The Crucial Biochemical Link: Why Does Vitamin B12 Deficiency Cause Megaloblastic Anaemia?

December 16, 2025 •

4 min read

Globally, over 4% of people are affected by anaemia, with vitamin B12 deficiency being a major contributing factor. The critical nutrient is vital for DNA synthesis, and its absence directly explains why vitamin B12 deficiency causes megaloblastic anaemia.

Quick Summary

Vitamin B12 deficiency impairs DNA synthesis, causing bone marrow stem cells to produce abnormally large, immature red blood cells known as megaloblasts, which leads to anaemia.

Key Points

DNA Synthesis Impairment: Vitamin B12 is crucial for DNA replication, and its deficiency halts the production of new genetic material in red blood cell precursors.
The Methylfolate Trap: In the absence of B12, a specific form of folate becomes metabolically trapped and unusable, causing a functional folate deficiency that impairs DNA synthesis.
Asynchronous Cell Growth: Affected red blood cell precursors grow in size but fail to divide properly, resulting in large, immature cells called megaloblasts.
Ineffective Hematopoiesis: Many of these abnormal cells are prematurely destroyed within the bone marrow, severely reducing the number of circulating red blood cells.
Neurological Consequences: Unlike folate deficiency, B12 deficiency can lead to demyelination of nerves, causing potentially irreversible neurological symptoms such as numbness and balance problems.
Diverse Etiologies: Common causes range from autoimmune conditions like pernicious anemia and dietary inadequacy to gastric and intestinal malabsorption issues.

The Core Mechanism: Impaired DNA Synthesis

To understand why vitamin B12 deficiency causes megaloblastic anaemia, one must first grasp the nutrient's essential role in DNA synthesis. All rapidly dividing cells, especially the red blood cell precursors in the bone marrow, rely on a constant supply of nucleotides to replicate their DNA. Vitamin B12 acts as a crucial cofactor for the enzyme methionine synthase, which is necessary for this process.

Without sufficient vitamin B12, the methionine synthase reaction is stalled. This causes a cascade of biochemical problems that ultimately disrupt DNA production. The cell cycle cannot progress normally from the G2 stage to mitosis, resulting in cells that continue to grow in size without dividing. This creates the hallmark abnormally large, immature cells found in megaloblastic anaemia.

The "Methylfolate Trap" and DNA Starvation

A key part of the process is the "methylfolate trap" hypothesis, which explains how a lack of vitamin B12 functionally starves the body of usable folate, even if overall folate levels are adequate.

The Normal Cycle: Folate (Vitamin B9) enters the cell in a methylated form, 5-methyl-tetrahydrofolate (5-methyl-THF). For this folate to be used in DNA synthesis, it must be converted back into its unmethylated form. This conversion relies on the enzyme methionine synthase, for which vitamin B12 is a cofactor.
The Trapped State: When vitamin B12 is deficient, the methionine synthase enzyme is inactive. This prevents the removal of the methyl group from 5-methyl-THF. As a result, usable folate is effectively "trapped" in its inactive form, unable to be converted into the intermediates needed for DNA synthesis, particularly the creation of thymidine.

This functional folate deficiency is the immediate cause of the defective DNA synthesis that drives the development of megaloblastic anaemia.

The Result: Abnormally Large and Fragile Blood Cells

In the bone marrow, the cell precursors of red blood cells, known as erythroblasts, are in a constant state of rapid division. Their nuclei require frequent DNA synthesis to mature. However, during vitamin B12 deficiency, this process is hampered, while cytoplasmic growth (driven by RNA and protein synthesis) continues relatively unimpaired.

This leads to an asynchronous maturation, where the cell nucleus lags behind the cytoplasm, resulting in:

Megaloblasts: The presence of these large, immature, and fragile red blood cell precursors in the bone marrow. These cells are dysfunctional and often destroyed before they can be released into the bloodstream.
Macrocytes: Some megaloblasts do mature enough to be released into the circulation, but they remain abnormally large and are often misshapen (macro-ovalocytes).
Ineffective Hematopoiesis: The premature destruction of developing cells within the bone marrow, known as intramedullary hemolysis, leads to a significant decrease in overall red blood cell production. The remaining macrocytes have a shortened lifespan and are cleared from the circulation by the spleen and liver, a process called extramedullary hemolysis.

