Which Vitamin Deficiency Causes Macrocytosis?

January 10, 2026 •

4 min read

According to the National Institutes of Health, macrocytic anemia affects 2% to 4% of the population, often linked to nutritional issues. The two primary vitamin deficiencies responsible for causing macrocytosis are vitamin B12 (cobalamin) and vitamin B9 (folate).

Quick Summary

Vitamin B12 and folate deficiencies are the two main nutritional causes of macrocytosis, a condition where red blood cells are abnormally large. This occurs because both vitamins are essential for proper DNA synthesis and red blood cell maturation.

Key Points

Primary Cause: Vitamin B12 (cobalamin) and folate (B9) deficiencies are the two most common nutritional causes of macrocytosis.
Megaloblastic Anemia: Macrocytosis caused by B12 or folate deficiency is a form of megaloblastic anemia, where red blood cells are both large and immature due to impaired DNA synthesis.
Causes of Deficiency: Deficiencies can result from inadequate diet, malabsorption issues (like celiac disease or pernicious anemia), increased bodily demand (such as during pregnancy), and excessive alcohol use.
Non-Megaloblastic Causes: Macrocytosis can also result from conditions unrelated to DNA synthesis, including liver disease, hypothyroidism, and certain medications.
Diagnosis: Diagnosis involves blood tests to check vitamin levels and mean corpuscular volume (MCV), as well as looking at blood cells under a microscope.
Treatment: Treatment focuses on correcting the underlying deficiency with supplements (oral or injection) or addressing the root medical problem.

Understanding Macrocytosis and Its Causes

Macrocytosis is a condition in which a person has abnormally large red blood cells, often leading to a type of anemia known as macrocytic anemia. This abnormality arises from impaired DNA synthesis, which affects the maturation process of red blood cell precursors in the bone marrow. The two most common vitamin deficiencies that cause macrocytosis are a lack of vitamin B12 and folate. When deficient, these vitamins disrupt DNA formation, causing the red blood cells to grow larger than normal before they can fully mature and divide.

The Role of Vitamin B12 and Folate

Both vitamin B12 and folate are crucial for the body's metabolic processes, particularly in the creation of new red blood cells.

Vitamin B12 (Cobalamin): This vitamin is a cofactor in the synthesis of DNA. A deficiency inhibits DNA synthesis, disrupting cell division and causing red blood cells to become large and immature, a condition known as megaloblastic anemia. Vitamin B12 is stored in the liver, and the body can rely on these stores for years, making dietary deficiency a slower process. However, malabsorption is a more common issue.
Folate (Vitamin B9): Like B12, folate is essential for DNA and RNA synthesis. Without enough folate, cells cannot divide properly, leading to the production of large, immature red blood cells. Folate stores in the body are much smaller and can be depleted in a matter of months if dietary intake is insufficient.

Why Deficiencies Occur

Deficiencies in vitamin B12 and folate are not always due to a poor diet. They can also result from underlying medical conditions that affect absorption or increase the body's requirements.

Common causes of B12 deficiency include:

Pernicious Anemia: An autoimmune condition where the body attacks the stomach cells that produce intrinsic factor, a protein necessary for B12 absorption.
Malabsorption Issues: Conditions like Crohn's disease, celiac disease, gastric bypass surgery, and certain infections (e.g., fish tapeworm) can impair B12 absorption in the intestines.
Dietary Factors: Strictly vegan diets can lead to B12 deficiency if not supplemented, as B12 is primarily found in animal products.
Medications: Some drugs, such as metformin and proton pump inhibitors, can interfere with B12 absorption.

Common causes of folate deficiency include:

Inadequate Diet: A diet low in fruits, leafy green vegetables, and fortified grains can lead to a deficiency.
Increased Body Demands: Pregnancy and certain medical conditions like hemolytic anemia, which increase the demand for folate, can cause a deficiency.
Alcohol Misuse: Excessive alcohol consumption interferes with folate absorption and metabolism.
Malabsorptive Conditions: Similar to B12 deficiency, diseases like celiac disease can hinder the absorption of folate.

Non-Megaloblastic Causes of Macrocytosis

While vitamin deficiencies are the most common cause of megaloblastic macrocytosis, other conditions can also lead to abnormally large red blood cells in a non-megaloblastic manner. This means they are not caused by impaired DNA synthesis.

