Why Vitamin B12 Deficiency Should be on your Radar Screen

Why Vitamin B12 Deficiency Should be on your Radar Screen

Why Vitamin B12 Deficiency Should be on your Radar Screen


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<str<strong>on</strong>g>Why</str<strong>on</strong>g> <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> <str<strong>on</strong>g>Should</str<strong>on</strong>g> Be<br />

<strong>on</strong> Your <strong>Radar</strong> <strong>Screen</strong><br />

A C<strong>on</strong>tinuing Educati<strong>on</strong> Update<br />

Course WB1349<br />

Prepared for the<br />

Nati<strong>on</strong>al Center <strong>on</strong> Birth Defects and Developmental Disabilities<br />

Centers for Disease C<strong>on</strong>trol and Preventi<strong>on</strong><br />

by<br />

Marian L. Evatt, MD 1<br />

Patricia W. Mersereau, MN, CPNP 2<br />

Janet Kay Bobo, PhD 3<br />

Joel Kimm<strong>on</strong>s, PhD 4<br />

Jennifer Williams, MSN, MPH, FNP-BC 5<br />

The findings and c<strong>on</strong>clusi<strong>on</strong>s in this report are those of the authors<br />

and do not necessarily represent the views of the<br />

Centers for Disease C<strong>on</strong>trol and Preventi<strong>on</strong>.<br />

1 Department of Neurology, Emory University, Atlanta, Georgia.<br />

2 SciMetrika, LLC, Atlanta, Georgia.<br />

3 Battelle Centers for Public Health Research and Evaluati<strong>on</strong>, Atlanta, GA and Seattle, Washingt<strong>on</strong>.<br />

4 Nati<strong>on</strong>al Center for Chr<strong>on</strong>ic Disease Preventi<strong>on</strong> and Health Promoti<strong>on</strong>, CDC, Atlanta, Georgia.<br />

5 Nati<strong>on</strong>al Center <strong>on</strong> Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia.<br />


C<strong>on</strong>tents<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Goal and Objectives .................................................................................1<br />

Accreditati<strong>on</strong> ...........................................................................................2<br />

Introducti<strong>on</strong> ............................................................................................3<br />

Case Studies ............................................................................................6<br />

Natural History and Prevalence of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>......................14<br />

Risk Factors for <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> ..................................................20<br />

Manifestati<strong>on</strong>s of Low <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Levels ..............................................23<br />

<strong>Screen</strong>ing Patients .................................................................................27<br />

Detecti<strong>on</strong> and Diagnosis ........................................................................28<br />

Managing Patients With Evidence of a <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>................35<br />

Preventi<strong>on</strong> of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Deficiencies...................................................40<br />

Summary ...............................................................................................42<br />

References.............................................................................................43<br />

References for Text in Boxes .................................................................49<br />

Appendix A: Answers to Case Study Questi<strong>on</strong>s ......................................51<br />

Appendix B: Additi<strong>on</strong>al Articles <strong>on</strong> <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> .....................53<br />

Appendix C: Evaluati<strong>on</strong> Questi<strong>on</strong>naire, Pretest, and Posttest ................56<br />

2/11/2010<br />


Figure and Tables<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Figure 1. The Biochemical Role of Cobalamin........................................ 16<br />

Table 1. Neurologic and Psychiatric Symptoms of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

<str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> and Parkins<strong>on</strong> Disease (PD) ................................... 13<br />

Table 2. Typical Stages in the Development of a<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>.............................................................. 17<br />

Table 3. Prevalence of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Serum Levels for the U.S.<br />

Populati<strong>on</strong> By Age, Nati<strong>on</strong>al Health and Nutriti<strong>on</strong> Examinati<strong>on</strong><br />

Survey 2001–2004 …………………………… 19<br />

Table 4. Prevalence of Nati<strong>on</strong>al Health and Nutriti<strong>on</strong> Examinati<strong>on</strong> Survey<br />

Participants With Biochemically Defined <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>*<br />

By Age Group, United States, 2001–2004 …………………………… 31<br />

Table 5. Tailored Diagnostic Approach for <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>………34<br />

Table 6. Examples of Treatment Regimens for <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>…38<br />

2/11/2010<br />

Disclosure<br />

CDC, planners, and other c<strong>on</strong>tent experts wish to disclose<br />

they have no financial interests or other relati<strong>on</strong>ships with the<br />

manufacturers of commercial products, suppliers of commercial<br />

services, or commercial supporters.<br />

This module will not include any discussi<strong>on</strong>s of the unla<str<strong>on</strong>g>be</str<strong>on</strong>g>led use<br />

of a product or a product under investigati<strong>on</strong>al use.<br />


<str<strong>on</strong>g>Why</str<strong>on</strong>g> <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

