Why Vitamin B 12 Deficiency Should Be on Your Radar Screen

Transcription

1 Why Vitamin B 12 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, MD 1 Patricia W. Mersereau, MN, CPNP 2 Janet Kay Bobo, PhD 3 Joel Kimmons, PhD 4 Jennifer Williams, MSN, MPH, FNP-BC 5 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. 2 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. i

2 Contents Goal and Objectives...1 Accreditation...2 Introduction...3 Case Studies...6 Natural History and Prevalence of Vitamin B 12 Deficiency...14 Risk Factors for Vitamin B 12 Deficiency...20 Manifestations of Low Vitamin B 12 Levels...23 Screening Patients...27 Detection and Diagnosis...28 Managing Patients With Evidence of a Vitamin B 12 Deficiency...35 Prevention of Vitamin B 12 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 B 12 Deficiency...53 Appendix C: Evaluation Questionnaire, Pretest, and Posttest /11/2010 ii

3 Figure and Tables Figure 1. The Biochemical Role of Cobalamin Table 1. Neurologic and Psychiatric Symptoms of Vitamin B 12 Deficiency and Parkinson Disease (PD) Table 2. Typical Stages in the Development of a Vitamin B 12 Deficiency Table 3. Prevalence of Vitamin B 12 Serum Levels for the U.S. Population By Age, National Health and Nutrition Examination Survey Table 4. Prevalence of National Health and Nutrition Examination Survey Participants With Biochemically Defined Vitamin B 12 Deficiency* By Age Group, United States, Table 5. Tailored Diagnostic Approach for Vitamin B 12 Deficiency 34 Table 6. Examples of Treatment Regimens for Vitamin B 12 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

4 Why Vitamin B 12 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 B 12 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 B 12 deficiency among adults 51 years of age or older. List three neurologic effects of a vitamin B 12 deficiency. List three hematologic effects of a vitamin B 12 deficiency. Identify the most common presentation of a vitamin B 12 deficiency. Discuss the changes in absorption of vitamin B 12 that occur with age. List at least two pharmacologic options for treatment of a vitamin B 12 deficiency. 2/11/2010 1

5 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 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

6 Introduction Vitamin B 12 (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 B 12 deficiency. Vitamin B 12 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 B 12 levels below 200 picograms per milliliter (pg/ml). Vitamin B 12 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 B 12 deficiencies can lead to development of severe, irreversible neurologic damage. The clinical importance of vitamin B 12 was established over 50 years ago, when ingesting raw animal liver (the primary storage organ for vitamin B 12 ) was found to be an effective treatment for pernicious anemia. Research has shown that the water-soluble vitamin B 12 is required for the completion of several biochemical processes (see Figure 1). The following five top things to remember about vitamin B 12 in primary care practice summarize the implications of these and other cobalamin-related findings. 3

7 The top five things to remember about vitamin B Vitamin B 12 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 B 12 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 B 12 deficiency. If found, the cause should should be determined. 3. Today, megaloblastic anemia is most likely due to vitamin B 12 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 B 12 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 B 12 through supplements containing vitamin B 12 or foods fortified with vitamin B 12. 4

8 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 B 12 status? o Introduction o Case studies o Natural history and prevalence of vitamin B 12 deficiencies o Manifestations of low vitamin B 12 levels Which of my patients are at high risk for vitamin B 12 deficiency? o Risk factors for a vitamin B 12 deficiency How do I detect and diagnose a vitamin B 12 deficiency? o Screening patients o Detection and diagnosis How should I manage a patient with evidence of vitamin B 12 deficiency? o Managing patients with evidence of a vitamin B 12 deficiency o Preventing vitamin B 12 deficiencies 5

9 Case Studies The following case studies are not actual patients. They combine elements from different cases to emphasize important aspects of vitamin B 12 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 B 12 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

10 Case Study Question 2 What risk factors does this woman appear to have for a vitamin B 12 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

11 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 B 12 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 B 12 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 B 12 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

12 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 B 12 deficiency. You decide to investigate the cause of her vitamin B 12 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 B 12 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 B 12 intramuscular (IM) injections. She gets IM cyanocobalamin 1,000 micrograms (µg) two times per week for 2 weeks and then switches to oral vitamin B 12 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

13 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. 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 B 12 deficiency by avoiding meat, the dietary source of vitamin B 12. 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

