Mona Abraham is a 78-year-old widow who sees you for refill of her arthritis and antihypertensive medications. She recently relocated from another state to be closer to her daughter, although she lives in her own "senior" apartment. Through history taking, you learn that she has a long history of osteoarthritis, mild hypertension requiring medication for the past 5 years, and occasional gastroesophageal reflux. Surgical history includes appendectomy as a teenager, a ventral hernia repair after her last child was born, and right knee arthroscopy about 5 years ago.

Figure. No caption available.

Her medications include triamterene/hydrochlorthiazide 37.5/25 mg daily, acetaminophen 650 mg (2) twice daily, calcium citrate 600 mg/vitamin D 400 international units twice daily, omeprazole 20 mg daily p.r.n for heartburn, and hydrocodone/acetaminophen 5/325 mg every 6h p.r.n. for severe pain. You perform a physical exam, discuss healthy diet and physical activity, order serum electrolytes and creatinine, refill her prescriptions, and advise her to schedule a follow-up appointment in 3 months for preventative screening. You are about to conclude the visit and leave the room when Mrs. Abraham asks if she can get a vitamin B12 shot now. You question her about her need for B12 and Mrs. Abraham states she never knew how her previous primary care provider knew she had a vitamin B12 deficiency, but monthly shots have helped boost her energy over the past year.

Introduction

Vitamin B₁₂ (cobalamin) is the largest and most complex of the B vitamins. It is required for synthesis of DNA used for red blood cells (RBCs), myelin, and other tissues. Deficiency occurs in approximately 5% to 20% of the elderly.1,2 Vitamin B₁₂ is defined as serum cobalamin less than 200 pg/mL (150 pmol/L) on two separate occasions, or one instance of decreased cobalamin with either elevated homocysteine or methylmalonic acid (MMA) in the absence of renal failure or folate or B₆ deficiency.2 It may take many years to develop and may be subclinical or mildly symptomatic, affecting the hematologic, neurologic, and gastrointestinal (GI) systems. The most common cause is food malabsorption, in which enough vitamin B₁₂ is consumed in the diet but not released from carrier proteins and thus not absorbed. Food malabsorption accounts for 60% to 70% of cases, and pernicious anemia, the second most common cause, occurs in 15% to 20% of cases.2 Other causes of malabsorption also occur to a lesser extent, and dietary deficiency of vitamin B₁₂ is rare because of the prevalence of B₁₂ in the diet and availability of fortified foods and supplements.

Many people believe that supplementation of vitamin B₁₂ with or without evidence of deficiency will result in increased energy, improved cognitive status, improved mood, and even weight loss. There are many claims like these on the Internet, and supplements, even injections that can be bought online. The likelihood that a clinician will prescribe vitamin B₁₂ injections without assessing for deficiency rises with the patient's age.3 Although no gold standard exists for determining a precise serum concentration that defines B₁₂ deficiency, additional metabolites have been identified, namely MMA and homocysteine, that can help identify deficiency in cases where serum B₁₂ levels are borderline or normal. Additionally, studies have shown that oral B₁₂ therapy is as effective as I.M. injection in many cases.4

Overview of vitamin B₁₂ absorption

Vitamin B₁₂ and folic acid are required for the synthesis of DNA in many tissues, primarily RBCs. Although deficiency because of dietary deficiency is rare, it often occurs because of inadequate absorption. Multiple steps at multiple locations in the gut are needed for adequate absorption. Vitamin B₁₂ is derived from animal products (meat or dairy). Following ingestion, vitamin B₁₂/animal protein bonds are severed in the presence of gastric secretions (see Absorption of vitamin B12).

