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Cobalamin deficiency

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Vitamin B12 deficiency causes distinctive dyserythropoietic abnormalities in the bone marrow – hallmark megaloblastic anemia characterized by large, abnormally nucleated red blood cells, as well as low counts of white and red blood cells, platelets, or combination (1).

Pernicious anaemia is the most common cause of clinically evident vitamin B12 deficiency around the world; other conditions at risk for vitamin b12 inadequacy include atrophic gastritis, vegan-based diet, inflammatory bowel disease, and those who have had gastrointestinal surgery (1) .

Vitamin B12 is found in foods of animal origin including milk, cheese, yoghurt and eggs.

  • Recommended daily requirement of vitamin B12 is small (1-2 µg/day) compared with total body stores (2000-5000 µg) much of which is stored in the liver. This explains why it takes a long time, usually years, for vitamin B12 deficiency to develop (2).
  • Dietary vitamin B12 is freed from the food protein by pepsin in the acid gastric environment and binds to haptocorrin, a cobalamin-binding protein in the saliva. In the duodenum, haptocorrin is degraded by pancreatic enzymes, the vitamin B12 is released and binds with intrinsic factor (IF), which is secreted by gastric parietal cells (1,2).
    • The IF-B12 complex is carried through the small intestine and binds to receptors in the terminal ileum where it is actively absorbed.
    • A small fraction (1-2%) of the daily intake is passively absorbed across the entire absorptive surface of the intestinal tract.

The cutoff varies by method and laboratory. The following observations are offered (2,3):

  • serum B12 180-1000 pg/ml (3)
    • reference ranges provided are for adults
    • reference ranges for infants and children are dependent on age
    • results should be interpreted along with clinical features and other laboratory results
  • B12 levels may be falsely low in pregnant women because of the increased plasma volume rather than actual deficiency (2)
    • if the mother has otherwise unexplained anaemia (or has other clinical signs of B12 deficiency), consider a treatment trial of B12 replacement as suggested below (following local standard advice for non-pregnant individuals with low serum B12 values)
  • in clear cut deficiency, levels of B12 are nearly always <150 pg/ml and usually <100 pg/ml (2,3)
    • Pernicious anaemia is the cause of the majority of severe deficiencies in adults
      • around 50% of patients with pernicious anaemia have intrinsic factor antibodies while this antibody is rarely seen in normal controls
      • parietal cell antibodies are present in 90% of patients but are also seen in 1-2% of normal controls
  • patients with B12 in the borderline range (150-180 pg/ml) may have either early B12 deficiency or be healthy "low normal"
  • neurological disease or glossitis may occur without anaemia or macrocytosis and may be irreversible (3)
  • interpretation of early megaloblastic change in the marrow is difficult and cannot be reliably distinguished from myelodysplasia (3)

Oral vitamin B12 supplementation compared with intramuscular supplementation in patients with vitamin B12 deficiency (4)

  • for normalizing serum vitamin B12 levels, oral and intramuscular vitamin B12 supplementation are equivalent after one to four months
  • for increasing vitamin B12 levels, oral supplementation at 2,000 mcg per day is more effective than intramuscular supplementation at 1,000 mcg per day; however, 1,000 mcg per day orally is equivalent to 1,000 mcg per day intramuscularly

Healthcare professionals prescribing vitamin B12 products to patients with known cobalt allergy should advise patients to be vigilant for signs and symptoms of cobalt sensitivity and treat as appropriate (5):

  • is evidence within the literature of cobalt sensitivity reactions occurring following administration of vitamin B12
  • cobalt sensitivity may present with cutaneous symptoms such as chronic or subacute allergic contact dermatitis
  • cobalt allergy may also trigger an erythema multiforme-like eruption
  • vitamin B12 use is not contraindicated in patients with cobalt allergy that presents only as cutaneous symptoms
    • note though, where previous serious allergic reaction is established in known cobalt allergy patients, individual assessment of the benefits and risks should be conducted before starting treatment
  • hydroxocobalamin products which are indicated in the treatment of known or suspected cyanide poisoning are excluded from these precautions, considering it is a medical emergency in which the potentially life-saving benefit of treatment would outweigh the risk of allergic reaction

Advice for healthcare professionals (5):

  • cobalt sensitivity reactions typically present with cutaneous symptoms of chronic or subacute allergic contact dermatitis. Infrequently, cobalt allergy may trigger an erythema multiforme-like reaction. Symptom onset may be immediate or delayed up to 72 hours post-administration
  • cobalt allergy is estimated to affect 1 to 3% of the general population
  • if cobalt sensitivity-type reactions occur, assess the individual benefits and risks of continuing treatment and, if necessary to continue, advise patients on appropriate management of symptoms
  • report suspected adverse drug reactions to the Yellow Card scheme

Notes (6):

  • considerable variability exists between the different commercially available serum B12 assays
  • day-to-day variation of serum B12 may occur; for example, a concentration of 150 pmol/L on one day may be 120 pmol/L another day
  • neurological symptoms resulting from B12 deficiency may take several months or even years to resolve completely
  • in patients who are already taking some form of oral B12 supplementation, demonstrating B12 deficiency can be a challenge, even when symptoms are typical (including those of neuropathy-like paraesthesia and numbness) as serum B12 concentrations may be just within, or sometimes above, the “normal” range


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The content herein is provided for informational purposes and does not replace the need to apply professional clinical judgement when diagnosing or treating any medical condition. A licensed medical practitioner should be consulted for diagnosis and treatment of any and all medical conditions.


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