Why Vitamin B12 Deficiency Should Be on Your Radar Screen A Continuing Education Update Course WB1349 Prepared for the National Center on Birth Defects and Developmental Disabilities Centers for Disease Control and Prevention by Marian L. Evatt, MD1 Patricia W. Mersereau, MN, CPNP2 Janet Kay Bobo, PhD3 Joel Kimmons, PhD4 Jennifer Williams, MSN, MPH, FNP-BC5 The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention. 1 Department of Neurology, Emory University, Atlanta, Georgia. SciMetrika, LLC, Atlanta, Georgia. 3 Battelle Centers for Public Health Research and Evaluation, Atlanta, GA and Seattle, Washington. 4 National Center for Chronic Disease Prevention and Health Promotion, CDC, Atlanta, Georgia. 5 National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia. 2 i Vitamin B12 Deficiency Contents Goal and Objectives .................................................................................1 Accreditation ...........................................................................................2 Introduction ............................................................................................3 Case Studies ............................................................................................6 Natural History and Prevalence of Vitamin B12 Deficiency......................14 Risk Factors for Vitamin B12 Deficiency ..................................................20 Manifestations of Low Vitamin B12 Levels ..............................................23 Screening Patients .................................................................................27 Detection and Diagnosis ........................................................................28 Managing Patients With Evidence of a Vitamin B12 Deficiency................35 Prevention of Vitamin B12 Deficiencies...................................................40 Summary ...............................................................................................42 References .............................................................................................43 References for Text in Boxes .................................................................49 Appendix A: Answers to Case Study Questions ......................................51 Appendix B: Additional Articles on Vitamin B12 Deficiency .....................53 Appendix C: Evaluation Questionnaire, Pretest, and Posttest ................56 2/11/2010 ii Vitamin B12 Deficiency Figure and Tables Figure 1. The Biochemical Role of Cobalamin........................................ 16 Table 1. Neurologic and Psychiatric Symptoms of Vitamin B12 Deficiency and Parkinson Disease (PD) ................................... 13 Table 2. Typical Stages in the Development of a Vitamin B12 Deficiency .............................................................. 17 Table 3. Prevalence of Vitamin B12 Serum Levels for the U.S. Population By Age, National Health and Nutrition Examination Survey 2001–2004 …………………………… 19 Table 4. Prevalence of National Health and Nutrition Examination Survey Participants With Biochemically Defined Vitamin B12 Deficiency* By Age Group, United States, 2001–2004 …………………………… 31 Table 5. Tailored Diagnostic Approach for Vitamin B12 Deficiency………34 Table 6. Examples of Treatment Regimens for Vitamin B12 Deficiency…38 Disclosure CDC, planners, and other content experts wish to disclose they have no financial interests or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This module will not include any discussions of the unlabeled use of a product or a product under investigational use. 2/11/2010 iii Why Vitamin B12 Deficiency Should Be on Your Radar Screen: A Continuing Education Update Goal and Objectives The goal of this continuing education activity is to increase the number of primary care providers (physicians and midlevel providers) who prevent, detect, and treat vitamin B12 deficiencies among their high-risk patients. After completing this continuing education material, you should be able to • • • • • • Describe the prevalence in the United States of vitamin B12 deficiency among adults 51 years of age or older. List three neurologic effects of a vitamin B12 deficiency. List three hematologic effects of a vitamin B12 deficiency. Identify the most common presentation of a vitamin B12 deficiency. Discuss the changes in absorption of vitamin B12 that occur with age. List at least two pharmacologic options for treatment of a vitamin B12 deficiency. 2/11/2010 1 Vitamin B12 Deficiency Accreditation Continuing Medical Education (CME): This activity for 1.5 credits is provided by the Centers for Disease Control and Prevention (CDC), accredited by the Accreditation Council for Continuing Medical Education to provide category 1 credits towards the American Medical Association (AMA) Physician’s Recognition Award. Continuing Nursing Education (CNE): This activity for 1.5 contact hours is provided by CDC, which is accredited as a provider of continuing education in nursing by the American Nurses Credentialing Center’s Commission on Accreditation (ANCC). Registration To register for the course and receive free continuing education credit:        Go to http://www.cdc.gov/tceonline.. Log in as a participant (note: the first time you use the online system you will need to log in as a new participant and create a participant profile). Find the course by searching the catalog using the following course number: WB1349. You will need to enter the verification code (B12) to complete the course. Select the type of credit you wish to receive and register for the course. Take the examination and complete the course evaluation. Print your continuing education certificate. To receive continuing education credit, you must complete the entire course, take the post-test, and complete the evaluation online. During this lesson, you will find highlighted terms. Roll your mouse over each term for further information. 2 Vitamin B12 Deficiency Introduction Vitamin B12 (cobalamin) deficiency should be on your radar screen for several reasons. Prevention, early detection, and treatment of vitamin B deficiency are important public health issues, because they are essential to prevent development of irreversible neurologic damage which can impact quality of life. Although most health care providers already recognize the occasional person who presents with obvious signs and symptoms, they are far less likely to screen and diagnose the majority of patients who have a subclinical or mildly symptomatic vitamin B12 deficiency. Vitamin B12 deficiency is more common among older adults than many health care providers realize. Unpublished analysis at the Centers for Disease Control and Prevention (CDC) of laboratory data from communitybased samples of U.S. adults 51 years of age or older suggest about 1 (3.2%) of every 31 persons have serum vitamin B12 levels below 200 picograms per milliliter (pg/mL). Vitamin B12 has profound effects on human health. Adequate body stores are essential for several crucial neurologic and hematologic functions. Delays in the diagnosis and treatment of vitamin B12 deficiencies can lead to development of severe, irreversible neurologic damage. The clinical importance of vitamin B12 was established over 50 years ago, when ingesting raw animal liver (the primary storage organ for vitamin B12) was found to be an effective treatment for pernicious anemia. Research has shown that the water-soluble vitamin B12 is required for the completion of several biochemical processes (see Figure 1). The following five top things to remember about vitamin B12 in primary care practice summarize the implications of these and other cobalamin-related findings. 3 Vitamin B12 Deficiency The top five things to remember about vitamin B12 1. Vitamin B12 deficiencies occur in adults 51 years of age or older at a frequency of 1 (3.2%) in every 31 persons, and manifest as serum vitamin B12 levels below the cutpoint of 200 picograms per milliliter. 2. All patients with unexplained hematologic or neurologic signs or symptoms should be evaluated for a vitamin B12 deficiency. If found, the cause should should be determined. 3. Today, megaloblastic anemia is most likely due to vitamin B12 deficiency and needs prompt evaluation. In the United States, folic acid fortification has made folate deficient megaloblastic anemia a very rare condition. 4. Although the body’s ability to absorb naturally occurring vitamin B12 decreases with age, most people can readily use the synthetic form of cobalamin. 5. All people 51 years of age or older should get most of their daily vitamin B12 through supplements containing vitamin B12 or foods fortified with vitamin B12. 4 Vitamin B12 Deficiency This update has been prepared and organized to address four questions pertinent to primary health care providers:  Why should I be concerned about my patient’s vitamin B12 status? o Introduction o Case studies o Natural history and prevalence of vitamin B12 deficiencies o Manifestations of low vitamin B12 levels  Which of my patients are at high risk for vitamin B12 deficiency? o Risk factors for a vitamin B12 deficiency  How do I detect and diagnose a vitamin B12 deficiency? o Screening patients o Detection and diagnosis  How should I manage a patient with evidence of vitamin B12 deficiency? o Managing patients with evidence of a vitamin B12 deficiency o Preventing vitamin B12 deficiencies 5 Vitamin B12 Deficiency Case Studies The following case studies are not actual patients. They combine elements from different cases to emphasize important aspects of vitamin B12 deficiency. Case Study 1 Presentation During a checkup for hypertension, a 65-year-old female reports a 2-month history of tiredness, feeling faint from “getting up too fast”, and “memory problems”. Case Study Question 1 Do any of the presenting complaints raise your index of suspicion about a possible vitamin B12 deficiency? If so, why? History On review of systems, she reports difficulty concentrating, fatigue, feeling faint when she stands quickly, and vague gastrointestinal discomfort with some decrease in appetite. She denies any history of previous trauma, diplopia, dysphagia, vertigo, vision loss, loss of consciousness, back pain, or symptoms of bowel or bladder dysfunction. Her family history is negative for neurologic, psychiatric, and autoimmune diseases. Her medications include an antihypertensive, as well as an occasional antiinflammatory drug for episodic headaches. Her social history reveals a single woman who smokes about onehalf pack of cigarettes per day, drinks alcohol only socially, and denies illicit drug use. She has a high school education and, until recently, had worked in the office of a trucking company. 6 Vitamin B12 Deficiency Case Study Question 2 What risk factors does this woman appear to have for a vitamin B12 deficiency? Physical Examination Pale 65 y.o. WF who appears well-nourished, alert, and oriented. Vital Signs T-98.6, HR-76, R-18, B/P-130/80 supine and 95/52 upon standing, Height/Weight 5’4”/120 lbs. Head Normocephalic; oropharynx clear but pale; palpebral conjunctivae pale. Neck Supple, full active and passive ROM without pain, without audible bruits; no lymphadenopathy; no thyromegaly Back No spine tenderness Lungs Clear to auscultation Heart Regular rate and rhythm; no murmurs Abdomen Soft, nontender; no organomegaly Rectal Normal rectal tone; no fissures Extremities No clubbing, cyanosis, or edema; FROM Skin Pale; no rash The general physical examination is unremarkable except for orthostatic hypotension and a weight loss of 3 pounds since her last visit 6 months ago. She is alert and oriented times three. Her Mini-Mental Status Exam score is 26 out of 30. She misses one point on serial 7s and is able to recall three of three items. There is evidence of bilateral mildly diminished vibration and proprioception. Her reflexes are 3+/4+ throughout, with negative Babinski reflex. Cranial Nerves II—Visual acuity 20/25 in both eyes (corrected); normal fundoscopic examination; visual fields intact with no central scotoma III, IV, VI—Extraocular movements intact; pupils equal, round, and reactive to light with no afferent pupillary defect V, VII, XII—Intact facial sensation; intact 7 Vitamin B12 Deficiency masseter motor strength, without dysarthria; tongue protruded in midline VIII—Hearing grossly normal XI, X—Swallowing intact XI—Muscle strength equal bilaterally Motor Normal muscle bulk; muscle strength 5/5 in all muscle groups Cerebellar Normal finger-to-nose, heel-to-shin, and rapid alternating movements Case Study Questions 3. Does the fact that she appears to be “well-nourished” indicate she is unlikely to have a vitamin deficiency? Why or why not? 4. Are there any aspects of her physical examination that suggest a vitamin B12 deficiency? 