History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include age >65 years, history of gastric surgery (gastrectomy, or bypass for obesity), vegan and vegetarian diet, chronic gastrointestinal illnesses (e.g., Crohn's disease or coeliac disease), and use of known causative medications (proton-pump inhibitors, H2 receptor antagonists, metformin, anticonvulsants).
old age
history of gastric surgery (gastrectomy, or bypass for obesity)
Other diagnostic factors
common
paraesthesias
May be an early and subtle symptom of neurological damage.[18]
uncommon
vegan and strict vegetarian diet
chronic gastrointestinal disease (e.g., Crohn's disease or coeliac disease)
medicine (proton-pump inhibitors, H2 receptor antagonists, metformin, anticonvulsants)
ataxia
Vitamin B12 deficiency can cause posterior column degeneration and eventually lead to ataxic gait.[75]
decreased vibration sense
Classic sign for posterior column degeneration.
positive Romberg's 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 anaemia.[11]
gastric surgery (bypass or resection)
In one systematic review, vitamin B12 deficiency was found in 6.5% of patients 12 months after Roux-en-Y gastric bypass surgery compared with only 2.3% of patients prior to surgery.[27] A retrospective study reported deficiency in 12% of patients prior to Roux-en-Y gastric bypass, which increased to 19% in 1 year after surgery and 29% in 3 years.[44]
Parietal cells of the stomach produce intrinsic factor, which binds to free vitamin B12 and promotes absorption in the terminal ileum. Those who have had gastric surgery or bypass are at high risk of vitamin B12 deficiency due to inadequate absorption.[27][45]
chronic gastrointestinal (GI) disease
Chronic GI illnesses (e.g., Crohn's disease and coeliac 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.[46] In one study, evidence of vitamin B12 deficiency was found in over 50% of patients with Crohn's disease who had >20 cm of terminal ileum removed.[47]
vegan or strict vegetarian diet
The exact prevalence of deficiency among vegans and strict vegetarians (who do not take additional dietary supplementation) is difficult to estimate due to study method heterogeneity; however, it may range from as low as 11% to as high as 90% depending on age.[25][26]
One randomised 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).[48]
metformin use
Chronic metformin use has been shown to cause low serum vitamin B12 levels and place patients at risk of vitamin B12 deficiency.[32][49][50][51]
In one randomised 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 (number needed to harm of 13.8).[52]
The mechanism is unclear but may be related to malabsorption.
H2 receptor antagonist or proton-pump inhibitor 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 proton-pump inhibitors may be at risk for vitamin B12 deficiency.[31]
One large case-control study found that more than 2 years' use of proton-pump inhibitors or H2 receptor antagonists increased the risk of vitamin B12 deficiency.[53]
weak
Helicobacter pylori infection
Studies suggest a link between H pylori infection and vitamin B12 deficiency.[33][34] However, it is unclear whether the organism, or associated atrophic gastritis, causes vitamin B12 deficiency.[35]
There does not appear to be an association between H pylori infection and B12 deficiency in pregnant women.[36]
anticonvulsant use
nitrous oxide misuse
Recreational nitrous oxide (N₂O) misuse may increase the risk of vitamin B12 deficiency.[39][39]
In one global systematic review and meta-analysis, up to 85% of reported recreational users were possibly or probably vitamin B12-deficient.[40]
N₂O converts the active monovalent form of vitamin B12 to its inactive bivalent form. The neurological sequelae of N₂O-induced vitamin B12 deficiency can include neuropathy and paralysis.[41]
diabetes mellitus
One study reported vitamin B12 deficiency in 22% of people with type 2 diabetes.[54] Vitamin B12 deficiency may be easily overlooked as a cause of neuropathy in people with type 2 diabetes.[54]
Older patients with diabetes taking metformin may be at greater risk for vitamin B12 deficiency (as metformin can cause vitamin B12 deficiency).[55]
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 levels of vitamin B12.[56][57]
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