Vitamin B12 Deficiency: Serious Consequences
Recognizing vitamin B12 (cobalamin) deficiencies in patients early on is key.
Recognizing vitamin B12 (cobalamin) deficiencies in patients early on is key.
Cobalamin (vitamin B12) deficiency has been largely ignored for many decades by physicians and members of the health care team. So, exactly how many patients have an undiagnosed B12 deficiency in the United States today and why should pharmacists take note?
Current literature reports that B12 deficiency strikes 16% of the population, or 48 million Americans.1 Others report the prevalence to be as high as 25%.2 The Framingham Offspring Study found that nearly 40% of people aged 26 to 83 years had B12 levels in the “low normal” range—a level at which many begin experiencing neurological symptoms. This is problematic because low B12 causes an array of neurologic and psychiatric manifestations. B12 deficiency has been severely underplayed in health care and largely ignored in favor of more recognized and more expensive-to-treat diagnoses. This has resulted in both substandard care and malpractice, costing millions of individuals their health and wasting billions of health care dollars.
Early Diagnosis and Treatment Are Critical
B12 deficiency strikes all ages, races, economic classes, and both sexes. It is arguably the most common nutritional deficiency causing injury in the United States. Early diagnosis and treatment is critical to prevent neurologic injury, disability, poor outcomes, and premature death. B12 deficiency causes demyelinating nervous system disease, dementia, psychiatric illness, anemia, vascular occlusions, fall-related trauma, suppressed immune system, and bone marrow failure.3
Vitamin B12 is a water-soluable vitamin synthesized by microorganisms and detected in trace amounts in foods of animal origin.4 It is crucial for DNA synthesis, methylation, folate metabolism, erythropoiesis, neurodevelopment, and nervous system function. B12 functions as a cofactor for methionine synthase and L-methylmalonyl-CoA mutase. A deficiency thereby causes elevated homocysteine and methylmalonic acid. Uptake depends on gastric parietal cells excreting hydrochloric acid, intrinsic factor, and pepsin. Pancreatic enzymes and receptors in the distal ileum must be present along with the blood protein transcobalamin II to process B12. Lastly, the liver converts B12 to the active forms adenosylcobalamin and methylcobalamin for utililzation.5,6
Because B12 must follow a complex pathway of several steps for proper absorption and assimilation, there are numerous causes of deficiency. These include malabsorption syndromes, autoimmune disease, diet, drugs, chemotherapy, radiation, eating disorders, Helicobacter pylori, gastrointestinal surgeries, nitrous oxide, hepatic disease, and genetic defects. Other groups at risk include vegans, vegetarians, alcoholics, and individuals with Crohn’s disease, small bowel bacterial overgrowth, celiac disease, gastric bypass, and AIDS.7,8
Up to 30% of older adults have atrophic gastritis with hypochlorhydria inhibiting the release dietary protein-bound B12 causing deficiency.9-12 Similarly, chronic use of drugs that decrease gastric acid, such as proton pump inhibitors, H2-blockers, and antacids will cause low B12.13-17 Medications such as metformin, colchicine, potassium, cholestyramine, neomycin, chloramphenicol, and para-aminosalicylic acid also interfere with B12 absorption.18-20
Untreated B12 deficiency can cause vascular disease, including stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis, because this deficiency causes hyperhomocystinemia. B12 is the cofactor for the conversion of homocysteine into methionine. Excess homocysteine causes blood vessels to lose their elasticity, making it harder for them to dilate and damaging their inner lining. That damage, in turn, allows cholesterol, collagen, and calcium to build up, causing plaque formation.21-27
The short- and long-term ramifications are enormous. Untreated B12 deficiency causes balance problems, paresthesias, weakness, dizziness, postural hypotension, and visual disturbances. These symptoms dramatically increase the risk of falls, which, in turn, lead to trauma (ie, fractures, subdural hematomas), hospital stays, loss of independence, nursing home placement, and premature death.
The B12 Deficiency Epidemic
The B12 deficiency epidemic is frustrating because well-educated health care providers overlook such an easily diagnosed and inexpensively treated condition. Not only does B12 deficiency cause severe neurologic disease, but it also causes chronic anemia, which contrary to popular belief is frequently not macrocytic.28 Often, prescription drugs such as epoetin alfa (Procrit and Epogen) are prescribed. Untreated B12 deficiency can cause hypercellular and dysplastic bone marrow, which can be mistaken for signs of acute leukemia.
In the emergency department (ED), we routinely diagnose B12 deficiency in patients presenting with generalized weakness, anemia, shortness of breath, neuropathy, difficulty ambulating, mental status changes, mental illness, and fall-related trauma. Diagnosing B12 deficiency in the ED indicates that these patients’ primary care physicians and other specialists failed to include B12 deficiency in the differential diagnosis of their complaints or perhaps blamed their conditions on “normal aging.”