<str<strong>on</strong>g>Should</str<strong>on</strong>g> Be <strong>on</strong> Your <strong>Radar</strong> <strong>Screen</strong>:<br />

A C<strong>on</strong>tinuing Educati<strong>on</strong> Update<br />

Goal and Objectives<br />

The goal of this c<strong>on</strong>tinuing educati<strong>on</strong> activity is to<br />

increase the num<str<strong>on</strong>g>be</str<strong>on</strong>g>r of primary care providers<br />

(physicians and midlevel providers) who prevent, detect,<br />

and treat vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies am<strong>on</strong>g their high-risk<br />

patients.<br />

After completing this c<strong>on</strong>tinuing educati<strong>on</strong> material, you<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> able to<br />

• Descri<str<strong>on</strong>g>be</str<strong>on</strong>g> the prevalence in the United States of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency am<strong>on</strong>g adults 51 years of<br />

age or older.<br />

• List three neurologic effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.<br />

• List three hematologic effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.<br />

• Identify the most comm<strong>on</strong> presentati<strong>on</strong> of a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

• Discuss the changes in absorpti<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

that occur with age.<br />

• List at least two pharmacologic opti<strong>on</strong>s for<br />

treatment of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

2/11/2010<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Accreditati<strong>on</strong><br />

C<strong>on</strong>tinuing Medical Educati<strong>on</strong> (CME): This<br />

activity for 1.5 credits is provided by the Centers<br />

for Disease C<strong>on</strong>trol and Preventi<strong>on</strong> (CDC),<br />

accredited by the Accreditati<strong>on</strong> Council for<br />

C<strong>on</strong>tinuing Medical Educati<strong>on</strong> to provide category 1<br />

credits towards the American Medical Associati<strong>on</strong><br />

(AMA) Physician’s Recogniti<strong>on</strong> Award.<br />

C<strong>on</strong>tinuing Nursing Educati<strong>on</strong> (CNE): This<br />

activity for 1.5 c<strong>on</strong>tact hours is provided by CDC,<br />

which is accredited as a provider of c<strong>on</strong>tinuing<br />

educati<strong>on</strong> in nursing by the American Nurses<br />

Credentialing Center’s Commissi<strong>on</strong> <strong>on</strong><br />

Accreditati<strong>on</strong> (ANCC).<br />

Registrati<strong>on</strong><br />

To register for the course and receive free c<strong>on</strong>tinuing<br />

educati<strong>on</strong> credit:<br />

Go to http://www.cdc.gov/tce<strong>on</strong>line..<br />

Log in as a participant (note: the first time you use<br />

the <strong>on</strong>line system you will need to log in as a new<br />

participant and create a participant profile).<br />

Find the course by searching the catalog using the<br />

following course num<str<strong>on</strong>g>be</str<strong>on</strong>g>r: WB1349.<br />

You will need to enter the verificati<strong>on</strong> code (<str<strong>on</strong>g>B12</str<strong>on</strong>g>)<br />

to complete the course.<br />

Select the type of credit you wish to receive and<br />

register for the course.<br />

Take the examinati<strong>on</strong> and complete the course<br />

evaluati<strong>on</strong>.<br />

Print <strong>your</strong> c<strong>on</strong>tinuing educati<strong>on</strong> certificate.<br />

To receive c<strong>on</strong>tinuing educati<strong>on</strong> credit, you must<br />

complete the entire course, take the post-test, and<br />

complete the evaluati<strong>on</strong> <strong>on</strong>line.<br />

During this less<strong>on</strong>, you will find highlighted<br />

terms. Roll <strong>your</strong> mouse over each term for<br />

further informati<strong>on</strong>.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Introducti<strong>on</strong><br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> (cobalamin) deficiency should <str<strong>on</strong>g>be</str<strong>on</strong>g> <strong>on</strong> <strong>your</strong><br />

radar screen for several reas<strong>on</strong>s. Preventi<strong>on</strong>, early<br />

detecti<strong>on</strong>, and treatment of vitamin B deficiency are<br />

important public health issues, <str<strong>on</strong>g>be</str<strong>on</strong>g>cause they are<br />

essential to prevent development of irreversible<br />

neurologic damage which can impact quality of life.<br />

Although most health care providers already recognize<br />

the occasi<strong>on</strong>al pers<strong>on</strong> who presents with obvious signs<br />

and symptoms, they are far less likely to screen and<br />

diagnose the majority of patients who have a subclinical<br />

or mildly symptomatic vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g><br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is more comm<strong>on</strong> am<strong>on</strong>g older adults than<br />

many health care providers realize. Unpublished<br />

analysis at the Centers for Disease C<strong>on</strong>trol and<br />

Preventi<strong>on</strong> (CDC) of laboratory data from communitybased<br />

samples of U.S. adults 51 years of age or older<br />

suggest about 1 (3.2%) of every 31 pers<strong>on</strong>s have serum<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels <str<strong>on</strong>g>be</str<strong>on</strong>g>low 200 picograms per milliliter<br />