5. Given her history and physical examination findings, what laboratory test(s) would you order? Laboratory Studies You order routine laboratory studies, which include complete blood count (CBC) with smear and chemistry screen. In addition, you order a serum vitamin B12 level to investigate further the etiology of her fatigue and pale mucosa. Results from the CBC and smear reveal a borderline macrocytic anemia. The chemistry panel is within normal limits. The serum vitamin B12 level you requested is 215 picograms per milliliter (pg/mL). This level is considered within a “normal range” by some laboratories, but you take into account her other signs and symptoms and request confirmatory testing with 8 Vitamin B12 Deficiency methylmalonic acid (MMA) and homocysteine (Hcy) levels. Results of Confirmatory Testing Both her MMA and Hcy levels are elevated. Her MMA is greater than 0.5 micromoles per liter (μmol/L), and her Hcy is greater than 17 μmol/L, confirming your suspicion that this patient has a vitamin B12 deficiency. You decide to investigate the cause of her vitamin B12 deficiency. Although she denies a history of pernicious anemia in her family and she has had no previous indication of autoimmune diseases, you order an antiintrinsic factor (IF) antibody test that confirms the presence of pernicious anemia. Management You explain that with the diagnosis of pernicious anemia she will have to continue vitamin B12 therapy for the remainder of her life, and you make a note on her chart to assess her compliance at each visit. You also advise her to inform her family of the diagnosis because there is possibly a genetic component. You start her on vitamin B12 intramuscular (IM) injections. She gets IM cyanocobalamin 1,000 micrograms (µg) two times per week for 2 weeks and then switches to oral vitamin B12 1,000 µg daily thereafter. Almost immediately after the initiation of injections, she reports improved concentration. Within 2 weeks, she notes less fatigue and normal appetite. Case Study 2 Presentation An 85-year-old female with a 15-year history of Parkinson disease (PD) is seen for her regularly scheduled follow-up with her neurologist. History On review of systems, family members report that she has become more withdrawn and irritable during the last 9 Vitamin B12 Deficiency 6 months. They also report that activities she previously accomplished without difficulty, such as going to church, seem to exhaust her. She acknowledges this symptom, stating that she feels her stamina is much lower than at the time of the last visit. She and her family do not report an appreciable difference in or worsening of her motor symptoms, but they do report that she has had some hallucinations in the form of seeing farm animals periodically in her room. Her current medications include Stalevo™(carbidopa, levodopa, and entacapone), amantadine, Evista® (raloxifene hydrochloride), Effexor® XL (venlafaxine hydrochloride), Detrol® LA (tolterodine tartrate), Mirapex® (pramipexole dihydrochloride), and Ambien® (zolpidem tartrate). She denies any obsessive or compulsive behaviors or any recent trauma, but she does admit having a decreased appetite and eating little or no meat. Her family describes her nutritional intake as poor, stating that she is just getting by on “tea and toast”. Her social history reveals a widowed elderly woman who lives with her son and daughter-in-law. She had lived independently until 5 years ago, when completing her activities of daily living (ADLs) became too difficult. She currently has a home health nurse visit once a day to assist with ADLs and noontime medications while her family is at work. Physical Examination A general examination reveals a frail, thin female with skin irritation and slight amount of saliva evident at the right corner of her mouth (the side where her PD symptoms are more pronounced). She has slight puffiness but no pitting of her ankles bilaterally. A neurological examination reveals that she is alert and oriented to person, place, and year. She remembers 3 out of 3 items, but can recall only one of three items 3 minutes later. She has definite facial masking and a decreased blink rate. Cranial nerve examination reveals moderate hypophonia (low voice volume) and an intermittent tremor. She is moderately stooped with a slight tilt to the right, and she has difficulty rising from a 10 Protein intake among patients with Parkinson disease (PD) might interfere with levodopa’s clinical benefit. Thus, PD patients might inadvertently increase their risk of vitamin B12 deficiency by avoiding meat, the dietary source of vitamin B12. Vitamin B12 Deficiency chair without assistance, even though her strength is normal. She has a mild-to-moderate intermittent resting tremor, worse on her right side. Sensory examination reveals decreased vibratory thresholds in both legs up to her ankles. Reflexes are 3+ out of 4 with crossed adductor spread in her legs, and her plantar reflex shows positive Babinski bilaterally. Laboratory Studies Her neurologist orders some routine laboratory studies, including a CBC with smear and chemistry panel. In addition, the neurologist decides to get a serum B12 level because she is considered at high risk for a vitamin B12 deficiency, and many of the symptoms of PD also can be attributed to vitamin B12 deficiency. Results from the CBC with smear demonstrate no evidence of anemia. The chemistry panel is within normal limits, with the exception of a slightly elevated serum creatinine (1.5 milligrams per deciliter). Her serum B12 level is 225 pg/mL, within the laboratory’s normal range of 180–900 pg/mL. The neurologist considers this value as “low-normal” and requests confirmatory testing with MMA and HCY levels. Slightly elevated creatinine could indicate age-related changes in renal function, dehydration, or mild renal insufficiency from other causes. Results of Confirmatory Testing Her HCY is elevated at 18 µmols/L; however, her neurologist recognizes that this finding alone is not considered diagnostic, given that levodopa has been known to alter HCY levels. Conversions 1,000 nmol/L* = 1 µmol/L Her MMA is borderline at 0.38 µmol/L but, again, this finding is not diagnostic. 376 nmol/L = 0.376 µmol/L Although PD can explain most of her symptoms, vitamin B12 deficiency can also account for some of them. Her age is a risk factor for atrophic gastritis, and her diet seems to be deficient in protein so both malabsorption and malnutrition could contribute to borderline vitamin B12 deficiency. 11 *nanomols per liter Vitamin B12 Deficiency Management Given the uncertain nature of the test results, her neurologist discusses vitamin B12 supplementation with her. She expresses disinterest in oral supplementation, stating “If I have to take one more pill, I will scream.” Because the laboratory findings are ambiguous, the neurologist and she agree to monitor her status rather than start injection therapy immediately. On her return visit 6 months later, her serum vitamin B12 is 189 pg/mL, and both her Hcy and MMA levels have increased. Her neurologist orders antiparietal cell antibody and anti-intrinsic factor antibody tests to rule out pernicious anemia. Both tests are negative. She is started on 1,000 µg of IM cyanocobalamin for 5 days, followed by monthly injections of 1,000 µg of IM cyanocobalamin. Her neurologist makes arrangements for the home health nurse to administer the injections. At the next visit, the patient and her family report that she is less fatigued, less irritable, and less withdrawn. There is no worsening of motor symptoms; however, she still experiences occasional hallucinations. 12 Vitamin B12 Deficiency Table 1. Neurologic and Psychiatric Symptoms of Vitamin B12 Deficiency and Parkinson Disease (PD) Vitamin PD B12 Deficiency Autonomic Impotence, urinary or fecal incontinence Orthostatic hypotension + + + + + + + +* + +* + + + + + + - + + + Cerebral Dementia, memory loss, cognitive impairment Depression Psychosis Myelopathic Subacute combined degeneration Ataxia Spasticity Lehrmitte sign (electric-shock–like sensations in the spine) Abnormal Gait†Spastic Shuffling Constitutional Fatigue *Seen in PD or resulting from dopaminergic PD treatment), or both †Note gait abnormalities do not always appear “typical” of textbook descriptions 13 Vitamin B12 Deficiency Natural History and Prevalence of Vitamin B12 Deficiency “Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important.” Baik and Russell, 1999 The case studies illustrate two important facts about vitamin B12 (cobalamin). First, low vitamin B12 levels can have profound effects on patient well-being. Although most patients with a vitamin B12 deficiency are in a subclinical stage(1-7) and do not present with symptoms or complaints such as those of the case study patients, some patients might be at risk for developing serious sequelae if the deficiency is not detected and the patients followed with reassessment, prophylaxis, or treatment, as needed. Second, treatment is safe and remarkably effective if provided before permanent damage occurs. Understanding the biochemistry of vitamin B12, the problems that might develop when cobalamin body stores are depleted, and current treatment strategies can help clinicians prevent significant morbidity among their patients. The nutritional value of vitamin B12 was initially established in the first half of the 20th century, when ingesting raw animal liver (the primary storage organ for this nutrient) was found to be an effective treatment for pernicious anemia.(8) Humans cannot manufacture cobalamin and must consume it on a regular basis. Vitamin B12 is a water-soluble compound that is naturally available for human use only through ingestion of animal proteins, such as beef, poultry, fish, eggs, and dairy products. Unfortified, plant-based foods do not contain vitamin B12.(2, 9, 10) 14 Vitamin B12 is naturally available for human use only through ingestion of animal proteins. Unfortified plantbased foods do not contain vitamin B12. Vitamin B12 Deficiency There are several important points about cobalamin absorption:      It occurs primarily during the active digestion of animal proteins in the stomach and terminal ileum, and it depends on the availability of adequate amounts of a number of compounds, including the R protein (haptocorrin from saliva), gastric acid, pepsin, and intrinsic factor (IF).(2, 3) Gastric acid is needed to digest animal protein. When the ability to secrete that acid is lost, a person cannot break down the protein to release vitamin B12 from food and can absorb only crystalline (synthetic) vitamin B12.(2) Loss of IF in pernicious anemia results in an inability to absorb vitamin B12. People with pernicious anemia must be treated with parenteral cyanocobalamin or high doses of oral cobalamin (1,000 micrograms [µg] daily).(2, 11) About 1% of large oral doses of vitamin B12 passively diffuses into the bloodstream from the small intestine.(2, 10) If any aspect of the digestion sequence begins to fail and malabsorption develops, the body can draw on the large amounts of vitamin B12 stored in the liver, so overt symptoms might not develop for several years.(2, 10, 12) However, with certain conditions, vitamin B12 deficiency might develop over a shorter period of time (months). Adequate serum levels of cobalamin are crucial to complete three enzymatic processes (Figure 1).  Methylcobalamin is a cofactor necessary to convert homocysteine (Hcy) to methionine. Thus, vitamin B12 deficiency increases Hcy.(1, 12, 13)  The cofactor adenosylcobalamin is required for the conversion of methylmalonyl coenzyme A to succinyl coenzyme A.(2, 10)  Methylcobalamin is needed to convert 5methyltetrahydrofolate to tetrahydrofolate and is necessary for DNA and red blood cell production. 15 Pernicious anemia is an autoimmune disease in which antibodies attack gastric cells, resulting in impaired production of intrinsic factor that is critical for absorption of vitamin B12. Vitamin B12 Deficiency Figure 1. The Biochemical Role of Cobalamin Vitamin B12 deficiencies often, but not always, develop gradually over many years and are accompanied by a slow and varied onset of nonspecific symptoms. Carmel describes vitamin B12 deficiency in two states: clinical and subclinical.