Many people of all ages suffering from severe anxiety, depression, and a host of other psychiatric disorders are prescribed dangerous and costly psychotropic drugs, narcotics, or benzodiazepines when the underlying problem actually may be B12 deficiency.29-35
Similarly, children diagnosed on the autism spectrum and prescribed psychiatric medications may have behavioral and neurologic manifestations because of low B12. Developmental delay and mental retardation caused by B12 deficiency is well documented.36-40 Infants often become B12 deficient because of their mother’s undiagnosed B deficiency during pregnancy and breast-feeding.
Every pharmacist needs to be aware of the neurologic consequence of B12 deficiency and how it can masquerade as mental illness, multiple sclerosis, Parkinson’s, dementia/Alzheimer’s, seizure disorders, autism, and other neurological disorders.41-47
If your patient has a B12 deficiency, injectable hydroxocobalamin is the most dependable medication, especially if neurologic symptoms are present. Hydroxocobalamin should replace cyanocobalamin injections because of improved retention, greater availability to cells, and no need for decyanation. Largely unknown, hydroxocobalamin does not cost more than cyanocobalamin, and it is readily available in the United States (distributed by Watson Pharmaceuticals, Inc). Hydroxocobalamin is the form used in infants and children with inborn errors of B12 metabolism and is the preferred form for use in smokers and patients with hepatic and renal disorders.48-51
High-dose, sublingual, or MicroLingual B12 tablets (2000 mcg or greater) are the next best alternative and are an effective approach for some patients. Compressed tablets and capsules contain many binders and fillers, making proper absorption difficult.
The Centers for Medicare & Medicaid Services is taking several actions to improve the quality of care in hospitals and reduce the number of “never events”—preventable medical errors that result in serious consequences for the patient. Undiagnosed and untreated B12 deficiency is an unrecognized preventable medical error that needs to be addressed and eliminated. Pharmacists are vital members of the health care team and are needed to spread B12 awareness to both patients and physicians.
Sally Pacholok has been researching cobalamin (vitamin B12) deficiency and practicing emergency nursing for 26 years. She is a frequent radio guest on nationally syndicated talk shows, lecturer, media personality, and co-author of Could It Be B12? An Epidemic of Misdiagnoses (2nd edition, 2011)—the winner of the Indie Excellence Award for best health book. Could It Be B12? has been translated into Dutch and Slovenian, and is now being published in India as well. Pacholok’s book was made into a documentary in 2012, and a screenplay has been completed to be made into a movie regarding Pacholok’s lifelong battle to improve the country’s health care system and expose substandard care. Pacholok is working with other countries to improve early diagnosis and treatment worldwide. She aspires to get September designated as B12 Awareness Month. Pacholok is also an educator and public speaker for Superior Source Vitamins. Visit www.B12Awareness.org.
- Allen LH. How common is vitamin B12 deficiency? Am J Clin Nutr. 2009;89(2):693S- 696S.
- Dharmarajan TS, Norkus EP. Approaches to vitamin B12 deficiency: early treatment may prevent devastating complications. Postgrad Med. 2001;110(1): 99-105.
- Pacholok SM, Stuart JJ. Could It Be B12? An Epidemic of Misdiagnoses. 2nd ed. Chicago, IL: Quill Driver Books—Linden Publishing; 2011.
- Herbert V, Das K. Vitamin B12 in Modern Nutrition in Health and Disease. 8th ed. Baltimore, MD: Williams & Wilkins; 1994.
- Zittoun J, Zittoun R. Modern clinical testing strategies in cobalamin and folate deficiency. Sem Hematol. 1999;36:35-46.
- Antony AC. Megaloblastic anemias. In: Hoffman R, et al. Hematology: Basic Principles and Practice. 3rd ed. Philadelphia, PA: Churchill Livingstone; 2000.
- Andrès E, Federici L, Affenberger S, et al. B12 deficiency: a look beyond pernicious anemia. J Fam Pract. 2007;56:537-542.
- Healton EB, et al. Neurological aspects of cobalamin deficiency. Medicine. 1991;70:229-244.
- Johnsen R, Bernersen B, Straume B, Førde OH, Bostad L, Burhol PG. Prevalences of endoscopic and histological findings in subjects with and without dyspepsia. Br Med J. 1991;302:749-752.
- Suter PM, Golner BB, Goldin BR, Morrow FD, Russell RM. Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis. Gastroenterology. 1991;101:1039-1045.
- Hurwitz A, Brady DA, Schaal SE, Samloff IM, Dedon J, Ruhl CE. Gastric acidity in older adults. JAMA. 1997;278:659-662.
- Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996;156:1097-1100.
- Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. 2000;30:29-33.
- Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422-428.
- Ruscin JM, Page RL 2nd, Valuck RJ. Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother. 2002;36:812-816.
- den Elzen WF, Groeneveld Y, de Ruijter W, et al. Long-term use of proton pump inhibitors (PPIs) and vitamin B12 status in elderly individuals. Aliment Pharmacol Ther. 2008;27:491-497.
- Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 absorption. Ann Pharmacother. 1992;26:1283-1286.
