Chemical structure of Vitamin B12
Find information on thousands of medical conditions and prescription drugs.

Vitamin B12 Deficiency

The term vitamin B12 (or B12 for short) is used in two different ways. In a broader sense it refers to a group of Co-containing compounds known as cobalamins - cyanocobalamin (an artefact formed as a result of the use of cyanide in the purification procedures), hydroxocobalamin and the two coenzyme forms of B12, methylcobalamin (MeB12) and 5-deoxyadenosylcobalamin (adenosylcobalamin - AdoB12). more...

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease

In a more specific way, the term B12 is used to refer to only one of these forms, cyanocobalamin, which is the principal B12 form used for foods and in nutritional supplements.

Pseudo-B12 refers to B12-like substances which are found in certain organisms, such as Spirulina spp. (blue-green algae, cyanobacteria). However, these substances do not have B12 biological activity for humans.


B12 is the most chemically complex of all the vitamins. B12's structure is based on a corrin ring, which, although similar to the porphyrin ring found in haem, chlorophyll, and cytochrome, has two of the pyrrole rings directly bonded. The central metal ion is Co (cobalt). Four of the six coordinations are provided by the corrin ring nitrogens, and a fifth by a dimethylbenzimidazole group. The sixth coordination partner varies, being a cyano group (-CN), a hydroxyl group (-OH), a methyl group (-CH₃) or a 5'-deoxyadenosyl group (here the C5' atom of the deoxyribose forms the covalent bond with Co), respectively, to yield the four B12 forms mentioned above. The covalent C-Co bond is the only carbon-metal bond known in biology. (p.32)


B12 cannot be made by plants or by animals, as the only type of organism that have the enzymes required for the synthesis of B12 are bacteria (eubacteria, archaebacteria).


Coenzyme B12's reactive C-Co bond participates in two types of enzyme-catalyzed reactions: (p.675)

  1. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent, X, which may be a carbon atom with substituents, an oxygen atom of an alcochol, or an amine.
  2. Methyl (-CH₃) group transfers between two molecules.

In humans there are only two coenzyme B12-dependent enzymes:

  1. MUT which uses the AdoB12 form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA). MUT's reaction converts MMl-CoA to Su-CoA, an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism)
  2. MTR, a methyl transfer enzyme, which uses the MeB12 and reaction type 2 to catalyzes the conversion of the amino acid Hcy into Met (for more see MTR's reaction mechanism).


[List your site here Free!]

Vitamin [B.sub.12] deficiency
From American Family Physician, 3/1/03 by Robert C. Oh

Vitamin [B.sub.12] (cobalamin) plays an important role in DNA synthesis and neurologic function. Deficiency can lead to a wide spectrum of hematologic and neuropsychiatric disorders that can often be reversed by early diagnosis and prompt treatment.

The true prevalence of vitamin [B.sub.12] deficiency in the general population is unknown. The incidence, however, appears to increase with age. In one study, (1) 15 percent of adults older than 65 years had laboratory evidence of vitamin [B.sub.12] deficiency. The nearly ubiquitous use of gastric acid-blocking agents, which can lead to decreased vitamin [B.sub.12] levels, (2) may have an underappreciated role in the development of vitamin [B.sub.12] deficiency. Taking the widespread use of these agents and the aging of the U.S. population into consideration, the actual prevalence of vitamin [B.sub.12] deficiency may be even higher than statistics indicate. Despite these facts, the need for universal screening in older adults remains a matter of controversy. (3,4)

Clinical Manifestations

Vitamin [B.sub.12] deficiency is associated with hematologic, neurologic, and psychiatric manifestations (Table 1). It is a common cause of macrocytic (megaloblastic) anemia and, in advanced cases, pancytopenia. Neurologic sequelae from vitamin [B.sub.12] deficiency include paresthesias, peripheral neuropathy, and demyelination of the corticospinal tract and dorsal columns (subacute combined systems disease). Vitamin [B.sub.12] deficiency also has been linked to psychiatric disorders, including impaired memory, irritability, depression, dementia and, rarely, psychosis. (5,6)