14 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 B 12 level because she is considered at high risk for a vitamin B 12 deficiency, and many of the symptoms of PD also can be attributed to vitamin B 12 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 B 12 level is 225 pg/ml, within the laboratory s normal range of 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. Her MMA is borderline at 0.38 µmol/l but, again, this finding is not diagnostic. Although PD can explain most of her symptoms, vitamin B 12 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 B 12 deficiency. Conversions 1,000 nmol/l* = 1 µmol/l 376 nmol/l = µmol/l *nanomols per liter 11

15 Management Given the uncertain nature of the test results, her neurologist discusses vitamin B 12 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 B 12 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

16 Table 1. Neurologic and Psychiatric Symptoms of Vitamin B 12 Deficiency and Parkinson Disease (PD) Vitamin PD B 12 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

17 Natural History and Prevalence of Vitamin B 12 Deficiency Although elderly people with low vitamin B 12 status frequently lack the classical signs and symptoms of vitamin B 12 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 B 12 (cobalamin). First, low vitamin B 12 levels can have profound effects on patient well-being. Although most patients with a vitamin B 12 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 B 12, 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 B 12 was initially established in the first half of the 20 th 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 B 12 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 B 12. (2, 9, 10) Vitamin B 12 is naturally available for human use only through ingestion of animal proteins. Unfortified plantbased foods do not contain vitamin B

18 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 B 12 from food and can absorb only crystalline (synthetic) vitamin B 12. (2) Loss of IF in pernicious anemia results in an inability to absorb vitamin B 12. 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 B 12 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 B 12 stored in the liver, so overt symptoms might not develop for several years.(2, 10, 12) However, with certain conditions, vitamin B 12 deficiency might develop over a shorter period of time (months). 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 B 12. 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 B 12 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 5- methyltetrahydrofolate to tetrahydrofolate and is necessary for DNA and red blood cell production. 15

19 Figure 1. The Biochemical Role of Cobalamin Vitamin B 12 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 B 12 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 ( 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 B 12 deficiency rather than in the classic, overtly apparent clinical vitamin B 12 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 B 12 deficiency. 16

20 The first to conceptualize the natural history of a vitamin B 12 deficiency, Herbert noted that vegetarians with dietary vitamin B 12 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 B 12 Deficiency. Herbert, 1994 Stage Manifestation Comment I Circulating serum B 12 levels depleted Patients are typically asymptomatic and can remain in this stage for several years. II III IV Cellular stores of B 12 are depleted Evidence of biochemical deficiency via increases in serum homocysteine and methylmalonic acid Clinical signs and symptoms apparent Patients can remain asymptomatic. This stage can also continue for several years. Vitamin B 12 is required for the conversion of these compounds. 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 B 12 deficiency, while malabsorption of cobalamin because of lack of IF in pernicious anemia is a less prevalent cause.(3) 17

21 Prevalence of Vitamin B 12 Deficiency The true prevalence of vitamin B 12 deficiency tends to be underestimated for several reasons. The common misconception that most vitamin B 12 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 B 12 deficient due to malabsorption. Clinical vitamin B 12 deficiencies are relatively rare. Most patients are far more likely to have mild, subclinical vitamin B 12 deficiency.(1) Most prevalence estimates are based solely on serum vitamin B 12 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 B 12 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 B 12 deficiency compared with findings based solely on serum vitamin B 12 levels. Unpublished data from the National Health and Nutrition Examination Survey (NHANES) 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 B 12 serum level. Most of these people are ambulatory and do not have overt symptoms of vitamin B 12 deficiency. Conversions ng/l = pg/ml pmol/l = pg/ml x pg/ml = pmol/l Keep in mind that ng/l has the same value as pg/ml but conversion to pmol/l requires multiplication of pg/ml by (200 pg/ml x = 148 pmol/l). 18

22 Table 3. Prevalence of Vitamin B 12 Serum Levels for the U.S. Population by Age, National Health and Nutrition Examination Survey Vitamin B Serum Level years years years years years of age of age of age of age of age 150 pg/ml 0 0.2% 0.2% 0.5% 1.2% % 0.6% 1.5% 1.0% 2.0% pg/ml % 2.5% 5.2% 6.1% 5.1% pg/ml % 5.4% 7.9% 6.9% 6.2% pg/ml % 9.4% 11.3% 10.7% 8.9% pg/ml % 9.2% 13.1% 13.5% 10.7% pg/ml > 400 pg/ml 88.0% 72.7% 60.8% 61.2% 65.8% 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 B 12 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. One study of outpatients in Oklahoma using a serum B 12 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 B pg/ml and MMA >271 nanomoles per liter (nmol/l).(rajan, 2002) When the threshold for B 12 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 B 12 deficient. (Matchar, 1994) 19

