Vitamin B12 Deficiency ROBERT C. OH, CPT, MC, USA, U.S. Army Health Clinic, Darmstadt, Germany DAVID L. BROWN, MAJ, MC, USA, Madigan Army Medical Center, Fort Lewis, Washington Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic anemia and has been implicated in a spectrum of neuropsychiatric disorders. The role of B12 deficiency O A patient informa- in hyperhomocysteinemia and the promotion of atherosclerosis is only now being tion handout on vita- min B12 deficiency, explored. Diagnosis of vitamin B12 deficiency is typically based on measurement of written by the authors serum vitamin B12 levels; however, about 50 percent of patients with subclinical dis- of this article, is pro- ease have normal B12 levels. A more sensitive method of screening for vitamin B12 defi- vided on page 993. ciency is measurement of serum methylmalonic acid and homocysteine levels, which are increased early in vitamin B12 deficiency. Use of the Schilling test for detection of pernicious anemia has been supplanted for the most part by serologic testing for pari- etal cell and intrinsic factor antibodies. Contrary to prevailing medical practice, studies show that supplementation with oral vitamin B12 is a safe and effective treatment for the B12 deficiency state. Even when intrinsic factor is not present to aid in the absorp- tion of vitamin B12 (pernicious anemia) or in other diseases that affect the usual absorption sites in the terminal ileum, oral therapy remains effective. (Am Fam Physi- cian 2003;67:979-86,993-4. Copyright© 2003 American Academy of Family Physicians.) itamin B12 (cobalamin) plays manifestations (Table 1).It is a common cause an important role in DNA of macrocytic (megaloblastic) anemia and, in synthesis and neurologic func- advanced cases, pancytopenia. Neurologic tion. Deficiency can lead to a sequelae from vitamin B12 deficiency include wide spectrum of hemato- paresthesias, peripheral neuropathy, and Vlogic and neuropsychiatric disorders that can demyelination of the corticospinal tract and often be reversed by early diagnosis and dorsal columns (subacute combined systems prompt treatment. The true prevalence of vitamin B12 defi- ciency in the general population is unknown. TABLE 1 The incidence, however, appears to increase Clinical Manifestations with age. In one study,1 15 percent of adults of Vitamin B12 Deficiency older than 65 years had laboratory evidence of vitamin B12 deficiency. The nearly ubiqui- Hematologic tous use of gastric acid–blocking agents, Megaloblastic anemia which can lead to decreased vitamin B12 lev- Pancytopenia (leukopenia, thrombocytopenia) els,2 may have an underappreciated role in the Neurologic development of vitamin B12 deficiency. Tak- Paresthesias ing the widespread use of these agents and the Peripheral neuropathy aging of the U.S. population into considera- Combined systems disease (demyelination of dorsal columns and corticospinal tract) tion, the actual prevalence of vitamin B12 deficiency may be even higher than statistics Psychiatric Irritability, personality change indicate. Despite these facts, the need for uni- Mild memory impairment, dementia versal screening in older adults remains a Depression 3,4 matter of controversy. Psychosis Cardiovascular Clinical Manifestations Possible increased risk of myocardial infarction Vitamin B12 deficiency is associated with and stroke hematologic, neurologic, and psychiatric MARCH 1, 2003 / VOLUME 67, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 979 ues to be a subject of great interest, there has been little emphasis on the potential role of vitamin B12 deficiency as a contributing factor The rightsholder did not in the development of cardiovascular disease. grant rights to reproduce This possibility becomes especially important when considering vitamin replacement ther- this item in electronic apy. Folic acid supplementation may mask an media. For the missing occult vitamin B12 deficiency and further item, see the original print exacerbate or initiate neurologic disease. version of this publication. Therefore, clinicians should consider ruling out vitamin B12 deficiency before initiating folic acid therapy.8 FIGURE 1. Normal Absorption of Vitamin B12 In humans, only two enzymatic reactions are known to be dependent on vitamin B12.In the first reaction, methylmalonic acid is con- verted to succinyl-CoA using vitamin B12 as a cofactor (Figure 1).Vitamin B12 deficiency, disease). Vitamin B12 deficiency also has been therefore, can lead to increased levels of serum linked to psychiatric disorders, including methylmalonic acid. In the second reaction, impaired memory, irritability, depression, homocysteine is converted to methionine by 5,6 dementia and, rarely, psychosis. using vitamin B12 and folic acid as cofactors. In