What causes pernicious anemia?

Causes of Pernicious Anemia

Pernicious anemia is primarily caused by autoimmune destruction of gastric parietal cells leading to intrinsic factor deficiency, which results in vitamin B12 malabsorption and subsequent megaloblastic anemia. 1, 2

Pathophysiology of Pernicious Anemia

Autoimmune Mechanism

• Pernicious anemia is characterized by autoimmune chronic atrophic gastritis where antibodies target gastric parietal cells and intrinsic factor 1
• The autoimmune process leads to destruction of gastric parietal cells that produce intrinsic factor, a protein essential for vitamin B12 absorption in the terminal ileum 3
• Two types of antibodies are involved: anti-parietal cell antibodies and anti-intrinsic factor antibodies, with the latter having 73% sensitivity and 100% specificity for pernicious anemia 1

Vitamin B12 Absorption Process

• Normal vitamin B12 absorption requires intrinsic factor produced by gastric parietal cells 4
• In the stomach, vitamin B12 binds to intrinsic factor and this complex travels to the terminal ileum where absorption occurs in the presence of calcium ions 4
• Without intrinsic factor, dietary vitamin B12 cannot be properly absorbed, leading to deficiency 4
• Only about 1% of vitamin B12 is absorbed by simple diffusion without intrinsic factor, which is inadequate to maintain normal levels 4

Relationship with Atrophic Gastritis

• Pernicious anemia represents the end-stage of atrophic body gastritis (ABG) 1
• Long-standing Helicobacter pylori infection may play a role in the development of autoimmune gastritis that eventually leads to pernicious anemia 1
• The active infectious process is gradually replaced by an autoimmune response that ultimately results in irreversible destruction of the gastric body mucosa 1

Risk Factors and Associated Conditions

Genetic Factors

• Human leukocyte antigen-DR (HLA-DR) genotypes suggest genetic susceptibility to pernicious anemia 1
• Certain polymorphisms in genes regulating folate metabolism (such as MTHFR C677T) may be associated with autoimmune conditions including pernicious anemia 5

Associated Autoimmune Disorders

• Pernicious anemia frequently coexists with other autoimmune disorders as part of autoimmune polyendocrine syndrome 1
• 40% of pernicious anemia patients have concurrent autoimmune thyroid disease 1
• 10% have concurrent diabetes mellitus 1
• Screening for autoimmune thyroid disease should be performed in patients with pernicious anemia 5

Demographic Factors

• While traditionally considered a disease of the elderly, approximately 15% of patients are younger individuals 1
• The prevalence may be higher in certain racial/ethnic groups and early-generation immigrants from high-risk countries 5

Clinical Manifestations and Diagnosis

Hematologic Manifestations

• Macrocytic anemia is the classic presentation, with mean corpuscular volume (MCV) >100 fL 5
• Hypersegmented neutrophils are characteristic findings on peripheral blood smear 6
• In severe cases, hemoglobin levels can drop dramatically, leading to life-threatening anemia 6

Neuropsychiatric Manifestations

• Vitamin B12 deficiency can cause subacute combined degeneration of the spinal cord 4, 6
• Neurologic symptoms may occur even without anemia and can become irreversible if not treated promptly 3
• Some patients may present with psychiatric symptoms that can mimic or exacerbate conditions like schizophrenia 6

Diagnostic Approach

• Laboratory findings include low vitamin B12 levels, elevated methylmalonic acid and homocysteine levels 6
• Detection of anti-intrinsic factor antibodies is crucial for diagnosis 6
• Endoscopy with biopsies showing corpus-predominant atrophic gastritis helps confirm the diagnosis 5
• Patients with unexplained vitamin B12 or iron deficiency should be evaluated for atrophic gastritis 5

Management Implications

• Parenteral vitamin B12 replacement is the mainstay of treatment as oral absorption is unreliable in pernicious anemia 4
• Patients should be monitored for the development of iron deficiency 5
• Endoscopic surveillance is recommended due to increased risk of gastric cancer and type 1 gastric neuroendocrine tumors 5, 2
• Small neuroendocrine tumors should be removed endoscopically, followed by surveillance endoscopy every 1-2 years 5