23 Risk Factors for Vitamin B 12 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 B 12 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 B 12 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. In the United States, most cases of vitamin B 12 deficiency are due to malabsorption. Demographic and Behavioral Risk Factors The risk of developing a vitamin B 12 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 B 12 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 B 12 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

24 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 B 12. Short-term adherence to strict vegetarian and vegan diets might not cause a problem because of the large amount of vitamin B 12 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 B 12 or eating a serving of vitamin B 12 fortified grain products.(10) The requirement for vitamin B 12 increases for pregnant and lactating women.(10) To review the vitamin B 12 content of a variety of vegetarian and vegan foods, see Physiologic Factors Malabsorption is the physiologic cause of vitamin B 12 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 B 12. In pernicious anemia, missing IF needed to attach B 12 in the small intestine impairs the uptake of vitamin B 12. Inadequate absorption Pernicious anemia Atrophic gastritis Small intestinal bacterial overgrowth Gastrointestinal surgery (e.g., ileal resection or gastrectomy) Presence of a cobalaminutilizing fish tapeworm, such as Diphyllobothrium latum Crohn disease HIV infection Celiac sprue Nitrous oxide causes the inactivation of vitamin B 12, which might result in acute hematologic or neurologic complications of vitamin B 12 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 B 12 deficiency. 21

25 Undiagnosed and untreated pernicious anemia affects 1% 2% of the elderly population.(24) 22

26 Manifestations of Low Vitamin B 12 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 B 12. Among older adults, the most frequently reported symptoms of vitamin B 12 deficiency are hematologic or neurologic in nature, but gastrointestinal and possibly vascular symptoms are also common. The typically nonspecific manifestations of a vitamin B 12 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 B 12 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 B 12 deficiency until proven otherwise. Although vitamin B 12 deficiency is not always accompanied by hematologic changes, the majority of Today, in the United States, megaloblastic anemia is most likely due to a vitamin B 12 deficiency until proven otherwise. Folic acid fortification does not have an effect on the prevalence of megaloblastic anemia attributable to vitamin B 12 deficiency. Very high doses of folic acid (>5,000 µg each day) can correct the hematologic manifestations of vitamin B 12 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 B 12 deficiency-induced anemia (FDA, 1996). 23

27 patients with clinical deficiency will have signs of megaloblastic anemia. In various studies conducted among patients with overt vitamin B 12 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 B 12 deficiency might even be correlated inversely with evidence of hematologic effects.(10, 39, 42) Many B 12 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 B 12 deficiency on the nervous system is unknown.(7) All patients with unexplained cognitive decline or dementia should be assessed for a possible vitamin B 12 deficiency.(41, 43-45) Several current case reports and studies support the common practice of assessing vitamin B 12 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 B 12 level. The American Academy of Neurology (AAN) has concluded that because vitamin B 12 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 B 12 levels should be included in routine assessments of dementia among the elderly.(44) All patients newly diagnosed with unexplained cognitive decline or dementia should be assessed for a possible vitamin B 12 deficiency. 24

28 Gastrointestinal Manifestations Vitamin B 12 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 B 12 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 B 12 deficiency and is completely absent in subclinical vitamin B 12 deficiency according to Carmel (Carmel RA. New York Methodist Hospital [personal communication] ). Vascular Manifestations Both low vitamin B 12 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 B 12 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 B 12 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 B 12 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 Nursing infants of mothers who adhere to a strict vegetarian or vegan diet throughout their pregnancy and while breastfeeding might also experience serious B 12 - related deficiency effects. 25

29 typically observed among older patients, several cases of significant vitamin B 12 deficiencies among infants and young children have been reported.(53-56) Low or marginal vitamin B 12 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 B 12 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 B 12 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

30 Screening Patients... It is daunting and probably unnecessary to actively seek out new asymptomatic cases [of vitamin B 12 deficiency] by screening... Carmel, 2003 Most experts do not recommend community-based mass screening programs for vitamin B 12 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 ( for recommendations related to vitamin B 12 monitoring among these high risk groups.) 27

