A new look at vitaminB

18 The Nurse Practitioner • Vol. 34, No. 11 www.tnpj.com 2.5 CONTACT HOURS 12 deficiency

By Sandra M. Nettina, APRN-BC, ANP, MSN

ona Abraham is a 78-year-old widow who sees you for refill of her arthritis and antihypertensive med- M ications. She recently relocated from another state to be closer to her daughter, although she lives in her own “se- nior” apartment. Through history taking, you learn that she has a long history of osteoarthritis, mild hypertension requir- ing medication for the past 5 years, and occasional gastroe- sophageal reflux. Surgical history includes as a teenager, a ventral repair after her last child was born, and right knee arthroscopy about 5 years ago. Her medications include triamterene/hydrochlorthiazide 37.5/25 mg daily, acetaminophen 650 mg (2) twice daily , cal- cium citrate 600 mg/vitamin D 400 international units twice daily, omeprazole 20 mg daily p.r.n for heartburn, and hy- drocodone/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 ap- pointment in 3 months for preventative screening. You are about to conclude the visit and leave the room when Mrs. Abra-

ham 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

, 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

www.tnpj.com The Nurse Practitioner • November 2009 19 A new look at vitamin B12 deficiency

occurs in approximately 5% to 20% of the elderly.1,2 Vita- with the patient’s age.3 Although no gold standard exists

min B12 is defined as serum cobalamin less than 200 pg/mL for determining a precise serum concentration that defines

(150 pmol/L) on two separate occasions, or one instance of B12 deficiency, additional metabolites have been identified, decreased cobalamin with either elevated homocysteine or namely MMA and homocysteine, that can help identify

methylmalonic acid (MMA) in the absence of renal failure deficiency in cases where serum B12 levels are borderline 2 or folate or B6 deficiency. It may take many years to develop or normal. Additionally, studies have shown that oral B12 and may be subclinical or mildly symptomatic, affecting the therapy is as effective as I.M. injection in many cases.4 hematologic, neurologic, and gastrointestinal (GI) systems. ■ The most common cause is food , in which Overview of vitamin B12 absorption

enough vitamin B12 is consumed in the diet but not released Vitamin B12 and folic acid are required for the synthesis of from carrier proteins and thus not absorbed. Food malab- DNA in many tissues, primarily RBCs. Although deficiency sorption accounts for 60% to 70% of cases, and pernicious because of dietary deficiency is rare, it often occurs because anemia, the second most common cause, occurs in 15% to of inadequate absorption. Multiple steps at multiple loca- 20% of cases.2 Other causes of malabsorption also occur to tions in the gut are needed for adequate absorption. Vita-

a lesser extent, and dietary deficiency of vitamin B12 is rare min B12 is derived from animal products (meat or dairy).

because of the prevalence of B12 in the diet and availability Following ingestion, vitamin B12/animal protein bonds are of fortified foods and supplements. severed in the presence of gastric secretions (see Absorption

Many people believe that supplementation of vitamin of vitamin B12 ).

B12 with or without evidence of deficiency will result in The vitamin B12 combines with R proteins from salivary increased energy, improved cognitive status, improved mood, and gastric sections. is secreted by parietal

and even weight loss. There are many claims like these on the cells in the gastric fundus but binding to B12 is weak in the

Internet, and supplements, even injections that can be bought presence of B12/R protein complexes. Intrinsic factor and

online. The likelihood that a clinician will prescribe vita- B12/R protein complexes travel to the duodenum and are

min B12 injections without assessing for deficiency rises 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

Absorption of vitamin B12 cobalamin and these complexes travel to the distal ileum for absorption. Absorption occurs through attachment to mucosal cell receptors and binding to transport proteins Dietary vitamin B12 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 B12 limited oral intake, or chronic malnutrition. Decreased ab-

sorption 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 , gas- Parietal cell tric bypass surgery, or autoimmune gastric atrophy, known Intrinsic factor (IF) as pernicious anemia. Decreased absorption also results from surgery or disease of the ileum such as Crohn’s disease. Cer- tain drugs can also interfere with unbinding and absorption. B /IF Ileum Portal Fortunately, B stores in the are significant; therefore, 12 vein 12 complexes manifestations of deficiency may not become apparent for Epithelial cell 5 to 10 years.2 with IF receptor RBCs formed in a state of B12 or folic acid deficiency are structurally abnormal. Increased numbers of myeloid

B 12 / transcobalamin II precursor cells are produced in the bone marrow, but they complex are large and bizarre in appearance. Many become trapped Source: Porth CM, Matfin, G. Pathophysiology Concepts of Altered Health in the bone marrow and are destroyed, so there are actually States. 8th ed. Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams fewer mature cells that enter the blood stream from the & Wilkins, 2009:291. myeloid line (RBC, platelet, nonlymphoid white blood