addition to hematologic and neuropsy- In this reaction, a deficiency of vitamin B12 or chiatric manifestations, vitamin B12 defi- folic acid may lead to increased homocysteine ciency may exert indirect cardiovascular levels. effects. Similar to folic acid deficiency, vita- An understanding of the vitamin B12 min B12 deficiency produces hyperhomocys- absorption cycle helps illuminate the potential teinemia, which is an independent risk factor causes of deficiency. The acidic environment for atherosclerotic disease.7 Although the role of the stomach facilitates the breakdown of of folic acid supplementation in reducing vitamin B12 that is bound to food. Intrinsic homocysteine levels as a method for prevent- factor, which is released by parietal cells in the ing coronary artery disease and stroke contin- stomach, binds to vitamin B12 in the duode- num. This vitamin B12–intrinsic factor com- plex subsequently aids in the absorption of vitamin B12 in the terminal ileum. The Authors In addition to this method of absorption, ROBERT C. OH, CPT, MC, USA, is a staff family physician at U.S. Army Health Clinic in evidence supports the existence of an alternate Darmstadt, Germany. Dr. Oh received his medical degree from Boston University system that is independent of intrinsic factor School of Medicine and completed residency training in family practice at DeWitt or even an intact terminal ileum. Approxi- Army Community Hospital in Fort Belvoir, Va. mately 1 percent of a large oral dose of vita- DAVID L. BROWN, MAJ, MC, USA, is director of primary care sports medicine at Madi- gan Army Medical Center, Fort Lewis, Wash. He received his medical degree from the min B12 is absorbed by this second mecha- Uniformed Services University of the Health Sciences F. Edward Hébert School of Med- nism.9 This pathway is important in relation icine, Bethesda, Md. He completed a residency in family practice at Tripler Army Med- to oral replacement. Once absorbed, vitamin ical Center, Honolulu, and a fellowship in primary care sports medicine at the Uni- formed Services University of Health Sciences. B12 binds to transcobalamin II and is trans- Address correspondence to Robert C. Oh, CPT, MC, USA, CMR 431, Box 284, APO AE ported throughout the body. The interruption 09175 (e-mail: [email protected]). Reprints are not available from the authors. of one or any combination of these steps 980 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 5 / MARCH 1, 2003 Vitamin B12 places a person at risk of developing defi- ciency (Figure 2). Elevated levels of methylmalonic acid and homocysteine are a much more sensitive diagnostic clue than a low serum B12 Diagnosis of Vitamin B12 Deficiency level in the diagnosis of vitamin B12 deficiency. The diagnosis of vitamin B12 deficiency has traditionally been based on low serum vita- min B12 levels, usually less than 200 pg per mL (150 pmol per L), along with clinical evidence homocysteine have been shown to be more of disease. However, studies indicate that older sensitive in the diagnosis of vitamin B12 defi- patients tend to present with neuropsychiatric ciency than measurement of serum B12 levels disease in the absence of hematologic find- alone.3,10-14 ings.5,6 Furthermore, measurements of meta- In a large study10 of 406 patients with bolites such as methylmalonic acid and known vitamin B12 deficiency, 98.4 percent Vitamin B12 (cobalamin) . Intrinsic factor (IF) B12-transcobalamin complex Stomach B -IF complex . 12 . Transcobalamin II . Mesenteric . veins . Parietal cell . IF receptor . Epithelial cells of terminal ileum . Ileum Epithelial cells ILLUSTRATION BY JOAN M. BECK FIGURE 2. Vitamin B12 absorption and transport. MARCH 1, 2003 / VOLUME 67, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 981 had elevated serum methylmalonic acid levels, are used for diagnosis. Interestingly, 28 per- and 95.9 percent had elevated serum homo- cent of the patients in this study had normal cysteine levels (defined as three standard devi- hematocrit levels, and 17 percent had normal ations above the mean). Only one patient out mean corpuscular volumes. of 406 had normal levels of both metabolites, In another study13 of patients with known resulting in a sensitivity of 99.8 percent when pernicious anemia who had not received methylmalonic acid and homocysteine levels maintenance vitamin B12 injections for Suspected Vitamin B12 Deficiency Hematologic, neurologic, or psychiatric abnormalities Gastric or ileal surgery Prolonged use of histamine H2-receptor blockers or proton pump inhibitors Chronic gastrointestinal symptoms Age >65 years Measure serum vitamin B12 Recheck vitamin B12 and folic acid levels. and folic acid levels. Folic acid normal Folic acid low Treat with folic acid. Serum vitamin B12