Why Does Vitamin B12 Deficiency Cause Pernicious Anaemia?

Pernicious anaemia is an autoimmune disorder that impacts approximately 0.1% of the general population, with a higher prevalence in those over 60, by disrupting the body's ability to absorb dietary vitamin B12.

Quick Summary

An autoimmune attack on stomach cells that produce intrinsic factor prevents vitamin B12 absorption. This malabsorption hinders DNA synthesis, causing the production of large, immature red blood cells and leading to pernicious anaemia.

Key Points

• Autoimmune Cause: Pernicious anaemia is an autoimmune disease, where the immune system attacks stomach cells or intrinsic factor needed for B12 absorption.

• Intrinsic Factor Failure: The autoimmune attack results in a lack of intrinsic factor, preventing dietary vitamin B12 from being absorbed in the small intestine.

• Impaired DNA Synthesis: Without absorbed B12, DNA synthesis is defective, which severely impacts rapidly dividing blood cells in the bone marrow.

• Megaloblastic Anemia: This leads to the production of abnormally large, immature, and poorly functioning red blood cells, causing megaloblastic anemia.

• Lifelong Treatment: Treatment requires lifelong B12 injections to bypass the digestive tract, as absorption is the core problem.

• Neurological and Cancer Risk: Long-term untreated deficiency can cause permanent nerve damage, and the underlying condition increases the risk of gastric cancer.

The Normal Process of Vitamin B12 Absorption

To understand why a deficiency in vitamin B12 can lead to pernicious anaemia, it is essential to first understand the multi-step process of normal B12 absorption. Unlike most vitamins, B12 is not absorbed directly into the bloodstream from food alone. It requires the help of a crucial protein called intrinsic factor (IF).

1. Release in the stomach: When you consume foods containing vitamin B12 (cobalamin), such as meat, dairy, and eggs, stomach acid and enzymes work to detach B12 from the food proteins it is bound to.
2. Binding with Intrinsic Factor: The freed B12 molecule then binds with intrinsic factor. This vital protein is secreted by the parietal cells located in the lining of the stomach.
3. Absorption in the small intestine: The newly formed B12-IF complex travels through the digestive tract to the terminal ileum, the final section of the small intestine. Here, specific receptors bind to the complex, allowing for the vitamin's absorption into the bloodstream.

The Autoimmune Attack in Pernicious Anaemia

Pernicious anaemia is a specific type of B12 deficiency caused by an autoimmune process, not by a lack of B12 in the diet. In this condition, the body's own immune system mistakenly attacks healthy cells and proteins in the stomach.

There are two primary ways this autoimmune reaction occurs:

• Targeting Parietal Cells: The immune system produces antibodies that attack and destroy the parietal cells of the stomach lining. This diminishes and eventually eliminates the production of intrinsic factor, leaving the body unable to properly absorb vitamin B12. The destruction of parietal cells also reduces stomach acid production, further complicating the release of B12 from food.
• Targeting Intrinsic Factor: In some cases, the immune system creates antibodies that specifically target and bind to the intrinsic factor protein. This blocks the intrinsic factor from attaching to vitamin B12, effectively preventing absorption in the small intestine.

The destruction of the stomach lining and the lack of intrinsic factor mean that even if a person consumes plenty of vitamin B12 through their diet, the body cannot absorb and utilize it. The body's large stores of B12 in the liver mean it can take several years for a deficiency to manifest with noticeable symptoms.

Megaloblastic Anemia: The Cellular Consequence

Vitamin B12 plays a crucial role as a cofactor in the synthesis of DNA. This is particularly important for cells that divide and replicate rapidly, such as the precursors to red blood cells in the bone marrow. The B12 deficiency caused by pernicious anaemia leads to a specific type of blood disorder known as megaloblastic anemia.

In this condition:

• Impaired DNA Synthesis: The lack of B12 impairs the ability of bone marrow cells to synthesize DNA effectively. This prevents the cells from dividing properly.
• Enlarged, Immature Cells: While the nucleus is delayed, the cytoplasm of the cells continues to mature. This results in the production of abnormally large, immature, and fragile red blood cell precursors called megaloblasts. In the blood, these appear as abnormally large red blood cells called macrocytes.
• Ineffective Erythropoiesis: The bone marrow becomes ineffective at producing a sufficient number of healthy red blood cells. The dysfunctional cells are often destroyed prematurely, leading to anemia.