20 The Nurse Practitioner • Vol. 34, No. 11 www.tnpj.com A new look at vitamin B12 deficiency

cells). Pancytopenia may occur, and be- cause the RBCs are large, megaloblastic Causes of vitamin B12 deficiency anemia is the prominent feature. Since RBCs have flimsy membranes and are Pathophysiology Condition oddly shaped, their life span is short. Folic Nutritional deficiency of B • Malnutrition acid deficiency also causes megaloblas- 12 • Alcohol abuse tic anemia, and it develops much more • Institutionalization quickly than with B12 deficiency, because • Strict vegan diet the body stores very little folic acid. Lack of intrinsic factor • Pernicious anemia (autoimmune gastric atrophy) ■ Manifestations of B12 deficiency • Total and partial gastrectomy is the most com- Food-bound B12 malabsorption • Atrophic gastritis of aging or chronic mon feature of vitamin B12 deficiency. alcohol abuse Signs of anemia may develop slowly • Chronic Helicobacter pylori infection depending on the body’s ability to com- • Long-term use of metformin pensate. Signs and symptoms include • Reduced acid environment through listlessness, fatigue, dyspnea, and pallor. long-term use of histamine-2 receptor antagonists and proton pump inhibitors Prominent lab features are elevated mean corpuscular volume (MCV) of 110 mm3 Pancreatic exocrine failure • Chronic pancreatitis, or greater, reflecting the large RBCs, and Small intestinal malabsorption • Crohn’s disease, lymphoma, through damage to last 80 cm tuberculosis, amyloidosis, varying size and shape of RBCs (aniso - of ileum scleroderma, Whipple’s disease, celiac poikilocytosis). Hypersegmented neu- disease, chronic ingestion of colchicine trophils (mature neutrophils with more or cholestyramine, ileal resection than five distinct lobes) may be seen on Genetic deficiency of transport • Imerslund-Grasbeck syndrome peripheral blood smear. Folic acid defi- proteins • Transcobalamin II deficiency ciency causes the same findings, but does not cause the additional neurologic and GI manifestations and vitamin B12 is also deficient, anemia may improve but seen in vitamin B12 deficiency. Neurologic manifestations irreversible neurologic symptoms may develop. Reference seen with B12 deficiency may be prominent and irreversible. ranges for vitamin B12 vary by lab with ranges of 200 to Abnormal synthesis of myelin protein causes demyelination 220 pg/mL identified as the lower limit. A recent study of the dorsal and lateral columns of the spinal cord. Signs using recommendations from the National Committee and symptoms include confusion, numbness and paresthe- for Clinical Laboratory Standards and International Feder- sias of the lower extremities, disequilibrium, and loss of po- ation of Clinical Chemistry found the central 95% reference sition and vibratory sense. GI manifestations seen with B12 interval to be 101 to 666 pg/mL for women and 100 to deficiency are smooth, sore, red tongue, and mild diarrhea. 699 pg/mL for men.6

Symptoms may wax and wane for many years, with partial A more sensitive early indicator of B12 deficiency is remission occurring when any vitamin B12 is replaced, determination of MMA. Increased MMA indicates de- but in severe cases death due to heart failure secondary to creased tissue B12. A patient with neurologic symptoms anemia is possible. indicative of deficiency, but normal hematologic studies and

serum B12 level, may show significantly increased level of ■ 7 Identifying deficiency MMA, indicating B12 deficiency. Homocysteine levels

Vitamin B12 deficiency is often identified through mega- may also be increased due to a deficiency of B12, folate, loblastic anemia with decreased RBC count, hematocrit, and or vitamin B6 because of their role in its metabolism. hemoglobin, as well as elevated MCV and anisopoikilocyto- Hence elevated homocysteine levels may indicate vitamin 8 sis. Once megaloblastic anemia is identified, deficiency of B12 deficiency. folic acid or vitamin B12 should be suspected. Folic acid level Cause must then be differentiated as deficiency of in- should be checked, however, even a small amount recently trinsic factor, gastric or pancreatic issues with absorption, ingested may falsely increase the level, so RBC folate is a malabsorption in the ileum, or lack of B12 intake. This can more accurate test. Vitamin B12 level should also be checked be done through the Schilling test or intrinsic factor block- and will be found to be decreased. It is important to check ing antibody test. The antibody test identifies antibodies both vitamin B12 and folate, because if only folate is replaced that prevent vitamin B12 from binding to instrinsic factor. www.tnpj.com The Nurse Practitioner • November 2009 21 A new look at vitamin B12 deficiency

