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Home , Folate, Folate deficiency, Methylmalonic acid, Vitamin B12, Vitamin B12 deficiency

Vitamin B12 Deficiency ROBERT C. OH, CPT, MC, USA, U.S. Army Health Clinic, Darmstadt, DAVID L. BROWN, MAJ, MC, USA, Madigan Army Medical Center, Fort Lewis, Washington

Vitamin B12 (cobalamin) deficiency is a common cause of macrocytic and has been implicated in a spectrum of neuropsychiatric disorders. The role of B12 deficiency O A patient informa- in and the promotion of atherosclerosis is only now being tion handout on vita- min B12 deficiency, explored. Diagnosis of 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 and levels, which are increased early in vitamin B12 deficiency. Use of the for detection of pernicious anemia has been supplanted for the most part by serologic testing for pari- etal cell and 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 , 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, . Neurologic

tion. Deficiency can lead to a sequelae from vitamin B12 deficiency include wide spectrum of hemato- , , and logicV 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 –blocking agents, which can lead to decreased vitamin B12 lev- Pancytopenia (, ) 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 , personality change indicate. Despite these facts, the need for uni- Mild impairment, versal screening in older adults remains a 3,4 matter of controversy. Cardiovascular Clinical Manifestations Possible increased risk of myocardial infarction

Vitamin B12 deficiency is associated with and 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 . 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

(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 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 facilitates the breakdown of

of folic acid supplementation in reducing vitamin B12 that is bound to . Intrinsic homocysteine levels as a method for prevent- factor, which is released by parietal cells in the

ing 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

. . .

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 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 level

<100 pg per mL 100 to 400 pg per mL >400 pg per mL (74 pmol per L) (74 to 295 pmol per L)

Vitamin B12 deficiency Check serum methylmalonic No vitamin B12 deficiency acid and homocysteine levels.

Either level is elevated. Both levels are normal.

Vitamin B12 deficiency* No vitamin B12 deficiency

*—If levels of metabolites normalize with vitamin B12 supplementation.

FIGURE 3. Suggested approach to the patient with suspected vitamin B12 deficiency.

Information from Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am Geri-

atr Soc 1995:43:1295, and Snow CF. Laboratory diagnosis of vitamin B12 and deficiency. Arch Intern Med 1999;159:1297.

982 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 5 / MARCH 1, 2003 Vitamin B12

months to years, the rise of methylmalonic acid and homocysteine levels was found to Any process that interferes with gastric acid production, precede the decrease in serum vitamin B12 and such as prolonged use of acid-suppressing , the decline in hematocrit. This finding sug- can lead to vitamin B deficiency. gests that methylmalonic acid and homocys- 12 teine levels can be early markers for tissue vit- amin B12 deficiency, even before hematologic manifestations occur. as the sole means of diagnosis may miss up to

Use of methylmalonic acid and homocys- one half of patients with actual tissue B12 defi- teine levels in the diagnosis of vitamin B12 ciency. Other studies have shown similar find- deficiency has led to some surprising findings. ings, with the rate of missed diagnosis ranging If increased homocysteine or methylmalonic from 10 to 26 percent when diagnosis is based 3 acid levels and a normalization of these on low serum vitamin B12 levels alone. metabolites in response to replacement ther- There are, however, a few caveats to keep in apy are used as diagnostic criteria for vitamin mind. Looking at the reactions that use vita- 3 B12 deficiency, approximately 50 percent of min B12 (Figure 1), an elevated methylmalonic these patients have serum vitamin B12 levels acid level is clearly more specific for vitamin 1 above 200 pg per mL. This observation sug- B12 deficiency than an elevated homocysteine gests that use of a low serum vitamin B12 level level. Vitamin B12 or folic acid deficiency can cause the homocysteine level to rise, so folic acid levels also should be checked in patients TABLE 2 with isolated hyperhomocysteinemia. Etiologies of Vitamin B12 Deficiency In addition, folic acid deficiency can cause