In addition to hematologic and neuropsychiatric manifestations, vitamin [B.sub.12] deficiency may exert indirect cardiovascular effects. Similar to folic acid deficiency, vitamin [B.sub.12] deficiency produces hyperhomocysteinemia, which is an independent risk factor for atherosclerotic disease. (7) Although the role of folic acid supplementation in reducing homocysteine levels as a method for preventing coronary artery disease and stroke continues to be a subject of great interest, there has been little emphasis on the potential role of vitamin [B.sub.12] deficiency as a contributing factor in the development of cardiovascular disease. This possibility becomes especially important when considering vitamin replacement therapy. Folic acid supplementation may mask an occult vitamin [B.sub.12] deficiency and further exacerbate or initiate neurologic disease. Therefore, clinicians should consider ruling out vitamin [B.sub.12] deficiency before initiating folic acid therapy. (8)

Normal Absorption of Vitamin [B.sub.12]

In humans, only two enzymatic reactions are known to be dependent on vitamin [B.sub.12]. In the first reaction, methylmalonic acid is converted to succinyl-CoA using vitamin [B.sub.12] as a cofactor (Figure 1). Vitamin [B.sub.12] deficiency, therefore, can lead to increased levels of serum methylmalonic acid. In the second reaction, homocysteine is converted to methionine by using vitamin [B.sub.12] and folic acid as cofactors. In this reaction, a deficiency of vitamin [B.sub.12] or folic acid may lead to increased homocysteine levels.


An understanding of the vitamin [B.sub.12] absorption cycle helps illuminate the potential causes of deficiency. The acidic environment of the stomach facilitates the breakdown of vitamin [B.sub.12] that is bound to food. Intrinsic factor, which is released by parietal cells in the stomach, binds to vitamin [B.sub.12] in the duodenum. This vitamin [B.sub.12]-intrinsic factor complex subsequently aids in the absorption of vitamin [B.sub.12] in the terminal ileum.

In addition to this method of absorption, evidence supports the existence of an alternate system that is independent of intrinsic factor or even an intact terminal ileum. Approximately 1 percent of a large oral dose of vitamin [B.sub.12] is absorbed by this second mechanism. (9) This pathway is important in relation to oral replacement. Once absorbed, vitamin [B.sub.12] binds to transcobalamin II and is transported throughout the body. The interruption of one or any combination of these steps places a person at risk of developing deficiency (Figure 2).

Diagnosis of Vitamin [B.sub.12] Deficiency

The diagnosis of vitamin [B.sub.12] deficiency has traditionally been based on low serum vitamin [B.sub.12] levels, usually less than 200 pg per mL (150 pmol per L), along with clinical evidence of disease. However, studies indicate that older patients tend to present with neuropsychiatric disease in the absence of hematologic findings. (5,6) Furthermore, measurements of metabolites such as methylmalonic acid and homocysteine have been shown to be more sensitive in the diagnosis of vitamin [B.sub.12] deficiency than measurement of serum [B.sub.12] levels alone. (3,10-14)

In a large study (10) of 406 patients with known vitamin [B.sub.12] deficiency, 98.4 percent had elevated serum methylmalonic acid levels, and 95.9 percent had elevated serum homocysteine levels (defined as three standard deviations above the mean). Only one patient out of 406 had normal levels of both metabolites, resulting in a sensitivity of 99.8 percent when methylmalonic acid and homocysteine levels are used for diagnosis. Interestingly, 28 percent of the patients in this study had normal hematocrit levels, and 17 percent had normal mean corpuscular volumes.

In another study (13) of patients with known pernicious anemia who had not received maintenance vitamin [B.sub.12] injections for months to years, the rise of methylmalonic acid and homocysteine levels was found to precede the decrease in serum vitamin [B.sub.12] and the decline in hematocrit. This finding suggests that methylmalonic acid and homocysteine levels can be early markers for tissue vitamin [B.sub.12] deficiency, even before hematologic manifestations occur.