31 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 B 12 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 B 12 deficiency in new patients who report they were treated with vitamin B 12 injections or high doses of oral vitamin B 12 supplements by a former provider, but have since discontinued their use. Elderly patients often fail to understand that a true vitamin B 12 deficiency due to malabsorption requires lifelong treatment. Early detection and prompt treatment of a vitamin B 12 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 B 12, even completely deficient diets in healthy adults might not result in low serum vitamin B 12 levels for several years. Conversely, apparently healthy adults, especially the elderly, consuming diets rich in naturally occurring vitamin B 12 can still develop a significant deficiency because of undetected malabsorption. It is possible for vitamin B 12 deficiency to develop in a much shorter period of time (months) in some people. 28

32 The vitamin B 12 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 B 12 deficiency, you should include a complete blood count (CBC), peripheral blood smear, and serum cobalamin (B 12 ) as part of the initial laboratory assessment.(58) The serum cobalamin test is readily available and generally affordable, and can detect low serum vitamin B 12 levels even among patients who are not anemic.(59, 60) However, not all patients with a vitamin B 12 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 B 12 concentrations are generally accurate,(61) many conditions can complicate the interpretation of vitamin B 12 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 B 12 level does not automatically mean a deficiency. From 20% 40% of elderly people with low serum B 12 levels have normal metabolite (homocysteine [Hcy] and methylmalonic acid [MMA]) levels and should not be considered as having a B deficiency.(11) 12 Sometimes, a true cobalamin deficiency will not be detected by the serum vitamin B 12 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 e vidence of a vitamin B 12 deficiency and a normal serum B 12 level, it is important to evaluate further. 29 The complete blood count, smear, and serum cobalamin (B 12 ) test should be included in the initial laboratory assessment of vitamin B 12 Oral contraceptive users generally have lower serum vitamin B 12 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 B 12 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 B 12 would therefore appear to be somewhat poorly defined. Ward, 2002

33 Opinions differ as to the optimal laboratory cutpoint for the serum vitamin B 12 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 B 12 deficiency (defined as those who have objective clinical responses to appropriate therapy ): less than 100 pg/ml, approximately 50%; pg/ml, approximately 40%; 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 B 12 results are suspect, it is helpful to obtain more information.(1) Several tests can be used to rule out a vitamin B 12 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 B 12 deficiency are tests for Hcy and MMA.(1) Because cobalamin is necessary for the synthesis of methionine from Hcy, low levels of vitamin B 12 lead to increases in total serum Hcy. The total serum Hcy test is a sensitive indicator for a vitamin B 12 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 B 12 deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels also increase in the presence of low vitamin B 12 levels 30

34 because cobalamin is required to convert methylmalonyl coenzyme A to succinyl coenzyme A.(2) In one study, 98.4% of people with a vitamin B 12 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 B 12. Data from the National Health and Nutrition Examination Survey (NHANES) in Table 4 shows the prevalence of vitamin B 12 deficiency using combinations of serum B 12 levels and MMA levels. Table 4. Prevalence of National Health and Nutrition Examination Survery Participants With Biochemically Defined Vitamin B 12 Deficiency* By Age Group, United States, Age Group B B12 > 200 pg/ml (Years of Age) pg/ml and MMA and MMA nmol/l nmol/l 9 13 years of age 0.1% 2.5% years of age 0.2% 3.7% years of age 0.4% 3.5% years of age 0.6% 3.6% 51 years of age 1.6% 7.9% *Biochemically defined vitamin B 12 deficiency is serum B 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 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 Conversions 1,000 nmol/l* = 1 µmol/l 376 nmol/l = µmol/l *nanomols per liter micromols per liter 31

35 [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 2- methylcitrate, are also present in vitamin B 12 deficiency. However, measuring either of these metabolites has no advantage over measuring MMA to diagnose a vitamin B 12 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 B 12 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 B 12 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 B 12. (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 B 12 or folate.(58) However, DUST 32

36 is used rarely in the clinical setting because it is not necessary in the evaluation of a vitamin B 12 deficiency. DUST is also a complicated, expensive, and timeconsuming test.(58) The Schilling test is included in most lists of possible vitamin B 12 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 B 12. However, a person s ability to absorb crystalline vitamin B 12 can differ from his or her ability to absorb the naturally occurring vitamin B 12. (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 B 12 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

37 Table 5. Tailored Diagnostic Approach for Vitamin B 12 Deficiency Problem Goal Suggested Tests Patient with mild to severe hematologic or neurologic signs or symptoms, or both Patient with hematologic or neurologic signs or symptoms, or both, unlikely due to vitamin B 12 deficiency Confirm suspected vitamin B 12 deficiency Ensure if vitamin B 12 deficiency exists, it is not missed Serum B 12 Serum B 12 MMA* and Hcy Asymptomatic Determine if MMA (metabolic patient with vitamin B 12 changes often condition known to deficiency has precede low cause vitamin B 12 developed yet cobalamin levels) deficiency Asymptomatic patient accidentally found to have low B 12 level or high Hcy *MMA methylmalonic acid Hcy homocysteine Determine if vitamin B 12 deficiency exists MMA 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 B 12 deficiency before initiating treatment; however, determining the cause of the deficiency is important ultimately in individualizing the treatment approach.(1) 34

