History and exam
Key diagnostic factors
common
old age
history of gastric surgery (gastrectomy, or bypass for obesity)
Other diagnostic factors
common
paresthesias
May be an early and subtle symptom of neurologic damage.[18]
uncommon
vegan and strict vegetarian diet
chronic gastrointestinal disease (e.g., Crohn disease or celiac disease)
drug (proton-pump inhibitors [PPIs], H2 receptor antagonists, metformin, anticonvulsants)
ataxia
Vitamin B12 deficiency can cause posterior column degeneration and eventually lead to ataxic gait.[79]
decreased vibration sense
Classic sign for posterior column degeneration.
positive Romberg test
Classic sign for posterior column degeneration.
pallor
Generally late sign of vitamin B12 deficiency.
petechiae
Generally late sign of vitamin B12 deficiency.
glossitis
Generally late sign of vitamin B12 deficiency.[18]
angular cheilitis
Patients with angular cheilitis should be tested for vitamin B12 deficiency.
Risk factors
strong
age >65 years
Prevalence increases with advancing age, and ranges from 5% to 35% in older people depending on the population studied and the methods of diagnosis.[11][12][13][14][15][16][17]
Risk of vitamin B12 deficiency in this population is likely the result of dietary deficiency, decline in gastric function causing malabsorption, and an increased incidence of pernicious anemia.[11]
gastric surgery (bypass or resection)
Those who have had gastric surgery or bypass are at high risk of vitamin B12 deficiency due to inadequate absorption.[27][51][52]
Intrinsic factor, which binds to vitamin B12 and facilitates its absorption in the ileum, may be reduced following gastric surgery.
In one systematic review, vitamin B12 deficiency was found in 6.5% of patients at 12 months after Roux-en-Y gastric bypass surgery compared with only 2.3% of patients prior to surgery.[27] One retrospective study reported vitamin B12 deficiency in 12.3% of patients prior to Roux-en-Y gastric bypass, which increased to 19% at 1 year after surgery, and to 29% at 3 years after surgey.[51]
chronic gastrointestinal (GI) disease
Chronic GI illnesses (e.g., Crohn disease and celiac disease) can cause malabsorption or inadequate absorption of vitamin B12.
Vitamin B12 absorption occurs in the terminal ileum; therefore, those with terminal ileum disease are at high risk of vitamin B12 deficiency.[53][54] In one study, evidence of vitamin B12 deficiency was found in over 50% of patients with Crohn disease who had >20 cm of terminal ileum removed.[54]
Patients with chronic intestinal failure may also be at increased risk of vitamin B12 deficiency.[55]
Vitamin B12 deficiency occurs more frequently in patients with Crohn disease, which can affect any part of the digestive tract, than in ulcerative colitis (where disease is limited to the colon).[56]
vegan or strict vegetarian diet
Prevalence of vitamin B12 deficiency among vegans and strict vegetarians (who do not take additional dietary supplementation) may range from as low as 11% to as high as 90%, depending on age.[25][26]
One randomized study found that a 4-week vegan diet led to a significant decrease in serum vitamin B12 levels (362 nanograms/dL to 296 nanograms/dL).[57]
metformin use
Chronic metformin use is associated with low serum vitamin B12 levels, placing patients at risk of vitamin B12 deficiency.[32][58][59][60][61]
In one randomized controlled trial of patients with type 2 diabetes, the absolute risk of vitamin B12 deficiency was 7.2% higher in patients treated long-term (4.3 years) with insulin and metformin than in patients receiving insulin and placebo.[62]
Concomitant use of metformin with proton-pump inhibitor appears to increase risk for vitamin B12 deficiency (in type 2 diabetes) compared with metformin monotherapy.[63]
The mechanism is unclear but may be related to malabsorption.
H2 receptor antagonist or proton-pump inhibitor (PPI) use
Vitamin B12 bound to food must be freed by peptic acid (secreted from the stomach). Therefore, those who are taking chronic H2 receptor antagonists or PPIs may be at risk for vitamin B12 deficiency.[31][61][64][65]
One large case-control study found that more than 2 years' use of PPIs or H2 receptor antagonists increased the risk of vitamin B12 deficiency.[66]
weak
Helicobacter pylori infection
Studies suggest a link between Helicobacter pylori infection and vitamin B12 deficiency.[33][34][37][38][39]
In patients with H pylori infection, it is unclear whether the organism, or associated atrophic gastritis, causes vitamin B12 deficiency.[41] There does not appear to be an association between H pylori infection and B12 deficiency in pregnant women.[42]
anticonvulsant use
nitrous oxide misuse
Recreational nitrous oxide (N₂O) misuse may increase the risk of vitamin B12 deficiency.[45][46][61]
In one systematic review and meta-analysis, up to 85% of reported recreational users were possibly or probably vitamin B12-deficient.[46]
N₂O converts the active monovalent form of vitamin B12 to its inactive bivalent form. The neurologic sequelae of N₂O-induced vitamin B12 deficiency can include neuropathy and paralysis.[47][67]
diabetes mellitus
One study reported vitamin B12 deficiency in 22% of people with type 2 diabetes.[68] Patients receiving metformin were at increased risk.[68]
Risk for vitamin B12 deficiency may be greater for older patients with type 2 disease who are taking metformin, or for patients with type 2 diabetes who are taking a proton-pump inhibitor concomitantly with metformin.[63][69]
Vitamin B12 deficiency may be easily overlooked as a cause of neuropathy in people with type 2 diabetes.[68]
pregnancy
Vitamin B12 deficiency may be seen in 20% to 30% of women during pregnancy, and is particularly common if the woman is vegetarian or vegan.[11][29]
One systematic review found that levels of vitamin B12 decrease from the first to the third trimester.[30]
Vitamin B12 deficiency in pregnancy may be associated with an increased risk for preterm delivery, lower birth weight, and lower infant levels of vitamin B12.[70][71]
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