falsely low serum vitamin B12 levels. One Nutritional deficiency study14 revealed that approximately one Inadequate intake (e.g., alcoholics, elderly, vegans) third of patients with folic acid deficiency syndromes had low serum vitamin B12 levels—less than Food-bound B malabsorption 12 100 pg per mL (74 pmol per L) in some Prolonged use of proton pump inhibitors patients. Also, methylmalonic acid levels can Prolonged use of histamine H2 receptor blockers Lack of intrinsic factor or parietal cells be elevated in patients with renal disease Pernicious anemia (the result of decreased urinary ); Atrophic thus, elevated levels must be interpreted Postgastrectomy with caution.10 Other gastrointestinal causes An algorithm for the diagnosis of vitamin 3,14 Ileal malabsorption B12 deficiency is provided in Figure 3. Enteritis (Crohn’s disease)

Ileal resection Causes of Vitamin B12 Deficiency States Biologic competition Once vitamin B12 deficiency is confirmed, a Bacterial overgrowth search for the etiology should be initiated. Tapeworm infestation Causes of vitamin B deficiency can be Defective transport 12 Transcobalamin II deficiency divided into three classes: nutritional defi- ciency, malabsorption syndromes, and other 14 Adapted with permission from Snow CF. Laboratory gastrointestinal causes (Table 2). diagnosis of vitamin B12 and . Arch Intern Med 1999;159:1289-98. Copyrighted 1999, NUTRITIONAL DEFICIENCY American Medical Association. Dietary sources of vitamin B12 are primar- ily meats and dairy products. In a typical

MARCH 1, 2003 / VOLUME 67, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 983 TABLE 3 Interpretation of the Schilling Test

Results* Possible interpretation

Stage 1, normal* Dietary deficiency Food-bound malabsorption Partial Stage 1, abnormal; Pernicious anemia stage 2, normal Gastrectomy Oral vitamin B12 replacement is as effective as intramuscular Inadequate collection injections, even in patients with pernicious anemia or ileal in stage 1 disease. Stages 1 and 2, Ileal disease or resection abnormal Renal insufficiency Inadequate urine collection Bacterial overgrowth syndrome Western , a person obtains approximately Tapeworm infestation

5 to 15 mcg of vitamin B12 daily, much more

than the recommended daily allowance of *—Stage 1: radiolabeled B12 administered and 24- 2 mcg. Normally, humans maintain a large vit- hour urine measured for B12 excretion; the presence of high levels of radiolabeled B12 in the urine indicates amin B12 reserve, which can last two to five adequate absorption. Stage 2: if stage 1 is abnormal, years even in the presence of severe malab- stage 2 is performed by adding radiolabeled intrinsic 14 sorption. Nevertheless, nutritional deficiency factor to B12 and obtaining another 24-hour urine can occur in specific populations. Elderly sample. patients with “tea and toast” diets and chronic Adapted with permission from Snow CF. Laboratory

alcoholics are at especially high risk. The diagnosis of vitamin B12 and folate deficiency. Arch dietary limitations of strict vegans make them Intern Med 1999;159:1289-98. another, less common at-risk population.

MALABSORPTION SYNDROMES The classic disorder of malabsorption is ment can still be achieved with oral replace- pernicious anemia, an autoimmune disease ment therapy. that affects the gastric parietal cells. Destruc- Thus, the utility of the Schilling test has tion of these cells curtails the production of been brought into question.3 The Schilling test intrinsic factor and subsequently limits vita- also has fallen out of favor because it is com-

min B12 absorption. Laboratory evidence of plicated to perform, the radiolabeled vitamin

parietal cell antibodies is approximately 85 to B12 is difficult to obtain, and interpretation of 90 percent sensitive for the diagnosis of perni- test results can be problematic in patients with cious anemia. However, the presence of pari- renal insufficiency. etal cell antibodies is nonspecific and occurs The phenomenon of food-bound malab-

