What else should I check for if a patient's intrinsic factor (IF) is normal, but they have impaired vitamin B12 absorption, despite a normal diet and not being a vegetarian?

Causes of B12 Malabsorption with Normal Intrinsic Factor

When intrinsic factor is negative (normal) but a patient still has vitamin B12 malabsorption despite adequate dietary intake and not being vegetarian, you should check for several other potential causes including celiac disease, atrophic gastritis, small intestinal bacterial overgrowth (SIBO), pancreatic insufficiency, medications affecting B12 absorption, and consider methylmalonic acid (MMA) and homocysteine levels to confirm functional B12 deficiency 1, 2.

Diagnostic Workup Algorithm

Step 1: Confirm B12 Deficiency Status

• Check serum methylmalonic acid (MMA) and homocysteine levels
  • These are more sensitive functional markers of B12 status than serum B12 alone 2
  • Elevated levels indicate functional B12 deficiency even when serum B12 appears normal

Step 2: Evaluate for Gastrointestinal Causes

1. Celiac Disease

   • Check anti-tissue transglutaminase antibodies (tTG-IgA) and total IgA
   • Up to 12% of celiac patients have low B12 without concurrent pernicious anemia 3, 4
   • Celiac disease can cause B12 malabsorption even though it primarily affects the proximal small intestine 3

2. Atrophic Gastritis without Autoimmunity

   • Consider gastric biopsies to evaluate for non-autoimmune atrophic gastritis
   • Can occur without positive intrinsic factor or parietal cell antibodies 5

3. Small Intestinal Bacterial Overgrowth (SIBO)

   • Consider hydrogen/methane breath testing
   • Bacterial overgrowth can consume B12 before absorption 6

4. Pancreatic Insufficiency

   • Check fecal elastase-1
   • Pancreatic enzymes are needed to release B12 from R proteins and transfer to intrinsic factor 6

Step 3: Evaluate for Medication Effects

• Review current medications that may impair B12 absorption:
  • Proton pump inhibitors (PPIs)
  • H2 receptor antagonists 1
  • Metformin 1
  • Colchicine 1
  • Phenobarbital, pregabalin, primidone 1

Step 4: Consider Other Conditions

• Inflammatory bowel disease affecting the terminal ileum
• History of ileal resection or ileal disease
• Chronic radiation enteritis affecting the distal ileum
• Parasitic infestations (e.g., fish tapeworm)
• Zollinger-Ellison syndrome 6

Key Points to Remember

• Vitamin B12 absorption is complex and requires:

  1. Adequate gastric acid to release B12 from food
  2. Pancreatic enzymes to cleave B12 from R proteins
  3. Intrinsic factor for binding
  4. Healthy ileal mucosa and receptors for absorption 6

• Serum B12 levels alone may not be reliable indicators of deficiency

  • Consider measuring methylmalonic acid and homocysteine for more accurate assessment 2

• Celiac disease is a surprisingly common cause of B12 deficiency

  • Studies show 41% of untreated celiac patients may have B12 deficiency 3
  • Most will normalize on a gluten-free diet alone, but supplementation may be needed 3

• Even without positive intrinsic factor antibodies, patients can have atrophic gastritis affecting B12 absorption 5

Treatment Considerations

Once the cause is identified, treatment should address both the underlying condition and the B12 deficiency:

• For confirmed B12 deficiency, consider:

  • Oral supplementation (1000-2000 μg daily) for most patients 2
  • Intramuscular injections (1000 μg monthly) for severe deficiency or neurological symptoms 2

• Monitor response to treatment by checking methylmalonic acid and homocysteine levels within 3 months 2

By systematically evaluating these potential causes, you can identify the reason for B12 malabsorption despite normal intrinsic factor and appropriate dietary intake.