RESEARCH STARTER

Pernicious anemia

Pernicious anemia is a type of megaloblastic anemia caused by the body's inability to absorb vitamin B12, which is essential for the production of healthy red blood cells and the maintenance of nerve function. This condition arises when there is a lack of intrinsic factor, a protein produced in the stomach necessary for the absorption of vitamin B12. Although it can occur due to dietary deficiencies, pernicious anemia is often linked to autoimmune conditions that damage the stomach lining, particularly in older adults. Symptoms include fatigue, depression, and neurological issues, including numbness and difficulty walking. Diagnosis typically involves blood tests that evaluate red blood cell characteristics and vitamin B12 levels. Treatment varies based on the underlying cause but may include dietary changes or vitamin B12 injections. Early detection and treatment are crucial, as untreated pernicious anemia can lead to severe complications, including neurological damage and even death. The condition is more prevalent among older adults and certain ethnic groups, notably those of Northern European descent.

Full Article

Pernicious anemia is a type of vitamin B12 deficiency anemia caused by an autoimmune response that impairs the body’s production of intrinsic factor, which is essential for absorbing vitamin B12 from food. Vitamin B12 is an essential vitamin that the body cannot make; however, even with adequate intake of vitamin B12 in the diet, the condition of the stomach lining and the presence of intrinsic factor determines whether the body can absorb the nutrient from food. Vitamin B12 is responsible for keeping nerves and red blood cells healthy. In healthy individuals, the liver can store two to five years of vitamin B12. Estimates vary but research suggests that vitamin B12 deficiency due to pernicious anemia may affect 2 to 5 percent of older adults, particularly in populations of Northern European descent. In the United States, estimates suggest that about 151 in 100,000 people develop pernicious anemia, although reported rates vary. Though pernicious anemia is easily treatable when detected in the early stages, the disease can be fatal if allowed to progress.

Background

Pernicious anemia was first discovered in 1855 by British physician Thomas Addison, who observed a cluster of symptoms in patients, including pallor, fatigue, and progressive weakness. After this case, many physicians over the next thirty years noticed patients who were also pale, weak, and had enlarged, sore, red tongues. Some patients had numbness and tingling in their fingers and toes which progressed to difficulty walking—symptoms now recognized as neurologic complications of vitamin B12 deficiency. Blood samples from affected individuals revealed abnormally large, oval-shaped red blood cells (macro-ovalocytes), a hallmark of megaloblastic anemia, as well as achlorhydria, or the absence of stomach acid. Using these symptoms to characterize the disease, it was called pernicious anemia. By 1908, physician Richard Cabot reported that once patients became symptomatic (showing signs of a disease), they only lived between one and three years.

Francis Weld Peabody, a physician-scientist of the early twentieth century, further characterized the disease’s effects on erythrocytes removed from a patient’s bone marrow. Also, George Whipple conducted experiments using dogs to show how diet (specifically liver) could help regenerate the quantity and integrity of erythrocytes after depleting the animal’s supply with phlebotomy. Armed with this important discovery, George Richards Minot and William Murphy began conducting experiments in human patients, using a diet rich in liver, in hopes of regenerating erythrocytes. After a week, the patient’s blood showed a significant increase in erythrocytes. After two to four months of treatment, the patient’s erythrocyte counts were within normal range, and symptoms had largely disappeared. In 1934, Minot, Murphy, and Whipple received the Nobel Prize in Physiology or Medicine for this important discovery. Later, scientists discovered that vitamin B12 was the liver component responsible for improved erythrocyte count.

Overview

Pernicious anemia is one of many types of megaloblastic anemias. Anemia is a condition where the body does not have enough healthy erythrocytes to properly oxygenate tissues. There are several known factors that can lead to the development of the disease: lack of vitamin B12 in the diet, lack of intrinsic factor in the stomach to bind vitamin B12 and enable its absorption, and infection with Helicobacter pylori of the stomach lining, which may impair vitamin B12 absorption. Also, gastric removal surgery can cause an inability to absorb vitamin B12 if parts of the stomach that produce intrinsic factor are removed or bypassed. However, this may initially cause partial malabsorption, and the body’s liver storage of vitamin B12 is usually adequate to provide the body with enough of the nutrient until those stores are depleted.