(1) Clinical deficiency manifests with hematologic or neurologic signs and symptoms, cobalamin levels <200 picograms per milliliter (pg/mL), and levels for Hcy and methylmalonic acid (MMA) that are usually elevated. Subclinical deficiency includes absent signs and symptoms, although some patients might have subtle changes on neurologic examination; low to low-normal cobalamin levels (200–350 pg/mL); and at least one metabolic abnormality (elevated Hcy or elevated MMA), usually mild. You are likely to encounter more of your patients in the asymptomatic subclinical stage of vitamin B12 deficiency rather than in the classic, overtly apparent clinical vitamin B12 deficiency.(1, 12, 14) The challenge for you is how and when to respond to a patient without the typical signs and symptoms of clinical vitamin B12 deficiency. 16 Vitamin B12 Deficiency The first to conceptualize the natural history of a vitamin B12 deficiency, Herbert noted that vegetarians with dietary vitamin B12 insufficiency progressed through four stages: serum depletion; cell depletion; biochemical deficiency (defined as elevated levels of Hcy and MMA); and, finally, the classic signs and symptoms of clinical deficiency, such as anemia (Table 2).(9, 15) Table 2. Typical Stages in the Development of a Vitamin B12 Deficiency. Herbert, 1994 Stage Manifestation Comment I Circulating serum B12 levels depleted Patients are typically asymptomatic and can remain in this stage for several years. II Cellular stores of B12 are depleted Patients can remain asymptomatic. This stage can also continue for several years. III Evidence of biochemical deficiency via increases in serum homocysteine and methylmalonic acid Vitamin B12 is required for the conversion of these compounds. IV Clinical signs and symptoms apparent The spectrum of clinical manifestations is broad and the sequence of symptom development varies markedly. Although this model provides a useful perspective, untreated patients will not necessarily advance through the stages chronologically or linearly. Progression to a later stage is not inevitable, and some patients with evidence of an early stage deficiency might have normal laboratory values when retested.(11) Malabsorption of food-derived cobalamin because of decreased gastric acid production is a more likely reason for vitamin B12 deficiency, while malabsorption of cobalamin because of lack of IF in pernicious anemia is a less prevalent cause.(3) 17 Vitamin B12 Deficiency Prevalence of Vitamin B12 Deficiency The true prevalence of vitamin B12 deficiency tends to be underestimated for several reasons. The common misconception that most vitamin B12 deficiencies are due to inadequate dietary intake might lead to overlooking important high-risk groups. Older adults who routinely consume meat and other animal proteins can still be vitamin B12 deficient due to malabsorption. Clinical vitamin B12 deficiencies are relatively rare. Most patients are far more likely to have mild, subclinical vitamin B12 deficiency.(1) Most prevalence estimates are based solely on serum vitamin B12 results. Confusion can arise because cobalamin values are measured in picomoles per liter (pmol/L) in some research studies, while clinical laboratories express values in picograms per milliliter (pg/mL) or nanograms per liter (ng/L). The most frequently reported threshold value is 200 pg/mL (148 pmol/L).(1, 16) Studies that have established higher cutpoints invariably have reported higher prevalence estimates. In the research literature, some investigators have used diagnostic algorithms that combine serum B12 results with one or more additional laboratory findings, typically either serum Hcy or MMA.(1, 4, 17, 18) Depending on the approach used, the additional test findings have raised(4, 18, 19) or lowered(6, 19, 20) the observed prevalence of vitamin B12 deficiency compared with findings based solely on serum vitamin B12 levels. Unpublished data from the National Health and Nutrition Examination Survey (NHANES) 2001–2004 in Table 3 stratified by age have estimated that 1 (3.2%) of every 31 adults 51 years of age or older in the United States has a low vitamin B12 serum level. Most of these people are ambulatory and do not have overt symptoms of vitamin B12 deficiency. 18 Conversions ng/L = pg/mL pmol/L = pg/mL x 0.738 pg/mL = pmol/L ÷ 0.738 Keep in mind that ng/L has the same value as pg/mL but conversion to pmol/L requires multiplication of pg/mL by 0.738 (200 pg/mL x 0.738 = 148 pmol/L). Vitamin B12 Deficiency Table 3. Prevalence of Vitamin B12 Serum Levels for the U.S. Population by Age, National Health and Nutrition Examination Survey 2001–2004 Vitamin B12 Serum Level 9–13 years of age 14–18 years of age 19–30 years of age 31–50 years of age ≥ 51 years of age 0 0.2% 0.2% 0.5% 1.2% 151–200 pg/mL 0.1% 0.6% 1.5% 1.0% 2.0% 201–250 pg/mL 0.6% 2.5% 5.2% 6.1% 5.1% 251–300 pg/mL 1.6% 5.4% 7.9% 6.9% 6.2% 301–350 pg/mL 4.2% 9.4% 11.3% 10.7% 8.9% 351–400 pg/mL 5.4% 9.2% 13.1% 13.5% 10.7% > 400 pg/mL 88.0% 72.7% 60.8% 61.2% 65.8% ≤ 150 pg/mL Those prevalence figures are supported by other population-based studies. The Framingham study with a cohort of noninstitutionalized adults 67 through 96 years of age found that 5.3% of the participants had serum vitamin B12 levels <200 pg/mL.(4) As summarized in the pop-up box, inclusion criteria and differences in laboratory testing make prevalence estimates from clinic-based studies difficult to compare with population-based estimates. 19 One study of outpatients in Oklahoma using a serum B12 threshold value of <200 pg/mL found that 6% were deficient. (Barnard, 1998) In Seattle, Washington, researchers determined that 13% of the outpatient study participants were deficient, using values of B12 ≤300 pg/mL and MMA >271 nanomoles per liter (nmol/L).(Rajan, 2002) When the threshold for B12 was set at 300 pg/mL and two metabolic tests were included, 14.5% of participants were considered deficient in a sample of older outpatients in Denver, Colorado. (Pennypacker, 1992) One conservative study used a threshold value of 180 pg/mL and found that 5.2% of elderly inpatients and outpatients were diagnosed as vitamin B12 deficient. (Matchar, 1994) Vitamin B12 Deficiency Risk Factors for Vitamin B12 Deficiency “The clinical indications (for cobalamin deficiency) are of prime importance since routine screening tests, such as the blood count, are not always abnormal. The same criteria apply to both sexes and to all age groups, including preterm infants and children.” Amos, 1994 Patient characteristics that increase the likelihood of a vitamin B12 deficiency can be divided broadly into demographic and behavioral characteristics that increase the risk of inadequate dietary intake (malnutrition) and physiologic factors that increase the risk of malabsorption. Some factors, such as advanced age, might increase the risk of both malnutrition and malabsorption. In the United States, most cases of vitamin B12 deficiency are due to malabsorption rather than inadequate intake. We will review the more obvious demographic and behavioral “red flags” of aging and strict vegetarianism and vegan diets and then summarize the less readily apparent but more common physiologic factors that can affect absorption. Demographic and Behavioral Risk Factors The risk of developing a vitamin B12 deficiency increases with age.(1, 6, 16, 21-23) The elderly, defined as individuals 65 years of age or older, are more likely to develop a vitamin B12 deficiency because they are at risk for both malabsorption and malnutrition. The frail elderly, especially, might have dietary insufficiency for a number of reasons, including cognitive dysfunction, social isolation, mobility limitations, and poverty. In contrast to the importance of age, other demographic characteristics, including sex, race, and ethnicity, are not as important in predicting vitamin B12 deficiency. While several studies have found that mild cobalamin deficiency is most common among elderly White men and least common among Black or African-American and Asian-American women, (2, 3, 16, 24) the differences 20 In the United States, most cases of vitamin B12 deficiency are due to malabsorption. Vitamin B12 Deficiency are not sufficient to support sex- or race-specific nutrient recommendations.(10) A patient characteristic that should always raise the index of suspicion is long-term adherence to a strict vegetarian or vegan diet,(10, 16, 25, 26) because vegan diets exclude all forms of animal protein, including eggs and dairy products. Thoughtfully planned vegetarian diets that include eggs, milk, and yogurt can provide adequate amounts of vitamin B12. Short-term adherence to strict vegetarian and vegan diets might not cause a problem because of the large amount of vitamin B12 typically stored in the liver. However, it is prudent to advise all vegetarian and vegan patients, particularly if they are elderly or anticipating a pregnancy, to consume synthetic cobalamin daily, either by taking a supplement containing vitamin B12 or eating a serving of vitamin B12– fortified grain products.(10) The requirement for vitamin B12 increases for pregnant and lactating women.(10) To review the vitamin B12 content of a variety of vegetarian and vegan foods, see http://www.nal.usda.gov/fnic/foodcomp/search/. Physiologic Factors Malabsorption is the physiologic cause of vitamin B12 deficiency and can result from a number of conditions. Frequently mentioned are pernicious anemia; (7, 24) atrophic gastritis;(3, 10, 27) gastric surgery (e.g., ileal resection and gastrectomy);(11, 16, 28) presence of a cobalamin-utilizing fish tapeworm such as the Diphyllobothrium latum;(2, 29) and other concurrent diseases such as Crohn disease, HIV infection,(30-32) celiac sprue,(33, 34) and bacterial overgrowth in the small intestine.(35) Rare cases have been attributed to anesthetic nitrous oxide exposure.(2, 36) Among the elderly, atrophic gastritis and pernicious anemia are the main causes of malabsorption. Atrophic gastritis often develops as people age. With resulting hypochlorhydria and achlorhydria, the body does not produce enough pepsin and hydrochloric acid to release from protein the food-bound vitamin B12. In pernicious anemia, missing IF needed to attach B12 in the small intestine impairs the uptake of vitamin B12. 21 Inadequate absorption  Pernicious anemia  Atrophic gastritis  Small intestinal bacterial overgrowth  Gastrointestinal surgery (e.g., ileal resection or gastrectomy) Presence of a cobalamin utilizing fish tapeworm, such as Diphyllobothrium latum  Crohn disease  HIV infection  Celiac sprue Nitrous oxide causes the inactivation of vitamin B12, which might result in acute hematologic or neurologic complications of vitamin B12 deficiency. Because nitrous oxide is a commonly used anesthetic in surgery, people at risk (e.g., the elderly) should be monitored for a developing symptomatic vitamin B12 deficiency. Vitamin B12 Deficiency Undiagnosed and untreated pernicious anemia affects 1%–2% of the elderly population.(24) 22 Vitamin B12 Deficiency Manifestations of Low Vitamin B12 Levels “Although some clinical expressions remain mysterious, especially the neurological dysfunction, our view of cobalamin deficiency has expanded beyond the question of megaloblastic anemia.” Carmel, 2000 No single symptom, or cluster of symptoms, has been uniquely associated with inadequate levels of vitamin B12. Among older adults, the most frequently reported symptoms of vitamin B12 deficiency are hematologic or neurologic in nature, but gastrointestinal and possibly vascular symptoms are also common. The typically nonspecific manifestations of a vitamin B12 deficiency underscore the importance of encouraging all older adults to consume the synthetic form of the vitamin each day. Recent concerns have also been raised about potential adverse effects on infant growth and development in exclusively breastfed babies of mothers who adhere to a strict vegan diet.(11, 16) While this situation is rare in the United States, sequelae are often severe and irreversible in these children. Hematologic Manifestations Common symptoms associated with hematologic pathology include skin pallor, weakness, fatigue, syncope, shortness of breath, and palpitations.