(pg/mL).<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> has profound effects <strong>on</strong> human health.<br />

Adequate body stores are essential for several crucial<br />

neurologic and hematologic functi<strong>on</strong>s. Delays in the<br />

diagnosis and treatment of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies can<br />

lead to development of severe, irreversible neurologic<br />

damage.<br />

The clinical importance of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> was established<br />

over 50 years ago, when ingesting raw animal liver (the<br />

primary storage organ for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>) was found to <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

an effective treatment for pernicious anemia. Research<br />

has shown that the water-soluble vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> is required<br />

for the completi<strong>on</strong> of several biochemical processes (see<br />

Figure 1).<br />

The following five top things to remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r about vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> in primary care practice summarize the implicati<strong>on</strong>s<br />

of these and other cobalamin-related findings.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

The top five things to remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r<br />

about vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

1. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies occur in adults 51 years of<br />

age or older at a frequency of 1 (3.2%) in every 31<br />

pers<strong>on</strong>s, and manifest as serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>low the cutpoint of 200 picograms per milliliter.<br />

2. All patients with unexplained hematologic or<br />

neurologic signs or symptoms should <str<strong>on</strong>g>be</str<strong>on</strong>g> evaluated for<br />

a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. If found, the cause should<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> determined.<br />

3. Today, megaloblastic anemia is most likely due to<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency and needs prompt evaluati<strong>on</strong>.<br />

In the United States, folic acid fortificati<strong>on</strong> has made<br />

folate deficient megaloblastic anemia a very rare<br />

c<strong>on</strong>diti<strong>on</strong>.<br />

4. Although the body’s ability to absorb naturally<br />

occurring vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> decreases with age, most people<br />

can readily use the synthetic form of cobalamin.<br />

5. All people 51 years of age or older should get most of<br />

their daily vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> through supplements<br />

c<strong>on</strong>taining vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> or foods fortified with<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

This update has <str<strong>on</strong>g>be</str<strong>on</strong>g>en prepared and organized to address<br />

four questi<strong>on</strong>s pertinent to primary health care<br />

providers:<br />

<str<strong>on</strong>g>Why</str<strong>on</strong>g> should I <str<strong>on</strong>g>be</str<strong>on</strong>g> c<strong>on</strong>cerned about my patient’s<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> status?<br />

o Introducti<strong>on</strong><br />

o Case studies<br />

o Natural history and prevalence of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiencies<br />

o Manifestati<strong>on</strong>s of low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

Which of my patients are at high risk for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency?<br />

o Risk factors for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

How do I detect and diagnose a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency?<br />

o <strong>Screen</strong>ing patients<br />

o Detecti<strong>on</strong> and diagnosis<br />

How should I manage a patient with evidence of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency?<br />

o Managing patients with evidence of a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

o Preventing vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Case Studies<br />

The following case studies are not actual patients. They<br />

combine elements from different cases to emphasize<br />

important aspects of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

Case Study 1<br />

Presentati<strong>on</strong><br />

During a checkup for hypertensi<strong>on</strong>, a 65-year-old female<br />

reports a 2-m<strong>on</strong>th history of tiredness, feeling faint from<br />

“getting up too fast”, and “memory problems”.<br />

Case Study Questi<strong>on</strong> 1<br />

Do any of the presenting complaints raise <strong>your</strong> index of<br />

suspici<strong>on</strong> about a possible vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency? If so,<br />

why?<br />

History<br />

On review of systems, she reports difficulty<br />

c<strong>on</strong>centrating, fatigue, feeling faint when she stands<br />

quickly, and vague gastrointestinal discomfort with some<br />

decrease in appetite.<br />

She denies any history of previous trauma, diplopia,<br />

dysphagia, vertigo, visi<strong>on</strong> loss, loss of c<strong>on</strong>sciousness,<br />

back pain, or symptoms of bowel or bladder dysfuncti<strong>on</strong>.<br />

Her family history is negative for neurologic, psychiatric,<br />

and autoimmune diseases. Her medicati<strong>on</strong>s include an<br />

antihypertensive, as well as an occasi<strong>on</strong>al antiinflammatory<br />

drug for episodic headaches. Her social<br />

history reveals a single woman who smokes about <strong>on</strong>ehalf<br />

pack of cigarettes per day, drinks alcohol <strong>on</strong>ly<br />

socially, and denies illicit drug use. She has a high<br />

school educati<strong>on</strong> and, until recently, had worked in the<br />

office of a trucking company.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Case Study Questi<strong>on</strong> 2<br />

