What is pernicious anemia, including its pathophysiology, assessment, and pharmacological management?

Pernicious Anemia: Pathophysiology, Assessment, and Pharmacological Management

Pernicious anemia is an autoimmune disorder characterized by vitamin B12 deficiency due to autoantibody-mediated destruction of gastric parietal cells, resulting in intrinsic factor deficiency and impaired vitamin B12 absorption. Treatment requires lifelong vitamin B12 replacement therapy, typically through monthly intramuscular injections of cyanocobalamin to prevent irreversible neurological damage and manage hematologic manifestations. 1

Pathophysiology

Pernicious anemia involves several key pathophysiological mechanisms:

1. Autoimmune gastritis:

   • Autoantibodies target gastric parietal cells and intrinsic factor
   • Results in corpus-predominant atrophic gastritis 2
   • Characterized by destruction of gastric glands and replacement with connective tissue or metaplastic epithelium

2. Intrinsic factor deficiency:

   • Intrinsic factor is essential for vitamin B12 absorption in the terminal ileum
   • Autoantibodies against intrinsic factor block vitamin B12 binding or uptake 3

3. Vitamin B12 deficiency consequences:

   • Impaired DNA synthesis leading to megaloblastic anemia
   • Neurological damage due to impaired myelin synthesis
   • If untreated for >3 months, may cause permanent degenerative lesions of the spinal cord 1

Clinical Assessment

Laboratory Evaluation

1. Initial laboratory workup:

   • Complete blood count (CBC) with indices
     • Macrocytic anemia (MCV >100 fL)
     • Elevated RDW (red cell distribution width)
   • Vitamin B12 level (<200 pg/mL is diagnostic)
   • Serum methylmalonic acid and homocysteine (elevated in B12 deficiency)
   • Anti-parietal cell antibodies (present in 90% of cases)
   • Anti-intrinsic factor antibodies (highly specific but less sensitive) 2, 3

2. Additional testing:

   • Serum ferritin and iron studies (to rule out concomitant iron deficiency)
   • Folate levels (to exclude folate deficiency)
   • Reticulocyte count (typically low despite anemia) 4

Endoscopic Evaluation

Endoscopy with biopsies should be considered in individuals aged ≥50 years with laboratory evidence of pernicious anemia 2:

• Endoscopic features: thinning of gastric mucosa, loss of gastric folds, visible vasculature
• Biopsies should be obtained from:
  • Body and antrum/incisura (placed in separately labeled jars)
  • Any mucosal abnormalities
• Histology shows corpus-predominant atrophic gastritis 2

Clinical Manifestations

1. Hematologic:

   • Fatigue, weakness, pallor
   • Shortness of breath, tachycardia
   • Jaundice (due to ineffective erythropoiesis)

2. Neurological (may occur without anemia):

   • Peripheral neuropathy (tingling, numbness)
   • Ataxia, impaired proprioception
   • Cognitive changes, memory impairment
   • Subacute combined degeneration of the spinal cord 5

3. Gastrointestinal:

   • Glossitis (smooth, red tongue)
   • Anorexia, weight loss
   • Diarrhea or constipation 6

Pharmacological Management

Vitamin B12 Replacement

1. Intramuscular (IM) cyanocobalamin (traditional approach):

   • Initial dosing: 1000 μg IM daily for 1 week
   • Followed by 1000 μg weekly for 4 weeks
   • Maintenance: 1000 μg monthly for life 1
   • Patients must be informed that they will require monthly injections for the remainder of their lives 1

2. Oral vitamin B12 replacement (alternative approach):

   • High-dose oral vitamin B12 (1000 μg daily) can be effective even in pernicious anemia
   • Absorption occurs through passive diffusion, bypassing the need for intrinsic factor
   • May be considered after discussion of advantages and disadvantages 7

Monitoring Response

1. Laboratory monitoring:

   • Reticulocyte count should increase within 5-7 days of treatment
   • Hemoglobin should begin to rise within 10-14 days
   • Monitor serum potassium closely during initial treatment (first 48 hours) due to risk of hypokalemia from rapid cell production 1

2. Follow-up schedule:

   • CBC with reticulocyte count daily from days 5-7 of therapy
   • Continue frequent monitoring until hematocrit normalizes
   • Long-term monitoring to ensure adequate maintenance therapy 1

Associated Conditions and Complications

1. Autoimmune comorbidities:

   • Autoimmune thyroid disease (particularly common)
   • Type 1 diabetes mellitus
   • Vitiligo
   • Screen for autoimmune thyroid disease in patients with pernicious anemia 2

2. Gastric cancer risk:

   • Patients with pernicious anemia have approximately 3 times the incidence of gastric carcinoma
   • Consider endoscopic surveillance every 3 years in patients with advanced atrophic gastritis 2, 1

3. Gastric neuroendocrine tumors:

   • Hypergastrinemia due to achlorhydria can lead to ECL cell hyperplasia
   • Screen for type 1 gastric neuroendocrine tumors with endoscopy
   • Small tumors should be removed endoscopically with surveillance every 1-2 years 2

Important Clinical Pitfalls

1. Neurological damage:

   • Neurological symptoms may persist or become irreversible if treatment is delayed
   • Do not delay treatment while awaiting confirmatory test results if clinical suspicion is high 1, 5

2. Folic acid masking:

   • Doses of folic acid >0.1 mg daily may produce hematologic improvement without addressing neurological damage
   • Warn patients about the danger of taking folic acid in place of vitamin B12 1

3. Vegetarian/vegan diets:

   • A vegetarian diet containing no animal products does not supply vitamin B12
   • Patients following such diets should take oral vitamin B12 regularly 1

4. Pregnancy considerations:

   • Vitamin B12 requirements increase during pregnancy and lactation
   • Deficiency has been recognized in infants of vegetarian mothers who were breastfed 1

Pernicious anemia requires prompt diagnosis and lifelong treatment to prevent serious complications. The combination of clinical features, laboratory findings, and endoscopic evaluation allows for accurate diagnosis, while appropriate vitamin B12 replacement therapy effectively manages the condition.