(2, 10) A classic hematologic sign of severe vitamin B12 deficiency is megaloblastic anemia.(2) Hematologic manifestations might also be due to folate deficiency. However, since 1998, the U.S. Food and Drug Administration has required fortification of all enriched grain and cereal products with 140 micrograms (µg) of folic acid per 100 grams of cereal grain product,(37) and that fortification of the U.S. food supply essentially has eliminated the prevalence of folate deficiency.(21) Today, in the United States, a case of megaloblastic anemia most likely is due to vitamin B12 deficiency until proven otherwise. Although vitamin B12 deficiency is not always accompanied by hematologic changes, the majority of 23 Today, in the United States, megaloblastic anemia is most likely due to a vitamin B12 deficiency until proven otherwise. Folic acid fortification does not have an effect on the prevalence of megaloblastic anemia attributable to vitamin B12 deficiency. Very high doses of folic acid (>5,000 µg each day) can correct the hematologic manifestations of vitamin B12 deficiency; however, the amount of folic acid available through fortification as specified by the U.S. Food and Drug Administration (FDA) is not likely to affect a vitamin B12 deficiency-induced anemia (FDA, 1996). Vitamin B12 Deficiency patients with clinical deficiency will have signs of megaloblastic anemia. In various studies conducted among patients with overt vitamin B12 deficiency, 56%– 77% of people had signs of macrocytosis or anemia.(5, 38-41) Furthermore, some researchers have found that the presence of neurologic manifestations of a vitamin B12 deficiency might even be correlated inversely with evidence of hematologic effects.(10, 39, 42) Many B12–deficient patients do have anemia or macrocytosis. Neurologic Manifestations Common neurologic complaints include paresthesias (with or without objective signs of neuropathy), weakness, motor disturbances (including gait abnormalities), vision loss, and a wide range of cognitive and behavioral changes (e.g., dementia, hallucinations, psychosis, paranoia, depression, violent behavior, and personality changes). Tingling of the hands and feet is perhaps the most common neurologic complaint.(2, 41, 42) The pathology of vitamin B12 deficiency on the nervous system is unknown.(7) All patients with unexplained cognitive decline or dementia should be assessed for a possible vitamin B12 deficiency.(41, 43-45) Several current case reports and studies support the common practice of assessing vitamin B12 levels during dementia workups.(41, 46-48) Although only a minority (1.5%) of all dementia cases are fully reversible following treatment,(49) many dementias from other etiologies (e.g., Parkinson or Alzheimer disease) are exacerbated when patients have a concomitant low vitamin B12 level. The American Academy of Neurology (AAN) has concluded that because vitamin B12 deficiency is a likely comorbidity among the elderly, and among patients with suspected dementia in particular, it should be recognized and treated. The AAN practice guideline states that B12 levels should be included in routine assessments of dementia among the elderly.(44) 24 All patients newly diagnosed with unexplained cognitive decline or dementia should be assessed for a possible vitamin B12 deficiency. Vitamin B12 Deficiency Gastrointestinal Manifestations Vitamin B12 deficiency might also manifest with gastrointestinal complaints. Some frequently mentioned symptoms include anorexia, flatulence, diarrhea, and constipation.(7, 10, 36, 50) These symptoms can develop among patients with a vitamin B12 deficiency without accompanying anemia, macrocytosis, or overt neurologic deficits. Glossitis, which is commonly thought to be a cardinal sign of some anemias, is actually a relatively rare manifestation of clinical vitamin B12 deficiency and is completely absent in subclinical vitamin B12 deficiency according to Carmel (Carmel RA. New York Methodist Hospital [personal communication] 20062007). Vascular Manifestations Both low vitamin B12 levels and low folate levels are associated with elevated levels of homocysteine (Hcy). Hyperhomocysteinemia increases the chance of developing a vascular occlusion,(51) thus potentially increasing the risk of coronary heart disease and ischemic stroke. Although the association of coronary heart disease or ischemic stroke with vitamin B12 or folate deficiency has not been proven, the SEARCH (Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine) study in the United Kingdom is seeking to obtain evidence about the effect of reducing Hcy on cardiovascular risk while treating patients with 2 milligrams (mg) of folic acid plus 1 mg of vitamin B12 daily. In addition, the SEARCH study is looking at the efficacy and safety of two different dosages of simvastatin in regard to risk reduction for major cardiovascular events.(52) This randomized study is scheduled to end in 2008 and should provide evidence about the causal relationship of Hcy to cardiovascular disease and about the value of folic acid and vitamin B12 supplementation, in addition to answering questions about simvastatin therapy. Effects on Infant Growth and Development Although the previously cited hematologic, neurologic, gastrointestinal, and cardiovascular consequences are 25 Nursing infants of mothers who adhere to a strict vegetarian or vegan diet throughout their pregnancy and while breastfeeding might also experience serious B12related deficiency effects. Vitamin B12 Deficiency typically observed among older patients, several cases of significant vitamin B12 deficiencies among infants and young children have been reported.(53-56) Low or marginal vitamin B12 status among pregnant women increases the risk for neural tube birth defects.(57) Exclusively breastfed infants of mothers who adhere to a strict vegetarian or vegan diet that excludes all animal proteins might also experience serious effects related to vitamin B12 deficiency.(50, 53, 54, 56) Clinical manifestations among infants and young children are widely varied, encompassing hematologic, neurologic, and gastrointestinal symptoms. Some potential effects include the following:  Failure to thrive  Hypotonia  Ataxia  Developmental delays  Macrocytosis or anemia  General weakness Many of these effects will improve with prompt vitamin B12 administration but, sometimes, irreversible neurologic damage occurs before the diagnosis is made and treatment is begun.(50, 53-56) Nursing infants of vegan mothers can develop significant problems even when the mother is not anemic or symptomatic in any way.(50, 53, 55) It is important for you to ask pregnant women and new mothers who breastfeed about their diets. 26 Vitamin B12 Deficiency Screening Patients “. . . It is daunting and probably unnecessary to actively seek out new asymptomatic cases [of vitamin B12 deficiency] by screening . . .” Carmel, 2003 Most experts do not recommend community-based mass screening programs for vitamin B12 deficiency, even among high–risk groups, such as the frail elderly. For example:  The U.S. Preventive Services Task Force has not published formal recommendations on screening asymptomatic older adults.  The major medical societies have no recommendations on routine cobalamin screening.  The National Guideline Clearinghouse website has no guidelines calling for periodic assessment in asymptomatic patients. (However, if you provide primary care to patients with dementia or altered mental status and celiac sprue or other gastrointestinal conditions, you might wish to consult the website (http://www.guideline.gov) for recommendations related to vitamin B12 monitoring among these high–risk groups.) 27 Vitamin B12 Deficiency Detection and Diagnosis “It is particularly important that the diagnosis of cobalamin deficiency be established with a high degree of certainty because cobalamin therapy almost always must be given for the life-time of the patient.” Stabler and Allen, 2004 Keeping vitamin B12 deficiency on your radar screen means staying vigilant during your review of your patient’s history and during the physical examination. Watch for even subtle signs of neurologic or cognitive impairment. Also, note any elements of the patient’s history that might suggest potential malabsorption or malnutrition, such as previously diagnosed pernicious anemia, previous gastrointestinal surgery, vegan diet, and advanced age. Maintain an especially high index of suspicion of vitamin B12 deficiency in new patients who report they were treated with vitamin B12 injections or high doses of oral vitamin B12 supplements by a former provider, but have since discontinued their use. Elderly patients often fail to understand that a true vitamin B12 deficiency due to malabsorption requires lifelong treatment. Early detection and prompt treatment of a vitamin B12 deficiency are essential to prevent development of irreversible neurologic damage, but making an accurate and timely diagnosis can be challenging. The list of related signs and symptoms is long, varied, and nonspecific. Many risk factors have been identified, but there are no known necessary or sufficient causes. Complicating things further is the fact that because the liver is a very efficient storage organ for vitamin B12, even completely deficient diets in healthy adults might not result in low serum vitamin B12 levels for several years. Conversely, apparently healthy adults, especially the elderly, consuming diets rich in naturally occurring vitamin B12 can still develop a significant deficiency because of undetected malabsorption. It is possible for vitamin B12 deficiency to develop in a much shorter period of time (months) in some people. 28 Vitamin B12 Deficiency The vitamin B12 literature contains many articles on the relative merits and limitations of the various laboratory testing options. Some tests are used more commonly for the initial assessment, while others, because of their cost, inconvenience, or difficulty of interpretation, are reserved for confirmatory testing in ambivalent situations or are used only in the research setting. Initial Assessment After conducting a thorough history and physical examination, if you suspect vitamin B12 deficiency, you should include a complete blood count (CBC), peripheral blood smear, and serum cobalamin (B12) as part of the initial laboratory assessment.(58) The serum cobalamin test is readily available and generally affordable, and can detect low serum vitamin B12 levels even among patients who are not anemic.(59, 60) However, not all patients with a vitamin B12 deficiency will have hematologic manifestations. As Carmel succinctly noted, “the proscription that cobalamin deficiency should not be diagnosed unless megaloblastic changes are found is akin to requiring jaundice to diagnose liver disease.”(11) While serum vitamin B12 concentrations are generally accurate,(61) many conditions can complicate the interpretation of vitamin B12 laboratory values. Falsely low values have been associated with multiple myeloma, oral contraceptives,(62-64) folate deficiency,(58, 59) and pregnancy.(10) Additionally, a low serum B12 level does not automatically mean a deficiency. From 20%– 40% of elderly people with low serum B12 levels have normal metabolite (homocysteine [Hcy] and methylmalonic acid [MMA]) levels and should not be considered as having a B12 deficiency.(11) Sometimes, a true cobalamin deficiency will not be detected by the serum vitamin B12 test. Some examples of falsely normal serum cobalamin results might be seen with (but not limited to) liver disease,(58) myeloproliferative disorders,(58) and renal insufficiency.(4, 65) If a patient has clinical evidence of a vitamin B12 deficiency and a normal serum B12 level, it is important to evaluate further. 29 The complete blood count, smear, and serum cobalamin (B12) test should be included in the initial laboratory assessment of vitamin B12 Oral contraceptive users generally have lower serum vitamin B12 levels than nonusers; however, the evidence of tissue depletion, as detected by high values of methylmalonic acid and homocysteine, is lacking. “Accepted lower limits of serum B12 levels in adults range between 170 and 250 pg/ml; however, higher levels (but less than 350 pg/ml) have been recorded in 15% of ostensibly healthy elderly patients with other findings suggestive of a deficiency state, most notably increased levels of serum methylmalonic acid. The true lower limits of normal serum B12 would therefore appear to be somewhat poorly defined.” Ward, 2002 Vitamin B12 Deficiency Opinions differ as to the optimal laboratory cutpoint for the serum vitamin B12 test, due in part to the insidious onset and slow progression of the disorder and limitations of current assays. Research studies and clinical laboratories have tended to dichotomize low values at 200 picograms per milliliter(pg/mL).