in other autoimmune states. Intrinsic factor sorption occurs when vitamin B12 bound to antibody is only 50 percent sensitive, but it is protein in cannot be cleaved and far more specific for the diagnosis of perni- released. Any process that interferes with gas- cious anemia. tric acid production can lead to this impair- A Schilling test, which distinguishes intrin- ment. , with resulting hypo- sic factor-related malabsorption, can be used chlorhydria, is a major cause, especially in the to diagnose pernicious anemia (Table 3).14 elderly.3 Subtotal gastrectomy, once common Specifically, Schilling test results were once before the availability of effective medical ther- used to determine whether a patient required apy for peptic ulcer disease, also can lead to vit-

parenteral or oral vitamin B12 supplementa- amin B12 deficiency by this mechanism. tion. This distinction is now unnecessary, As mentioned previously, the widespread

because evidence points to a B12 absorption and prolonged use of histamine H2-receptor pathway independent of intrinsic factor, and blockers and proton pump inhibitors for ulcer studies have proved that oral replacement is disease also may cause impaired breakdown of 9 equal in efficacy to intramuscular therapy. vitamin B12 from food, causing malabsorption

Regardless of the test result, successful treat- and eventual depletion of B12 stores. Recent

984 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 67, NUMBER 5 / MARCH 1, 2003 Vitamin B12

studies have confirmed that long-term use of therapy group received 1,000 mcg of vitamin can lead to lower serum vitamin B12 intramuscularly on days 1, 3, 7, 10, 14, 21, 15,16 B12 levels. While more studies are needed 30, 60, and 90, while those in the oral treat- to identify the incidence and prevalence of vit- ment group received 2,000 mcg daily for 120 amin B12 deficiency in this subset of patients, days. At the end of 120 days, patients who screening for subclinical B12 deficiency should received oral therapy had significantly higher be a consideration in patients who have serum vitamin B12 levels and lower methyl- received long-term acid-suppression therapy.2 levels than those in the par- enteral therapy group. The actual transport OTHER CAUSES mechanism used in this pathway remains

Other etiologies of vitamin B12 deficiency, unproved, but vitamin B12 is thought to be although less common, deserve mention. absorbed “en masse” in high doses. Surpris- 20 Patients with evidence of vitamin B12 defi- ingly, one study showed that even in patients ciency and chronic gastrointestinal symptoms who had undergone gastrectomy, vitamin B12 such as dyspepsia, recurrent peptic ulcer dis- deficiency could be easily reversed with oral ease, or may warrant evaluation for supplementation. such entities as Whipple’s disease (a rare bac- Intramuscular injections, although safe and terial infection that impairs absorption), inexpensive, have several drawbacks. Injec- Zollinger-Ellison syndrome (gastrinoma tions are painful, medical personnel giving the causing peptic ulcer and diarrhea), or Crohn’s injections are placed at risk of needlestick disease. Patients with a history of intestinal injuries, and administration of intramuscular surgery, strictures, or blind loops may have injections often adds to the cost of therapy. bacterial overgrowth that can compete for Treatment schedules for intramuscular dietary vitamin B12 in the small bowel, as can administration vary widely but usually consist infestation with tapeworms or other intestinal of initial loading doses followed by monthly parasites. Congenital transport-protein defi- maintenance injections. One regimen consists ciencies, including transcobalamin II defi- of daily injections of 1,000 mcg for one to two ciency, are another rare cause of vitamin B12 weeks, then a maintenance dose of 1,000 mcg deficiency. every one to three months. Although the daily requirement of vitamin

Oral vs. Parenteral Therapy B12 is approximately 2 mcg, the initial oral re- Because most clinicians are generally placement dosage consists of a single daily dose unaware that oral vitamin B12 therapy is effec- of 1,000 to 2,000 mcg (Table 4).This high dose 17 tive, the traditional treatment for B12 defi- is required because of the variable absorption ciency has been intramuscular injections. However, since as early as 1968, oral vitamin