The most common cause of intrinsic factor deficiency is an autoimmune condition known as autoimmune gastritis, which leads to the destruction of gastric parietal cells. However, many health conditions and lifestyle choices can increase one’s risk, including having celiac disease, Crohn’s disease, small intestine bacterial overgrowth (SIBO), hypoparathyroidism, Graves’ disease, or a tapeworm infection, as well as some diets, like vegan or vegetarian diets, that do not include enough vitamin B12.

When foods that contain vitamin B12 are consumed, it is first released from food proteins by stomach acid, then temporarily binds to haptocorrin. After reaching the small intestine, it binds to intrinsic factor, which facilitates its absorption in the ileum. The compound is then absorbed through the small intestine and stored in the liver to be used and released as needed for bodily functions.

Pernicious anemia progresses slowly. Signs and symptoms of pernicious anemia are low erythrocyte count, fatigue, depression, low-grade fever, diarrhea, nausea, weight loss, sore tongue, pain in the limbs (neuropathic pain), and sores in the corners of the mouth (angular cheilitis). Patients who have more advanced disease can also exhibit nervous system changes, such as impaired thinking and memory, psychosis, impaired urination, loss of sensation in feet, walking difficulties, and muscle weakness. In children and adolescents, pernicious anemia can cause stunted growth or even delay puberty in certain individuals. Advanced cases may present with neurological symptoms such as paresthesia, impaired proprioception, memory loss, and—rarely—psychiatric disturbances such as depression or even psychosis. These effects are due to demyelination of nerves resulting from prolonged B12 deficiency.

The Schilling test was historically used to determine vitamin B12 absorption and diagnose pernicious anemia but is now considered obsolete due to limited availability and the development of more accurate testing. The Schilling test involved the patient taking an oral dose of radiolabeled vitamin B12. Then, the amount of radioactive metabolites excreted within twenty-four hours was measured. Next, the patient took another dose of radiolabeled vitamin B12 with the addition of a dose of intrinsic factor, and the amount of radioactive metabolites excreted was measured. If the patient had more radioactive metabolites after the dose of intrinsic factor, then a diagnosis of vitamin B12 deficiency due to lack of intrinsic factor was made. Diagnostic tools include anti-intrinsic factor antibodies and anti-parietal cell antibodies, both of which support the diagnosis of pernicious anemia when present. Elevated levels of methylmalonic acid (MMA) and homocysteine can also indicate functional vitamin B12 deficiency.

To diagnose this condition, a medical professional completes a physical exam, looks for signs of nervous system problems, and inquires about any known conditions that may cause vitamin B12 deficiency. Sometimes, the doctor may conduct an upper endoscopy to inspect the stomach and esophagus for signs of degeneration. Diagnostic testing may include vitamin B12 levels, complete blood count, reticulocyte count, a lactate dehydrogenase test, serum bilirubin levels, methylmalonic acid, or homocysteine levels. A person with pernicious anemia may have enlarged, oval erythrocytes and a low erythrocyte count in a blood smear.

The underlying cause determines pernicious anemia treatment. If there are low dietary levels of vitamin B12, the physician will prescribe more vitamin B12-rich foods, such as liver, red meat, and even supplements. If the cause is due to a lack of intrinsic factor, the physician will prescribe vitamin B12 injections at varying intervals. Once B12 levels normalize, the underlying atrophic gastritis may continue to be problematic and require additional treatment. Early diagnosis improves the likelihood of long-term health outcomes. Left untreated, neurological complications, fatigue, heart failure, depression, and even death can occur. Long-term pernicious anemia can also increase one’s risk of gastric cancer.


Bibliography

Akinola, Olawale O., et al. “Unveiling the Pernicious Truth: A Case Report on the Rare Presentation of Severe Vitamin B12 Deficiency.” Cureus, vol. 18, no. 1, 2026, p. e101860, doi:10.7759/cureus.101860. Accessed 1 Apr. 2026.

