vitamin B12 deficiency

Etiology

• pernicious anemia (autoimmune atrophic gastritis) {most common cause}
• food-cobalamin malabsorption
  • inability to split cobalamin from its binding in food (50% of cases)
• transcobalamin II deficiency
• dietary: vegans
• hypochlorhydria, atrophic gastritis
• post surgical: gastrectomy or ileal resection
• pancreatic insufficiency
• Crohn's disease
• parasitic or bacterial overgrowth of small intestine
  • blind loop syndrome
  • Diphyllobothrium latum, Giardia lamblia, Taenia
  • high serum folate
• inherited condition in which a histologically normal stomach secretes either an abnormal intrinsic factor or none at all
• pharmaceutical agents may contribute
  • chronic use of nitrous oxide oxidizes cobalamin
  • drugs which interfere with absorption of vit B12
    • neomycin
    • colchicine
    • ethanol (alcohol abuse)
    • metformin (esp without Ca+2 supplementation)
  • chronic gastric acid suppression (> 2 years)
    • proton pump inhibitor use
    • histamine H2 receptor antagonist use
• Helicobacter pylori infection
• age > 75 years

Epidemiology

• 3-5% of elderly
• in the UK & USA: 6% of adults < 60 years, 20% > 60 years

Pathology

• subacute combined degeneration of peripheral nerves & spinal cord
  • changes begin in the posterior columns &/or lateral columns of the lower cervical & upper thoracic spinal cord
  • demyelination & wallerian axonal degeneration
  • phagocytosis by macrophages & reactive astrocytosis
  • increased tissue levels of methylmalonyl CoA & its precursor propionyl CoA lead to synthesis of non-physiologic fatty acids & their incorporation into neuronal lipids
• cerebral hemisphere pathology less well defined
• pernicious anemia (chronic autoimmune atrophic gastritis)
• megaloblastic anemia
  • ineffective erythropoiesis may result in hemolytic anemia
• not associated with vascular brain changes

Clinical manifestations

• paresthesias early in the course of the illness
• abnormal sensation of position & vibration
  • positive Romberg sign
• muscle weakness
  • calf muscle atrophy
• spasticity
• gait disturbance, ataxia
• diminished deep tendon reflexes
  • case of hyperreflexia & positive Babinski reflex
• decreased pain & temperature sensation
• psychiatric disturbances
  • mood & personality changes
  • psychosis
  • delirium
  • memory impairment (dementia, Wernicke's syndrome)
    • dementia due to vitamin B12 deficiency is rare
• signs & symptoms of anemia
  • neurologic changes may precede anemia
• jaundice may result from ineffective erythropoiesis
• 'beefy red' glossitis (macroglossia)
• orthostatic tremor (may be presenting symptom)
• seizures (unusual)
• non-specific GI symptoms, abdominal pain (GRS9)
• weight loss with more severe vitamin B12 deficiency
• not a cause of changes in bowel or bladder function

Laboratory

• features of megaloblastic anemia may be observed
  • complete blood count (CBC) may show pancytopenia
    • anemia may or may not be present
    • MCV may be elevated or normal
    • RDW may be elevated
    • red cell indexes may be difficult to interpret if also iron-deficiency
    • thrombocytopenia
    • leukopenia
  • peripheral blood smear may show macrocytes & hypersegmented neutrophils
  • may show evidence of hemolysis
• serum vitamin B12 level
  • < 200 pg/mL suggestive of vitamin B12 deficiency
  • < 100 pg/mL is diagnostic
  • serum levels may be normal with defective conversion of cobalamin to active coenzyme
  • preferred initial diagnostic test for vitamin B12 deficiency
• serum methylmalonic acid is increased
  • more sensitive & specific than serum vitamin B12 level
• increased urinary methylmalonic acid
• serum homocysteine may be elevated
• Schilling test (gold standard)
• evidence of pernicious anemia
  • serum gastrin levels is often high
  • anti-parietal cell antibody is often positive
  • intrinsic factor antibody is often positive
    • testing not indicated for diagnostic purposes
  • gastric pH may be high with pernicious anemia
• deoxyuridine suppression test (dUST) {rarely done}
• vitamin B12 binding capacity
• serum holotranscobalamin 2 is diminished
  • may not be useful in patients with renal insufficiency
• ineffective erythopoiesis may result in hemolytic anemia
  • increased serum unconjugated bilirubin
  • increased serum lactate dehydrogenase
  • direct antiglobulin test is negative
• cobalamin/propionate/homocysteine metabolism related disorders panel (ARUP)
• bone marrow biopsy unnecessary

Diagnostic procedures

• electroencephalography is abnormal (50%)
• evoked potentials are abnormal (50%)

Radiology

• magnetic resonance imaging of the cervical/thoracic spine
  • hyperintensity of the posterior columns &/or lateral columns on T2-weighted images
  • MRI abnormalities may persist after treatment
  • pathology generally involves both posterior columns & lateral columns or cord in general at thoracic level

Complications

• poor response to pneumovax in elderly patients with vitamin B12 deficiency
• increased risk of gastric cancer & gastric carcinoid
• atrophic gastritis, pernicious anemia
  • small intestinal bacterial overgrowth
• no association of low plasma vitamin B12 levels & dementia & association (or lack of) unaffected by vitamin B12 supplementation
• no evidence that vitamin B12 deficiency is associated with vascular pathology even though there is an association between low vitamin B12 & increased homocysteine levels
• no evidence vitamin B12 deficiency increases risk of Alzheimer's disease

• disease interaction(s) of vitamin B12 deficiency with iron deficiency anemia
• disease interaction(s) of vitamin B12 deficiency with urinary incontinence

Differential diagnosis

• copper deficiency (overlap of clinical manifestations)
• coexisting vitamin B12 deficiency & iron deficiency

Management

• simple vitamin B12 deficiency includng food-cobalmin malabsorption
  • oral vitamin B12 (cyanocobalamin) 1000-2000 ug PO QD
    • RDA is 2.4 ug/day
  • initial treatment of choice for all vitamin B12 deficiency
  • folate supplementation can improve (or mask) the anemia of vitamin B12 deficiency, but will not prevent or improve the neuropathology
• parenteral vitamin B12 may be required in special circumstances
  • indications
    • intrinsic factor deficiency & failure of ileal absorption
    • severe anemia
    • neurologic dysfunction
    • failure to respond to oral therapy
    • malabsorption syndromes
  • dosage
    • 1 mg IM weekly for 1 month (former recommendation)
    • 1 mg IM monthly until absorption malfunction corrected
• consider endoscopy:
  • increased risk of gastric cancer & gastric carcinoid
• prognosis
  • behavioral symptoms & peripheral neuropathy respond within 6 months of treatment, but often fail to completely remit
  • it is rare for the dementia to reverse
  • hematologic values normalize in 2 months
  • no evidence that finding a cause for B12 deficiency improves outcomes;
    • treat emipirically with cyanocobalamin 1 mg sublingual QD

More general terms

• vitamin B deficiency
• gastrointestinal disease

More specific terms

• transcobalamin II deficiency

Additional terms

• intrinsic factor; gastric intrinsic factor; IF; INF (GIF, IFMH)
• megaloblastic anemia
• methylmalonate in serum
• pernicious anemia
• Schilling test
• subacute combined degeneration of spinal cord; Lichtheim's disease; Putnam-Dana Syndrome
• vitamin B12 in serum/plasma
• vitamin B12; cobalamin

Database

• OMIM: https://mirror.omim.org/entry/250940