Pernicious Anemia

Etiology and Risk Factors

Pernicious anemia results from autoimmune destruction of gastric parietal cells, which produce both hydrochloric acid and intrinsic factor. Patients have a higher incidence of other autoimmune diseases, such as Graves disease, and a genetic predisposition is recognized (Davoren & Hsu, 2019).

Pernicious anemia is one cause of B12 deficiency among several. Other causes include (Davoren & Hsu, 2019; Norris, 2020; Pereiras & Arnall, 2026):

• Gastrectomy or gastric bypass
• Terminal ileal disease or resection, as in Crohn disease
• Small intestinal bacterial overgrowth
• Long-term proton pump inhibitor use
• Strict vegan diets, because cobalamin is found almost exclusively in animal products
• Other malabsorption syndromes

Epidemiology and Clinical Context

Pernicious anemia occurs across genders and racial groups and becomes more common with age. Genetic predisposition and clustering with other autoimmune disease are recognized. Malabsorption-related vitamin B12 deficiency affects an estimated 5% to 20% of older adults (Davoren & Hsu, 2019; Norris, 2020).

Pathophysiology

The disease begins in the stomach. Autoantibodies and cytotoxic T cells target the parietal cell proton pump (H⁺/K⁺ ATPase), producing chronic atrophic gastritis. More than 90% of patients have parietal cell antibodies, and more than half have antibodies to intrinsic factor or the intrinsic factor-cobalamin complex (Davoren & Hsu, 2019).

Loss of parietal cells interrupts B12 absorption at two points. Gastric acid is required to release cobalamin from dietary protein, and intrinsic factor must bind cobalamin for absorption in the terminal ileum (Davoren & Hsu, 2019; Norris, 2020). Because hepatic stores last several years, deficiency develops slowly after acid and intrinsic factor are lost (Davoren & Hsu, 2019).

Cobalamin and folate act together in DNA synthesis. Cobalamin accepts a methyl group from methyltetrahydrofolate, generating methylcobalamin, which converts homocysteine to methionine, and tetrahydrofolate, which is needed for purine and thymidine synthesis. Without cobalamin, folate is trapped in its methyl form and cannot be retained in cells, producing a functional folate deficiency (Davoren & Hsu, 2019).

DNA synthesis slows while cytoplasmic growth and hemoglobin synthesis continue. Dividing cells develop nuclei that are large and immature for their cytoplasm, the defining feature of megaloblastic hematopoiesis. The change affects marrow precursors and gastrointestinal epithelium, and many abnormal red cell precursors are destroyed within the marrow, which compounds the anemia (Davoren & Hsu, 2019).

The mechanism of neurologic injury is less settled. Proposed contributors include impaired methionine and S-adenosylmethionine production, dysregulated myelinolytic cytokines such as tumor necrosis factor, and incorporation of abnormal fatty acids into neuronal lipids. The result is demyelination of the posterior and lateral columns of the spinal cord, called subacute combined degeneration, along with peripheral nerve demyelination and eventual neuronal death (Davoren & Hsu, 2019; Norris, 2020).

Clinical Manifestations

Hematologic

• Fatigue
• Dyspnea
• Dizziness
• Pallor
• Mild jaundice from destruction of red cell precursors within the marrow
• Tachycardia and flow murmur
• High-output heart failure in severe anemia

The anemia can be profound, with hemoglobin values as low as 4 g/dL, a degree rarely seen in iron deficiency. Because it develops slowly, symptoms may be milder than the hemoglobin suggests (Davoren & Hsu, 2019; Norris, 2020).

Gastrointestinal

Glossitis, with a smooth or beefy red tongue, is the most common gastrointestinal finding. Diarrhea and malabsorption are less frequent (Davoren & Hsu, 2019).

Neurologic

• Symmetric paresthesias of the feet and hands
• Loss of vibration and position sense
• Impaired balance and coordination
• Spastic ataxia in advanced disease
• Cognitive changes, neuropsychiatric symptoms, or dementia

Paresthesias are the most common neurologic symptom. Neurologic findings may occur without anemia or macrocytosis, and confusion or neuropsychiatric changes can precede hematologic changes (Davoren & Hsu, 2019; Norris, 2020). Severe deficiency can also cause thrombosis, sometimes at unusual sites such as the cerebral venous sinuses, which is attributed to hyperhomocysteinemia (Davoren & Hsu, 2019).

Diagnostic Evaluation

History

Assess:

• Onset and progression of fatigue and exertional symptoms
• Numbness, tingling, gait change, falls, or memory change
• Diet, including vegan or restricted diets
• Gastric or bariatric surgery
• Ileal disease or resection
• Long-term proton pump inhibitor use
• Personal or family history of autoimmune disease
• Alcohol use and other causes of folate deficiency

Laboratory Testing

• Complete blood count (CBC): Macrocytic anemia, often with a mean corpuscular volume (MCV) above 100 fL and a normal mean corpuscular hemoglobin concentration (MCHC). Leukopenia and thrombocytopenia may occur in advanced disease because megaloblastic change affects every cell line (Davoren & Hsu, 2019; Norris, 2020).
• Peripheral smear: Macro-ovalocytes, marked variation in size and shape, and hypersegmented neutrophils (Davoren & Hsu, 2019).
• Reticulocyte count: Low (Davoren & Hsu, 2019).
• Lactate dehydrogenase and indirect bilirubin: Often elevated because of red cell destruction within the marrow (Davoren & Hsu, 2019).
• Serum B12: Usually low, but false-positive and false-negative results are common because most measured B12 is bound to haptocorrin, which cells cannot use (Davoren & Hsu, 2019).
• Methylmalonic acid and homocysteine: Elevated levels are highly predictive of B12 deficiency and are measured when serum B12 is equivocal (Davoren & Hsu, 2019).
• Intrinsic factor and parietal cell antibodies: Identify pernicious anemia as the cause once B12 deficiency is established (Norris, 2020).
• Folate: Should be measured with B12 in macrocytic anemia (Pereiras & Arnall, 2026).