What risk factors does this woman appear to have for a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency?<br />

Physical Examinati<strong>on</strong><br />

Pale 65 y.o. WF who appears well-nourished, alert, and<br />

oriented.<br />

Vital Signs T-98.6, HR-76, R-18, B/P-130/80 supine<br />

and 95/52 up<strong>on</strong> standing,<br />

Height/Weight 5’4”/120 lbs.<br />

Head Normocephalic; oropharynx clear but<br />

pale; palpebral c<strong>on</strong>junctivae pale.<br />

Neck Supple, full active and passive ROM<br />

without pain, without audible bruits; no<br />

lymphadenopathy; no thyromegaly<br />

Back No spine tenderness<br />

Lungs Clear to auscultati<strong>on</strong><br />

Heart Regular rate and rhythm; no murmurs<br />

Abdomen Soft, n<strong>on</strong>tender; no organomegaly<br />

Rectal Normal rectal t<strong>on</strong>e; no fissures<br />

Extremities No clubbing, cyanosis, or edema; FROM<br />

Skin Pale; no rash<br />

The general physical examinati<strong>on</strong> is unremarkable<br />

except for orthostatic hypotensi<strong>on</strong> and a weight loss of 3<br />

pounds since her last visit 6 m<strong>on</strong>ths ago. She is alert<br />

and oriented times three. Her Mini-Mental Status Exam<br />

score is 26 out of 30. She misses <strong>on</strong>e point <strong>on</strong> serial 7s<br />

and is able to recall three of three items. There is<br />

evidence of bilateral mildly diminished vibrati<strong>on</strong> and<br />

propriocepti<strong>on</strong>. Her reflexes are 3+/4+ throughout, with<br />

negative Babinski reflex.<br />

Cranial II—Visual acuity 20/25 in both eyes<br />

Nerves (corrected); normal fundoscopic<br />

examinati<strong>on</strong>; visual fields intact with no<br />

central scotoma<br />

III, IV, VI—Extraocular movements<br />

intact; pupils equal, round, and reactive<br />

to light with no afferent pupillary defect<br />

V, VII, XII—Intact facial sensati<strong>on</strong>; intact<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

masseter motor strength, without<br />

dysarthria; t<strong>on</strong>gue protruded in midline<br />

VIII—Hearing grossly normal<br />

XI, X—Swallowing intact<br />

XI—Muscle strength equal bilaterally<br />

Motor Normal muscle bulk; muscle strength 5/5<br />

in all muscle groups<br />

Cere<str<strong>on</strong>g>be</str<strong>on</strong>g>llar Normal finger-to-nose, heel-to-shin, and<br />

rapid alternating movements<br />

Case Study Questi<strong>on</strong>s<br />

3. Does the fact that she appears to <str<strong>on</strong>g>be</str<strong>on</strong>g> “well-nourished”<br />

indicate she is unlikely to have a vitamin deficiency? <str<strong>on</strong>g>Why</str<strong>on</strong>g><br />

or why not?<br />

4. Are there any aspects of her physical examinati<strong>on</strong> that<br />

suggest a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency?<br />

5. Given her history and physical examinati<strong>on</strong> findings,<br />

what laboratory test(s) would you order?<br />

Laboratory Studies<br />

You order routine laboratory studies, which include<br />

complete blood count (CBC) with smear and chemistry<br />

screen. In additi<strong>on</strong>, you order a serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> level<br />

to investigate further the etiology of her fatigue and pale<br />

mucosa. Results from the CBC and smear reveal a<br />

borderline macrocytic anemia. The chemistry panel is<br />

within normal limits. The serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> level you<br />

requested is 215 picograms per milliliter (pg/mL). This<br />

level is c<strong>on</strong>sidered within a “normal range” by some<br />

laboratories, but you take into account her other signs<br />

and symptoms and request c<strong>on</strong>firmatory testing with<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