- de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181.
- Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age Ageing. 2006;35:200-201.
- Buvat DR. Use of metformin is a cause of vitamin B12 deficiency. Am Fam Phys. 2004;69:264.
- Refsum H, Nurk E, Smith AD, et al. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease. J Nutr. 2006;136(6 suppl):1731S-1740S.
- Schulz RJ. Homocysteine as a biomarker for cognitive dysfunction in the elderly. Curr Opin Clin Nutr Metab Care. 2007;10:718-723.
- Lichtenstein AH, Appel LJ, Brands, et al. American Heart Association Nutrition Committee. Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee. Circulation. 2006;114:82-96.
- Malinow MR. Plasma homocyst(e)ine and arterial occlusive diseases: a mini-review. Clin Chem. 1995;41:173-176.
- Selhub J, Jacques PF, Bostom AG, et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med. 1995;332:286-291.
- Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279:359-364.
- Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62.
- Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med 1988;318:1720-1728.
- Catalano G, Catalano MC, O’Dell KJ, Humphrey DA, Fritz EB. The utility of laboratory screening in medically ill patients with psychiatric symptoms. Ann Clin Psychiatry. 2001;13(3):135-140.
- Silver H. Vitamin B12 levels are low in hospitalized psychiatric patients. Israeli J Psychiatry Relat Sci. 2000;37(1):41-45.
- Hermesh H, Weizman A, Shahar A, Munitz H. Vitamin B12 and folic acid serum levels in obsessive compulsive disorder. Acta Psychiatr Scand. 1988;78(1):8-10.
- Hector M, Burton J. What are the psychiatric manifestations of vitamin B12 deficiency? J Am Geriatr Soc. 1988;36:1105-1112.
- Catalano G, Catalano MC, Roenberg EI, Embi PJ, Embi CS. Catatonia: another neuropsychiatric presentation of vitamin B12 deficiency? Psychosomatics. 1998;39(5):456.
- Buchman N, Mendelsson E, Lerner V, Kotler M. Delirium associated with vitamin B12 deficiency after pneumonia. Clin Neuropharmacol. 1999;22(6):356-358.
- Turner MR, Talbot K. Functional vitamin B12 deficiency. Pract Neurol. 2009;9:37-45.
- Castella EB, Valente M, Medeiros de Navarro J, et al. Vitamin B12 deficiency in infancy as a cause of developmental regression. Brain Dev. 2005;27:592-594.
- Honzik T, Adamovicova M, Smolka V, et al. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional vitamin B12 deficiency—what have we learned? Eur J Paediatr Neuro. 2010;14:488-495.
- Muhammad R, Fernhoff P, et al. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin—Georgia, 2001. MMWR Morb Mortal Wkly Rep. 2003;52(4):61-64.
- Graham SM, Arvela OM, Wise GA. Long-term neurologic consequences of nutritional vitamin B12 deficiency in infants. J Pediatr. 1992;121:710-714.
- Pearson HA, Vinson R, Smith RT. Pernicious anemia with neurologic involvement in childhood. J Pediatr. 1964;65:334.
- Kumar S. Vitamin B12 deficiency presenting with an acute reversible extrapyramidal syndrome. Neurol India. 2004;52:507-509.
- Kalita J, Misra UK. Vitamin B12 deficiency neurological syndromes: correlation of clinical, MRI and cognitive evoked potential. J Neurol. 2008;255:353-359.
- Matrana MR, Gauthier C, Lafaye KM. Paralysis and pernicious anemia in a young woman. J La State Med Soc. 2009;161(4):228-232.
- Isajiw G. To peg or not to peg: a case of a hospice referral for vitamin B12 deficiency. The Linacre Quarterly. 2009;76(2):212-217.
- Paul I, Reichard RR. Subacute combined degeneration mimicking traumatic spinal cord injury. Am J Forensic Med Pathol. 2009;30:47-48.
- Svenson J. Case report: neurologic disease and vitamin B12 deficiency. Am J Emerg Med. 2007;25:987.e3-987.e4.
- Kumar S. Recurrent seizures: an unusual manifestation of vitamin B12 deficiency. Neurol India. 2004;52:122-123.
- Kuzminski AM, Del Giacco EJ, Allen RH, Stabler SP, Lindenbaum J. Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 1998;92(4):1191-1198.
- Andrès E. Comment: treatment of vitamin B12 deficiency anemia: oral versus parenteral therapy. Ann Pharmacother. 2002;36:1268-1272.
- Lane LA, Rojas-Fernandez C. Treatment of vitamin B12-deficiency anemia: oral versus parenteral therapy. Ann Pharmacother. 2002;36:1268-1271.
- Hertz H, Kristensen HPØ, Hoff-JØrgensen E. Studies on vitamin B12 retention comparison of retention following intramuscular injection of cyanocobalamin and hydroxocobalamin. Scand J Haematol. 1964;1:5-15. doi: 10.1111/j.1600-0609.1964.tb00001.x.