(18, 66, 67) Stabler and Allen noted the following ranges of serum cobalamin levels among patients with a clinically confirmed B12 deficiency (defined as those who “have objective clinical responses to appropriate therapy”): less than 100 pg/mL, approximately 50%; 100–200 pg/mL, approximately 40%; 200–350 pg/mL, approximately 10%; and more than 350 pg/mL, approximately 0.1% to 1%.(7) Adequate follow-up for suspect normal or low-normal results is needed through either additional confirmatory testing or a prolonged therapeutic trial followed by metabolic and clinical reassessment. Confirmatory Testing When the serum vitamin B12 results are suspect, it is helpful to obtain more information.(1) Several tests can be used to rule out a vitamin B12 deficiency either among patients with borderline serum cobalamin levels or among symptomatic patients with normal serum cobalamin levels. Homocysteine (Hcy) and Methylmalonic Acid (MMA) By far, the most common, accurate, and widely used confirmatory tests for identifying vitamin B12 deficiency are tests for Hcy and MMA.(1) Because cobalamin is necessary for the synthesis of methionine from Hcy, low levels of vitamin B12 lead to increases in total serum Hcy. The total serum Hcy test is a sensitive indicator for a vitamin B12 deficiency; however, its utility is limited as a sole confirmatory test because elevated Hcy levels among patients also can be caused by familial hyperhomocysteinemia, levodopa therapy,(68) renal insufficiency, and folate deficiency.(1, 7, 69, 70) The serum MMA test is more specific for vitamin B12 deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels also increase in the presence of low vitamin B12 levels 30 Vitamin B12 Deficiency because cobalamin is required to convert methylmalonyl coenzyme A to succinyl coenzyme A.(2) In one study, 98.4% of people with a vitamin B12 level less than 200 pg/mL also had elevated MMA levels (defined as values more than 376 nanomoles per liter [nmol/L]).(70) Note that false-positive increases in serum MMA have been identified among patients with impaired renal function. It is necessary to rule out whether your patient has either marked intravascular volume depletion or renal insufficiency when interpreting the MMA level, especially in the absence of a low cobalamin level.(70) Elevated MMA levels among most patients indicate tissue depletion of vitamin B12. Data from the National Health and Nutrition Examination Survey (NHANES) 2001–2004 in Table 4 shows the prevalence of vitamin B12 deficiency using combinations of serum B12 levels and MMA levels. Table 4. Prevalence of National Health and Nutrition Examination Survery Participants With Biochemically Defined Vitamin B12 Deficiency* By Age Group, United States, 2001–2004 Age Group (Years of Age) B12 ≤ 200 pg/mL and MMA ≥ 270 nmol/L B12 > 200 pg/mL and MMA ≥ 270 nmol/L 9–13 years of age 0.1% 2.5% 14–18 years of age 0.2% 3.7% 19–30 years of age 0.4% 3.5% 31–50 years of age 0.6% 3.6% ≥ 51 years of age 1.6% 7.9% Conversions *Biochemically defined vitamin B12 deficiency is serum B12 ≤ 200 picograms per milliliter (pg/mL) and methylmalonic acid (MMA) ≥ 270 nanomoles per liter (nmol/L) or serum B12 > 200 pg/mL and MMA ≥ 270 nmol/L 1,000 nmol/L* = 1 µmol/L†376 nmol/L = 0.376 Two popular methods for interpreting diagnostic thresholds for MMA and Hcy elevations are the use of cutpoints determined by laboratory norms (e.g., 3 standard deviations above the mean) and specific values (e.g., MMA greater than 0.26 micromole per liter 31 *nanomols per liter †micromols per liter µmol/L Vitamin B12 Deficiency [µmol/L](69) or greater than 0.4 µmol/L;(59) Hcy greater than 15 µmol/L(71, 72)). Many clinicians rely on ranges specified by the clinical laboratories they use. The cost of testing for MMA or Hcy might be a concern. Quotes from Quest Laboratories (Atlanta, Georgia, May 2006) state that the direct patient (no insurance) cost for a serum MMA is $212 and for a serum Hcy is $191. Other metabolites, serum propionate and serum 2methylcitrate, are also present in vitamin B12 deficiency. However, measuring either of these metabolites has no advantage over measuring MMA to diagnose a vitamin B12 deficiency,(2) and they are not available routinely in many clinical laboratories. Again, it is important to remember that abnormal metabolite levels might be due to conditions other than a vitamin B12 deficiency, such as renal insufficiency. In one study of the elderly, renal insufficiency was associated with 20% or greater of all abnormal metabolite levels.(11) Other Tests If the root cause of vitamin B12 deficiency is not obvious, you should consider ordering additional tests to determine it. Antibodies to intrinsic factor and gastrin or pentagastrin I levels are often used to diagnose pernicious anemia.(10, 36, 60) Serum holotranscobalamin II measures one of the bloodbinding proteins used to transport vitamin B12.(60) Some investigators recommend it;(73) others are concerned about the lack of convincing evidence of its value.(2, 9, 10, 60) Theoretically, it is attractive, but early claims of its value have been poorly documented. While immunoassays have replaced the older crude methods, it is too early to determine whether measurement of holotranscobalamin II is better than measurement of serum cobalamin. (1) The deoxyuridine suppression test ( or “DUST”) has been described as a sensitive indicator of impaired thymidine synthesis due to either deficiency or metabolic inactivation of vitamin B12 or folate.(58) However, DUST 32 Vitamin B12 Deficiency is used rarely in the clinical setting because it is not necessary in the evaluation of a vitamin B12 deficiency. DUST is also a complicated, expensive, and timeconsuming test.(58) The Schilling test is included in most lists of possible vitamin B12 deficiency confirmatory tests, but it is not available in U.S. clinical practices at this time. The Shilling test is the classic test for determining whether a person can absorb vitamin B12. However, a person’s ability to absorb crystalline vitamin B12 can differ from his or her ability to absorb the naturally occurring vitamin B12.(59) While, it is not an accurate test for identifying cobalamin deficiency, it can be a helpful tool in determining the root cause of an identified deficiency. It reveals cobalamin malabsorption such as that found in pernicious anemia and ileal disease. A normal Schilling test cannot rule out vitamin B12 deficiency.(29, 36) There is no gold standard for determining cobalamin deficiency. Part of the problem is related not to the tests used, but to “an uncertain boundary between cobalamin depletion and disease.”(1, 20) A diagnostic approach to tailor testing to the nature of a patient’s clinical problem is suggested by Carmel and summarized in Table 5(1) 33 Vitamin B12 Deficiency Table 5. Tailored Diagnostic Approach Vitamin B12 Deficiency Problem Goal Patient with mild to Confirm suspected severe hematologic vitamin B12 or neurologic signs deficiency or symptoms, or both Patient with Ensure if vitamin hematologic or B12 deficiency neurologic signs or exists, it is not missed symptoms, or both, unlikely due to vitamin B12 deficiency Asymptomatic Determine if patient with vitamin B12 condition known to deficiency has cause vitamin B12 developed yet deficiency Determine if Asymptomatic patient accidentally vitamin B12 deficiency exists found to have low B12 level or high Hcy†for Suggested Tests Serum B12 Serum B12 MMA* and Hcy†MMA (metabolic changes often precede low cobalamin levels) MMA *MMA–methylmalonic acid †Hcy–homocysteine Flagging the patient’s chart will help you remember to follow-up if choosing to “watch and wait” with an asymptomatic patient. Experienced clinicians differ on the importance of tracking down the root cause of a vitamin B12 deficiency before initiating treatment; however, determining the cause of the deficiency is important ultimately in individualizing the treatment approach.(1) 34 Vitamin B12 Deficiency Managing Patients With Evidence of a Vitamin B12 Deficiency “A caregiver must manage a subclinically deficient patient with pernicious anemia as a cause quite differently and pay closer attention than to a similar patient without it.” Carmel, 2006 Clinical Vitamin B12 Deficiency Options available for treating a clinical vitamin B12 deficiency include oral and parenteral (intramuscular or subcutaneous) preparations. Intravenous dosing is not recommended because this will result in most of the vitamin being lost in the urine.(74) The response of a patient with vitamin B12 deficiency anemia to treatment is usually rapid, with reticulocytosis occurring within 2–5 days, and the hematocrit normalizing within weeks.(10) Treatment with cobalamin effectively halts progression of the deficiency process, but might not fully reverse more advanced neurologic effects.(39, 42) If the underlying cause of the vitamin B12 deficiency is treatable (e.g., fish tapeworm infection or bacterial overgrowth), then treatment should include addressing the underlying etiology.(7) Vitamin B12 is considered safe, even at levels much higher than the recommended dose. It has not been shown to be toxic or cause cancer, birth defects, or mutations.(10, 75) Be aware, however, that patients who have a vitamin B12 deficiency with associated megaloblastic anemia might experience hypokalemia and fluid overload early in treatment due to increased erythropoiesis, cellular uptake of potassium, and increased blood volume.(76, 77) While the route, dosage, treatment timing, and follow-up might vary somewhat, there is no question about the decision to treat patients with pernicious anemia or with a low serum B12 level and hematologic or neurologic signs or symptoms without pernicious anemia (clinical 35 Cobalamin replacement is effective because crystalline forms of B12 can be absorbed even when animal protein-bound forms cannot be digested. Vitamin B12 is not carcinogenic, teratogenic, or mutagenic. It is considered safe even at 1,000 times the RDA. Baik and Russell, 1999 Vitamin B12 Deficiency vitamin B12 deficiency). Once treated for a vitamin B12 deficiency due to pernicious anemia or other irreversible severe problems with absorption, patients need to continue some form of cobalamin therapy for life.(7) Parenteral (Intramuscular or Subcutaneous) Administration of parenteral crystalline cobalamin has been the standard treatment protocol for vitamin B12 deficiency for decades.(78, 79) Few side effects have been reported, and patient acceptance is generally high. Anecdotally, the subcutaneous route causes less burning than does the intramuscular route (Carmel RA. New York Methodist Hospital [personal communication] 20062007). Regimens for parenteral administration vary. An approach suggested by Stabler and Allen is 1 milligram (mg) (or 1,000 micrograms [µg]) of vitamin B12 given weekly for 8 weeks, then once monthly for life.(7) Some providers have used quarterly injections after the initial dosing protocol. However, experts state that in pernicious anemia or severe malabsorptive deficiency quarterly injections are not sufficient, noting that cobalamin levels start to fall prior to the 1 month followup (Allen RH. University of Colorado [personal communication] 2006 -2007). Oral Large, daily oral replacement doses might be an acceptable alternative if patients are compliant.(7) Sufficient amounts of vitamin B12 are absorbed via passive diffusion in the small intestine.(2, 11) A study by Eussen et al. demonstrated a linear response in the reduction of metabolites and increased serum B12 levels with increasing dosages of oral cyanocobalamin.(80) A common therapy is 1 mg (1,000 µg) of vitamin B12 to be consumed daily.(2, 11, 14) Intranasal A relatively new vehicle for vitamin B12 therapy is a cyanocobalamin gel for intranasal use. Some experts are not convinced of its efficacy, and the cost is $30 for 36 Vitamin B12 Deficiency 500 µg (Carmel RA. New York Methodist Hospital [personal communication] 2006-2007). If chosen, the intranasal gel should be used for maintenance only after treatment with parenteral or oral vitamin therapy has established adequate metabolic status among patients with no nervous system involvement.