methylmal<strong>on</strong>ic acid (MMA) and homocysteine (Hcy)<br />

levels.<br />

Results of C<strong>on</strong>firmatory Testing<br />

Both her MMA and Hcy levels are elevated. Her MMA is<br />

greater than 0.5 micromoles per liter (μmol/L), and her<br />

Hcy is greater than 17 μmol/L, c<strong>on</strong>firming <strong>your</strong> suspici<strong>on</strong><br />

that this patient has a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

You decide to investigate the cause of her vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency. Although she denies a history of pernicious<br />

anemia in her family and she has had no previous<br />

indicati<strong>on</strong> of autoimmune diseases, you order an antiintrinsic<br />

factor (IF) antibody test that c<strong>on</strong>firms the<br />

presence of pernicious anemia.<br />

Management<br />

You explain that with the diagnosis of pernicious anemia<br />

she will have to c<strong>on</strong>tinue vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> therapy for the<br />

remainder of her life, and you make a note <strong>on</strong> her chart<br />

to assess her compliance at each visit. You also advise<br />

her to inform her family of the diagnosis <str<strong>on</strong>g>be</str<strong>on</strong>g>cause there<br />

is possibly a genetic comp<strong>on</strong>ent.<br />

You start her <strong>on</strong> vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> intramuscular (IM)<br />

injecti<strong>on</strong>s. She gets IM cyanocobalamin 1,000<br />

micrograms (µg) two times per week for 2 weeks and<br />

then switches to oral vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> 1,000 µg daily<br />

thereafter. Almost immediately after the initiati<strong>on</strong> of<br />

injecti<strong>on</strong>s, she reports improved c<strong>on</strong>centrati<strong>on</strong>. Within 2<br />

weeks, she notes less fatigue and normal appetite.<br />

Case Study 2<br />

Presentati<strong>on</strong><br />

An 85-year-old female with a 15-year history of<br />

Parkins<strong>on</strong> disease (PD) is seen for her regularly<br />

scheduled follow-up with her neurologist.<br />

History<br />

On review of systems, family mem<str<strong>on</strong>g>be</str<strong>on</strong>g>rs report that she<br />

has <str<strong>on</strong>g>be</str<strong>on</strong>g>come more withdrawn and irritable during the last<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

6 m<strong>on</strong>ths. They also report that activities she previously<br />

accomplished without difficulty, such as going to church,<br />

seem to exhaust her. She acknowledges this symptom,<br />

stating that she feels her stamina is much lower than at<br />

the time of the last visit.<br />

She and her family do not report an appreciable<br />

difference in or worsening of her motor symptoms, but<br />

they do report that she has had some hallucinati<strong>on</strong>s in<br />

the form of seeing farm animals periodically in her room.<br />

Her current medicati<strong>on</strong>s include Stalevo(carbidopa,<br />

levodopa, and entacap<strong>on</strong>e), amantadine, Evista ®<br />

(raloxifene hydrochloride), Effexor ® XL (venlafaxine<br />

hydrochloride), Detrol ® LA (tolterodine tartrate),<br />

Mirapex ® (pramipexole dihydrochloride), and Ambien ®<br />

(zolpidem tartrate). She denies any obsessive or<br />

compulsive <str<strong>on</strong>g>be</str<strong>on</strong>g>haviors or any recent trauma, but she<br />

does admit having a decreased appetite and eating little<br />

or no meat. Her family descri<str<strong>on</strong>g>be</str<strong>on</strong>g>s her nutriti<strong>on</strong>al intake<br />

as poor, stating that she is just getting by <strong>on</strong> “tea and<br />

toast”.<br />

Her social history reveals a widowed elderly woman who<br />

lives with her s<strong>on</strong> and daughter-in-law. She had lived<br />

independently until 5 years ago, when completing her<br />

activities of daily living (ADLs) <str<strong>on</strong>g>be</str<strong>on</strong>g>came too difficult. She<br />

currently has a home health nurse visit <strong>on</strong>ce a day to<br />

assist with ADLs and no<strong>on</strong>time medicati<strong>on</strong>s while her<br />

family is at work.<br />

Physical Examinati<strong>on</strong><br />

A general examinati<strong>on</strong> reveals a frail, thin female with<br />

skin irritati<strong>on</strong> and slight amount of saliva evident at the<br />

right corner of her mouth (the side where her PD<br />

symptoms are more pr<strong>on</strong>ounced). She has slight<br />

puffiness but no pitting of her ankles bilaterally.<br />

A neurological examinati<strong>on</strong> reveals that she is alert and<br />

oriented to pers<strong>on</strong>, place, and year. She remem<str<strong>on</strong>g>be</str<strong>on</strong>g>rs 3<br />