Use of methylmalonic acid and homocysteine levels in the diagnosis of vitamin [B.sub.12] deficiency has led to some surprising findings. If increased homocysteine or methylmalonic acid levels and a normalization of these metabolites in response to replacement therapy are used as diagnostic criteria for vitamin [B.sub.12] deficiency, approximately 50 percent of these patients have serum vitamin [B.sub.12] levels above 200 pg per mL. (1) This observation suggests that use of a low serum vitamin [B.sub.12] level as the sole means of diagnosis may miss up to one half of patients with actual tissue [B.sub.12] deficiency. Other studies have shown similar findings, with the rate of missed diagnosis ranging from 10 to 26 percent when diagnosis is based on low serum vitamin [B.sub.12] levels alone. (3)

There are, however, a few caveats to keep in mind. Looking at the reactions that use vitamin [B.sub.12] (Figure 1), (3) an elevated methylmalonic acid level is clearly more specific for vitamin [B.sub.12] deficiency than an elevated homocysteine level. Vitamin [B.sub.12] or folic acid deficiency can cause the homocysteine level to rise, so folic acid levels also should be checked in patients with isolated hyperhomocysteinemia.

In addition, folic acid deficiency can cause falsely low serum vitamin [B.sub.12] levels. One study (14) revealed that approximately one third of patients with folic acid deficiency had low serum vitamin [B.sub.12] levels--less than 100 pg per mL (74 pmol per L) in some patients. Also, methylmalonic acid levels can be elevated in patients with renal disease (the result of decreased urinary excretion); thus, elevated levels must be interpreted with caution. (10)

An algorithm for the diagnosis of vitamin [B.sub.12] deficiency is provided in Figure 3. (3,14)


Causes of Vitamin [B.sub.12] Deficiency States

Once vitamin [B.sub.12] deficiency is confirmed, a search for the etiology should be initiated. Causes of vitamin [B.sub.12] deficiency can be divided into three classes: nutritional deficiency, malabsorption syndromes, and other gastrointestinal causes (Table 2). (14)


Dietary sources of vitamin [B.sub.12] are primarily meats and dairy products. In a typical Western diet, a person obtains approximately 5 to 15 mcg of vitamin [B.sub.12] daily, much more than the recommended daily allowance of 2 mcg. Normally, humans maintain a large vitamin [B.sub.12] reserve, which can last two to five years even in the presence of severe malabsorption. (14) Nevertheless, nutritional deficiency can occur in specific populations. Elderly patients with "tea and toast" diets and chronic alcoholics are at especially high risk. The dietary limitations of strict vegans make them another, less common at-risk population.


The classic disorder of malabsorption is pernicious anemia, an autoimmune disease that affects the gastric parietal cells. Destruction of these cells curtails the production of intrinsic factor and subsequently limits vitamin [B.sub.12] absorption. Laboratory evidence of parietal cell antibodies is approximately 85 to 90 percent sensitive for the diagnosis of pernicious anemia. However, the presence of parietal cell antibodies is nonspecific and occurs in other autoimmune states. Intrinsic factor antibody is only 50 percent sensitive, but it is far more specific for the diagnosis of pernicious anemia.

A Schilling test, which distinguishes intrinsic factor-related malabsorption, can be used to diagnose pernicious anemia (Table 3). (14) Specifically, Schilling test results were once used to determine whether a patient required parenteral or oral vitamin [B.sub.12] supplementation. This distinction is now unnecessary, because evidence points to a [B.sub.12] absorption pathway independent of intrinsic factor, and studies have proved that oral replacement is equal in efficacy to intramuscular therapy. (9) Regardless of the test result, successful treatment can still be achieved with oral replacement therapy.

Thus, the utility of the Schilling test has been brought into question. (3) The Schilling test also has fallen out of favor because it is complicated to perform, the radiolabeled vitamin [B.sub.12] is difficult to obtain, and interpretation of test results can be problematic in patients with renal insufficiency.

The phenomenon of food-bound malabsorption occurs when vitamin [B.sub.12] bound to protein in foods cannot be cleaved and released. Any process that interferes with gastric acid production can lead to this impairment. Atrophic gastritis, with resulting hypochlorhydria, is a major cause, especially in the elderly. (3) Subtotal gastrectomy, once common before the availability of effective medical therapy for peptic ulcer disease, also can lead to vitamin [B.sub.12] deficiency by this mechanism.