Bunn, H. Franklin. “Vitamin B12 and Pernicious Anemia—the Dawn of Molecular Medicine.” The New England Journal of Medicine, vol. 370, no. 8, 2014, pp. 773–76, doi:10.1056/NEJMcibr1315544. Accessed 1 Apr. 2026.

Esposito, Gianluca, et al. “Pernicious Anemia: The Hematological Presentation of a Multifaceted Disorder Caused by Cobalamin Deficiency.” Nutrients, vol. 14, no. 8, 2022, p. 1672, doi:10.3390/nu14081672. Accessed 1 Apr. 2026.

Hooper, Martyn, et al. “Patient Journeys: Diagnosis and Treatment of Pernicious Anaemia.” British Journal of Nursing, vol. 23, no. 7, 2014, pp. 376–81, doi:10.12968/bjon.2014.23.7.376. Accessed 1 Apr. 2026.

Krsnik, Isabel. “The Contribution of F. W. Peabody to the Study of Pernicious Anaemia.” British Journal of Haematology, vol. 113, no. 4, 2001, pp. 1076–89, doi:10.1046/j.1365-2141.2001.02821-6.x. Accessed 1 Apr. 2026.

Osborne, David, and Agata Sobczyńska-Malefora. “Autoimmune Mechanisms in Pernicious Anaemia & Thyroid Disease.” Autoimmunity Reviews, vol. 14, no. 9, 2015, pp. 763–68, doi:10.1016/j.autrev.2015.04.011. Accessed 1 Apr. 2026.

“Pernicious Anemia.” Cleveland Clinic, 7 Feb. 2022, my.clevelandclinic.org/health/diseases/22377-pernicious-anemia. Accessed 1 Apr. 2026.

Seage, Catherine Heidi, et al. “A Systematic Review of Symptoms of Pernicious Anemia.” Food and Nutrition Bulletin, vol. 45, 2024, pp. S34–39, doi:10.1177/03795721241227016. Accessed 1 Apr. 2026.

Thain, Alfie, et al. “Addressing the Gaps in the Vitamin B12 Deficiency 2024 NICE Guidelines: Highlighting the Need for Better Recognition, Diagnosis, and Management of Pernicious Anaemia.” European Journal of Clinical Nutrition, 2025, doi:10.1038/s41430-025-01583-4. Accessed 1 Apr. 2026.

“What Is Pernicious Anaemia?” The Pernicious Anaemia Society, pernicious-anaemia-society.org/pernicious-anaemia. Accessed 1 Apr. 2026.

Full Article

Pernicious anemia is a type of vitamin B12 deficiency anemia caused by an autoimmune response that impairs the body’s production of intrinsic factor, which is essential for absorbing vitamin B12 from food. Vitamin B12 is an essential vitamin that the body cannot make; however, even with adequate intake of vitamin B12 in the diet, the condition of the stomach lining and the presence of intrinsic factor determines whether the body can absorb the nutrient from food. Vitamin B12 is responsible for keeping nerves and red blood cells healthy. In healthy individuals, the liver can store two to five years of vitamin B12. Estimates vary but research suggests that vitamin B12 deficiency due to pernicious anemia may affect 2 to 5 percent of older adults, particularly in populations of Northern European descent. In the United States, estimates suggest that about 151 in 100,000 people develop pernicious anemia, although reported rates vary. Though pernicious anemia is easily treatable when detected in the early stages, the disease can be fatal if allowed to progress.

Background

Pernicious anemia was first discovered in 1855 by British physician Thomas Addison, who observed a cluster of symptoms in patients, including pallor, fatigue, and progressive weakness. After this case, many physicians over the next thirty years noticed patients who were also pale, weak, and had enlarged, sore, red tongues. Some patients had numbness and tingling in their fingers and toes which progressed to difficulty walking—symptoms now recognized as neurologic complications of vitamin B12 deficiency. Blood samples from affected individuals revealed abnormally large, oval-shaped red blood cells (macro-ovalocytes), a hallmark of megaloblastic anemia, as well as achlorhydria, or the absence of stomach acid. Using these symptoms to characterize the disease, it was called pernicious anemia. By 1908, physician Richard Cabot reported that once patients became symptomatic (showing signs of a disease), they only lived between one and three years.