out of 3 items, but can recall <strong>on</strong>ly <strong>on</strong>e of three items 3<br />

minutes later. She has definite facial masking and a<br />

decreased blink rate. Cranial nerve examinati<strong>on</strong> reveals<br />

moderate hypoph<strong>on</strong>ia (low voice volume) and an<br />

intermittent tremor. She is moderately stooped with a<br />

slight tilt to the right, and she has difficulty rising from a<br />

10<br />

Protein intake am<strong>on</strong>g patients<br />

with Parkins<strong>on</strong> disease (PD)<br />

might interfere with levodopa’s<br />

clinical <str<strong>on</strong>g>be</str<strong>on</strong>g>nefit. Thus, PD patients<br />

might inadvertently increase their<br />

risk of vitamin B 12 deficiency by<br />

avoiding meat, the dietary source<br />

of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

chair without assistance, even though her strength is<br />

normal. She has a mild-to-moderate intermittent resting<br />

tremor, worse <strong>on</strong> her right side. Sensory examinati<strong>on</strong><br />

reveals decreased vibratory thresholds in both legs up to<br />

her ankles. Reflexes are 3+ out of 4 with crossed<br />

adductor spread in her legs, and her plantar reflex<br />

shows positive Babinski bilaterally.<br />

Laboratory Studies<br />

Her neurologist orders some routine laboratory studies,<br />

including a CBC with smear and chemistry panel. In<br />

additi<strong>on</strong>, the neurologist decides to get a serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>cause she is c<strong>on</strong>sidered at high risk for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency, and many of the symptoms of PD also can <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

attributed to vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

Results from the CBC with smear dem<strong>on</strong>strate no<br />

evidence of anemia. The chemistry panel is within<br />

normal limits, with the excepti<strong>on</strong> of a slightly elevated<br />

serum creatinine (1.5 milligrams per deciliter). Her<br />

serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level is 225 pg/mL, within the laboratory’s<br />

normal range of 180–900 pg/mL. The neurologist<br />

c<strong>on</strong>siders this value as “low-normal” and requests<br />

c<strong>on</strong>firmatory testing with MMA and HCY levels.<br />

Results of C<strong>on</strong>firmatory Testing<br />

Her HCY is elevated at 18 µmols/L; however, her<br />

neurologist recognizes that this finding al<strong>on</strong>e is not<br />

c<strong>on</strong>sidered diagnostic, given that levodopa has <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

known to alter HCY levels.<br />

Her MMA is borderline at 0.38 µmol/L but, again, this<br />

finding is not diagnostic.<br />

Although PD can explain most of her symptoms, vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency can also account for some of them. Her<br />

age is a risk factor for atrophic gastritis, and her diet<br />

seems to <str<strong>on</strong>g>be</str<strong>on</strong>g> deficient in protein so both malabsorpti<strong>on</strong><br />

and malnutriti<strong>on</strong> could c<strong>on</strong>tribute to borderline vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

11<br />

Slightly elevated creatinine<br />

could indicate age-related<br />

changes in renal functi<strong>on</strong>,<br />

dehydrati<strong>on</strong>, or mild renal<br />

insufficiency from other<br />

causes.<br />

C<strong>on</strong>versi<strong>on</strong>s<br />

1,000 nmol/L* = 1 µmol/L<br />

376 nmol/L = 0.376 µmol/L<br />

*nanomols per liter

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Management<br />

Given the uncertain nature of the test results, her<br />

neurologist discusses vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> supplementati<strong>on</strong> with<br />

her. She expresses disinterest in oral supplementati<strong>on</strong>,<br />

stating “If I have to take <strong>on</strong>e more pill, I will scream.”<br />

Because the laboratory findings are ambiguous, the<br />

neurologist and she agree to m<strong>on</strong>itor her status rather<br />

than start injecti<strong>on</strong> therapy immediately.<br />

On her return visit 6 m<strong>on</strong>ths later, her serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

is 189 pg/mL, and both her Hcy and MMA levels have<br />

increased. Her neurologist orders antiparietal cell<br />

antibody and anti-intrinsic factor antibody tests to rule<br />

out pernicious anemia. Both tests are negative. She is<br />

started <strong>on</strong> 1,000 µg of IM cyanocobalamin for 5 days,<br />

followed by m<strong>on</strong>thly injecti<strong>on</strong>s of 1,000 µg of IM<br />

cyanocobalamin. Her neurologist makes arrangements<br />

for the home health nurse to administer the injecti<strong>on</strong>s.<br />

At the next visit, the patient and her family report that<br />

she is less fatigued, less irritable, and less withdrawn.<br />

There is no worsening of motor symptoms; however, she<br />

still experiences occasi<strong>on</strong>al hallucinati<strong>on</strong>s.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Table 1. Neurologic and Psychiatric Symptoms of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