As mentioned previously, the widespread and prolonged use of histamine H2-receptor blockers and proton pump inhibitors for ulcer disease also may cause impaired breakdown of vitamin [B.sub.12] from food, causing malabsorption and eventual depletion of [B.sub.12] stores. Recent studies have confirmed that long-term use of omeprazole can lead to lower serum vitamin [B.sub.12] levels. (15,16) While more studies are needed to identify the incidence and prevalence of vitamin [B.sub.12] deficiency in this subset of patients, screening for subclinical [B.sub.12] deficiency should be a consideration in patients who have received long-term acid-suppression therapy. (2)


Other etiologies of vitamin [B.sub.12] deficiency, although less common, deserve mention. Patients with evidence of vitamin [B.sub.12] deficiency and chronic gastrointestinal symptoms such as dyspepsia, recurrent peptic ulcer disease, or diarrhea may warrant evaluation for such entities as Whipple's disease (a rare bacterial infection that impairs absorption), Zollinger-Ellison syndrome (gastrinoma causing peptic ulcer and diarrhea), or Crohn's disease. Patients with a history of intestinal surgery, strictures, or blind loops may have bacterial overgrowth that can compete for dietary vitamin [B.sub.12] in the small bowel, as can infestation with tapeworms or other intestinal parasites. Congenital transport-protein deficiencies, including transcobalamin II deficiency, are another rare cause of vitamin [B.sub.12] deficiency.

Oral vs. Parenteral Therapy

Because most clinicians are generally unaware that oral vitamin [B.sub.12] therapy is effective, (17) the traditional treatment for [B.sub.12] deficiency has been intramuscular injections. However, since as early as 1968, oral vitamin [B.sub.12] has been shown to have an efficacy equal to that of injections in the treatment of pernicious anemia and other [B.sub.12] deficiency states. (9,17-19) Although the majority of dietary vitamin [B.sub.12] is absorbed in the terminal ileum through a complex with intrinsic factor, evidence for the previously mentioned alternate transport system is mounting.

In one study, (18) 38 patients with vitamin [B.sub.12] deficiency were randomized to receive oral or parenteral therapy. Patients in the parenteral therapy group received 1,000 mcg of vitamin [B.sub.12] intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90, while those in the oral treatment group received 2,000 mcg daily for 120 days. At the end of 120 days, patients who received oral therapy had significantly higher serum vitamin [B.sub.12] levels and lower methylmalonic acid levels than those in the parenteral therapy group. The actual transport mechanism used in this pathway remains unproved, but vitamin [B.sub.12] is thought to be absorbed "en masse" in high doses. Surprisingly, one study20 showed that even in patients who had undergone gastrectomy, vitamin [B.sub.12] deficiency could be easily reversed with oral supplementation.

Intramuscular injections, although safe and inexpensive, have several drawbacks. Injections are painful, medical personnel giving the injections are placed at risk of needlestick injuries, and administration of intramuscular injections often adds to the cost of therapy. Treatment schedules for intramuscular administration vary widely but usually consist of initial loading doses followed by monthly maintenance injections. One regimen consists of daily injections of 1,000 mcg for one to two weeks, then a maintenance dose of 1,000 mcg every one to three months.

Although the daily requirement of vitamin [B.sub.12] is approximately 2 mcg, the initial oral replacement dosage consists of a single daily dose of 1,000 to 2,000 mcg (Table 4). This high dose is required because of the variable absorption of oral vitamin [B.sub.12] in doses of 500 mcg or less. (19) This regimen has been shown to be safe, cost-effective, and well tolerated by patients. (19)


After the diagnosis of vitamin [B.sub.12] deficiency has been made and a treatment plan has been initiated, follow-up is important to determine the patient's response to therapy. If vitamin [B.sub.12] deficiency is associated with severe anemia, correction of the deficiency state should lead to a marked reticulocytosis in one to two weeks. In mild vitamin [B.sub.12] deficiency, we recommend repeat measurements of serum vitamin [B.sub.12], homocysteine, and methylmalonic acid levels two to three months after initiating treatment.

The authors thank Linda L. Brown, M.D., Department of Internal Medicine, Walter Reed Army Medical Center, Washington, D.C., for review of the manuscript.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the U.S. Army Medical Department or the U.S. Army Service at large.