Comparing B12 and Folate Deficiency

Although both B12 and folate deficiencies cause megaloblastic anaemia due to impaired DNA synthesis, there are important distinguishing features, particularly concerning the nervous system.


Feature	Vitamin B12 Deficiency	Folate Deficiency
Mechanism	Impairs methionine synthase, trapping folate and hindering DNA synthesis. Also impairs metabolism of methylmalonic acid.	Direct lack of folate, impairing DNA synthesis.
Neurological Symptoms	Common and can be severe, including tingling, numbness, and balance issues. Can occur even without anaemia.	Rare, unless caused by specific drugs.
Methylmalonic Acid (MMA)	Elevated.	Normal.
Homocysteine (HCY)	Elevated.	Elevated.
Absorption Issues	Often related to malabsorption (e.g., pernicious anemia, stomach surgery).	Less common, but possible with certain diseases.

Causes of Vitamin B12 Deficiency

The most common causes of this deficiency include:

Pernicious Anaemia: An autoimmune condition where the body attacks the intrinsic factor protein needed to absorb vitamin B12.
Dietary Factors: Inadequate intake, most commonly seen in those following vegan or vegetarian diets, as B12 is primarily found in animal products.
Gastric Conditions: Disorders or surgeries affecting the stomach, such as atrophic gastritis or gastric bypass, can prevent the production of intrinsic factor or stomach acid needed for absorption.
Intestinal Malabsorption: Conditions like Crohn's disease, celiac disease, or certain bacterial overgrowths can interfere with absorption in the small intestine.

Conclusion

Vitamin B12 deficiency leads to megaloblastic anaemia by critically disrupting the complex process of DNA synthesis. This occurs because the body lacks the vital cofactor needed to convert folate into its usable form, creating a functional folate deficiency. The impaired DNA synthesis results in the production of large, immature, and fragile red blood cells that are ineffective at carrying oxygen, leading to the clinical symptoms of anaemia. Early diagnosis and appropriate treatment with B12 supplementation are essential not only to correct the anaemia but also to prevent the irreversible neurological damage that is uniquely associated with B12 deficiency.

For more information on the functions of vitamin B12, you can visit the NIH Office of Dietary Supplements website.

Frequently Asked Questions

Vitamin B12 deficiency causes impaired DNA synthesis in red blood cell precursors. This leads to a mismatch between nuclear and cytoplasmic maturation, where the cell nucleus fails to divide normally while the cytoplasm continues to grow, resulting in abnormally large and immature cells called megaloblasts.

Yes. Folic acid treatment can correct the anaemia symptoms caused by the B12 deficiency but does not address the underlying problem or prevent the progression of neurological damage. This can delay the diagnosis of a potentially serious B12 deficiency.

The key difference lies in the potential for neurological damage. While both deficiencies cause similar haematological issues, only vitamin B12 deficiency can lead to demyelination of nerves and subsequent neurological symptoms.

Symptoms can include fatigue, weakness, pale skin, shortness of breath, a sore and red tongue, and neurological signs like tingling, numbness, and balance issues.

Diagnosis typically involves blood tests, including a complete blood count (CBC) to check for macrocytosis, measuring serum vitamin B12 and folate levels, and testing for elevated methylmalonic acid (MMA) and homocysteine levels.

No. The impaired DNA synthesis affects all rapidly dividing cells, including white blood cell and platelet precursors. This can lead to pancytopenia (a reduction in all blood cell types) in severe cases, as well as affecting cells in the gastrointestinal tract.

Treatment involves B12 supplementation, which may be administered via injections or oral tablets. The method and duration depend on the underlying cause of the deficiency, such as whether it's dietary or due to a lifelong absorption issue like pernicious anaemia.