B₁₂ deficiency: A look beyond pernicious anemia

If an image of an elderly patient with pernicious anemia is the first thing that comes to mind when you think of B₁₂ deficiency, take note: That image could obfuscate a more common case of B₁₂ deficiency—one caused by food-B₁₂ malabsorption.

Food-B₁₂ malabsorption, characterized by the inability to release B₁₂ from food or its binding proteins, is actually the leading cause of B₁₂ malabsorption, especially in elderly patients.^1-4 And unlike pernicious anemia, it’s more likely to be associated with mild, preclinical B₁₂ deficiency.^1,5

Spotting this form of B₁₂ deficiency requires that you focus on its nuances, such as its link to Helicobacter pylori infection and long-term antacid and biguanide use. It also requires that you consider not only a patient’s serum B₁₂ levels, but his homocysteine and methylmalonic acid levels, since they are considered more sensitive indicators of cobalamin deficiency.⁶ Keying in on these indicators early will ensure prompt treatment, which typically includes intramuscular injections of the vitamin, but which could revolve around a more convenient option: oral B₁₂.

A common problem that comes in many shades

B₁₂ deficiency is common in elderly patients⁷ and its incidence increases with age.^7,8 The Framingham study revealed a prevalence of 12% among elderly people living in the community.⁸ Other studies focusing on those who are in institutions or who are sick and malnourished, have suggested a higher prevalence of 30% to 40%.^3,9

The clinical manifestations of B₁₂ deficiency are highly polymorphic and of varying severity ranging from milder conditions such as the common sensory neuropathy and isolated anomalies of macrocytosis and hypersegmentation of neutrophils, to severe disorders, including combined sclerosis of the spinal cord, hemolytic anemia and even pancytopenia (TABLE 1).^1,5,6,10-13

B₁₂ deficiency is often unrecognized or not investigated because the clinical manifestations can be very subtle. In fact, one of its manifestations—mild memory loss—can mimic the early stages of dementia.¹⁴

Further muddying the waters is the fact that B₁₂ deficiency appears to be more common among patients who have a variety of chronic neurologic conditions such as stroke, Parkinson’s disease, dementia, Alzheimer’s disease, and depression—although it is unclear if these are causal relationships.^1,15 In our own studies in which we administered B₁₂ to patients with dementia, we did not observe any improvement.^2,5 Other studies have had similar results.^16,17

B₁₂ deficiency is typically defined in terms of the serum concentration of B₁₂, as well as the concentration of homocysteine and methyl malonic acid—2 components of the cobalamin metabolic pathway. A deficiency exists if the patient’s blood work reveals the following:^2,18

• Serum B₁₂ levels <150 pmol/L and either total serum homocysteine levels >13 μmol/L or methylmalonic acid levels >0.4 μmol/L (in the absence of renal failure and folate and vitamin B₆ deficiencies).
• Low serum holotranscobalamin levels <35 pmol/L.

TABLE 1
Clinical features of B₁₂ deficiency^1,5,6,10-13

The “classic” cause is not the most common

The principal causes of B₁₂ deficiency include pernicious anemia, dietary deficiency, postsurgical malabsorption, and food-B₁₂ malabsorption. Of note is the fact that there is typically a 5- to 10-year delay between the onset of B₁₂ deficiency and the development of clinical illness, in part because of hepatic stores of cobalamin (>1.5 mg).^1,19

In elderly patients, B₁₂ deficiency is classically caused by pernicious anemia,^3,7 the principal characteristics of which have been reported in detail in several reviews.^20-22 The one thing, of course, that bears repeating is that this form of anemia is associated with a lack of intrinsic factor, which facilitates the absorption of B₁₂.

B₁₂ deficiency caused by dietary deficiency is more rare. Dietary causes of deficiency are limited to elderly people who are already malnourished, such as those living in institutions (they may consume inadequate amounts of foods containing vitamin B₁₂) and strict vegetarians.^1,19 (A typical Western diet contributes 3–30 mcg of B₁₂ per day towards the recommended dietary allowance set by the Food and Nutrition Board of the Institute of Medicine (US) of 2.4 mcg/day for adults and 2.6 to 2.8 mcg/day during pregnancy.²³)