(1.) Pennypacker LC, Allen RH, Kelly JP, Matthews LM, Grigsby J, Kaye K, et al. High prevalence of cobalamin deficiency in elderly outpatients. J Am Geriatr Soc 1992;40:1197-204.

(2.) Bradford GS, Taylor CT. Omeprazole and vitamin [B.sub.12] deficiency. Ann Pharmacother 1999;33:641-3.

(3.) Stabler SP. Screening the older population for cobalamin (vitamin [B.sub.12]) deficiency. J Am Geriatr Soc 1995;43:1290-7.

(4.) Green R. Screening for vitamin [B.sub.12] deficiency: caveat emptor [Editorial]. Ann Intern Med 1996; 124:509-11.

(5.) Lee GR. Pernicious anemia and other causes of vitamin [B.sub.12] (cobalamin) deficiency. In: Lee GR, et al., eds. Wintrobe's Clinical hematology. 10th ed. Baltimore: Williams & Wilkins, 1999:941-64.

(6.) Lindenbaum J, Healton EB, Savage DG, Brust JC, Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988; 318:1720-8.

(7.) Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.

(8.) Tucker KL, Mahnken B, Wilson PW, Jacques P, Selhub J. Folic acid fortification of the food supply. Potential benefits and risks for the elderly population. JAMA 1996;276:1879-85.

(9.) Elia M. Oral or parenteral therapy for [B.sub.12] deficiency. Lancet 1998;352:1721-2.

(10.) Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine derterminations for diagnosing cobalamin and folate deficiencies. Am J Med 1994;96:239-46.

(11.) Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ, Allen RH, et al. Elevated methylmalonic acid and total homocysteine levels show high prevalence of vitamin [B.sub.12] deficiency after gastric surgery. Ann Intern Med 1996;124:469-76.

(12.) Frenkel EP, Yardley DA. Clinical and laboratory features and sequelae of deficiency of folic acid (folate) and vitamin [B.sub.12] (cobalamin) in pregnancy and gynecology. Hematol Oncol Clin North Am 2000;14:1079-100.

(13.) Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematol 1990;34:99-107.

(14.) Snow CF. Laboratory diagnosis of vitamin [B.sub.12] and folate deficiency: a guide for the primary care physician. Arch Intern Med 1999;159:1289-98.

(15.) Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin [B.sub.12]). Ann Intern Med 1994;120:211-5.

(16.) Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin [B.sub.12] levels in patients with Zollinger-Ellison syndrome. Am J Med 1998; 104:422-30.

(17.) Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geriatr Soc 1998;46:1125-7.

(18.) Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 1998;92: 1191-8.

(19.) Lederle FA. Oral cobalamin for pernicious anemia. Medicine's best kept secret? JAMA 1991;265:94-5.

(20.) Adachi S, Kawamoto T, Otsuka M, Fukao K. Enteral vitamin [B.sub.12] supplements reverse postgastrectomy [B.sub.12] deficiency. Ann Surg 2000;232:199-201.

ROBERT C. OH, CPT, MC, USA, is a staff family physician at U.S. Army Health Clinic in Darmstadt, Germany. Dr. Oh received his medical degree from Boston University School of Medicine and completed residency training in family practice at DeWitt Army Community Hospital in Fort Belvoir, Va.

DAVID L. BROWN, MAJ, MC, USA, is director of primary care sports medicine at Madigan Army Medical Center, Fort Lewis, Wash. He received his medical degree from the Uniformed Services University of the Health Sciences F. Edward Hebert School of Medicine, Bethesda, Md. He completed a residency in family practice at Tripler Army Medical Center, Honolulu, and a fellowship in primary care sports medicine at the Uniformed Services University of Health Sciences.

Address correspondence to Robert C. Oh, CPT, MC, USA, CMR 431, Box 284, APO AE 09175 (e-mail: Reprints are not available from the authors.

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

COPYRIGHT 2003 American Academy of Family Physicians
COPYRIGHT 2003 Gale Group

Return to Vitamin B12 Deficiency
Home Contact Resources Exchange Links ebay