The vitamin B₁₂ combines with R proteins from salivary and gastric sections. Intrinsic factor is secreted by parietal cells in the gastric fundus but binding to B₁₂ is weak in the presence of B₁₂/R protein complexes. Intrinsic factor and B₁₂/R protein complexes travel to the duodenum and are joined by biliary B₁₂/R protein complexes. Both types of B₁₂ complexes are now easily degraded by pancreatic enzymes, releasing free cobalamin. Here instrinsic factor binds with cobalamin and these complexes travel to the distal ileum for absorption. Absorption occurs through attachment to mucosal cell receptors and binding to transport proteins known as transcobalamin I, II, and III.5

Vitamin B₁₂ deficiency can develop from decreased intake or absorption (see Causes of vitamin B12 deficiency). Decreased intake may result from strict vegetarian diet, very limited oral intake, or chronic malnutrition. Decreased absorption may result from lack of unbinding of vitamin B₁₂ from protein in food sources; lack of intrinsic factor from the stomach as in cases of total or partial gastrectomy, gastric bypass surgery, or autoimmune gastric atrophy, known as pernicious anemia. Decreased absorption also results from surgery or disease of the ileum such as Crohn's disease. Certain drugs can also interfere with unbinding and absorption. Fortunately, B₁₂ stores in the liver are significant; therefore, manifestations of deficiency may not become apparent for 5 to 10 years.2

RBCs formed in a state of B₁₂ or folic acid deficiency are structurally abnormal. Increased numbers of myeloid precursor cells are produced in the bone marrow, but they are large and bizarre in appearance. Many become trapped in the bone marrow and are destroyed, so there are actually fewer mature cells that enter the blood stream from the myeloid line (RBC, platelet, nonlymphoid white blood cells). Pancytopenia may occur, and because the RBCs are large, megaloblastic anemia is the prominent feature. Since RBCs have flimsy membranes and are oddly shaped, their life span is short. Folic acid deficiency also causes megaloblastic anemia, and it develops much more quickly than with B₁₂ deficiency, because the body stores very little folic acid.

Manifestations of B₁₂ deficiency

Megaloblastic anemia is the most common feature of vitamin B₁₂ deficiency. Signs of anemia may develop slowly depending on the body's ability to compensate. Signs and symptoms include listlessness, fatigue, dyspnea, and pallor. Prominent lab features are elevated mean corpuscular volume (MCV) of 110 mm³ or greater, reflecting the large RBCs, and varying size and shape of RBCs (aniso-poikilocytosis). Hypersegmented neutrophils (mature neutrophils with more than five distinct lobes) may be seen on peripheral blood smear. Folic acid deficiency causes the same findings, but does not cause the additional neurologic and GI manifestations seen in vitamin B₁₂ deficiency. Neurologic manifestations seen with B₁₂ deficiency may be prominent and irreversible. Abnormal synthesis of myelin protein causes demyelination of the dorsal and lateral columns of the spinal cord. Signs and symptoms include confusion, numbness and paresthesias of the lower extremities, disequilibrium, and loss of position and vibratory sense. GI manifestations seen with B₁₂ deficiency are smooth, sore, red tongue, and mild diarrhea. Symptoms may wax and wane for many years, with partial remission occurring when any vitamin B₁₂ is replaced, but in severe cases death due to heart failure secondary to anemia is possible.

Identifying deficiency

Vitamin B₁₂ deficiency is often identified through megaloblastic anemia with decreased RBC count, hematocrit, and hemoglobin, as well as elevated MCV and anisopoikilocytosis. Once megaloblastic anemia is identified, deficiency of folic acid or vitamin B₁₂ should be suspected. Folic acid level should be checked, however, even a small amount recently ingested may falsely increase the level, so RBC folate is a more accurate test. Vitamin B₁₂ level should also be checked and will be found to be decreased. It is important to check both vitamin B₁₂ and folate, because if only folate is replaced and vitamin B₁₂ is also deficient, anemia may improve but irreversible neurologic symptoms may develop. Reference ranges for vitamin B₁₂ vary by lab with ranges of 200 to 220 pg/mL identified as the lower limit. A recent study using recommendations from the National Committee for Clinical Laboratory Standards and International Federation of Clinical Chemistry found the central 95% reference interval to be 101 to 666 pg/mL for women and 100 to 699 pg/mL for men.6

A more sensitive early indicator of B₁₂ deficiency is determination of MMA. Increased MMA indicates decreased tissue B₁₂. A patient with neurologic symptoms indicative of deficiency, but normal hematologic studies and serum B₁₂ level, may show significantly increased level of MMA, indicating B₁₂ deficiency.7 Homocysteine levels may also be increased due to a deficiency of B₁₂, folate, or vitamin B₆ because of their role in its metabolism. Hence elevated homocysteine levels may indicate vitamin B₁₂ deficiency.8

