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Natural History and Prevalence of Vitamin B12 Deficiency

"Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important." Baik and Russell, 1999

The case studies illustrate two important facts about vitamin B12 (cobalamin). First, low vitamin B12 levels can have profound effects on patient well-being. Although most patients with a vitamin B12 deficiency are in a subclinical stage 1-7 and do not present with symptoms or complaints such as those of the case study patients, some patients might be at risk for developing serious sequelae if not detected and followed with reassessment, prophylaxis, or treatment as needed. Second, treatment is safe and remarkably effective if provided before permanent damage occurs. Understanding the biochemistry of vitamin B12, the problems that might develop when cobalamin body stores are depleted and current treatment strategies can help clinicians prevent significant morbidity in their patients.

The nutritional value of vitamin B12 was initially established in the first half of the twentieth century when ingesting raw animal liver (the primary storage organ for this nutrient) was found to be an effective treatment for pernicious anemia.8 Humans cannot manufacture vitamin B12 and must consume it on a regular basis. Vitamin B12 is a water-soluble compound that is naturally available for human use only through animal proteins, such as beef, poultry, fish, eggs, and dairy products. Unfortified plant-based foods do not contain vitamin B12.2, 9, 10

There are several important points about cobalamin absorption:

  • It occurs primarily during the active digestion of animal proteins in the stomach and terminal ileum, and it depends on the availability of adequate amounts of a number of compounds, including R protein (haptocorrin from saliva), gastric acid, pepsin, and intrinsic factor (IF).2,3
  • Gastric acid is needed to digest animal protein. When the ability to secrete that acid is lost, a person cannot break down the protein to release vitamin B12 from food and can absorb only crystalline (synthetic) vitamin B12.2
  • Loss of IF in pernicious anemia results in an inability to absorb vitamin B12. People with pernicious anemia must be treated with parenteral cyanocobalamin or high doses of oral cobalamin (1,000 µg daily).2, 11
  • About 1% of large oral doses of vitamin B12 passively diffuses into the bloodstream from the small intestine.2, 10
  • If any aspect of the digestion sequence begins to fail and malabsorption develops, the body can draw on the large amounts of vitamin B12 stored in the liver, so overt symptoms might not develop for several years. 2, 10, 12 However, with certain conditions, vitamin B12 deficiency might develop over a shorter period of time (months).

Adequate serum levels of cobalamin are crucial to complete three enzymatic processes (see Figure 1 below).

  • Methylcobalamin is a cofactor necessary to convert homocysteine (Hcy) to methionine. Thus, vitamin B12 deficiency increases Hcy.1, 12, 13
  • The cofactor adenosylcobalamin is required for the conversion of methylmalonyl coenzyme A to succinyl coenzyme A.2,10
  • Methylcobalamin is needed to convert 5-methyltetrahydrofolate to tetrahydrofolate and is necessary for DNA and red blood cell production.

Figure 1. The Biochemical Role of Cobalamin

Vitamin B12 deficiencies often, but not always, develop gradually over many years and are accompanied by a slow and varied onset of nonspecific symptoms. Carmel describes vitamin B12 deficiency in two states: clinical and subclinical.1 Clinical deficiency manifests with hematologic or neurologic signs and symptoms, cobalamin levels <200 picograms per milliliter (pg/mL), and levels for Hcy and methylmalonic acid (MMA) that are usually elevated. Subclinical deficiency includes absent signs and symptoms, although some patients might have subtle changes on neurologic examination; low to low-normal cobalamin levels (200–350 pg/mL); and at least one metabolic abnormality (elevated homocysteine or elevated methylmalonic acid), usually mild. You are likely to encounter more of your patients in the asymptomatic subclinical stage of vitamin B12 deficiency rather than in the classic, overtly apparent clinical vitamin B12 deficiency.1, 12, 14 The challenge for you is how and when to respond to a patient without the typical signs and symptoms of clinical vitamin B12 deficiency.

The first to conceptualize the natural history of a vitamin B12 deficiency, Herbert noted that vegetarians with dietary vitamin B12 insufficiency progressed through four stages: serum depletion; cell depletion; biochemical deficiency (defined as elevated levels of Hcy and MMA); and, finally, the classic signs and symptoms of clinical deficiency, such as anemia (Table 2).9, 15

Although this model provides a useful perspective, untreated patients will not necessarily advance through the stages chronologically or linearly. Progression to a later stage is not inevitable, and some patients with evidence of an early stage deficiency might have normal laboratory values when retested.11 Malabsorption of food-derived cobalamin because of decreased gastric acid production is a more likely reason for vitamin B12 deficiency, while malabsorption of cobalamin because of lack of IF in pernicious anemia accounts for a smaller portion.3

Prevalence of Vitamin B12 Deficiency


ng/L = pg/mL

pmol/L = pg/mL X 0.738

pg/mL = pmol/L ÷ 0.738

The true prevalence of vitamin B12 deficiency tends to be underestimated for several reasons. The common misconception that most vitamin B12 deficiencies are due to inadequate dietary intake might lead to overlooking important high-risk groups. Older adults who routinely consume meat and other animal proteins can still be vitamin B12 deficient due to malabsorption. Clinical vitamin B12 deficiencies are relatively rare. Most patients are far more likely to have mild, subclinical vitamin B12 deficiency. 1

Most prevalence estimates are based solely on serum vitamin B12 results. Confusion can arise because cobalamin values are measured in picomoles per liter (pmol/L) in some research studies, while clinical laboratories express values in pg/mL or nanograms per liter (ng/L). The most frequently reported threshold value is 200 pg/mL (148 pmol/L).1,16 Studies that have established higher cutpoints invariably reported higher prevalence estimates. In the research literature, some investigators have used diagnostic algorithms that combine serum B12 results with one or more additional laboratory findings, typically either serum Hcy or MMA.1,4,17,18 Depending on the approach used, the additional test findings have raised4,18,19 or lowered6,19,20 the observed prevalence of vitamin B12 deficiency compared with findings based solely on serum vitamin B12 levels.

Unpublished data from the National Health and Nutrition Examination Survey (NHANES) 2001-2004 in Table 3 stratified by age have estimated that 1 (3.2%) of every 31 adults 51 years of age or older in the United States will have a low vitamin B12 serum level (≤ 200 pg/mL). Most of these people are ambulatory and do not have overt symptoms of vitamin B12 deficiency.

Those prevalence figures are supported by other population-based studies. The Framingham study with a cohort of noninstitutionalized adults 67 through 96 years of age found that 5.3% of the participants had serum vitamin B12 levels <200 pg/mL.4

As summarized in the pop-up box, inclusion criteria and differences in laboratory testing make prevalence estimates from other clinic-based studies difficult to compare with population-based estimates.


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  • Page last updated: June 29, 2009 The U.S. Government's Official Web PortalDepartment of Health and Human Services
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