What is intrinsic factor?

Intrinsic Factor: Essential Protein for Vitamin B12 Absorption

Intrinsic factor is a glycoprotein produced by gastric parietal cells that binds to vitamin B12 and enables its absorption in the terminal ileum, without which vitamin B12 deficiency and pernicious anemia can develop.

Definition and Production

Intrinsic factor is a specialized glycoprotein with the following characteristics:

• Produced exclusively by gastric parietal cells in the stomach 1
• Secretion is stimulated via the same pathways that stimulate gastric acid secretion: histamine, gastrin, and acetylcholine 2
• Unlike acid secretion, intrinsic factor secretion is not affected by secretin or hydrogen-potassium ATPase antagonists (like omeprazole) 2

Physiological Role in Vitamin B12 Absorption

The absorption of vitamin B12 (cobalamin) is a complex multi-step process:

1. Gastric Phase:

   • Vitamin B12 from food is released from protein binding by gastric acid and pepsin 3
   • Initially binds to R-proteins (haptocorrins) in the stomach 4

2. Duodenal Phase:

   • Pancreatic enzymes degrade R-proteins in the duodenum 4
   • Vitamin B12 transfers from R-proteins to intrinsic factor 4

3. Ileal Phase:

   • The intrinsic factor-B12 complex travels to the terminal ileum 1
   • Complex binds to specific receptors (cubilin and amnionless) on ileal enterocytes 4
   • Receptor-mediated endocytosis internalizes the complex 5
   • Inside the enterocyte, B12 is released from intrinsic factor through lysosomal proteolysis 5
   • B12 then binds to transcobalamin for transport in the bloodstream 5

Clinical Significance

Pernicious Anemia

• Most common cause of vitamin B12 deficiency due to intrinsic factor deficiency 2
• Autoimmune condition where antibodies target:
  • Parietal cells (destroying intrinsic factor-producing cells)
  • Intrinsic factor itself (blocking B12 binding)
• Intrinsic factor antibody test is highly specific for diagnosing pernicious anemia 6

Other Causes of B12 Malabsorption

Despite adequate intrinsic factor production, B12 malabsorption can occur due to:

• Gastric causes: Achlorhydria, gastrectomy, bariatric surgery 4
• Pancreatic insufficiency: Impaired R-protein degradation 2
• Ileal disease or resection: Crohn's disease, celiac disease, radiation enteritis 2
• Bacterial overgrowth: Gram-negative anaerobes binding the IF-B12 complex 2
• Parasitic infections: Fish tapeworm, Giardia lamblia 2

Treatment Implications

When intrinsic factor is absent or dysfunctional:

• Oral vitamin B12 supplementation is inadequate as it requires intrinsic factor for absorption
• Parenteral (intramuscular) B12 administration bypasses the need for intrinsic factor 3
• Approximately 1% of oral B12 can be absorbed by passive diffusion, but this requires very large doses 3

Important Clinical Considerations

• Strict vegetarians (vegans) are at risk for B12 deficiency as vitamin B12 is not present in plant foods 3
• The liver is the main storage organ for vitamin B12, with reserves lasting 12-36 months 1
• Intrinsic factor deficiency can be hereditary (rare) or acquired (more common, as in pernicious anemia) 5
• The ileum is the exclusive site for intrinsic factor-mediated B12 absorption 7

Understanding intrinsic factor's role is crucial for diagnosing and managing vitamin B12 deficiency disorders, particularly pernicious anemia, which can lead to severe hematologic and neurologic complications if left untreated.