Francis Weld Peabody, a physician-scientist of the early twentieth century, further characterized the disease’s effects on erythrocytes removed from a patient’s bone marrow. Also, George Whipple conducted experiments using dogs to show how diet (specifically liver) could help regenerate the quantity and integrity of erythrocytes after depleting the animal’s supply with phlebotomy. Armed with this important discovery, George Richards Minot and William Murphy began conducting experiments in human patients, using a diet rich in liver, in hopes of regenerating erythrocytes. After a week, the patient’s blood showed a significant increase in erythrocytes. After two to four months of treatment, the patient’s erythrocyte counts were within normal range, and symptoms had largely disappeared. In 1934, Minot, Murphy, and Whipple received the Nobel Prize in Physiology or Medicine for this important discovery. Later, scientists discovered that vitamin B12 was the liver component responsible for improved erythrocyte count.

Overview

Pernicious anemia is one of many types of megaloblastic anemias. Anemia is a condition where the body does not have enough healthy erythrocytes to properly oxygenate tissues. There are several known factors that can lead to the development of the disease: lack of vitamin B12 in the diet, lack of intrinsic factor in the stomach to bind vitamin B12 and enable its absorption, and infection with Helicobacter pylori of the stomach lining, which may impair vitamin B12 absorption. Also, gastric removal surgery can cause an inability to absorb vitamin B12 if parts of the stomach that produce intrinsic factor are removed or bypassed. However, this may initially cause partial malabsorption, and the body’s liver storage of vitamin B12 is usually adequate to provide the body with enough of the nutrient until those stores are depleted.

The most common cause of intrinsic factor deficiency is an autoimmune condition known as autoimmune gastritis, which leads to the destruction of gastric parietal cells. However, many health conditions and lifestyle choices can increase one’s risk, including having celiac disease, Crohn’s disease, small intestine bacterial overgrowth (SIBO), hypoparathyroidism, Graves’ disease, or a tapeworm infection, as well as some diets, like vegan or vegetarian diets, that do not include enough vitamin B12.

When foods that contain vitamin B12 are consumed, it is first released from food proteins by stomach acid, then temporarily binds to haptocorrin. After reaching the small intestine, it binds to intrinsic factor, which facilitates its absorption in the ileum. The compound is then absorbed through the small intestine and stored in the liver to be used and released as needed for bodily functions.

Pernicious anemia progresses slowly. Signs and symptoms of pernicious anemia are low erythrocyte count, fatigue, depression, low-grade fever, diarrhea, nausea, weight loss, sore tongue, pain in the limbs (neuropathic pain), and sores in the corners of the mouth (angular cheilitis). Patients who have more advanced disease can also exhibit nervous system changes, such as impaired thinking and memory, psychosis, impaired urination, loss of sensation in feet, walking difficulties, and muscle weakness. In children and adolescents, pernicious anemia can cause stunted growth or even delay puberty in certain individuals. Advanced cases may present with neurological symptoms such as paresthesia, impaired proprioception, memory loss, and—rarely—psychiatric disturbances such as depression or even psychosis. These effects are due to demyelination of nerves resulting from prolonged B12 deficiency.

The Schilling test was historically used to determine vitamin B12 absorption and diagnose pernicious anemia but is now considered obsolete due to limited availability and the development of more accurate testing. The Schilling test involved the patient taking an oral dose of radiolabeled vitamin B12. Then, the amount of radioactive metabolites excreted within twenty-four hours was measured. Next, the patient took another dose of radiolabeled vitamin B12 with the addition of a dose of intrinsic factor, and the amount of radioactive metabolites excreted was measured. If the patient had more radioactive metabolites after the dose of intrinsic factor, then a diagnosis of vitamin B12 deficiency due to lack of intrinsic factor was made. Diagnostic tools include anti-intrinsic factor antibodies and anti-parietal cell antibodies, both of which support the diagnosis of pernicious anemia when present. Elevated levels of methylmalonic acid (MMA) and homocysteine can also indicate functional vitamin B12 deficiency.

