Cause of Pernicious Anemia
Pernicious anemia is caused by autoimmune destruction of gastric parietal cells, leading to intrinsic factor deficiency and subsequent vitamin B12 malabsorption. 1, 2
Primary Autoimmune Mechanism
The fundamental pathophysiology involves autoimmune atrophic gastritis, predominantly affecting the gastric fundus and body, which destroys the parietal cells responsible for producing intrinsic factor—the protein essential for vitamin B12 absorption in the terminal ileum. 2, 3
- Anti-intrinsic factor antibodies are the hallmark diagnostic finding, present with 73% sensitivity and 100% specificity for pernicious anemia. 1
- Anti-parietal cell antibodies are also commonly detected as surrogate markers of the autoimmune process. 1
- The autoimmune destruction results in corpus-predominant atrophic gastritis, which can be confirmed via endoscopy with biopsies. 4
Contributing Factors and Disease Evolution
Infectious Trigger
Long-standing Helicobacter pylori infection likely plays an initiating role in many patients, where the chronic infectious process gradually transitions to an autoimmune disease that ultimately results in irreversible destruction of gastric body mucosa—a "burned-out infection" pattern. 1
Genetic Susceptibility
- HLA-DR genotypes suggest genetic predisposition to developing pernicious anemia. 1
- Certain MTHFR C677T polymorphisms regulating folate metabolism may be associated with autoimmune conditions including pernicious anemia. 4
- Higher prevalence occurs in certain racial/ethnic groups and early-generation immigrants from high-risk countries. 4
Pathophysiological Cascade
The destruction of parietal cells leads to:
- Intrinsic factor deficiency → vitamin B12 malabsorption 2, 5
- Loss of gastric acid production → elevated fasting gastrin levels and decreased pepsinogen I 1
- Vitamin B12 deficiency → megaloblastic anemia with MCV >100 fL 6, 4
- Secondary iron deficiency may develop due to achlorhydria impairing iron absorption 4, 3
Clinical Context
Pernicious anemia represents 20-50% of all causes of vitamin B12 deficiency in adults and has a prevalence of 0.1% in the general population, rising to 1.9% in those over 60 years. 2 It is frequently associated with other autoimmune conditions, including autoimmune thyroid disease (40%) and diabetes mellitus (10%), as part of autoimmune polyendocrine syndrome. 1
Common Pitfall
The disease is often underdiagnosed because its onset is insidious, and patients may become acclimatized to subtle symptoms, with the underlying condition missed unless a complete blood count is performed. 7 Additionally, younger patients represent about 15% of cases, so age alone should not exclude the diagnosis. 1