Pernicious anemia is a type of megaloblastic anemia that is caused by vitamin B12 deficiency, which in turn is caused by a lack of a protein called Intrinsic Factor (IF). “Megaloblastic” refers to the abnormally large, immature red blood cells that the bone marrow produces when it doesn’t have enough vitamin B12.

To understand pernicious anemia, it is crucial to understand the normal process of vitamin B12 absorption.

1. We consume vitamin B12 in foods like meat, fish, eggs, and dairy products.
2. In the stomach, stomach acid separates B12 from the food protein it is attached to.
3. Specialized cells in the stomach lining, called parietal cells, produce Intrinsic Factor.
4. Intrinsic Factor binds to the newly freed vitamin B12. This B12-IF complex then travels through the small intestine.
5. At the very end of the small intestine (the terminal ileum), there are special receptors that can only recognize and absorb the B12 when it is escorted by Intrinsic Factor.

A helpful analogy is to think of Vitamin B12 as a VIP guest arriving at a large hotel (your body). To get from the lobby (your stomach) to the exclusive penthouse suite where it is needed (the bloodstream), the VIP guest requires a special, personalized keycard, Intrinsic Factor. The hotel’s front desk staff (the parietal cells) are the only ones who can issue this keycard. In pernicious anemia, the front desk has been shut down by an autoimmune attack. No keycards are issued. No matter how many VIPs arrive in the lobby, without the keycard, they cannot get past security and be properly absorbed into the system.

This lack of vitamin B12 has two major consequences for the body. First, B12 is essential for the proper formation of red blood cells in the bone marrow. Without it, the cells grow large but cannot divide properly, leading to anemia. Second, vitamin B12 is critical for maintaining the health of the nervous system, particularly the protective myelin sheath that surrounds nerves. A deficiency can cause severe and sometimes irreversible nerve damage.

I’ve often diagnosed this condition in patients who just felt “off”, tired, foggy, or numb in their hands. They were surprised to learn it was all due to a lack of B12, not iron or stress.

Pernicious anemia is caused by the failure of the stomach to produce Intrinsic Factor. The underlying cause of this failure is an autoimmune disease called autoimmune atrophic gastritis.

In this condition, the body’s own immune system mistakenly identifies the parietal cells of the stomach lining as foreign invaders. The immune system produces autoantibodies that attack and gradually destroy these cells. As the parietal cells are destroyed over many years, the stomach loses its ability to produce both stomach acid and, critically, Intrinsic Factor. The resulting inflammation and thinning of the stomach lining is called atrophic gastritis. Once the production of Intrinsic Factor falls below a critical level, the body can no longer absorb dietary vitamin B12, and the signs and symptoms of deficiency begin to develop.

Patients are often confused why they’re deficient despite a good diet. I explain that pernicious anemia isn’t about what you eat, it’s about how your body fails to use the B12 you already have.

Pernicious anemia is an autoimmune disease. It is not contagious and is not directly caused by a poor diet. A person can eat a diet rich in vitamin B12 and still develop pernicious anemia if they cannot absorb it. The factors leading to the development of this specific autoimmune condition are a combination of genetics and other risk factors.

• Genetic Predisposition: Pernicious anemia has a clear tendency to run in families. Having a close relative with the condition significantly increases your own risk, suggesting an inherited genetic susceptibility to this type of autoimmune response.
• Association with Other Autoimmune Diseases: A major risk factor is having another autoimmune condition. Individuals with one autoimmune disease are more likely to develop another. Pernicious anemia is frequently associated with:
  • Autoimmune thyroid disease (Hashimoto’s thyroiditis or Graves’ disease).
  • Type 1 diabetes.
  • Vitiligo (a condition causing patches of lost skin color).
  • Addison’s disease (adrenal insufficiency).
• Age: The risk increases with age. While it can occur in younger people, it is most often diagnosed in individuals over the age of 60.
• Ancestry: The condition is more common in people of Northern European or African descent, but it can affect people of all ethnic backgrounds.

Many of my older patients are surprised to find out they’re B12 deficient, especially if they’ve taken acid-reducing drugs for years. I always ask about diet, medications, and any autoimmune history.

The symptoms of pernicious anemia often develop very slowly and insidiously over many years. Because the body is very good at storing vitamin B12, it can take a long time after the loss of Intrinsic Factor for a deficiency to become apparent. The symptoms are wide-ranging and affect multiple body systems.

Symptoms of Anemia

These symptoms are caused by the body’s lack of healthy red blood cells to carry oxygen.

• Profound fatigue, weakness, and lethargy.
• Shortness of breath, especially with exertion.
• Dizziness or lightheadedness.
• Pale or yellowish skin (jaundice).
• A rapid heartbeat or palpitations.
• Headaches.

Neurological Symptoms

These are the most serious potential consequences of untreated pernicious anemia. They are caused by the demyelination of nerves in the spinal cord and peripheral nervous system.

• Paresthesias: Numbness, tingling, “pins-and-needles,” or burning sensations, typically starting in the hands and feet.
• Balance Problems and Unsteady Gait (Ataxia): Difficulty walking, stumbling, and a loss of balance, especially in the dark.
• Muscle Weakness.
• Cognitive and Psychiatric Changes: This can include memory loss, difficulty concentrating, confusion, irritability, depression, and, in severe, long-standing cases, paranoia or dementia.