This test is fairly specific, but only has a sensitivity of with B vitamins. Many recommend that prevention should about 50%, therefore missing about half the patients include vitamin supplement or fortified foods for older with pernicious anemia. Another antibody, antigastric adults, due to many possible causes of malabsorption parietal cell antibody, has a high sensitivity but is only that occur frequently with age. A recommended daily

50% specific. The combination of low vitamin B12, mega- allowance (RDA) of 2.4 mcg/day can easily be met. One loblastic anemia, and intrinsic factor blocking antibodies study showed that people who ate fortified cereal more is diagnostic for pernicious anemia and the Schilling test than four times a week appeared to be protected from 7 10 is not necessary. deficient levels of B12. The Schilling test involves measuring a radioactive A widespread myth has been that supplementation must

tracer in the urine within 24 hours of ingesting radio-labeled be accomplished by I.M. administration when vitamin B12

vitamin B12 orally. A parenteral dose of B12 is also given to deficiency exists. Supplementation is effective as oral vita- aid in renal excretion. If more than 8% of the radioactive min supplement or even fortified foods in many cases. Even tracer is found in the 24-hour urine sample, then vitamin in pernicious anemia, where there is a total lack of intrinsic 9 B12 was absorbed, and the cause is deficient B12 intake. Sup- factor, passive diffusion of B12 occurs along the small intes- plementation can be given orally in this case. If no radioac- tine at a rate of about 1%. Therefore, an oral supplement of tive tracer is found in the 24-hour urine sample, then the 1,000 mcg/day will result in 10 mcg by passive diffusion, well 5 oral vitamin B12 remained in the GI tract and the cause may above the RDA. Other effective means of administration in be lack of intrinsic factor or ileal malabsorption. In this case, pernicious anemia include 1,000 mcg I.M. the test will be repeated, but intrinsic factor is added to the or as a nasal gel formulation, cyanocobalamin low viscosity

radio-labeled B12. If radioactive tracer is found in the urine, aqueous formulation (Nascobal), both by prescription. While

then the B12 was absorbed in the presence of intrinsic factor I.M. is often the preferred clinical practice, oral administra- and the diagnosis is pernicious anemia. No radioactive tion is considered to be as effective.11 tracer in the urine means there is malabsorption in the Oral supplementation is the preferred method of treat- ileum. Supplementation in both cases has traditionally ment for other causes of deficiency due to malabsorption. been parenteral. Many practitioners, however, give I.M. therapy, perhaps

Serum vitamin B12 level screening is recommended for because they are concerned about missing a diagnosis of various populations including the elderly who are malnour- 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 Vitamin B12 deficiency and elevated deficiency symptoms and build up B homocysteine have been associated with greater 12 stores quickly, parenteral injection risk for dementia and Alzheimer’s disease. of 100 to 1,000 mcg/day is given for 1 week, then 1,000 mcg /week for 1 month. ished, those living in institutions and psychiatric facilities, Maintenance therapy may be given at a dose up to 1,000 those who have had gastric surgery or small bowel surgery mcg/month until the cause of deficiency is corrected, or for or disease, and those who have unexplained neurologic life. Oral management of deficiency consists of 1,000 mcg/day manifestations. Since a number of drugs may interfere with for 1 month, then 125 to 500 mcg daily for food malabsorp- 2 B12 absorption, patients should be checked for deficiency if tion, and 1,000 mcg/day for pernicious anemia. they have been on long-term metformin or proton pump 8 ■ inhibitor therapy. Factors that may cause false vitamin B12 Are there other benefits of vitamin B12?

deficiency include pregnancy, mild transcobalamin 1 defi- A common belief by patients seeking B12 injections is that ciency, HIV infection, myeloma, folate deficiency, anticon- it will help relieve fatigue. There have been only a few vulsants, and oral contraceptives. small controlled studies to evaluate the effect of vitamin

B12 on fatigue and they do not support the claim that vita- ■ 12 To supplement or not? min B12 therapy will improve fatigue. One study of

Many nutritional experts believe that vitamin B12 supple- crossover design of 29 subjects showed that the treatment mentation is necessary for older adults. Prevention of de- group rated general well-being and happiness over the ficiency should be considered with a balanced diet that placebo group, but there was no statistically significant contains animal products (meat or dairy) or food fortified difference in rating fatigue.13 Another study of 15 patients

22 The Nurse Practitioner • Vol. 34, No. 11 www.tnpj.com A new look at vitamin B12 deficiency

with chronic fatigue syndrome tested an I.M. injection of ■ Take the time to educate bovine liver extract, folic acid, and cyanocobalamin against Vitamin B12 is an important vitamin for hematologic, neu- placebo. There was no significant difference between the rologic, and GI health. Deficiency most often occurs among groups.14 the elderly and is usually the result of food malabsorption.