To diagnose this condition, a medical professional completes a physical exam, looks for signs of nervous system problems, and inquires about any known conditions that may cause vitamin B12 deficiency. Sometimes, the doctor may conduct an upper endoscopy to inspect the stomach and esophagus for signs of degeneration. Diagnostic testing may include vitamin B12 levels, complete blood count, reticulocyte count, a lactate dehydrogenase test, serum bilirubin levels, methylmalonic acid, or homocysteine levels. A person with pernicious anemia may have enlarged, oval erythrocytes and a low erythrocyte count in a blood smear.

The underlying cause determines pernicious anemia treatment. If there are low dietary levels of vitamin B12, the physician will prescribe more vitamin B12-rich foods, such as liver, red meat, and even supplements. If the cause is due to a lack of intrinsic factor, the physician will prescribe vitamin B12 injections at varying intervals. Once B12 levels normalize, the underlying atrophic gastritis may continue to be problematic and require additional treatment. Early diagnosis improves the likelihood of long-term health outcomes. Left untreated, neurological complications, fatigue, heart failure, depression, and even death can occur. Long-term pernicious anemia can also increase one’s risk of gastric cancer.


Bibliography

Akinola, Olawale O., et al. “Unveiling the Pernicious Truth: A Case Report on the Rare Presentation of Severe Vitamin B12 Deficiency.” Cureus, vol. 18, no. 1, 2026, p. e101860, doi:10.7759/cureus.101860. Accessed 1 Apr. 2026.

Bunn, H. Franklin. “Vitamin B12 and Pernicious Anemia—the Dawn of Molecular Medicine.” The New England Journal of Medicine, vol. 370, no. 8, 2014, pp. 773–76, doi:10.1056/NEJMcibr1315544. Accessed 1 Apr. 2026.

Esposito, Gianluca, et al. “Pernicious Anemia: The Hematological Presentation of a Multifaceted Disorder Caused by Cobalamin Deficiency.” Nutrients, vol. 14, no. 8, 2022, p. 1672, doi:10.3390/nu14081672. Accessed 1 Apr. 2026.

Hooper, Martyn, et al. “Patient Journeys: Diagnosis and Treatment of Pernicious Anaemia.” British Journal of Nursing, vol. 23, no. 7, 2014, pp. 376–81, doi:10.12968/bjon.2014.23.7.376. Accessed 1 Apr. 2026.

Krsnik, Isabel. “The Contribution of F. W. Peabody to the Study of Pernicious Anaemia.” British Journal of Haematology, vol. 113, no. 4, 2001, pp. 1076–89, doi:10.1046/j.1365-2141.2001.02821-6.x. Accessed 1 Apr. 2026.

Osborne, David, and Agata Sobczyńska-Malefora. “Autoimmune Mechanisms in Pernicious Anaemia & Thyroid Disease.” Autoimmunity Reviews, vol. 14, no. 9, 2015, pp. 763–68, doi:10.1016/j.autrev.2015.04.011. Accessed 1 Apr. 2026.

“Pernicious Anemia.” Cleveland Clinic, 7 Feb. 2022, my.clevelandclinic.org/health/diseases/22377-pernicious-anemia. Accessed 1 Apr. 2026.

Seage, Catherine Heidi, et al. “A Systematic Review of Symptoms of Pernicious Anemia.” Food and Nutrition Bulletin, vol. 45, 2024, pp. S34–39, doi:10.1177/03795721241227016. Accessed 1 Apr. 2026.

Thain, Alfie, et al. “Addressing the Gaps in the Vitamin B12 Deficiency 2024 NICE Guidelines: Highlighting the Need for Better Recognition, Diagnosis, and Management of Pernicious Anaemia.” European Journal of Clinical Nutrition, 2025, doi:10.1038/s41430-025-01583-4. Accessed 1 Apr. 2026.

“What Is Pernicious Anaemia?” The Pernicious Anaemia Society, pernicious-anaemia-society.org/pernicious-anaemia. Accessed 1 Apr. 2026.

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