Liver Disease: Chronic liver disease can cause an increased deposition of cholesterol on the red blood cell membranes, increasing their surface area and leading to macrocytosis.
Hypothyroidism: An underactive thyroid can be associated with macrocytosis, though the exact mechanism is not fully understood.
Medications: Certain drugs, including some chemotherapy and HIV medications, can directly cause macrocytosis.
Reticulocytosis: An increased count of reticulocytes (immature red blood cells) can raise the overall mean corpuscular volume (MCV) because these cells are larger than mature red blood cells.

Comparison of Macrocytosis Causes


Feature	Megaloblastic Macrocytosis	Non-Megaloblastic Macrocytosis
Primary Cause	Vitamin B12 or folate deficiency leading to impaired DNA synthesis.	Other underlying medical conditions affecting red blood cell structure or production.
Red Blood Cell Appearance	Large, oval-shaped red blood cells (macro-ovalocytes) are common.	Red blood cells are typically round, not oval.
Bone Marrow Findings	Presence of megaloblasts, which are large, immature red blood cell precursors.	Bone marrow is not megaloblastic; other changes may be present depending on the underlying cause.
Associated Symptoms	Can include fatigue, weakness, and neurological issues (B12 deficiency).	Symptoms often relate to the primary underlying condition (e.g., liver disease).
Diagnostic Markers	Low B12/folate levels, and elevated methylmalonic acid (MMA) and/or homocysteine.	No specific vitamin markers, but liver function tests or thyroid panels may show abnormalities.

Diagnosis and Treatment

Diagnosing the specific cause of macrocytosis requires a thorough evaluation, including a complete blood count (CBC), vitamin B12 and folate level tests, and potentially methylmalonic acid (MMA) and homocysteine tests. A peripheral blood smear can also reveal characteristic cell shapes associated with megaloblastic anemia.

Treatment depends on the root cause. For nutritional deficiencies, supplementation is the standard approach. This may involve oral supplements for folate or for B12 in some cases, while others may require regular B12 injections, especially with absorption issues like pernicious anemia. Addressing underlying conditions, such as reducing alcohol intake or treating liver disease, is also critical.

Conclusion

Macrocytosis is a condition of abnormally large red blood cells most commonly caused by a deficiency in vitamin B12 or folate. These deficiencies disrupt the body's ability to produce mature, healthy red blood cells by interfering with DNA synthesis. While poor diet can be a factor, underlying malabsorption issues, autoimmune disorders, and other medical conditions are often the root cause. Proper diagnosis is crucial to determine if the macrocytosis is megaloblastic or non-megaloblastic and to begin the correct course of treatment, which typically involves vitamin supplementation or addressing the underlying health problem.

Optional Link: For more in-depth information on blood disorders, consult the National Center for Biotechnology Information (NCBI) Bookshelf for medical articles on topics like macrocytic anemia: https://www.ncbi.nlm.nih.gov/books/NBK459295/.

Frequently Asked Questions

The primary vitamin deficiencies that cause macrocytosis are a lack of vitamin B12 and folate (vitamin B9), both of which are essential for proper red blood cell production.

During macrocytosis, red blood cells become abnormally large and are not fully developed. This is often caused by a disruption in DNA synthesis, leading to fewer but larger, less efficient red blood cells.

Yes, pernicious anemia is a specific autoimmune condition that causes macrocytosis. It prevents the absorption of vitamin B12, which is critical for making healthy red blood cells.

Vitamin deficiency-related macrocytosis, known as megaloblastic anemia, is due to impaired DNA synthesis, producing oval-shaped red blood cells. Liver disease-related macrocytosis is non-megaloblastic and is caused by the deposition of lipids on the red blood cell membrane, resulting in rounder cells.

Symptoms can include fatigue, weakness, shortness of breath, a sore tongue, and potential neurological issues like tingling or numbness in the hands and feet, especially with B12 deficiency.

Macrocytosis is diagnosed through blood tests, including a complete blood count (CBC) to check the Mean Corpuscular Volume (MCV) and specific vitamin B12 and folate levels. A blood smear is also used to examine the size and shape of red blood cells.

Yes, macrocytosis caused by a vitamin deficiency can typically be treated effectively by correcting the deficiency with supplements. Treatment can reverse the blood cell abnormalities and improve symptoms.