Table. Causes of vitamin B

Cause must then be differentiated as deficiency of intrinsic factor, gastric or pancreatic issues with absorption, malabsorption in the ileum, or lack of B₁₂ intake. This can be done through the Schilling test or intrinsic factor blocking antibody test. The antibody test identifies antibodies that prevent vitamin B₁₂ from binding to instrinsic factor. This test is fairly specific, but only has a sensitivity of about 50%, therefore missing about half the patients with pernicious anemia. Another antibody, antigastric parietal cell antibody, has a high sensitivity but is only 50% specific. The combination of low vitamin B₁₂, megaloblastic anemia, and intrinsic factor blocking antibodies is diagnostic for pernicious anemia and the Schilling test is not necessary.7

The Schilling test involves measuring a radioactive tracer in the urine within 24 hours of ingesting radio-labeled vitamin B₁₂ orally. A parenteral dose of B₁₂ is also given to aid in renal excretion. If more than 8% of the radioactive tracer is found in the 24-hour urine sample, then vitamin B₁₂ was absorbed, and the cause is deficient B₁₂ intake.9 Supplementation can be given orally in this case. If no radioactive tracer is found in the 24-hour urine sample, then the oral vitamin B₁₂ remained in the GI tract and the cause may be lack of intrinsic factor or ileal malabsorption. In this case, the test will be repeated, but intrinsic factor is added to the radio-labeled B₁₂. If radioactive tracer is found in the urine, then the B₁₂ was absorbed in the presence of intrinsic factor and the diagnosis is pernicious anemia. No radioactive tracer in the urine means there is malabsorption in the ileum. Supplementation in both cases has traditionally been parenteral.

Serum vitamin B₁₂ level screening is recommended for various populations including the elderly who are malnourished, those living in institutions and psychiatric facilities, those who have had gastric surgery or small bowel surgery or disease, and those who have unexplained neurologic manifestations. Since a number of drugs may interfere with B₁₂ absorption, patients should be checked for deficiency if they have been on long-term metformin or proton pump inhibitor therapy.8 Factors that may cause false vitamin B₁₂ deficiency include pregnancy, mild transcobalamin 1 deficiency, HIV infection, myeloma, folate deficiency, anticonvulsants, and oral contraceptives.

To supplement or not?

Many nutritional experts believe that vitamin B₁₂ supplementation is necessary for older adults. Prevention of deficiency should be considered with a balanced diet that contains animal products (meat or dairy) or food fortified with B vitamins. Many recommend that prevention should include vitamin supplement or fortified foods for older adults, due to many possible causes of malabsorption that occur frequently with age. A recommended daily allowance (RDA) of 2.4 mcg/day can easily be met. One study showed that people who ate fortified cereal more than four times a week appeared to be protected from deficient levels of B₁₂.10

A widespread myth has been that supplementation must be accomplished by I.M. administration when vitamin B₁₂ deficiency exists. Supplementation is effective as oral vitamin supplement or even fortified foods in many cases. Even in pernicious anemia, where there is a total lack of intrinsic factor, passive diffusion of B₁₂ occurs along the small intestine at a rate of about 1%. Therefore, an oral supplement of 1,000 mcg/day will result in 10 mcg by passive diffusion, well above the RDA.5 Other effective means of administration in pernicious anemia include 1,000 mcg cyanocobalamin I.M. or as a nasal gel formulation, cyanocobalamin low viscosity aqueous formulation (Nascobal), both by prescription. While I.M. is often the preferred clinical practice, oral administration is considered to be as effective.11

Oral supplementation is the preferred method of treatment for other causes of deficiency due to malabsorption. Many practitioners, however, give I.M. therapy, perhaps because they are concerned about missing a diagnosis of pernicious anemia, or because they fear the development of neurologic symptoms if they do not replace vitamin B fast enough. Several protocols have been suggested. To treat deficiency symptoms and build up B₁₂ stores quickly, parenteral injection of 100 to 1,000 mcg/day is given for 1 week, then 1,000 mcg /week for 1 month.

Maintenance therapy may be given at a dose up to 1,000 mcg/month until the cause of deficiency is corrected, or for life. Oral management of deficiency consists of 1,000 mcg/day for 1 month, then 125 to 500 mcg daily for food malabsorption, and 1,000 mcg/day for pernicious anemia.2

Are there other benefits of vitamin B₁₂?