Vitamin B12 deficiency and elevated homocysteine Oral supplementation may be indicated; however, I.M. re- have been associated with greater risk for dementia and placement therapy is most often instituted for pernicious Alzheimer’s disease compared with normal levels.5,15-17 A Cochrane Review sought to assess previously published Serum vitamin B12 level screening is clinical trials for the effect of vitamin recommended for various populations, B12 supplementation on cognitive function later in life. In pooled data including the elderly. from three available studies of people with Alzheimer’s disease or other cog- nitive impairment and low serum vitamin B12, the review anemia and symptomatic or severely deficient individuals. found no evidence that vitamin B12 supplementation im- There is no evidence that supplementation is needed in in- proves cognitive function.18 There was difficulty in pool- dividuals who are not deficient through measurement of ing results of clinical trials, however, because of a variety of serum B12, MMA, and homocysteine levels; however, pre- measurement scales and uncertainty about diagnostic cri- venting deficiency through fortified foods or oral prepa- teria used for vitamin B12 deficiency. A recently published rations has been recommended for the elderly and other prospective study of 107 community-dwelling elderly with groups. There is very low potential for toxicity with vita- 30 no cognitive impairment at baseline examined the relation- min B12, and therefore is safe to use in all populations. ship between vitamin B12 status and brain-volume loss over Mrs. Abraham, the patient presented in the case sce- 19 a 5-year period. Decrease in brain volume was greater nario, should be checked for vitamin B12 status. The NP among those with lower B12 and higher homocysteine and should do a review of systems to determine any general, neu- MMA at baseline. rologic, GI, or hematologic symptoms that may be associ- The relationship between folic acid supplementation ated with deficiency. Blood work should include a complete and lowered risk of neural tube defects has been well docu- blood cell count, serum and RBC folate, and serum vitamin mented. The role of vitamin B12 and neural tube defects is B12 level. If there is still a question of deficiency, MMA and less clear. A large Canadian cohort study assessed bioavail- homocysteine may be ordered. If there is no indication of able B12 status (MMA and holotranscobalamin levels) and pernicious anemia, oral supplementation will likely be ac- risk of neural tube defects.20 A three-fold increase in the risk ceptable. of neural tube defects was found in mothers whose B12 sta- Education about vitamin intake is an important task tus was in the lowest quartile, regardless of folic acid status. that often gets overlooked in busy clinical practice. Many Homocysteine is an independent risk factor for coro- patients, especially the elderly, have risk factors for vitamin nary heart disease and stroke. Folic acid has been shown to deficiency. Others may have questions about their diet and provide the greatest decrease in homocysteine; however, tri- supplements they are interested in taking. A wellness visit is als now show that vitamin B12 supplementation provides ad- the ideal time to include vitamin B12 education, especially ditional benefit.21,22 To date, there is no evidence that reducing for those with risk factors for developing deficiency. homocysteine through vitamin supplementation will reduce cardiovascular risk;23 however, clinical trials are ongoing. REFERENCES

1. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. Vitamin B12 status may also be related to cancer and 1999;19:357-377. depression. Because of the role of vitamin B12 in the methy- 2. Andres E, Loukili NH, Noel E, et al. Vitamin B12 (cobalamin) deficiency in lation of DNA, deficiency may cause an elevated rate of elderly patients. CMAJ. 2004;171(3):251-259. 3. Van Walraven CG, Naylor CD. Use of vitamin B injections among elderly 5 12 DNA damage, which is a risk factor of cancer. Observational patients by primary practitioners in Ontario. CMAJ. 1999;161:146-149. studies have shown a relationship between low levels of 4. Dali-Youcef N, Andres E. An update on cobalamin deficiency in adults. QJM. 24-26 2009;102(1):17-28. vitamin B12 and breast cancer, but cause has not been 5. Higdon J. Vitamin B12. Linus Pauling Institute. Micronutrient Information established. Likewise, several observational studies have Center. Updated August 2007. http://lpi.oregonstate.edu/infocenter/vitamins/ shown the relationship between low levels of vitamin B and vitaminB12/index.html. 12 6. Tanyalcin T, Aslan D, Kurtulmus Y, Gökalp N, Kumanlioˇglu K. Reference in- 27-29 higher rates of depression, however, a causal role has not tervals of serum folate and vitamin B12 developed from data of healthy sub- yet been determined. jects. J Qual Comparability Reliability Clin Meas. 2000;5(9):383-387. www.tnpj.com The Nurse Practitioner • November 2009 23 A new look at vitamin B12 deficiency