B12 has been shown to have an efficacy equal TABLE 4 to that of injections in the treatment of perni- Schedule for Vitamin B12 Therapy cious anemia and other B12 deficiency states.9,17-19 Although the majority of dietary Route of administration Initial dosage Maintenance dosage vitamin B12 is absorbed in the terminal ileum through a complex with intrinsic factor, evi- Oral 1,000 to 2,000 mcg per day 1,000 mcg per day for life dence for the previously mentioned alternate for one to two weeks transport system is mounting. Intramuscular 100 to 1,000 mcg every day 100 to 1,000 mcg every one 18 In one study, 38 patients with vitamin B12 or every other day for one to three months deficiency were randomized to receive oral or to two weeks parenteral therapy. Patients in the parenteral

MARCH 1, 2003 / VOLUME 67, NUMBER 5 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 985 Vitamin B12

19 Garrett TJ, Podell ER, et al. Neuropsychiatric disor- of oral vitamin B12 in doses of 500 mcg or less. ders caused by cobalamin deficiency in the absence This regimen has been shown to be safe, cost- of anemia or . N Engl J Med 1988; 19 effective, and well tolerated by patients. 318:1720-8. 7. Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Follow-Up Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery dis- After the diagnosis of vitamin B12 deficiency ease. N Engl J Med 1997;337:230-6. has been made and a treatment plan has been 8. Tucker KL, Mahnken B, Wilson PW, Jacques P, Sel- hub J. Folic acid fortification of the food supply. initiated, follow-up is important to determine Potential benefits and risks for the elderly popula- the patient’s response to therapy. If vitamin B12 tion. JAMA 1996;276:1879-85. deficiency is associated with severe anemia, 9. Elia M. Oral or parenteral therapy for B12 defi- ciency. Lancet 1998;352:1721-2. correction of the deficiency state should lead to 10. Savage DG, Lindenbaum J, Stabler SP, Allen RH. a marked reticulocytosis in one to two weeks. Sensitivity of serum methylmalonic acid and homocysteine derterminations for diagnosing In mild vitamin B12 deficiency, we recommend cobalamin and folate deficiencies. Am J Med repeat measurements of serum vitamin B12, 1994;96:239-46. homocysteine, and methylmalonic acid levels 11. Sumner AE, Chin MM, Abrahm JL, Berry GT, two to three months after initiating treatment. Gracely EJ, Allen RH, et al. Elevated methylmalonic acid and total homocysteine levels show high

prevalence of vitamin B12 deficiency after gastric The authors thank Linda L. Brown, M.D., Depart- surgery. Ann Intern Med 1996;124:469-76. ment of Internal Medicine, Walter Reed Army Med- 12. Frenkel EP, Yardley DA. Clinical and laboratory fea- ical Center, Washington, D.C., for review of the tures and sequelae of deficiency of folic acid

manuscript. (folate) and vitamin B12 (cobalamin) in and gynecology. Hematol Oncol Clin North Am The authors indicate that they do not have any con- 2000;14:1079-100. flicts of interest. Sources of funding: none reported. 13. Lindenbaum J, Savage DG, Stabler SP, Allen RH. Diagnosis of cobalamin deficiency: II. Relative sen- sitivities of serum cobalamin, methylmalonic acid, The opinions and assertions contained herein are and total homocysteine concentrations. Am J the private views of the authors and are not to be Hematol 1990;34:99-107. construed as official or as reflecting the views of the 14. Snow CF. Laboratory diagnosis of vitamin B12 and U.S. Army Medical Department or the U.S. Army folate deficiency: a guide for the primary care Service at large. physician. Arch Intern Med 1999;159:1289-98. 15. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole REFERENCES therapy causes malabsorption of (vitamin B12). Ann Intern Med 1994;120:211-5. 1. Pennypacker LC, Allen RH, Kelly JP, Matthews LM, 16. Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Grigsby J, Kaye K, et al. High prevalence of cobal- Jensen RT. Effect of long-term gastric acid suppres-

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4. Green R. Screening for vitamin B12 deficiency: Lindenbaum J. Effective treatment of cobalamin caveat emptor [Editorial]. Ann Intern Med 1996; deficiency with oral cobalamin. 1998;92: 124:509-11. 1191-8. 5. Lee GR. Pernicious anemia and other causes of vit- 19. Lederle FA. Oral cobalamin for pernicious anemia.

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