A complete blood count (CBC) includes measurements for Mean Corpuscular Volume (MCV) and Mean Corpuscular Hemoglobin (MCH), which characterize red blood cells. MCV measures the average size of the red blood cells, typically 80 to 100 femtoliters (fL) in a healthy adult. MCH indicates the average amount of hemoglobin protein within each red blood cell. When both values are high, it signifies macrocytosis, meaning the red blood cells are larger than normal. This enlargement increases the average hemoglobin content per cell, elevating the MCH reading alongside the MCV. This finding prompts investigation into the underlying cause, which can range from nutritional deficiencies to more serious organ or bone marrow issues.
Macrocytic Anemia Caused by Nutritional Deficiencies
The most frequent cause of high MCV and MCH is a deficiency in either Vitamin B12 or Folate, which leads to a condition known as megaloblastic anemia. These two B vitamins are cofactors required for DNA synthesis, a process particularly active in rapidly dividing cells like those in the bone marrow. Without sufficient amounts of these nutrients, the bone marrow is unable to complete the cell division process efficiently, even though the cell cytoplasm continues to mature.
This impaired DNA synthesis causes the red blood cell precursors, called megaloblasts, to grow larger than normal before division is attempted. The resulting abnormally large red blood cells, or macro-ovalocytes, are released into the bloodstream, increasing the MCV and MCH measurements. The high MCV values in megaloblastic anemia are often more pronounced, sometimes reaching between 116 and 130 fL, compared to other causes of macrocytosis.
Vitamin B12 deficiency often develops because of malabsorption rather than poor dietary intake, as the body stores large amounts of the vitamin in the liver. The body needs Intrinsic Factor, a protein produced in the stomach, to absorb B12 in the small intestine. Pernicious anemia is an autoimmune condition where the body attacks the cells that make Intrinsic Factor, leading to poor B12 absorption. Other causes include gastrointestinal surgeries, certain medications, or strict vegan diets that lack B12 sources.
Folate, or Vitamin B9, works closely with B12 in the metabolic pathways necessary for DNA production. Unlike B12, the body’s folate stores are rapidly depleted, meaning a poor diet can quickly lead to a deficiency. Conditions that increase the body’s demand for cell production, such as pregnancy or chronic hemolysis, can also rapidly deplete folate reserves. Certain medications, including some anticonvulsants and chemotherapy drugs, can also interfere with folate metabolism, contributing to this deficiency.
Organ Dysfunction, Metabolism, and Toxic Exposure
When nutritional causes like B12 and folate deficiency are ruled out, the macrocytosis is classified as non-megaloblastic, indicating different underlying mechanisms. Chronic exposure to alcohol is one of the most common non-nutritional causes of elevated MCV, even before anemia develops. Alcohol directly interferes with the maturation of red blood cells in the bone marrow, leading to the production of larger cells.
Severe liver disease also causes macrocytosis through a distinct mechanism involving changes to the red blood cell membrane. Altered lipid metabolism in the liver leads to an abnormal deposition of cholesterol onto the red blood cell surface. This added material increases the cell’s surface area, resulting in a physically larger cell, known as a round macrocyte, which raises the MCV.
Thyroid dysfunction, specifically hypothyroidism, can also lead to an increase in red cell size. The reduced thyroid hormone levels can affect the composition of the red blood cell membrane, contributing to the macrocytosis. This cause is usually identified through a thyroid function test as part of a broader diagnostic evaluation.
Myelodysplastic Syndromes (MDS) represent a more serious, though less common, cause involving a defect in the bone marrow’s stem cells. In MDS, the bone marrow produces blood cells that are structurally abnormal and dysfunctional, including abnormally large red blood cells. This condition is a primary disorder of the blood-forming machinery and is often suspected if macrocytosis is accompanied by low counts of other blood cells.
Several classes of medications can also cause macrocytosis by interfering with DNA synthesis or red cell membrane integrity. Drugs like methotrexate and certain antiretroviral agents used for HIV treatment, such as zidovudine, are known to disrupt the bone marrow’s ability to divide cells normally. Discontinuing the medication often leads to a gradual normalization of the MCV.
Diagnostic Evaluation and Interpretation
Identifying an elevated MCV and MCH requires a comprehensive patient history to narrow the possible causes. This assessment includes detailed questions about diet, alcohol consumption habits, and a complete review of all current medications, as these factors account for a large percentage of macrocytosis cases. A physical examination may reveal subtle neurological symptoms or other signs pointing toward a specific vitamin deficiency or underlying organ disease.
Follow-up laboratory tests are then used to differentiate between the nutritional and non-nutritional causes. Specific blood tests measure the levels of Vitamin B12 and folate to check for deficiency. If these vitamin levels are normal, the investigation moves to tests like liver function panels and thyroid function tests to explore organ dysfunction.
Another important test is the reticulocyte count, which measures the number of newly released, immature red blood cells. Since reticulocytes are naturally larger than mature red cells, a high count (reticulocytosis) can temporarily elevate the MCV. This transient elevation often occurs in response to acute blood loss or conditions where red cells are being rapidly destroyed.
If the initial assessment remains inconclusive, or if other blood cell lines are also abnormal, a bone marrow examination may be necessary. This procedure helps rule out primary disorders of the blood-forming machinery, such as Myelodysplastic Syndromes.