38 Managing Patients With Evidence of a Vitamin B 12 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 B 12 Deficiency Options available for treating a clinical vitamin B 12 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 B 12 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 B 12 deficiency is treatable (e.g., fish tapeworm infection or bacterial overgrowth), then treatment should include addressing the underlying etiology.(7) Vitamin B 12 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 B 12 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) Cobalamin replacement is effective because crystalline forms of B 12 can be absorbed even when animal protein-bound forms cannot be digested. Vitamin B 12 is not carcinogenic, teratogenic, or mutagenic. It is considered safe even at 1,000 times the RDA. Baik and Russell, 1999 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 B 12 level and hematologic or neurologic signs or symptoms without pernicious anemia (clinical 35

39 vitamin B 12 deficiency). Once treated for a vitamin B 12 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 B 12 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] ). Regimens for parenteral administration vary. An approach suggested by Stabler and Allen is 1 milligram (mg) (or 1,000 micrograms [µg]) of vitamin B 12 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] ). Oral Large, daily oral replacement doses might be an acceptable alternative if patients are compliant.(7) Sufficient amounts of vitamin B 12 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 B 12 levels with increasing dosages of oral cyanocobalamin.(80) A common therapy is 1 mg (1,000 µg) of vitamin B 12 to be consumed daily.(2, 11, 14) Intranasal A relatively new vehicle for vitamin B 12 therapy is a cyanocobalamin gel for intranasal use. Some experts are not convinced of its efficacy, and the cost is $30 for 36

40 500 µg (Carmel RA. New York Methodist Hospital [personal communication] ). 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 B 12 deficiency are listed in Table 6. 37

41 Table 6. Examples of Treatment Regimens for Clinical Vitamin B 12 Deficiency Due to Initial Cyanocobalamin Maintenance Cyanocobalamin Pernicious Varies, not limited 1 mg IM or SQ q anemia to: month for life 1 mg OR intramuscularly (IM) or subcutaneously (SQ) every (q) week x 8 OR 1 mg 2 mg orally (PO) every day (QD) for life 1 mg IM or SQ x 7 in 1 month Other food- Varies, not limited 1 mg IM or SQ q bound B 12 to: month possibly malabsorption 1 mg IM or SQ q for life problems week x 8 OR 1 mg IM or SQ x 7 in 1 month OR 650 µg 1 mg PO QD possibly for life OR 1 mg 2 mg PO QD Rarer Treat underlying 1 mg IM or SQ q malabsorption condition month problems AND OR (tape worms, Cyanocobalamin 650 µg 1 mg PO bacterial varies, not limited QD overgrowth) to: 1 mg IM or SQ q week x 8 OR 1 mg IM or SQ x 7 in 1 month Treating underlying condition might resolve B 12 deficiency. If cyanocobalamin is d/c d, follow up with regular assessment of metabolites. 38

42 Subclinical Vitamin B 12 Deficiency The far more prevalent patient presentation is by an asymptomatic individual with borderline serum B 12 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 B 12 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 B 12 deficiency category, taking a vitamin with B 12 (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 B 12 deficiency is 500 1,000 µg daily.(80, 82) The providers who test for and treat patients with subclinical vitamin B 12 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

43 Prevention of Vitamin B 12 Deficiencies The... Recommended Dietary Allowance (RDA) (2.4 mcg/day) for B 12 for adults ages 51 and older are the same as for younger adults but with the recommendation that B 12 fortified foods (such as fortified ready-to-eat cereals) or B 12 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 B 12 deficiency provides strong support for the value of prevention.(44, 50, 83) Fortunately, a vitamin B 12 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 B 12 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 B 12. The irreversible nature of the late-stage neurologic effects of a vitamin B 12 deficiency provides strong support for the value of prevention. The Institute of Medicine (IOM) recommends that all adults 18 years of age or older consume 2.4 micrograms (µg) per day of vitamin B 12. (10) Subclinical vitamin B 12 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 B 12 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 B 12. Most multivitamins contain 6 25 µg cyanocobalamin; some contain more. Single 40