(74) The recommended dose for therapy is 500 µg intranasally once a week.(74) Absorption can be inconsistent. Treatment approaches vary somewhat in the initial treatment and the route used.(7, 77, 81) Given the long-term nature of cobalamin therapy, consideration of the patient’s condition (e.g., cognitive impairment), convenience of getting the treatment, and ease of administration should heavily influence the method and dosage selected.(7, 11) For example, oral therapy is less painful and can be self-administered. However, because cognitive impairment is a frequent reason for noncompliance, patients might be more compliant with clinic or home health nurse-administered injections. Additionally, Carmel observed that many patients prefer the convenience of monthly injections to daily consumption of pills.(11) Examples of treatment regimens from different sources for clinical vitamin B12 deficiency are listed in Table 6. 37 Vitamin B12 Deficiency Table 6. Examples of Treatment Regimens for Clinical Vitamin B12 Deficiency Due to Initial Cyanocobalamin Pernicious Varies, not limited anemia to:  1 mg intramuscularly (IM) or subcutaneously (SQ) every (q) week x 8 OR  1 mg IM or SQ x 7 in 1 month Other foodVaries, not limited to: bound B12 malabsorption  1 mg IM or SQ q problems week x 8 OR  1 mg IM or SQ x 7 in 1 month OR  1 mg–2 mg PO QD Rarer  Treat underlying malabsorption condition problems AND (tape worms, Cyanocobalamin bacterial varies, not limited overgrowth) to:  1 mg IM or SQ q week x 8 OR  1 mg IM or SQ x 7 in 1 month Maintenance Cyanocobalamin  1 mg IM or SQ q month for life OR  1 mg–2 mg orally (PO) every day (QD) for life  1 mg IM or SQ q month possibly for life OR  650 µg–1 mg PO QD possibly for life  1 mg IM or SQ q month OR  650 µg–1 mg PO QD Treating underlying condition might resolve B12 deficiency. If cyanocobalamin is d/c’d, follow up with regular assessment of metabolites. 38 Vitamin B12 Deficiency Subclinical Vitamin B12 Deficiency The far more prevalent patient presentation is by an asymptomatic individual with borderline serum B12 levels and elevated homocysteine or methylmalonic acid levels, or both. These patients pose a dilemma for providers because there are no guidelines for the treatment of patients with subclinical vitamin B12 deficiency. Some providers prefer to treat these patients and check to see that metabolite markers have normalized, while others prefer to “wait and watch”. For patients in the subclinical vitamin B12 deficiency category, taking a vitamin with B12 (usual dosages are 6–25 µg) is not sufficient to correct the metabolites. Two recent studies have suggested that the lowest dose of oral cyanocobalamin needed to normalize metabolites in subclinical vitamin B12 deficiency is 500–1,000 µg daily.(80, 82) The providers who test for and treat patients with subclinical vitamin B12 deficiency, especially those patients with possible pernicious anemia or elevated metabolites, or both, can prevent potential subsequent hematologic and neurologic manifestations. Whether treating or “waiting and watching”, you should remember that routine monitoring of and educating the patient are important. 39 Vitamin B12 Deficiency Prevention of Vitamin B12 Deficiencies “The . . . Recommended Dietary Allowance (RDA) (2.4 mcg/day) for B12 for adults ages 51 and older are the same as for younger adults but with the recommendation that B12–fortified foods (such as fortified ready-to-eat cereals) or B12–containing supplements be used to meet much of the requirements.” Institute of Medicine, 1999 The irreversible nature of the late-stage neurologic effects of a vitamin B12 deficiency provides strong support for the value of prevention.(44, 50, 83) Fortunately, a vitamin B12 deficiency is easily treated and prevented. Because of the high prevalence of mild, subclinical cobalamin deficiency among asymptomatic individuals, it is important to remain vigilant, especially with individuals at high risk for a vitamin B12 deficiency. If “watch and wait” is the selected plan of care, periodic reassessment of untreated asymptomatic patients is important to identify progressive depletion of vitamin B12. The Institute of Medicine (IOM) recommends that all adults 18 years of age or older consume 2.4 micrograms (µg) per day of vitamin B12.(10) Subclinical vitamin B12 deficiency, often undiagnosed and untreated, has been estimated to occur among 5%–15% of the elderly population.(4, 6, 16, 19, 65) However, a recent clinical study demonstrates that it takes 650–1,000 µg of cyanocobalamin daily to provide 80%–90% of the estimated maximum reduction in methylmalonic acid.(80) Given the high prevalence of atrophic gastritis (loss of acid secretion) among older adults, the IOM suggests that adults older than 50 years of age use vitamin B12– fortified foods and supplements (e.g., multivitamins or single supplements) as the primary means to meet this requirement because crystalline formulations are much more readily absorbed and used than naturally occurring vitamin B12. Most multivitamins contain 6–25 µg cyanocobalamin; some contain more. Single 40 The irreversible nature of the late-stage neurologic effects of a vitamin B12 deficiency provides strong support for the value of prevention. Vitamin B12 Deficiency supplements typically come in doses of 100 µg, 250 µg, 500 µg, 1,000 µg, and 2,000 µg. For more information on vitamin supplements for adults, see the National Institutes of Health Office of Dietary Supplements website at http://ods.od.nih.gov/factsheets/cc/vitb12.html. Vegans, or strict vegetarians, must obtain their per-day dose of vitamin B12 by consuming a vitamin supplement or eating a fortified cereal product. Currently available data do not support the suggestion that vegans can meet their minimum daily requirements for vitamin B12 by consuming unfortified plant-based foods, nutritional yeast, algae, or seaweed products. For more information on the vitamin B12 levels of over 1,100 common food items, visit the U.S. Department of Agriculture and Agricultural Research website at http://www.ars.usda.gov/ba/bhnrc/ndl. Several experts in the field find that even higher doses of oral cobalamin are necessary for the prevention of vitamin B12 deficiency among the elderly and have stated that the amount in the IOM recommendation is insufficient.(80)(Carmel RA. New York Methodist Hospital [personal communication] 2006-2007; Allen RH. University of Colorado [personal communication] 20062007) Lindenbaum’s findings of the prevalence of cobalamin deficiency among the elderly survivors from the Framingham study suggests “deficiencies can, at least in part, be prevented by oral supplementation, although . . . the dose of cobalamin administered may have to be much larger than that usually given in routine multivitamin preparations.”(4) 41 Vitamin B12 Deficiency Summary Low vitamin B12 levels occur among 1 in 31 adults 51 years of age or older among the U.S. population. Vitamin B12 deficiency is simple to prevent and simple to treat, but the diagnosis is easy to miss and is often overlooked in the outpatient setting. All patients with unexplained hematologic or neurologic symptoms should be evaluated for a vitamin B12 deficiency. If such a deficiency is found, the cause should be determined.(7, 44) Irreversible neurologic damage can occur if diagnosis and treatment are delayed. A complete blood count, peripheral blood smear, and serum vitamin B12 level are the tests of choice for initial assessment of cobalamin deficiency. Keep in mind that megaloblastic anemia and changes in mean corpuscular value are not always present when there is a vitamin B12 deficiency. Homcysteine and methylmalonic acid can be used to confirm a vitamin B12 deficiency for cases with ambiguous initial results because metabolic changes often precede low cobalamin levels. You have inexpensive treatment options available to treat a vitamin B12 deficiency. Remember that treatment is safe, effective, and has no known toxicity level. To prevent a vitamin B12 deficiency, you should advise all patients 51 years of age or older to consume synthetic vitamin B12 daily. Dosage recommendations vary. Acknowledgements: The authors thank Christine Pfeiffer, PhD, for assistance with laboratory interpretation, and Quanhe Yang, PhD,and Heather Carter Hamner, MS, MPH, for statistical support. We also appreciate the comments and suggestions from our panel of reviewers Sonja Rasmussen, MD; Joe Mulinare, MD; R.J. Berry, MD; Lorraine Yeung, MD; Sharon Roy, MD; Mary Dott, MD; John Mersereau, MD; Jennifer Zreloff, MD; Jason Bell, MD; Pauline Terebuh, MD; Dan Watkins, PA; Gail Walls, MSN; Sally Lehr, MSN; Darla Ura, MSN; Sue Ann Bell, MSN; Christa Purnell, MSN; Molly Cogswell, RN, PhD, and Malissa Perritt, MSN. 42 Vitamin B12 Deficiency References 1. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program). 2003:62-81. 2. Baik H RR. Vitamin B12 deficiency in the elderly. 1999(19):357-77. 3. Carmel R. Cobalamin, the stomach, and aging. Am J Clin Nutr. 1997 Oct;66(4):750-9. 4. Lindenbaum J, Rosenberg IH, Wilson PW, Stabler SP, Allen RH. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J Clin Nutr. 1994 Jul;60(1):2-11. 5. Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C, Williamson RE, et al. Low vitamin B-12 concentrations in patients without anemia: the effect of folic acid fortification of grain. Am J Clin Nutr. 2003 Jun;77(6):1474-7. 6. Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA, Stabler SP. Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake. J Am Geriatr Soc. 2002 Apr;50(4):624-30. 7. Stabler SP, Allen RH. Megoblastic anemias. In: Goldman L, Ausiello D, editors. Cecil Textbook of Medicine. 22nd ed. Philadelphia: W. B. Saunders Company; 2004. p. 1050-7. 8. Hoffbrand AV, Herbert V. Nutritional anemias. Semin Hematol. 1999 Oct;36(4 Suppl 7):13-23. 9. Herrmann W, Geisel J. Vegetarian lifestyle and monitoring of vitamin B-12 status. Clin Chim Acta. 2002 Dec;326(1-2):47-59. 10. Institute of Medicine (IOM). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline. Washington, D.C.: National Academy Press; 1998. 11. Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357-75. 12. Herbert V. Vitamin B 12. In: Present knowledge in nutrition. Ziegler EE, Filer LJ Jr., eds. 7th ed. Washington, D.C.: ILSI Press; 1996. p. 191-205. 13. Knopman DL. Dementia. In: Goldman L, Ausiello D, editors. Cecil Textbook of Medicine. 22nd ed. Philadelphia: Elsevier W.B. Saunders Company; 2004. 14. Allen LH, Casterline J. Vitamin B-12 deficiency in elderly individuals: diagnosis and requirements. Am J Clin Nutr. 1994 Jul;60(1):12-4. 15. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S22S. 16. Stabler S, Allen R. Vitamin B12 Deficiency As A Worldwide Problem. Annu Rev Nutr. 2004;24:299-326. 43 Vitamin B12 Deficiency 17. Allen RH, Stabler SP, Savage DG, Lindenbaum J. Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations. Am J Hematol. 1990 Jun;34(2):90-8. 18. Bernard MA, Nakonezny PA, Kashner TM. The effect of vitamin B12 deficiency on older veterans and its relationship to health. J Am Geriatr Soc. 1998 Oct;46(10):1199-206. 19. 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 Dec;40(12):1197-204. 20. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci. 1994 Nov;308(5):27683. 21. Pfeiffer C, Caudill S, Gunter E, Osterloh J, Sampson E. Biochemical indicators of B vitamin status in the U.S. population after folic acid fortification: results from the National Health and Nutrition Examination Survey 1999-2000. AJCN. 2005;82(2):442-50. 22. Clarke R, Refsum H, Birks J, Evans JG, Johnston C, Sherliker P, et al. Screening for vitamin B-12 and folate deficiency in older persons. Am J Clin Nutr. 2003 May;77(5):1241-7. 23. Wright JD, Bialostosky K, Gunter EW, Carroll MD, Najjar MF, Bowman BA, et al. Blood folate and vitamin B12: United States, 1988-94. Vital Health Stat 11. 1998 Dec(243):1-78. 24. Carmel R. Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med. 1996 May 27;156(10):1097-100. 25. Gibson R. Assessment of the status of folate and vitamin B-12. Principles of Nutritional Assessment. New York: Oxford University Press; 1990. p. 311-22. 26. Obeid R, Geisel J, Schorr H, Hubner U, Herrmann W. The impact of vegetarianism on some haematological parameters. Eur J Haematol. 