<str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> and Parkins<strong>on</strong> Disease (PD)<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> PD<br />

Aut<strong>on</strong>omic<br />

Impotence, urinary or fecal inc<strong>on</strong>tinence<br />

Orthostatic hypotensi<strong>on</strong><br />

Cerebral<br />

Dementia, memory loss, cognitive impairment<br />

Depressi<strong>on</strong><br />

Psychosis<br />

Myelopathic<br />

Subacute combined degenerati<strong>on</strong><br />

Ataxia<br />

Spasticity<br />

Lehrmitte sign (electric-shock–like sensati<strong>on</strong>s in the<br />

spine)<br />

Abnormal Gait †<br />

Spastic<br />

Shuffling<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

<str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

C<strong>on</strong>stituti<strong>on</strong>al<br />

+<br />

Fatigue<br />

*Seen in PD or resulting from dopaminergic PD treatment), or<br />

both<br />

†<br />

Note gait abnormalities do not always appear “typical” of<br />

textbook descripti<strong>on</strong>s<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+<br />

+*<br />

+<br />

+*<br />

-<br />

-<br />

-<br />

+<br />

+ -<br />

- +<br />

13<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Natural History and Prevalence of<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

“Although elderly people with low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> status frequently<br />

lack the classical signs and symptoms of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency,<br />

e.g. megaloblastic anemia, precise evaluati<strong>on</strong> and treatment in<br />

this populati<strong>on</strong> is important.” Baik and Russell, 1999<br />

The case studies illustrate two important facts about<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> (cobalamin). First, low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels can<br />

have profound effects <strong>on</strong> patient well-<str<strong>on</strong>g>be</str<strong>on</strong>g>ing. Although<br />

most patients with a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency are in a<br />

subclinical stage(1-7) and do not present with symptoms<br />

or complaints such as those of the case study patients,<br />

some patients might <str<strong>on</strong>g>be</str<strong>on</strong>g> at risk for developing serious<br />

sequelae if the deficiency is not detected and the<br />

patients followed with reassessment, prophylaxis, or<br />

treatment, as needed. Sec<strong>on</strong>d, treatment is safe and<br />

remarkably effective if provided <str<strong>on</strong>g>be</str<strong>on</strong>g>fore permanent<br />

damage occurs. Understanding the biochemistry of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>, the problems that might develop when<br />

cobalamin body stores are depleted, and current<br />

treatment strategies can help clinicians prevent<br />

significant morbidity am<strong>on</strong>g their patients.<br />

The nutriti<strong>on</strong>al value of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> was initially<br />

established in the first half of the 20 th century, when<br />

ingesting raw animal liver (the primary storage organ for<br />

this nutrient) was found to <str<strong>on</strong>g>be</str<strong>on</strong>g> an effective treatment for<br />

pernicious anemia.(8) Humans cannot manufacture<br />

cobalamin and must c<strong>on</strong>sume it <strong>on</strong> a regular basis.<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> is a water-soluble compound that is naturally<br />

available for human use <strong>on</strong>ly through ingesti<strong>on</strong> of animal<br />

proteins, such as <str<strong>on</strong>g>be</str<strong>on</strong>g>ef, poultry, fish, eggs, and dairy<br />

products. Unfortified, plant-based foods do not c<strong>on</strong>tain<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.(2, 9, 10)<br />

14<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> is naturally<br />

available for human use <strong>on</strong>ly<br />

through ingesti<strong>on</strong> of animal<br />

proteins. Unfortified plantbased<br />

foods do<br />

not c<strong>on</strong>tain<br />

vitamin B .<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

There are several important points about cobalamin<br />

absorpti<strong>on</strong>:<br />

It occurs primarily during the active digesti<strong>on</strong> of<br />

animal proteins in the stomach and terminal ileum,<br />

and it depends <strong>on</strong> the availability of adequate<br />

amounts of a num<str<strong>on</strong>g>be</str<strong>on</strong>g>r of compounds, including the R<br />

protein (haptocorrin from saliva), gastric acid, pepsin,<br />

and intrinsic factor (IF).(2, 3)<br />

Gastric acid is needed to digest animal protein. When<br />

the ability to secrete that acid is lost, a pers<strong>on</strong> cannot<br />

break down the protein to release vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> from<br />

food and can absorb <strong>on</strong>ly crystalline (synthetic)<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.(2)<br />