Cobalamin is required to convert methylmalonyl coenzyme A to succinyl coenzyme A, so methylmalonic acid rises in B12 deficiency and helps separate it from folate deficiency, in which homocysteine rises but methylmalonic acid does not (Davoren & Hsu, 2019).

Additional Testing

The Schilling test is no longer used. Bone marrow examination is unnecessary for diagnosis and can mislead because megaloblastic marrow can resemble acute leukemia (Davoren & Hsu, 2019).

Expected Findings

The characteristic pattern is (Davoren & Hsu, 2019; Norris, 2020):

• Macrocytic megaloblastic anemia with macro-ovalocytes, hypersegmented neutrophils, and a low reticulocyte count
• Low or borderline B12 with elevated methylmalonic acid and homocysteine
• Intrinsic factor or parietal cell antibodies; neurologic deficits may accompany or precede the anemia

Differential Diagnosis

Folate Deficiency

Folate deficiency produces the same megaloblastic blood picture without neurologic findings. Poor intake, alcohol use, pregnancy, malabsorption, and methotrexate are common causes (Norris, 2020).

Other Causes of B12 Deficiency

Gastrectomy, gastric bypass, ileal disease or resection, bacterial overgrowth, proton pump inhibitor use, and vegan diets produce B12 deficiency without the autoimmune gastritis of pernicious anemia (Davoren & Hsu, 2019; Norris, 2020).

Drug-Induced Macrocytosis and Myelodysplasia

Drugs that interfere with DNA synthesis and clonal marrow disorders such as the myelodysplastic syndromes can produce macrocytosis with normal B12 and folate (Davoren & Hsu, 2019).

Copper Deficiency

Copper deficiency can produce anemia, neutropenia, and neurologic complications, particularly after bariatric surgery or with excess zinc exposure, and may be misdiagnosed as myelodysplastic syndrome (Pereiras & Arnall, 2026).

Findings That Reduce Diagnostic Probability

Few laboratory findings exclude pernicious anemia by themselves. The following findings should lower its position in the differential or prompt evaluation for an alternative:

• Normal methylmalonic acid with elevated homocysteine favors folate deficiency over B12 deficiency (Davoren & Hsu, 2019).
• Negative intrinsic factor and parietal cell antibodies in a patient with established B12 deficiency should prompt evaluation for dietary, surgical, ileal, or medication-related causes (Davoren & Hsu, 2019; Norris, 2020).
• Microcytic indices suggest iron deficiency or thalassemia (Davoren & Hsu, 2019).
• Macrocytosis with a high reticulocyte count suggests hemolysis or recovery from blood loss rather than a DNA synthesis defect (Davoren & Hsu, 2019).

Treatment and Management

Vitamin B12 Replacement

Because the absorptive defect is permanent, pernicious anemia requires lifelong B12 replacement. Treatment options include (Pereiras & Arnall, 2026):

• A common regimen is cyanocobalamin 1000 mcg intramuscularly daily for 1 week, then weekly for about a month or until hemoglobin normalizes, then 1000 mcg monthly for life.
• High-dose oral cyanocobalamin, 1000 to 2000 mcg daily, is an alternative for maintenance, with B12 levels checked at least annually.
• Oral therapy is not recommended for patients with severe neurologic signs or central nervous system symptoms.
• Intravenous administration is avoided because of rapid clearance.

Monitoring and Follow-Up

Reticulocytosis and improvement in megaloblastic changes begin within the first week, and hemoglobin rises over the following weeks, and neurologic symptoms should be monitored for resolution (Pereiras & Arnall, 2026). Neurologic deficits are the least likely to improve, and long-standing damage may be permanent because dead neurons are not replaced. Long-term follow-up accounts for the increased risk of gastric adenocarcinoma and of other autoimmune diseases (Davoren & Hsu, 2019).

Complications and Red Flags

Urgent evaluation is required for:

• Rapidly progressive neurologic deficits
• Gait instability or falls
• Confusion or neuropsychiatric change
• Signs of high-output heart failure
• Severe anemia with chest pain or dyspnea at rest
• Pancytopenia
• Thrombosis at unusual sites

Clinical Reasoning Priorities

When serum B12 is equivocal, methylmalonic acid and homocysteine help confirm deficiency and antibody testing establishes pernicious anemia as the cause. Neurologic symptoms increase urgency because long-standing deficits may not reverse (Davoren & Hsu, 2019).

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References

Davoren, J. B., & Hsu, G. (2019). Blood disorders. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.

Pereiras, M. A., & Arnall, J. R. (2026). Anemia. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed.). McGraw Hill.