7. Laboratory Corporation of America. Directory of Services & Interpretive Guide. 21. Homocysteine Lowering Trialists’ Collaboration. Lowering blood homo- Hudson, OH: Lexi-Comp, Inc; 2009. cysteine with folic acid based supplements: meta-analysis of randomized 8. National Institutes of Health Office of Dietary Supplements. Dietary sup- trials. Homocysteine Lowering Trialists’ Collaboration. BMJ. 1998; 316(7135):894-898. plement fact sheet: vitamin B12. http://dietary-supplements.info.nih.gov/ factsheets/vitaminb12.asp. 22. McKay DL, Perrone G, Rasmussen H, Dallal G, Blumberg JB. Multivita- 9. Fischbach F, Dunning M. A Manual of Laboratory & Diagnostic Tests. 8th ed. min/mineral supplementation improves plasma B-vitamin status and homo- Philadelphia, PA: Lippincott, Williams & Wilkins; 2008. cysteine concentration in healthy older adults consuming a folate-fortified diet. J Nutr. 2000;130:3090-3096. 10. Tucker KL, Rich S, Rosenberg I, et al. Plasma vitamin B12 concentrations re- late to intake source in the Framingham Offspring Study. Am J Clin Nutr. 23. Clarke R , Lewington S, Sherliker P, Armitage J. Effects of B-vitamins on 2000;71:514-22. plasma homocysteine concentrations and on risk of cardiovascular disease and dementia. Curr Opin Clin Nutr Metab Care. 2007; 10(1): 32-39. 11. Vidal-Alaball J, Butler CC, Cannings-John R, et al. Oral vitamin B versus 12 24. Lajous M, Lazcano-Ponce E, Hernandez-Avila M, Willett W, Romieu I. intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. 2005;(3):CD004655. Folate, vitamin B(6), and vitamin B(12) intake and the risk of breast cancer among Mexican women. Cancer Epidemiol Biomarkers Prev. 2006;15 12. Sease JM. Does vitamin B relieve fatigue? Med Pharm. 2009. www. med- 12 (3):443-448. scape.com/viewarticle//585589. 25. Shrubsole MJ, Jin F, Dai Q , et al. Dietary folate intake and breast cancer 13. Ellis FR, Nasser S. A pilot study of vitamin B in the treatment of tiredness. 12 risk: results from the Shanghai Breast Cancer Study. Cancer Res. 2001;61(19): Br J Nutr. 1973;30:277-283. 7136-7141. 14. Kaslow JE, Rucker L, Onishi R. Liver extract-folic acid-cyanocobalamin vs 26. Lajous M, Romieu I, Sabia S, Boutron-Ruault MC, Clavel-Chapelon F. Fo- placebo for chronic fatigue syndrome. Arch Intern Med. 1989;149:2501-2503. late, vitamin B12 and postmenopausal breast cancer in a prospective study of 15. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, French women. Cancer Causes Control. 2006;17(9):1209-1213. vitamin B , and serum total homocysteine levels in confirmed Alzheimer 12 27. Hutto BR. Folate and cobalamin in psychiatric illness. Comparative Psychia- disease. Arch Neurol. 1998;55(11):1449-1455. try. 1997; 38(6):305-314. 16. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin 28. Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vita- B(12) and folate in relation to the development of Alzheimer’s disease. min B(12) deficiency and depression in physically disabled older women: Neurology. 2001;56(9):1188-1194. epidemiologic evidence from the Women’s Health and Aging Study. Am J of 17. Seshardi S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for Psychiatry. 2000.;157(5):715-721. dementia and Alzheimer’s disease. N Engl J Med. 2002;346(7):476-483. 29. Tiemeier H, van Tuijl HR, Hofman A, Meijer J, Kiliaan AJ, Breteler MM. 18. Malouf R, Areosa Sastre A. Vitamin B for cognition. Cochrane Database Syst 12 Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Rev. 2003; (3): CD004394. Am J of Psychiatry. 2002;159(12):2099-2101. 19. Vogiatzoglou A, Refsum H, Johnston C, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology. 2008;71 The author has disclosed she has no financial relationship related to this article. (11):826-832.

20. Thompson MD, Cole DE, Ray JG. Vitamin B12 and neural tube defects: the Sandra M. Nettina is a nurse practitioner at Columbia Medical Practice, Canadian experience. Am J Clin Nutr. 2009;89(2):697S-701S. Columbia, Md.

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