B12 Deficiency

Snapshot

• A 55-year-old man is brought to his primary care physician by his wife for increased confusion. He forgets to turn off the stove after cooking and frequently misplaces his keys. He fell approximately 1 week ago while walking in the dark. His physical examination is notable for impaired short-term memory, decreased vibration and proprioception sensation, and patellar hyperreflexia. On laboratory testing, he has a macrocytic anemia, reticulocytopenia, and low serum vitamin B12.

Introduction

• Overview
  • vitamin B12 (cobalamin) is a water-soluble vitamin that is involved in the formation of hematopoietic cells and maintainance of myelin integrity
  • vitamin B12 deficiency results in a
    • megaloblastic anemia
    • reversible dementia
    • subacute combined degeneration
• Etiology
  • decreased oral intake
    • strict vegan diet
    • breastfeeding in a vitamin B12 deficiency mother
    • decreased animal product intake
  • decreased absorption 
    • gastrointestinal surgeries 
      • bariatric surgery
      • grastrectomy
    • illness
      • Crohn disease
      • celiac disease
      • pancreatic insufficiency
      • Diphyllobothrium latum (fish tapeworm) 
      • gastric atrophy
    • medications
      • proton pump inhibitors
      • histamine receptor antagonist
      • metformin
    • autoimmune disease
      • pernicious anemia   
        • autoantibodies against intrinsic factor or gastric parietal cells
• Pathophysiology
  • absorption
    • protein-bound vitamin B12 is released from protein by pepsin
      • gastric acid converts pepsinogen to pepsin
    • R-binder binds to vitamin B12 to prevent its degradation by gastric acid
      • R-binder is produced in the salivary glands
    • proteases in the duodenum separate R-binder and vitamin B12, allowing vitamin B12 to bind to intrinsic factor
      • intrinsic factor is produced by gastric parietal cells
      • proteases in the duodenum are produced by the pancreas
    • intrinsic factor bound to vitamin B12 is absorbed in the terminal ileum 
  • DNA synthesis
    • vitamin B12 serves as a coenzyme for methionine synthase to produce
      • methionine
        • serves a vital role in methylation reactions
      • tetrahydrofolate
        • serves a vital role in DNA synthesis
  • myelin stabilization
    • methionine is converted to S-adenosylmethionine
      • associated with myelin stabilization
    • vitamin B12 serves as a coenzyme for methylmalonyl-CoA mutase to convert methylmalonyl-CoA (produced from methylmalonic acid) to succinyl-CoA
      • decreased methylmalonic acid is associated with myelin stabilization
  • vitamin B12 deficiency
    • impaired DNA synthesis significantly affects rapidly dividing cells (e.g., hematopoietic precursor cells) and leads to
      • megaloblastic changes, which is cased by slowing of nuclear division
        • due to nuclear-cytoplasmic dyssynchrony
      • ineffective erythropoiesis (intramedullary hemolysis)
        • erythropoietic precursor cells within the bone marrow prematurely die
          • results in a reticulocytopenia
    • impair neuronal function
      • mechanism is not fully clear but hypothesized to be due to decreased methylation of neuronal lipids and proteins (e.g., myelin basic protein)
• Prognosis
• atrophic gastritis increases risk of gastric cancer

Presentation

• Symptoms
  • anemia
    • fatigue
    • dyspnea
  • gastrointestinal
    • glossitis
  • neurologic
    • cognitive decline
• Physical examination
  • subacute combined degeneration
    • lateral corticospinal tracts
      • weakness
      • spasticity
      • hyperreflexia
    • dorsal columns
      • decreased vibration and proprioception sensation
      • gait difficulties
    • spinocerebellar tracts
      • gait difficulties
      • ataxia
      • decreased proprioception sensation
• impaired proprioception information from the spinal cord to the cerebellum

Labs

• Serum labs 
  • macrocytic and megaloblastic anemia
  • decreased serum B12 level
  • reticulocytopenia
  • ↑ serum methylmalonic acid and homocysteine levels
  • anti-intrinsic factor and parietal antibodies
    • seen in pernicious anemia
• Peripheral blood and marrow smear show
• hypersegmented neutrophils and megalocytes 

Differential

• Folate anemia
  • differentiating factors
    • no neurological manifestations
• methylmalonic acid levels are not elevated

Treatment

• Medical
  • intramuscular vitamin B12 
    • indication
• first-line for vitamin B12 deficiency

Complications

• Irreversible neurological damage if untreated