on 13-Apr-2021 (Tue)

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.

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.

● Adults – 80 to 96 fL (mean ± SD = 88 ± 4 fL)

● Children – varies by age (table 2);

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 [1]. 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.

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).

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).

We feel that 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 [3-8].

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).

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.

● 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 diameter less than that of the nucleus of a small lymphocyte on a peripheral smear are considered microcytic (picture 2). (See "Evaluation of the peripheral blood smear".)

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).

A large variation in RBC morphologies (and size), including target cells and teardrop cells, is characteristic of thalassemia.

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.

In the majority of cases of ACD/AI, RBCs are normal in size and shape; a subset may have smaller than average RBCs.

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.

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.

The three most common causes of microcytosis are iron deficiency, thalassemia, and anemia of chronic disease/anemia of inflammation (ACD/AI) (table 3).

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

Iron deficiency and thalassemia are both characterized by decreased hemoglobin production, due to insufficient availability of heme or globin, respectively.

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

In children, iron deficiency is more commonly due 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.

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.

Individuals with suspected iron deficiency should have laboratory testing that is stratified for their age and possible related conditions. For infants without risk factors for (or evidence of) lead toxicity, a complete blood count may be sufficient. For children and young adults, it is appropriate to obtain a reticulocyte count, review the RBC indices and/or the blood smear. For adults, the stool is tested for occult blood. For individuals with other medical conditions, it is appropriate to measure iron studies (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 deficiency (eg, individuals with severe iron deficiency may have dramatically reduced MCV), but the MCV is neither sensitive nor specific for making the diagnosis [ 38,39]. 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.

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 surgical treatment for obesity, especially surgery involving the duodenum (site of iron absorption) [37].

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 [40].

In some iron-replete individuals, iron is not accessible for RBC production due to decreased levels of erythropoietin 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; or to toxicity of heavy metals such as lead, which interferes with iron utilization. These individuals generally should not be treated with iron unless concomitant iron deficiency is identified; some of these individuals may actually have excess iron stores and be at risk for complications of iron overload.

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 capable of causing chronic inflammation in whom other causes of anemia have been eliminated (ie, it is a diagnosis of exclusion) [37]. 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.

The MCV is not especially helpful in making the diagnosis of ACD/AI. However, an MCV below 70 fL is unlikely to be due to ACD/AI alone. 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 ACD/AI rather than adequate iron stores. Additionally, some individuals with ACD/AI may also have (or develop) iron deficiency.

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 severity of the reduction in globin levels. Thalassemias are most prevalent in Africa, the Mediterranean, and Southeast Asia [37]. However, heterozygosity for thalassemia mutations is seen worldwide, and heterozygous individuals (eg, 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 may not be anemic (or have only mild anemia). A typical hemoglobin level is 10 to 13 g/dL in beta thalassemia minor, with an MCV of approximately 65 to 75 fL [37]. The peripheral smear may show hypochromia, microcytosis, target cells (picture 3), tear-drop RBC 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 not usually to the levels seen in iron deficiency anemia [41].

Rare causes of microcytosis and microcytic anemia include a number of conditions that interfere with hemoglobin synthesis or that cause hemolysis. These diagnoses generally are not considered unless the initial evaluation does not reveal one of the more common conditions discussed above. Exceptions may include an individual with a known family history of a rare sideroblastic anemia or 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 genetic defects affecting iron absorption, transport, utilization, or recycling [40,42-44]; these are discussed in more detail separately:

• X-linked and other types of 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 disease – (See "Introduction to hemoglobin mutations".)

Acquired causes of microcytic anemia include:

• Lead poisoning – (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Lead exposure 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'.)

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.

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.

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.

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.