Macrocytosis is an increase in the size of red blood cells. It may be linked to aging, vitamin B12 or folate deficiency, heavy alcohol use, or bone marrow changes.
Macrocytic red blood cells are often found on routine lab work, such as a complete blood count (CBC). This test may be ordered for symptoms such as unusual fatigue, shortness of breath, paleness, diarrhea, or numbness in the arms or legs.
Macrocytosis should be evaluated by a clinician in the context of other complete blood count (CBC) results. These include the mean corpuscular volume (MCV), red blood cell count, hemoglobin level, and red cell distribution width (RDW), which are typically reviewed together to determine the underlying cause and guide appropriate treatment.
Confirming a diagnosis
Macrocytosis is assessed using the mean corpuscular volume (MCV), which reflects the average size of red blood cells. The usual reference range is 80.0 to 100.0 fL, but this range can vary by laboratory.
Macrocytosis is typically considered when the MCV is above 100.0 fL.
For macrocytosis to have clinical relevance, the mean corpuscular volume (MCV) should be reviewed alongside other complete blood count (CBC) indices. These include the red blood cell count, hemoglobin, red cell distribution width (RDW, which reflects variation in red blood cell size), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).
Common symptoms
The main symptoms of macrocytosis are:
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Extreme tiredness or weakness;
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Paleness;
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Muscle pain;
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Difficulty breathing or shortness of breath;
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Numbness or tingling in the hands or feet;
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Diarrhea, canker sores, or a swollen tongue.
Symptoms of macrocytosis vary depending on the underlying cause. In many cases, macrocytosis does not cause symptoms and is discovered during routine testing.
If symptoms occur, evaluation by a hematologist, primary care provider, or pediatrician can help determine the cause of macrocytosis and whether treatment is needed.
Main causes
The main causes of macrocytosis are:
1. Aging
An increase in red blood cell size is more common in older adults.
This may happen because less oxygen is available, which can increase the body’s need to capture and carry oxygen, resulting in larger red blood cells.
What to do: specific treatment is usually not needed, since this can be a normal change.
Even so, medical follow-up is important, and red blood cell size should be interpreted together with other CBC results.
2. Vitamin B12 deficiency
Vitamin B12 deficiency is one of the most common causes of macrocytosis and can lead to pernicious anemia.
This type of anemia can cause symptoms such as weakness, marked fatigue, or shortness of breath.
Vitamin B12 deficiency may occur due to reduced intestinal absorption or inadequate daily intake.
What to do: measuring blood vitamin B12 levels can help confirm the diagnosis and guide treatment. Treatment may include increasing intake of vitamin B12-rich foods or using supplements, depending on guidance from a clinician or registered dietitian.
3. Folate deficiency
Folate deficiency is also a common cause of macrocytosis and may occur due to low intake, inflammatory bowel diseases, or pregnancy, for example.
This deficiency can lead to anemia and symptoms such as reduced appetite, nausea, vomiting, diarrhea, canker sores, and hair loss.
In addition to macrocytosis, a CBC may show red blood cell changes, hypersegmented neutrophils, and variation in red blood cell shape (poikilocytosis).
What to do: after identifying the cause of folate deficiency, treatment is selected accordingly and may include increasing dietary folate or taking supplements.
If folate deficiency is related to intestinal changes, a clinician may recommend treatment targeted to the underlying condition to help normalize folate levels.
4. Megaloblastic anemia
Megaloblastic anemia is a type of anemia caused by vitamin B12 and/or folate deficiency and can lead to macrocytosis.
It may cause symptoms such as paleness, diarrhea or constipation, muscle pain, tingling in the hands or feet, or shortness of breath.
What to do: treatment is managed by a hematologist or pediatrician and may include increasing intake of these vitamins or taking supplements.
5. Alcohol use disorder
Frequent alcohol use can gradually reduce folate levels, which can contribute to larger red blood cells. Alcohol can also trigger other biochemical changes.
What to do: reducing or stopping alcohol use is recommended, with medical support and psychological follow-up when appropriate.
6. Bone marrow changes
The bone marrow is responsible for producing blood cells and can release larger red blood cells when its function is disrupted.
Bone marrow-related causes of macrocytosis include some types of leukemia, and macrocytosis can also occur as a response to anemia.
What to do: if other abnormalities are present on blood tests, a clinician may recommend a bone marrow aspirate (myelogram) or bone marrow biopsy to confirm the cause and guide treatment.
7. Use of medications
Some medications can contribute to vitamin B12 or folate deficiency and lead to macrocytosis, such as omeprazole, metformin, methotrexate, phenytoin, or trimethoprim.
Other medications, including valproic acid, hydroxyurea, allopurinol, and some antiretrovirals, can also be associated with macrocytosis.
What to do: follow up with the clinician who prescribed the medication to review dosing and whether vitamin B12 or folate replacement is needed, or whether switching medications is appropriate.
Medication should not be stopped without medical guidance.
8. Hypothyroidism
Hypothyroidism is reduced production of thyroid hormones T3 and T4, which are important for red blood cell production and function. This can contribute to macrocytosis.
Symptoms may include tiredness, weakness, low energy, dry and rough skin, or weight gain.
What to do: treatment is managed by an endocrinologist and typically includes taking levothyroxine to replace thyroid hormone.
Is macrocytosis cancer?
Macrocytosis is not cancer, but it can occur with some cancers such as leukemia, myelodysplastic syndrome, or multiple myeloma. These conditions can affect red blood cell production in the bone marrow.
Macrocytosis may also occur due to chemotherapy or radiation therapy, or due to nutritional deficiencies associated with cancer.
Macrocytosis caused by cancer is not common and should be evaluated by an oncologist together with other tests to determine the cancer type.