2002 Nov-Dec;69(5-6):275-9. 27. Krasinski SD, Russell RM, Samloff IM, Jacob RA, Dallal GE, McGandy RB, et al. Fundic atrophic gastritis in an elderly population. Effect on hemoglobin and several serum nutritional indicators. J Am Geriatr Soc. 1986 Nov;34(11):800-6. 28. 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 B12 deficiency after gastric surgery. Ann Intern Med. 1996 Mar 1;124(5):469-76. 29. Beck WS. Diagnosis of megaloblastic anemia. Annu Rev Med. 1991;42:311-22. 30. Burkes RL, Cohen H, Krailo M, Sinow RM, Carmel R. Low serum cobalamin levels occur frequently in the acquired 44 Vitamin B12 Deficiency immune deficiency syndrome and related disorders. Eur J Haematol. 1987 Feb;38(2):141-7. 31. Harriman GR, Smith PD, Horne MK, Fox CH, Koenig S, Lack EE, et al. Vitamin B12 malabsorption in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1989 Sep;149(9):2039-41. 32. Remacha AF, Cadafalch J. Cobalamin deficiency in patients infected with the human immunodeficiency virus. Semin Hematol. 1999 Jan;36(1):75-87. 33. American Gastroenterological Association medical position statement: Celiac Sprue. Gastroenterology. 2001 May;120(6):1522-5. 34. Delco F, El-Serag HB, Sonnenberg A. Celiac sprue among US military veterans: associated disorders and clinical manifestations. Dig Dis Sci. 1999 May;44(5):966-72. 35. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003 Mar 1;67(5):979-86. 36. Green R, Kinsella LJ. Current concepts in the diagnosis of cobalamin deficiency. Neurology. 1995 Aug;45(8):1435-40. 37. U. S. Food and Drug Administration (FDA). Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. Fed Regist, 1996; 61(44): 8781-97. 38. Carmel R. Pernicious anemia. The expected findings of very low serum cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med. 1988 Aug;148(8):1712-4. 39. Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). 1991 Jul;70(4):229-45. 40. 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. Nutrition. 1995 Mar-Apr;11(2):180-2. 41. Stabler SP, Allen RH, Savage DG, Lindenbaum J. Clinical spectrum and diagnosis of cobalamin deficiency. Blood. 1990 Sep 1;76(5):871-81. 42. Savage DG, Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin Haematol. 1995 Sep;8(3):657-78. 43. Adelman AM, Daly MP. Initial evaluation of the patient with suspected dementia. Am Fam Physician. 2005 May 1;71(9):1745-50. 44. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, et al. Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2001 May 8;56(9):1143-53. 45. Wynn M, Wynn A. The danger of B12 deficiency in the elderly. Nutr Health. 1998;12(4):215-26. 45 Vitamin B12 Deficiency 46. Eastley R, Wilcock GK, Bucks RS. Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function. Int J Geriatr Psychiatry. 2000 Mar;15(3):226-33. 47. Goebels N, Soyka M. Dementia associated with vitamin B(12) deficiency: presentation of two cases and review of the literature. J Neuropsychiatry Clin Neurosci. 2000 Summer;12(3):389-94. 48. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997 Nov-Dec;38(6):305-14. 49. Boustani M, Peterson B, Hanson L, Harris R, Lohr KN. Screening for dementia in primary care: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2003 Jun 3;138(11):927-37. 50. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001 Jan;138(1):10-7. 51. Refsum H, Ueland PM, Nygard O, Vollset SE. Homocysteine and cardiovascular disease. Annu Rev Med. 1998;49:31-62. 52. Bowman L, Armitage J, Bulbulia R, Parish S, Collins R. Study of the effectiveness of additional reductions in cholesterol and homocysteine (SEARCH): characteristics of a randomized trial among 12064 myocardial infarction survivors. Am Heart J. 2007 Nov;154(5):815-23, 23 e1-6. 53. Monagle PT, Tauro GP. Infantile megaloblastosis secondary to maternal vitamin B12 deficiency. Clin Lab Haematol. 1997 Mar;19(1):23-5. 54. Muhammad R, Fernhoff P, Rasmussen G, Bowman B, Scalon K. Neurologic impairment in children associated with maternal dietary deficiency of cobalamin--Georgia, 2001. JAMA. 2003 Feb 26;289(8):979-80. 55. Turner RJ, Scott-Jupp R, Kohler JA. Infantile megaloblastosis secondary to acquired vitamin B12 deficiency. Pediatr Hematol Oncol. 1999 Jan-Feb;16(1):7981. 56. von Schenck U, Bender-Gotze C, Koletzko B. Persistence of neurological damage induced by dietary vitamin B-12 deficiency in infancy. Arch Dis Child. 1997 Aug;77(2):137-9. 57. Groenen PM, van Rooij IA, Peer PG, Gooskens RH, Zielhuis GA, Steegers-Theunissen RP. Marginal maternal vitamin B12 status increases the risk of offspring with spina bifida. Am J Obstet Gynecol. 2004;191:11-7. 58. Amos R, Dawson D, Fish D, Leeming R, Linnell J. Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the British Committee for Standards in Haematology. BCSH General Haematology Test Force. Clin Lab Haematol. 1994 Jun;16(2):101-15. 46 Vitamin B12 Deficiency 59. Klee GG. Cobalamin and folate evaluation: measurement of methylmalonic acid and homocysteine vs vitamin B(12) and folate. Clin Chem. 2000 Aug;46(8 Pt 2):1277-83. 60. Ward PC. Modern approaches to the investigation of vitamin B12 deficiency. Clin Lab Med. 2002 Jun;22(2):43545. 61. Mason JB. Consequences of altered micronutrients status. In: Goldman L, Bennett JC, editors. Cecil Textbook of Medicine. Philadelphia: W. B. Saunders, Inc.; 2000. p. 170-8. 62. Riedel B, Bjorke Monsen AL, Ueland PM, Schneede J. Effects of oral contraceptives and hormone replacement therapy on markers of cobalamin status. Clin Chem. 2005 Apr;51(4):778-81. 63. Shojania AM. Oral contraceptives: effect of folate and vitamin B12 metabolism. Can Med Assoc J. 1982 Feb 1;126(3):244-7. 64. Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T. Serum folate and vitamin B12 levels in women using modern oral conceptives (OC) containing 20 mcg ethinyl estradiol. Eur J Obstet Gynecol Reprod Biol 2003 Mar 107(1):57-61. 65. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea M, Azen C. Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities. Am J Clin Nutr. 1999 Nov;70(5):904-10. 66. Whyte EM, Mulsant BH, Butters MA, Qayyum M, Towers A, Sweet RA, et al. Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia. Am J Geriatr Psychiatry. 2002 May-Jun;10(3):3217. 67. Stabler SP. Screening the older population for cobalamin (vitamin B12) deficiency. J Am Geriatr Soc. 1995 Nov;43(11):1290-7. 68. O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L, Dewey RB, Jr., Bottiglieri T, et al. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations. Arch Neurol. 2004 Jun;61(6):865-8. 69. Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A, Stokkeland M, et al. Evaluation of indicators of cobalamin deficiency defined as cobalamin-induced reduction in increased serum methylmalonic acid. Clin Chem. 2000 Nov;46(11):1744-50. 70. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994 Mar;96(3):239-46. 47 Vitamin B12 Deficiency 71. Ray JG, Cole DE, Boss SC. An Ontario-wide study of vitamin B12, serum folate, and red cell folate levels in relation to plasma homocysteine: is a preventable public health issue on the rise? Clin Biochem. 2000 Jul;33(5):337-43. 72. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum H, Sandberg S. Cobalamin deficiency in general practice. Assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98. 73. Herbert V. The elderly need oral vitamin B-12. Am J Clin Nutr. 1998 Apr;67(4):739-40. 74. RXList I. Cyanocobalamin. WebMD; 2008. 75. Schauss AG. Recommended optimum nutrient intakes. In: Pizzorno, editor. Textbook of Natural Medicine. 2nd ed: Churchill Livingstone, Inc.; 1999. p. 909-27. 76. Hoffman R, Benz E, Shattil S, Furie B, Cohen H, Silberstein L, et al. Hematology: Basic Principles and Practice. 4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005. 77. Marks PW, Zukerberg LR. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 30-2004. A 37-year-old woman with paresthesias of the arms and legs. N Engl J Med. 2004 Sep 23;351(13):1333-41. 78. Lawhorne LW, Wright H, Cragen D. Characteristics of non-cobalamin deficient patients who receive regular cyanocobalamin injections. Fam Med. 1991 SepOct;23(7):506-9. 79. Hughes D, Elwood PC, Shinton NK, Wrighton RJ. Clinical trial of the effect of vitamin B12 in elderly subjects with low serum B12 levels. Br Med Journal. 1970;2:458-60. 80. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland PM, Hoefnagels WH, et al. Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial. Arch Intern Med. 2005 May 23;165(10):1167-72. 81. Solomon LR. Cobalamin-responsive disorders in the ambulatory care setting: unreliability of cobalamin, methylmalonic acid, and homocysteine testing. Blood. 2005 Feb 1;105(3):978-85. 82. Stabler SP, Allen RH, Dolce ET, Johnson MA. Elevated serum S-adenosylhomocysteine in cobalamin-deficient elderly and response to treatment. Am J Clin Nutr. 2006 Dec;84(6):1422-9. 83. Wolters M, Strohle A, Hahn A. Cobalamin: a critical vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66. 48 Vitamin B12 Deficiency References for Text in Boxes Amos R, Dawson D, Fish D, Leeming R, Linnell J. Guidelines on the investigation and diagnosis of cobalamin and folate deficiencies. A publication of the British Committee for Standards in Haematology. BCSH General Haematology Test Force. Clin Lab Haematol. 1994 Jun;16(2):101–15. Baik H, Russell R. Vitamin B12 deficiency in the elderly. Annual Rev Nutr.1999(19):357–77. Bernard MA, Nakonezny PA, Kashner TM. The effect of vitamin B12 deficiency on older veterans and its relationship to health. J Am Geriatr Soc. 1998 Oct;46(10):1199–206. Carmel R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–75. Carmel R, Green R, Rosenblatt DS, Watkins D. Update on cobalamin, folate, and homocysteine. Hematology (Am Soc Hematol Educ Program). 2003:62–81. U.S. Food and Drug Administration (FDA). Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid. . Fed Regist, 1996; 61(44): 8781-97. Herbert V. Staging vitamin B-12 (cobalamin) status in vegetarians. Am J Clin Nutr. 1994 May;59(5 Suppl):1213S–22S. Institute of Medicine (IOM). Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline. Washington, D.C.: National Academy Press; 1998. Matchar DB, McCrory DC, Millington DS, Feussner JR. Performance of the serum cobalamin assay for diagnosis of cobalamin deficiency. Am J Med Sci. 1994 Nov;308(5):276–83. 49 Vitamin B12 Deficiency 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 Dec;40(12):1197–204. Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA, Stabler SP. Screening for cobalamin deficiency in geriatric outpatients: prevalence and influence of synthetic cobalamin intake. J Am Geriatr Soc. 2002 Apr;50(4):624–30. Stabler SP, Allen RH. Megoblastic anemias. In: Goldman, ed. Cecil Textbook of Medicine, 22nd ed. Philadelphia: W. B. Saunders Company; 2004. p. 1050–7. Ward PC. Modern approaches to the investigation of vitamin B12 deficiency. Clin Lab Med. 2002 Jun;22(2):435–45. 50 Vitamin B12 Deficiency Appendix A Answers to Case Study Questions 1. Do any of the presenting complaints raise your index of suspicion about a possible vitamin B12 deficiency? If so, why? Yes. Complaints of tiredness for 2 months and memory problems in a woman 65 years of age might indicate a vitamin B12 deficiency. 2. What risk factors does this woman appear to have for a vitamin B12 deficiency? The only immediately apparent risk factor is her age. Risk of developing a deficiency begins to increase at 51 years of age. Sex is not an important predictor. The patient’s nutritional status is unclear at this stage. Future questions might usefully probe the patient for regular sources of vitamin B12, including meat and dairy products as well as fortified foods and nutritional supplements. 3. Does the fact that she appears to be “wellnourished” indicate she is unlikely to have a vitamin deficiency? Why or why not? No. The fact that she is well-nourished does not rule out a potential deficiency. Weight, or body mass index, is not a useful predictor. Normal and overweight individuals might still have a significant vitamin B12 deficiency because most deficiencies are due to malabsorption rather than malnutrition. Markedly underweight patients, who might truly be malnourished, are at increased risk for a vitamin B12 deficiency, particularly if they are elderly or have been adhering to a vegetarian or vegan diet for several years. 4. Are there any aspects of her physical examination that suggest a vitamin B12 deficiency? Mucosal and skin pallor are subtle signs. 