Applied Evidence

B12 deficiency: A look beyond pernicious anemia

Emmanuel Andrès, MD
Laure Federici, MD
Stéphan Affenberger, MD
Department of Internal Medicine, Diabetes and Metabolic Diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Josep Vidal-Alaball, MD
Department of General Practice, Cardiff University, United Kingdom

Noureddine Henoun Loukili, PhD
Department of Hygiene and Fight against Nosocomial Infections, Hôpital Calmette, CHRU de Lille, Lille, France

Jacques Zimmer, MD, PhD
Laboratoire d’Immunogénétique-Allergologie, Centre de Recherche Public de la Santé (CRP-Santé) de Luxembourg, Luxembourg

Georges Kaltenbach, MD
Department of Internal Medicine and Geriatrics, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

Emmanuel Andrès reports that his research on B12 deficiency was supported by a grant from the Fondation de France (Prix Robert et Jacqueline Zittoun 2004).

Food-B12 malabsorption—not pernicious anemia—is the leading cause of B12 malabsorption. It’s also very subtle.


Practice recommendations

  • Mild, preclinical B12 deficiency is associated with food-B12 malabsorption more often than with pernicious anemia. (C)
  • The classic treatment for B12 deficiency—particularly when the cause is not a dietary deficiency—is 100 to 1000 mcg per month of cyanocobalamin, IM. (B)
  • Oral crystalline cyanocobalamin is an effective treatment for food-B12 malabsorption, though it’s effectiveness in the long term has not been demonstrated. (B)

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.

Clinical features of B12 deficiency1,5,6,10-13

Hypersegmentation of the neutrophils
Aregenerative macrocytary anemia
Medullary megaloblastosis ("blue spinal cord")
Isolated thrombocytopenia and neutropenia
Hemolytic anemia
Thrombotic microangiopathy (presence of schistocytes)
Hunter’s glossitis
LDH and bilirubin elevation
Resistant and recurring mucocutaneous ulcers
Combined sclerosis of the spinal cord
Polyneurites (especially sensitive ones)
Babinski’s phenomenon
Cerebellar syndromes affecting the cranial nerves including optic neuritis, optic atrophy, urinary or fecal incontinence
Cognitive impairment
Stroke and atherosclerosis (hyperhomocysteinemia)
Parkinsonian syndromes
Multiple sclerosis
Atrophy of the vaginal mucosa
Chronic vaginal and urinary infections (especially mycosis)
Hypofertility and repeated miscarriages
Venous thromboembolic disease
Angina (hyperhomocysteinemia)
* Reported in practice and recent literature.

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)