Gastrointestinal Symptoms

• Glossitis: A classic sign is a sore, smooth, beefy-red tongue.
• Loss of appetite and unintentional weight loss.
• Diarrhea or constipation.

It is crucial to recognize that neurological symptoms can sometimes develop even before the anemia becomes severe.

I’ve had patients come in thinking they had early dementia or anxiety, but it turned out to be a B12 deficiency. The improvement after treatment can be dramatic, and a huge relief.

Pernicious anemia is diagnosed using blood tests and sometimes antibody tests or procedures to confirm vitamin B12 malabsorption.

1. Initial Blood Tests to Confirm B12 Deficiency and Anemia

• Complete Blood Count (CBC): This is the first step. It will show anemia (a low red blood cell count and low hemoglobin). A key finding is a high Mean Corpuscular Volume (MCV), which indicates that the red blood cells are abnormally large (megaloblastic).
• Peripheral Blood Smear: A pathologist will view a blood sample under a microscope. This can reveal the large, oval-shaped red blood cells and “hypersegmented neutrophils” that are characteristic of B12 deficiency.
• Vitamin B12 Level: A blood test to directly measure the level of vitamin B12 will show a low or borderline-low result.

2. Tests to Confirm Pernicious Anemia as the Cause

Once B12 deficiency is established, further tests are done to find out why.

• Antibody Tests: This is the key to diagnosing pernicious anemia. A blood test can detect the presence of the specific autoantibodies causing the disease.
  • Intrinsic Factor Blocking Antibodies: A positive test for these antibodies is highly specific and confirms the diagnosis of pernicious anemia.
  • Parietal Cell Antibodies: These are also often present, but are less specific as they can be found in other autoimmune conditions.
• Other Blood Tests: Doctors may also test for high levels of methylmalonic acid (MMA) and homocysteine, which build up in the blood when there is not enough B12 to process them.

In some cases, a doctor may recommend an endoscopy to examine the stomach lining and take a biopsy to look for the characteristic atrophic gastritis.

A large MCV (mean corpuscular volume) on routine blood work is often the first clue. If a patient also has numbness or tongue pain, I always check B12 levels, even if they don’t complain of fatigue.

Treatment of pernicious anemia involves replenishing vitamin B12 and managing long-term maintenance to prevent recurrence.

Vitamin B12 Replacement Therapy

Because the problem is with absorption, not intake, standard oral vitamin pills are not effective. The B12 must be delivered in a way that does not require Intrinsic Factor.

• Intramuscular Injections: This is the classic and most reliable treatment. It typically begins with a “loading dose” phase, where a patient receives several injections of vitamin B12 over the first week or two to build up the body’s stores. This is followed by a lifelong maintenance phase, with injections typically given once a month.
• High-Dose Oral B12: It is now known that very high daily doses of oral vitamin B12 (typically 1,000 to 2,000 micrograms) can also be an effective treatment. While the body cannot absorb B12 using Intrinsic Factor, a tiny percentage (about 1%) can be absorbed passively along the entire intestine. A massive oral dose allows enough B12 to be absorbed through this passive mechanism to meet the body’s needs.

Patients often feel an energy boost within weeks of starting B12 injections. I always remind them it’s not a cure, it’s lifelong maintenance, like wearing glasses for poor vision.

Prognosis

With consistent, lifelong B12 replacement therapy, the prognosis is excellent.

• The anemia will correct completely, and the related symptoms of fatigue and weakness will resolve.
• Neurological symptoms will stop progressing. If caught early, most nerve-related symptoms can improve significantly or resolve entirely. However, if neurological damage is severe and has been present for a long time, it may be irreversible. This is why early diagnosis is so critical.

Pernicious anemia, a condition whose name once signaled a fatal outcome, is now a powerful example of how medical understanding can transform a disease. We now know it is a specific autoimmune disorder that targets the stomach’s ability to produce Intrinsic Factor, leading to a profound inability to absorb dietary vitamin B12. This deficiency can cause not only severe anemia but also debilitating and sometimes permanent nerve damage. Proper diagnosis, confirmed by specific antibody tests, is the key to understanding the root cause. Although the condition is lifelong, its treatment is simple and completely effective. What I always tell patients is this: even though you’ll need treatment for life, it’s a simple fix with powerful results. Don’t ignore the signs, pernicious anemia is highly treatable once we catch it.

National Heart, Lung, and Blood Institute (NHLBI). (2022). Pernicious Anemia. Retrieved from https://www.nhlbi.nih.gov/health/anemia/pernicious-anemia

National Organization for Rare Disorders (NORD). (2022). Anemia, Pernicious. Retrieved from https://rarediseases.org/rare-diseases/anemia-pernicious/

Mayo Clinic. (2023). Vitamin B-12 deficiency anemia. Retrieved from https://www.mayoclinic.org/diseases-conditions/vitamin-deficiency-anemia/symptoms-causes/syc-20355025