The Major Cause of Pernicious Anemia: An Autoimmune Attack on Intrinsic Factor

December 27, 2025 •

3 min read

Pernicious anemia, once a deadly disease, is primarily a rare autoimmune disorder where the immune system attacks stomach cells, causing vitamin B12 deficiency. It is the most common cause of B12 deficiency in some regions, though it remains relatively uncommon in the general population.

Quick Summary

This condition is caused by the body's inability to absorb vitamin B12 due to a lack of intrinsic factor. This is often the result of an autoimmune process that damages the stomach lining, preventing the creation of the protein necessary for nutrient absorption.

Key Points

Autoimmune Attack: The major cause of pernicious anemia is an autoimmune disease that targets and destroys the parietal cells in the stomach lining.
Intrinsic Factor Deficiency: The destruction of parietal cells leads to a lack of intrinsic factor, a protein essential for vitamin B12 absorption.
Vitamin B12 Malabsorption: Without intrinsic factor, the body cannot absorb vitamin B12 from food, causing a severe deficiency.
Distinct from Dietary Deficiency: Pernicious anemia differs from B12 deficiency caused by poor diet, as the issue lies in the body's inability to absorb the vitamin, not in insufficient intake.
Lifelong Treatment: Treatment involves regular B12 supplementation, often via injections, to bypass the absorption problem.
Neurological Complications: If untreated, the B12 deficiency can lead to irreversible nerve and brain damage.
Associated Conditions: Pernicious anemia often co-occurs with other autoimmune disorders, such as Type 1 diabetes and thyroid disease.

Understanding the Autoimmune Connection

At its core, the major cause of pernicious anemia is an autoimmune process known as autoimmune atrophic gastritis. In this condition, the body's own immune system mistakenly targets and destroys the parietal cells in the stomach lining. These specialized cells are responsible for two critical functions: producing hydrochloric acid and secreting a protein called intrinsic factor. The destruction of these cells halts the production of intrinsic factor, which is vital for the absorption of vitamin B12 in the small intestine. The inability to absorb this essential nutrient, regardless of dietary intake, leads to a severe B12 deficiency that causes the characteristic megaloblastic anemia.

The Role of Intrinsic Factor Antibodies

In addition to destroying the parietal cells, the immune system may also produce antibodies that directly attack the intrinsic factor protein itself. These intrinsic factor antibodies (IFAB) are typically one of two types:

Type 1 (Blocking antibodies): These antibodies bind to the site on the intrinsic factor where vitamin B12 would normally attach, preventing the formation of the intrinsic factor-B12 complex.
Type 2 (Binding antibodies): These bind to the intrinsic factor-B12 complex itself, preventing it from attaching to receptors in the small intestine for absorption. The presence of IFAB is highly specific for pernicious anemia and helps confirm the diagnosis. The result is that even if some intrinsic factor is produced, it is neutralized by these antibodies, further exacerbating the vitamin B12 malabsorption.

The Digestive Process Gone Wrong

For a person without pernicious anemia, the vitamin B12 absorption process is a multi-step affair. The journey begins in the stomach, where stomach acid releases vitamin B12 from the food protein it's bound to. The free vitamin B12 then binds with intrinsic factor, and this complex travels to the small intestine. In the final part of the small intestine (the ileum), the intrinsic factor-B12 complex is absorbed into the bloodstream. In a person with pernicious anemia, this process is broken at the point of intrinsic factor production, and sometimes even at the point of the vitamin-protein interaction, due to the autoimmune attack.

Beyond the Autoimmune Attack: Other Factors

While the autoimmune assault on intrinsic factor is the major cause, other factors can also lead to vitamin B12 malabsorption, sometimes resulting in a clinically similar condition. It is important to differentiate between true pernicious anemia and other causes of B12 deficiency.

Here is a comparison of pernicious anemia and other causes of vitamin B12 deficiency:


Feature	Pernicious Anemia	Other Causes of B12 Deficiency
Underlying Cause	Autoimmune destruction of parietal cells, leading to intrinsic factor deficiency.	Inadequate dietary intake (e.g., vegan diet), stomach or intestinal surgery (gastrectomy or gastric bypass), intestinal diseases (e.g., Crohn's, Celiac), medications (e.g., metformin, PPIs), bacterial overgrowth, tapeworm.
Role of Intrinsic Factor	Absent or functionally blocked due to antibodies.	Often normal, but absorption may be compromised elsewhere in the digestive tract.
Immune Markers	Presence of intrinsic factor antibodies or parietal cell antibodies.	No specific immune markers related to intrinsic factor.
Treatment	Lifelong B12 supplementation, usually via injections, due to malabsorption. Oral supplements may be effective at very high doses.	Dependent on the specific cause. May be corrected with dietary changes, treating underlying conditions, or oral B12 supplements.

Why is it called 'pernicious'?

The term "pernicious" means "deadly". This name originated in the past when the condition was often fatal because its cause was unknown and no treatment was available. Before the discovery of vitamin B12 and the development of effective treatments like injections, a deficiency could lead to severe, irreversible nerve damage and death. Today, with proper diagnosis and lifelong vitamin B12 replacement therapy, the disease is manageable and patients can live normal, healthy lives. Early diagnosis is crucial to prevent long-term neurological complications.

Conclusion

In summary, the single most significant cause of pernicious anemia is the autoimmune destruction of stomach parietal cells, which eliminates the body's ability to produce intrinsic factor. This leads to a severe vitamin B12 malabsorption and subsequent deficiency. While other conditions and lifestyle factors can cause B12 deficiency, the autoimmune etiology is what specifically defines pernicious anemia. Recognizing this distinction is critical for accurate diagnosis and for ensuring patients receive the correct, often lifelong, treatment to manage the condition and prevent serious neurological and hematological complications. The prompt treatment of this once-fatal disease has transformed it into a manageable chronic illness.

Frequently Asked Questions

The key difference is the underlying cause. Regular vitamin B12 deficiency may result from poor diet (e.g., veganism) or other medical issues. Pernicious anemia, however, is specifically caused by an autoimmune attack that prevents the absorption of B12, regardless of how much is consumed.

The immune system in people with pernicious anemia can produce antibodies that specifically target the intrinsic factor protein or the stomach cells that produce it. This attack disables or blocks the intrinsic factor, preventing it from binding to and enabling the absorption of vitamin B12.

Symptoms often develop slowly and can be vague initially. They can include fatigue, weakness, a smooth and red tongue (glossitis), pale or yellowish skin, changes in balance, and tingling or numbness in the hands and feet.

While not directly inherited like some genetic disorders, pernicious anemia often has a genetic predisposition. It is more common in people with a family history of the disease or other autoimmune conditions.

Pernicious anemia is a lifelong condition and cannot be cured. However, it can be effectively managed with lifelong vitamin B12 replacement therapy, usually through regular injections.

Diagnosis involves several steps, including blood tests to check vitamin B12 levels and tests for the presence of intrinsic factor antibodies and parietal cell antibodies. A complete blood count is also used to check for megaloblastic anemia.

Yes, autoimmune atrophic gastritis, which leads to pernicious anemia, is also associated with an increased risk of developing gastric cancer and gastric neuroendocrine tumors. Regular monitoring via endoscopy may be recommended.