The resulting shortage of healthy, oxygen-carrying red blood cells throughout the body causes the fatigue, weakness, and other symptoms associated with anemia.

Comparison: Pernicious Anaemia vs. Other B12 Deficiencies

Pernicious anaemia is often confused with other causes of B12 deficiency. The key distinction lies in the underlying mechanism of malabsorption.

Feature	Pernicious Anaemia	Dietary B12 Deficiency
Cause	Autoimmune destruction of gastric parietal cells or intrinsic factor protein.	Inadequate dietary intake of B12, common in strict vegans.
Absorption Issue	Inability to absorb B12 due to lack of intrinsic factor.	No absorption issue; the problem is insufficient dietary intake.
Intrinsic Factor	Absent or blocked by antibodies.	Functional and present.
Treatment	Lifelong B12 injections, as absorption is bypassed.	Oral B12 supplements are often effective in correcting the deficiency.
Associated Risks	Higher risk of gastric cancer due to chronic atrophic gastritis.	Primarily nutritional, without the autoimmune pathology linked to gastric risks.

Diagnosis and Management

Diagnosing pernicious anaemia requires a comprehensive evaluation, as symptoms can be non-specific and overlap with other conditions. The process includes a complete blood count (CBC) to check for megaloblastic anemia and tests for autoantibodies against intrinsic factor or parietal cells. Elevated levels of methylmalonic acid (MMA) and homocysteine in the blood can also confirm a B12 deficiency.

Since the problem is malabsorption, treatment involves bypassing the digestive system with intramuscular vitamin B12 injections. The initial course of treatment typically involves frequent injections to rapidly replenish stores, followed by a lifelong schedule of maintenance injections. It is crucial to diagnose and treat the condition promptly, as delayed treatment can lead to irreversible neurological damage. Folic acid should not be used to treat the anemia without also addressing the B12 deficiency, as it can mask the blood symptoms while the neurological damage progresses.

Due to the chronic atrophic gastritis associated with pernicious anaemia, there is an increased risk of developing gastric cancer. Therefore, lifelong monitoring, potentially including regular endoscopic surveillance, is necessary for these patients.

Conclusion

Pernicious anaemia is a distinctive type of vitamin B12 deficiency where an autoimmune attack on the stomach prevents the absorption of this critical nutrient. The immune system's targeting of parietal cells and intrinsic factor is the root cause, leading to the malabsorption that distinguishes it from other B12 deficiencies. This malabsorption, in turn, disrupts DNA synthesis and causes the characteristic megaloblastic anemia and serious neurological issues. Given its chronic and potentially severe nature, timely diagnosis and lifelong, often injected, B12 supplementation are vital for managing the condition and mitigating long-term health risks.

For more detailed information on the pathophysiology and management of pernicious anaemia, visit the authoritative resource at the National Institutes of Health: Pernicious Anemia - StatPearls - NCBI Bookshelf.

Frequently Asked Questions

What is the main cause of pernicious anaemia?

The main cause is an autoimmune condition where the body's immune system attacks the gastric parietal cells that produce intrinsic factor or the intrinsic factor itself, preventing vitamin B12 absorption.

What does intrinsic factor do?

Intrinsic factor is a protein secreted by the stomach's parietal cells. It is essential for binding with vitamin B12, allowing the vitamin to be absorbed later in the small intestine.

How does lack of B12 cause megaloblastic anaemia?

B12 is a coenzyme for DNA synthesis. Without it, bone marrow cells cannot divide properly, resulting in abnormally large and immature red blood cells (megaloblasts) that don't function correctly.

Are there symptoms other than anemia?

Yes, long-term B12 deficiency can also cause neurological issues like tingling or numbness in the limbs, memory loss, and balance problems, as well as gastrointestinal and psychological symptoms.

Is pernicious anaemia treated with oral B12 supplements?

Typically, no. Since the problem is malabsorption, oral supplements are often ineffective. Lifelong intramuscular B12 injections are the standard treatment to bypass the absorption issue.

Can pernicious anaemia be cured?

No, it is a chronic, lifelong autoimmune condition. However, it can be effectively managed with lifelong B12 supplementation to prevent deficiency and its symptoms.

What are the risks if pernicious anaemia goes untreated?

Untreated pernicious anaemia can lead to severe neurological damage that may become permanent. The associated chronic atrophic gastritis also increases the risk of developing gastric cancer.