Donker AE, Raymakers RA, Vlasveld LT, et al. Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis. Blood 2014; 123:3873.
  48. Piva E, Brugnara C, Spolaore F, Plebani M. Clinical utility of reticulocyte parameters. Clin Lab Med 2015; 35:133.
Topic 4432 Version 48.0

References

1 : Establishing Pediatric and Adult RBC Reference Intervals With NHANES Data Using Piecewise Regression.

2 : Pediatric hematology normal ranges derived from pediatric primary care patients.

3 : Red cell indices in classification and treatment of anemias: from M.M. Wintrobes's original 1934 classification to the third millennium.

4 : Red blood cell distribution width in untreated pernicious anemia.

5 : Discriminant analysis of macrocytic red cells.

6 : Usefulness of certain red blood cell indices in diagnosing and differentiating thalassemia trait from iron-deficiency anemia.

7 : Red cell indices and discriminant functions in the detection of beta-thalassaemia trait in a population with high prevalence of iron deficiency anaemia.

8 : Validity assessment of nine discriminant functions used for the differentiation between iron deficiency anemia and thalassemia minor.

9 : Reliability of red blood cell indices and formulas to discriminate between beta thalassemia trait and iron deficiency in children.

10 : Efficacy of advanced discriminating algorithms for screening on iron-deficiency anemia andβ-thalassemia trait: a multicenter evaluation.

11 : Relation Between Red Blood Cell Distribution Width and Cardiovascular Event Rate in People With Coronary Disease.

12 : Validation and potential mechanisms of red cell distribution width as a prognostic marker in heart failure.

13 : Association of red blood cell distribution width with plasma lipids in a general population of unselected outpatients.

14 : Relation between lung function and RBC distribution width in a population-based study.

15 : Oxidative stress and hematologic and biochemical parameters in individuals with Down syndrome.

16 : Vitamin E-bonded hemodialyzer improves atherosclerosis associated with a rheological improvement of circulating red blood cells.

17 : Modulation of red blood cell population dynamics is a fundamental homeostatic response to disease.

18 : Multiplicative interaction between mean corpuscular volume and red cell distribution width in predicting mortality of elderly patients with and without anemia.

19 : Red blood cell distribution width and the risk of death in middle-aged and older adults.

20 : Red blood cell distribution width and mortality risk in a community-based prospective cohort.

21 : Exceptional mortality prediction by risk scores from common laboratory tests.

22 : Age-related clonal hematopoiesis associated with adverse outcomes.

23 : The relationship between red cell distribution width and all-cause and cause-specific mortality in a general population.

24 : Comparative analysis of red cell distribution width and high sensitivity C-reactive protein for coronary heart disease mortality prediction in multi-ethnic population: findings from the 1999-2004 NHANES.

25 : High mean corpuscular volume is a new indicator of prognosis in acute decompensated heart failure.

26 : Red cell distribution width (RDW) as a predictor of long-term mortality in patients undergoing percutaneous coronary intervention.

27 : Relation of red cell distribution width with CHA2DS2-VASc score in patients with nonvalvular atrial fibrillation.

28 : Elevated levels of RDW is associated with non-valvular atrial fibrillation.

29 : Red blood cell distribution width is associated with incidence of atrial fibrillation.

30 : Mean corpuscular volume and red cell distribution width as predictors of left atrial stasis in patients with non-valvular atrial fibrillation.

31 : The association between red cell distribution width and stroke in patients with atrial fibrillation.

32 : Red blood cell distribution width is associated with poor clinical outcome in acute cerebral infarction.

33 : Progressive rise in red cell distribution width is associated with poor outcome after transcatheter aortic valve implantation.

34 : Hematologic variables and venous thrombosis: red cell distribution width and blood monocyte count are associated with an increased risk.

35 : Association between red cell distribution width and risk of venous thromboembolism.

36 : Red cell distribution width is independently related to endothelial dysfunction in patients with chronic kidney disease.

37 : Renal function is independently associated with red cell distribution width in kidney transplant recipients: a potential new auxiliary parameter for the clinical evaluation of patients with chronic kidney disease.

38 : Relationship between red cell distribution width and microalbuminuria: a population-based study of multiethnic representative US adults.

39 : Elevated red cell distribution width is associated with advanced fibrosis in NAFLD.

40 : A diagnosis of discernment: Identifying a novel ATRX mutation in myelodysplastic syndrome with acquiredα-thalassemia.

41 : Microcytic anemia.

42 : Diagnosis of iron-deficient states.

43 : How I treat unexplained refractory iron deficiency anemia.

44 : Evaluation of red cell volume distribution width (RDW).

45 : How I manage patients with atypical microcytic anaemia.

46 : Two novel missense mutations in iron transport protein transferrin causing hypochromic microcytic anaemia and haemosiderosis: molecular characterization and structural implications.

47 : Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis.

48 : Clinical utility of reticulocyte parameters.

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