A common belief by patients seeking B₁₂ injections is that it will help relieve fatigue. There have been only a few small controlled studies to evaluate the effect of vitamin B₁₂ on fatigue and they do not support the claim that vitamin B₁₂ therapy will improve fatigue.12 One study of crossover design of 29 subjects showed that the treatment group rated general well-being and happiness over the placebo group, but there was no statistically significant difference in rating fatigue.13 Another study of 15 patients with chronic fatigue syndrome tested an I.M. injection of bovine liver extract, folic acid, and cyanocobalamin against placebo. There was no significant difference between the groups.14

Vitamin B₁₂ deficiency and elevated homocysteine have been associated with greater risk for dementia and Alzheimer's disease compared with normal levels.5,15-17 A Cochrane Review sought to assess previously published clinical trials for the effect of vitamin B₁₂ supplementation on cognitive function later in life. In pooled data from three available studies of people with Alzheimer's disease or other cognitive impairment and low serum vitamin B₁₂, the review found no evidence that vitamin B₁₂ supplementation improves cognitive function.18 There was difficulty in pooling results of clinical trials, however, because of a variety of measurement scales and uncertainty about diagnostic criteria used for vitamin B₁₂ deficiency. A recently published prospective study of 107 community-dwelling elderly with no cognitive impairment at baseline examined the relationship between vitamin B₁₂ status and brain-volume loss over a 5-year period.19 Decrease in brain volume was greater among those with lower B₁₂ and higher homocysteine and MMA at baseline.

The relationship between folic acid supplementation and lowered risk of neural tube defects has been well documented. The role of vitamin B₁₂ and neural tube defects is less clear. A large Canadian cohort study assessed bioavailable B₁₂ status (MMA and holotranscobalamin levels) and risk of neural tube defects.20 A three-fold increase in the risk of neural tube defects was found in mothers whose B₁₂ status was in the lowest quartile, regardless of folic acid status.

Homocysteine is an independent risk factor for coronary heart disease and stroke. Folic acid has been shown to provide the greatest decrease in homocysteine; however, trials now show that vitamin B₁₂ supplementation provides additional benefit.21,22 To date, there is no evidence that reducing homocysteine through vitamin supplementation will reduce cardiovascular risk;23 however, clinical trials are ongoing.

Vitamin B₁₂ status may also be related to cancer and depression. Because of the role of vitamin B₁₂ in the methylation of DNA, deficiency may cause an elevated rate of DNA damage, which is a risk factor of cancer.5 Observational studies have shown a relationship between low levels of vitamin B₁₂ and breast cancer,24-26 but cause has not been established. Likewise, several observational studies have shown the relationship between low levels of vitamin B₁₂ and higher rates of depression,27-29 however, a causal role has not yet been determined.

Take the time to educate

Vitamin B₁₂ is an important vitamin for hematologic, neurologic, and GI health. Deficiency most often occurs among the elderly and is usually the result of food malabsorption. Oral supplementation may be indicated; however, I.M. replacement therapy is most often instituted for pernicious anemia and symptomatic or severely deficient individuals. There is no evidence that supplementation is needed in individuals who are not deficient through measurement of serum B₁₂, MMA, and homocysteine levels; however, preventing deficiency through fortified foods or oral preparations has been recommended for the elderly and other groups. There is very low potential for toxicity with vitamin B₁₂, and therefore is safe to use in all populations.³⁰

Mrs. Abraham, the patient presented in the case scenario, should be checked for vitamin B₁₂ status. The NP should do a review of systems to determine any general, neurologic, GI, or hematologic symptoms that may be associated with deficiency. Blood work should include a complete blood cell count, serum and RBC folate, and serum vitamin B₁₂ level. If there is still a question of deficiency, MMA and homocysteine may be ordered. If there is no indication of pernicious anemia, oral supplementation will likely be acceptable.

Education about vitamin intake is an important task that often gets overlooked in busy clinical practice. Many patients, especially the elderly, have risk factors for vitamin deficiency. Others may have questions about their diet and supplements they are interested in taking. A wellness visit is the ideal time to include vitamin B₁₂ education, especially for those with risk factors for developing deficiency.

REFERENCES