B12 deficiency 

DDx:

• Decreased production of intrinsic factor (IF):
  • Atrophic gastritis:
    • H. pylori infection
    • DM
    • elderly
  • Rouz-en-Y Gastric Bypass and other post-gastrectomy syndromes 
  • Pernicious Anemia
    • Autoimmune parietal cell destruction as part of a chronic autoimmune Gastritis
    • Results in insufficient intrinsic factor production
    • B12 Deficiency is preceded by Iron Deficiency by 20 years, and asymptomatic Gastritis by 30 years
• Decreased absorption:
  • Crohn’s disease
  • Ileal resection
  • Zollinger-Ellison Syndrome (Gastrinoma)
  • Tapeworm infestation
  • Whipple
• Medications:
  • Metformin
  • PPI
  • H2 antagonists
• Genetic/ other:
  • Coeliac disease
  • Transcobalamin II deficiency
• Inadequate Vitamin B12 intake
  • Vegan patients
  • Elderly (over age 75 years old)
  • Alcoholism
  • Psychiatric patients
  • Exclusively Breastfed infants of vegan mothers

Ix:

• FBC
• serum B12(cost: $23.60)
• Pernicious Anemia specific labs
  • when indicated, in the absence of other B12 Deficiency risk factors)
    • Anti-intrinsic factor antibodies (increased) – First-line test
    • Serum Gastrin (increased) – Second line test, indicated if anti-intrinsic factor antibodies negative
  • Upper endoscopy – Recommended if Pernicious Anemia diagnosis (due to associated Gastric Cancer and Carcinoid)
• Secondary Deficiency markers- If Sx of B12 deficiency despite normal levels than test
  • Serum holoTC (cost $42.95)
    • Haptocorrin: binds the major portion of plasma vitamin B12 which is essentially inert as far as vitamin B12 delivery to cells is concerned, although I may reflect the general underlying state of vitamin B12 stores. 
    • The complex formed by the binding of haptocorrin to vitamin B12 is called holo-hapctocorrin (HoloHC)
    • Haptocorrin deficiency is associated with low serum vitamin B12 concentrations
  • MMA (methylmalonic acid)
    • MMA and homocysteines are functional markers of vitamin B12 status and levels increase when vitamin B12 deficiency is present
  • Alow serum vitamin B12 level as the sole means of diagnosis of vitamin B12 deficiency may miss up from 10 to 26% of patients with actual tissue B12 deficiency
  • holoTC assay used on its own is also not very predictive of vitamin B12 deficiency unless it is used in conjunction with plasma MMA or with the total plasma vitamin B12, and when combined may provide enhanced predictive power to identify true vitamin B12 deficiency

Mx:

• Improve diet
  • B12 Fortified foods (Cereals), Animal Source – Liver, muscle meat(beef), fish, Eggs, Dairy
  • Replace Vitamin B12 before replacing Folate (otherwise risk of spinal cord degeneration)
• Oral
  • high dose orally
  • 1-­2mg for 2-­3 months improves B12 levels similar to IM (less expensive and more convenient to IM, cochrane review in 2005 showed equivalence)
• IM
  • Initial: 1000 mcg IM daily for 2 weeks
  • Maintenance: 1000 mcg IM every 1-3 months
  • Neurologic symptoms warrants daily injections for up to 3 weeks, or until no further improvement
  • Expect improvement in symptoms and lab markers within 3 months of starting B12 supplementation
    • Lab markers (Homocysteine, methylmalonic acid, Reticulocyte Count) improve in the first week
    • Neurologic symptoms improve within 6 weeks to 3 months
    • Anemia, Leukopenia, MCV and Thrombocytopenia improve within 2 months
  • More than 50% of patients with B12 Deficiency related symptoms will have incomplete resolution despite treatment

Physiology of Vitamin B12

B12 Functional Roles

1. Neurologic Function:
   • Peripheral Neuropathy: Vitamin B12 deficiency can lead to nerve damage, causing symptoms like tingling, numbness, and burning sensations in the hands and feet.
   • Cognitive Impairment: Deficiency can result in memory loss, confusion, and cognitive decline.
   • Gait Impairment: Patients may experience balance problems and difficulty walking.
2. Red Blood Cell Production:
   • Macrocytic Anemia: B12 deficiency causes the production of abnormally large and immature red blood cells.
   • Pancytopenia: This condition can also lead to a decrease in all types of blood cells, including white blood cells and platelets.
3. DNA Synthesis:
   • B12-dependent Reactions:
     • Methylmalonic Acid to Succinyl-CoA: B12 is essential for converting methylmalonic acid to succinyl-CoA, a critical component of the Krebs cycle.
     • Homocysteine to Methionine: B12 helps convert homocysteine to methionine, which is vital for angiogenesis and other cellular functions.
     • 5-Methyltetrahydrofolate to Tetrahydrofolate: This conversion is crucial for DNA synthesis and red blood cell production.

Normal B12 Absorption Pathway

1. Ingestion:
   • B12 must be consumed through animal products or fortified cereals as it cannot be synthesized by humans.
2. Stomach Environment:
   • Acidic Stomach: Breaks down protein-bound B12, making it available for absorption. Proton pump inhibitors can suppress this process.
   • Intrinsic Factor (IF): Produced by stomach parietal cells, IF binds to B12 in the duodenum, facilitating its absorption.
3. Pernicious Anemia Mechanism:
   • Autoimmune destruction of parietal cells (Anti-IF antibodies inhibit the formation or absorption of the B12/IF complex) leads to insufficient IF production, resulting in decreased B12 absorption.
   • up to 25% of pernicious anemia patients have Autoimmune Gastritis, characterized by antiparietal cell antibodies destroying parietal cells that produce IF and hydrochloric acid.
   • Higher incidence of co-occurring conditions like type 1 diabetes, autoimmune thyroid disease, and vitiligo.
   • All ages, particularly those over 60 years old.
   • Progression: Develops slowly over 2-5 years; symptoms may not manifest until anemia is profound.
4. Vitamin B12 Absorption Pathways:
   • Primary Pathway:
     • B12 from animal products binds to IF in the terminal ileum, dissociates in erythrocytes, enters portal circulation, and binds to transcobalamin II.
   • Alternate Pathway:
     • Independent of IF and ileum, allows for absorption of up to 1% of a large oral dose, enabling oral B12 supplementation.

Vitamin B12 Storage

• Liver Storage: B12 is stored in the liver, with large stores potentially delaying deficiency presentation for more than five years.

Clinical Manifestations of Vitamin B12 Deficiency

1. Hematologic:
   • Megaloblastic Anemia: Characterized by large, immature red blood cells.
   • Pancytopenia: Reduction in all blood cell types.
   • Pernicious Anemia: Specific form of megaloblastic anemia due to B12 deficiency.
2. Neurologic:
   • Paresthesias: Unexplained burning or itching sensations.
   • Peripheral Neuropathy: Damage to peripheral nerves.
   • Posterior Spinal Column Neuropathy: Bilateral loss of proprioception and vibration sense, ataxia, hyporeflexia, spasticity, paraplegia, and incontinence.
3. Psychiatric:
   • Symptoms: Irritability, personality changes, mild memory impairment, dementia, depression, psychosis, and potential links to Alzheimer’s disease.
4. Cardiovascular:
   • Increased Risk: Potential for increased myocardial infarction and stroke risk.
5. Maternal Vitamin B12 Deficiency:
   • Consequences: Neural tube defects, developmental delays, failure to thrive, hypotonia, ataxia, and anemia in offspring.