51 Vitamin B12 Deficiency 5. Given her history and physical examination findings, what laboratory test(s) would you order? In addition to the usual chemistry panel and complete blood count with smear to check for anemia, a serum B12 test should be ordered. Lownormal levels indicate a need for further assessment because serum levels can be maintained at the expense of liver stores even in the presence of ongoing malabsorption. 52 Vitamin B12 Deficiency Appendix B Additional Articles on Vitamin B12 Deficiency Allen R, Lindenbaum J, Stabler S. High prevalence of cobalamin deficiency in the elderly. Trans Am Clin Climatol Assoc. 1995;107:37–45. Carmel R, Melnyk S, James J. Cobalamin deficiency with and without neurologic abnormalities: differences in homocysteine and methionine metabolism. Blood. 2003;101:3302–8. Carmel R. Pernicious anemia: the expected findings of very low cobalamin levels, anemia, and macrocytosis are often lacking. Arch Intern Med. 1988;148:1712–4. Clarke R. Prevention of vitamin B-12 deficiency in old age. Am J Clin Nutr. 2001;73:151–2. Fairfield K, Fletcher R. Vitamins for chronic disease prevention in adults - Scientific Review. JAMA. 2002;287:3116–26. Fletcher R, Fairfield K. Vitamins for chronic disease prevention in adults - clinical applications. JAMA. 2002;287:3127–9. Herbert V. Vitamin B12 and folic acid supplementation. Am J Clin Nutr. 1997;66:1479– 80. Herrmann W, Schorr H, Bodis M, Knaapp J, Muller A, Stein G, et al. Role of homocysteine, cystathionine and methylmalonic acid measurement for the diagnosis of vitamin deficiency in high-aged subjects. Eur J Clin Invest. 2000;30:1083–9. Ho G, Kauwell G, Bailey L. Practitioners’ guide to meeting the vitamin B12 recommended dietary allowances for people aged 51 years and older. J Am Diet Assoc. 1999;99:725–7. 53 Vitamin B12 Deficiency Holleland G, Schneede J, Ueland P, Lund P, Refsum H, Sandberg S, et al. Cobalamin deficiency in general practice: assessment of the diagnostic utility and cost-benefit analysis of methylmalonic acid determination in relation to current diagnostic strategies. Clin Chem. 1999;45:189–98. Hvas A, Ellegaard J, Nexo E. Increased plasma methylmalonic acid level does not predict clinical manifestations of vitamin B12 deficiency. Arch Intern Med. 2001;161:1535–41. Johnson M, Hawthorne N, Brackett W, Fischer J, Gunter E, Allen R, et al. Hyperhomocysteinemia and vitamin B12 deficiency in elderly using title IIIC nutrition services. Am J Clin Nutr. 2003;77:211–20. Lokk J, Nilsson M, Norberg B, Hultdin J, Sandstrom H, Westman G. Shifts in B12 opinions in primary health care of Sweden. Scand J Public Health. 2001;29:122–8. Malouf R, Areosa S. Vitamin B12 for cognition. Cochrane Database Syst Rev. 2003:3. Meins W, Muller-Thomsen T, Meier-Baumgartner H. Subnormal serum vitamin B12 and behavioral and psychological symptoms in Alzheimer’s disease. Int J Geriatr Psychiatry. 2000;15:415–8. Misra U, Kalita J, Das A. Vitamin B12 deficiency neurological syndromes: a clinical, MRI, and electrodiagnostic study. Electromyogr Clin Neurophysiol. 2003;43:57–64. Mitchell S, Rockwood K. The association between antiulcer medication and initiation of cobalamin replacement in older persons. J Clin Epidemiol. 2001;54:531–4. Naurath H, Joosten E, Riezler R, Stabler S, Allen R, Lindenbaum J. Effects of vitamin B12, folate, and vitamin B6 supplements in elderly people with normal serum vitamin concentrations. Lancet. 1995;346:85–9. 54 Vitamin B12 Deficiency Penninx BW, Guralnick JM, Ferrucci L. Fried LP, Allen R, Stabler S. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women’s Health and Aging Study. Am J Psychiatry. 2000;157:715–21. Stopeck A. Links between helicobacter pylori infection, cobalamin deficiency, and pernicious anemia. Arch Intern Med. 2000;160:1229–30. Tiemeier H, van Tuiji H, Hoffman A, Meijer J, Kilaan A, Breteler M. Vitamin B12, folate, and homocysteine in depression: the Rotterdam Study. Am J Psychiatry. 2002;159:2099–101. van Asselt D, Blom H, Zuiderent R, Wevers R, Jakobs C, van den Broek W, et al. Clinical significance of low cobalamin levels in older hospital patients. Neth J Med. 2000;57:41–9. 55 Vitamin B12 Deficiency Appendix C Why Vitamin B12 Deficiency Should Be on Your Radar Screen Evaluation Questionnaire and Posttest Course Goal: To increase the number of primary care providers (physicians and midlevel providers) who prevent, detect, and treat vitamin B12 deficiencies among their high-risk patients. Objectives: • • • • • • Describe the prevalence in the United States of vitamin B12 deficiency among adults 51 years of age or older. List three neurologic effects of a vitamin B12 deficiency. List three hematologic effects of a vitamin B12 deficiency. Identify the most common presentation of a vitamin B12 deficiency. Discuss the changes in absorption of vitamin B12 that occur with age. List at least two pharmacologic options for treatment of a vitamin B12 deficiency. 1. The learning outcomes (objectives) were relevant to the goal of this course. a. Strongly agree b.Agree c. Undecided d. Disagree e. Strongly disagree 2. The content was appropriate given the stated objectives of the course. a. Strongly agree b. Agree 56 Vitamin B12 Deficiency c. Undecided d. Disagree e. Strongly disagree 3. The content was presented clearly. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 4. The learning environment was conducive to learning. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 5. The delivery method (i.e., Web) helped me learn the material more easily. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 6. The instructional strategies helped me learn the material. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 7. Overall, the quality of the course materials was excellent. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 8. The course was a. Much too difficult b. A little too difficult c. Just right 57 Vitamin B12 Deficiency d. A little too easy e. Much too easy 9. Overall, the course was a. Much too long b. A little too long c. Just right d. A little too short e. Much too short 10. The availability of continuing education credit influenced my decision to participate in this activity. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree f. Not applicable 11. As a result of my completing this educational activity, it is likely that I will make changes in my practice. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree f. Not applicable 12. I am confident I can describe the prevalence in the United States of vitamin B12 deficiency among adults 51 years of age or older. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 13. I am confident I can list three neurologic effects of a vitamin B12 deficiency. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 58 Vitamin B12 Deficiency 14. I am confident I can list three hematologic effects of a vitamin B12 deficiency. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 15. I am confident that I can identify the most common presentation of vitamin B12 deficiency. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 16. I am confident that I can discuss the changes in absorption of vitamin B12 that occur with age. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 17. I am confident I can list at least two pharmacologic options for treatment of a vitamin B12 deficiency. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 18. The content expert(s) for this document demonstrated expertise in the subject matter. a. Strongly agree b. Agree c. Undecided d. Disagree e. Strongly disagree 19. Do you feel this course was commercially biased? Yes or No If yes, please explain 59 Vitamin B12 Deficiency 20. Please describe in the following space any technical difficulties you experienced with the course. 21. What could be done to improve future course offerings? 22. Do you have any further comments? 60 Vitamin B12 Deficiency Pretest and Posttest If you want to receive continuing education credit for this program, complete this posttest. Please read the case history and then answer the questions that follow. Choose the answer that is most correct for each question. Case A 60-year-old teacher with a history of hypothyroidism and gastroesophageal reflux disease (GERD) reports significant fatigue, hot flashes, and memory difficulty since her last annual visit. On detailed review of symptoms, she also admits to irritability, emotional lability, decreased appetite, difficulty sleeping, and occasional tingling of her fingertips. Her last monthly period was 2 years ago. She has been following a vegetarian diet for the past 5 years to try to lose weight. During the physical examination, she is alert and oriented x 3, but tearful at one point during the interview with an MMSE score of 28 out of 30. There are no abnormal physical findings. Her CBC results: RBC 4.6 (4.2–5.8) 10^6/µL MCV 90 (78–102) fL Hgb 15 (12.0–16.0) g/dL WBC 6.4 (4.3–11.0) 10^3/µL (normal differential) Plts 312 (144–440) 10^3/µL Smear shows normocytic, normochromic RBCs Chemistry results: Na 139 (136–148) mEq/L K 4.7 (3.5–5.5) mEq/L Cl 103 (98–110) mmol/L BUN 20.0 (9.34–23.35)mg/dL Cr 1.0 (0.4–1.5) mg/dL (21–33) mmol/L CO2 25 Gluc 80 (60–140) mg/dL GOT 26 (1–32) U/L GPT 14 (1–30) U/L AlkPhos 115 (31–121) U/L 61 Vitamin B12 Deficiency 1. Which of the following presenting symptoms suggest this patient might have a vitamin B12 deficiency? a. Fatigue b. Difficulty sleeping c. Hot flashes d. Emotional lability e. All of the above 2. All of the following factors might place this patient at high risk for a vitamin B12 deficiency except: a. Being 51 years of age or older b. Being female sex c. Having hypothyroidism d. Following a vegetarian diet 3. You might find ______ patients with evidence of low vitamin B12 levels in every 100 patients you see. (Hint: Use prevalence data from the research literature to determine your answer.) a. 0–1 b. 2–4 c. 8–10 d. 15 or more 4. What can you conclude from the CBC with smear results about the likelihood that this patient has a vitamin B12 deficiency? a. Her CBC and smear are abnormal so she must have a B12 deficiency. b. Her CBC and smear are normal so she does not have a B12 deficiency. c. A normal CBC and smear do not rule out a B12 deficiency. d. Nothing; it was a mistake to order a CBC and smear in the first place. You obtain a serum B12 level. Her results are: Serum B12 211 (211-911) pg/mL 5. What does this patient’s serum B12 result suggest? a. Her result is within normal limits so she does not have a vitamin B12 deficiency. 62 Vitamin B12 Deficiency b. She might have a vitamin B12 deficiency; further testing could be useful. c. None of the above. 6. A serum B12 result might be misleading for patients who: a. Are on oral contraceptives b. Are fasting c. Have liver disease or renal disease d. Answers (a) and (c) 7. Setting aside issues of cost and patient convenience, which one of the following additional tests would you consider the most informative at this time? a. Serum homocysteine b. Serum methylmalonic acid c. Serum holotranscobalamin d. Schilling test You order additional tests during the workup for this patient. Other laboratory results: TSH 2.3 (0.34–5.6) µ units/mL ESR 23 (0–30) mm/Hr CRP 3.1 (0–4.9) mg/L Hcy 20 (4–17) µmol/L MMA 0.71 (0.08–0.56) µmol/L 8. Considering all of the evidence presented for this patient, what would you do next? a. Ask the patient to increase consumption of animal food products and recheck her in 6 months b. Ask the patient to take a multivitamin with B12 and recheck her in 6 months c. Check for intrinsic factor antibodies and begin treatment d. Nothing 9. Which of the following treatment options would you select for this patient? a. Intramuscular injections, starting with frequent injections that are gradually tapered to monthly injections 63 Vitamin B12 Deficiency b. Oral formulation, same dosage throughout c. Intramuscular injections initially, switching to an oral formulation later d. One of the above, depending on issues of cost, convenience, and likely patient compliance 10. Pernicious anemia was confirmed. How do you advise this patient about her prognosis? a. You tell her that a course of treatment with vitamin B12 will cure her. b. You advise her that she must continue treatment with vitamin B12 for life. c. You tell her that seaweed, nutritional yeast, and algae will help prevent signs and symptoms from occurring later. d. A and C e. None of the above 64
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