Loss of IF in pernicious anemia results in an inability<br />

to absorb vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. People with pernicious anemia<br />

must <str<strong>on</strong>g>be</str<strong>on</strong>g> treated with parenteral cyanocobalamin or<br />

high doses of oral cobalamin<br />

(1,000 micrograms [µg] daily).(2, 11)<br />

About 1% of large oral doses of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> passively<br />

diffuses into the bloodstream from the small<br />

intestine.(2, 10)<br />

If any aspect of the digesti<strong>on</strong> sequence <str<strong>on</strong>g>be</str<strong>on</strong>g>gins to fail<br />

and malabsorpti<strong>on</strong> develops, the body can draw <strong>on</strong><br />

the large amounts of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> stored in the liver,<br />

so overt symptoms might not develop for several<br />

years.(2, 10, 12) However, with certain c<strong>on</strong>diti<strong>on</strong>s,<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency might develop over a shorter<br />

period of time (m<strong>on</strong>ths).<br />

Adequate serum levels of cobalamin are crucial to<br />

complete three enzymatic processes (Figure 1).<br />

Methylcobalamin is a cofactor necessary to c<strong>on</strong>vert<br />

homocysteine (Hcy) to methi<strong>on</strong>ine. Thus, vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency increases Hcy.(1, 12, 13)<br />

The cofactor adenosylcobalamin is required for the<br />

c<strong>on</strong>versi<strong>on</strong> of methylmal<strong>on</strong>yl coenzyme A to<br />

succinyl coenzyme A.(2, 10)<br />

Methylcobalamin is needed to c<strong>on</strong>vert 5methyltetrahydrofolate<br />

to tetrahydrofolate and is<br />

necessary for DNA and red blood cell producti<strong>on</strong>.<br />

15<br />

Pernicious anemia is an<br />

autoimmune disease in<br />

which antibodies attack<br />

gastric cells, resulting in<br />

impaired producti<strong>on</strong> of<br />

intrinsic factor that is<br />

critical for absorpti<strong>on</strong> of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Figure 1. The Biochemical Role of Cobalamin<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies often, but not always, develop<br />

gradually over many years and are accompanied by a<br />

slow and varied <strong>on</strong>set of n<strong>on</strong>specific symptoms. Carmel<br />

descri<str<strong>on</strong>g>be</str<strong>on</strong>g>s vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency in two states: clinical<br />

and subclinical.(1) Clinical deficiency manifests with<br />

hematologic or neurologic signs and symptoms,<br />

cobalamin levels

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

The first to c<strong>on</strong>ceptualize the natural history of a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, Her<str<strong>on</strong>g>be</str<strong>on</strong>g>rt noted that vegetarians with<br />

dietary vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> insufficiency progressed through four<br />

stages: serum depleti<strong>on</strong>; cell depleti<strong>on</strong>; biochemical<br />

deficiency (defined as elevated levels of Hcy and MMA);<br />

and, finally, the classic signs and symptoms of clinical<br />

deficiency, such as anemia (Table 2).(9, 15)<br />

Table 2. Typical Stages in the Development of a <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g><br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>. Her<str<strong>on</strong>g>be</str<strong>on</strong>g>rt, 1994<br />

Stage Manifestati<strong>on</strong> Comment<br />

I<br />

II<br />

III<br />

IV<br />

Circulating serum <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

levels depleted<br />

Cellular stores of <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

are depleted<br />

Evidence of biochemical<br />

deficiency via<br />

increases in serum<br />

homocysteine and<br />

methylmal<strong>on</strong>ic acid<br />

Clinical signs and<br />

symptoms apparent<br />

Patients are typically<br />

asymptomatic and can<br />

remain in this stage for<br />

several years.<br />

Patients can remain<br />

asymptomatic. This stage<br />

can also c<strong>on</strong>tinue for several<br />

years.<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> is required for<br />

the c<strong>on</strong>versi<strong>on</strong> of these<br />

compounds.<br />

The spectrum of clinical<br />

manifestati<strong>on</strong>s is broad and<br />

the sequence of symptom<br />

development varies<br />

markedly.<br />

Although this model provides a useful perspective,<br />

untreated patients will not necessarily advance through<br />

the stages chr<strong>on</strong>ologically or linearly. Progressi<strong>on</strong> to a<br />

later stage is not inevitable, and some patients with<br />

evidence of an early stage deficiency might have normal<br />

laboratory values when retested.(11) Malabsorpti<strong>on</strong> of<br />

food-derived cobalamin <str<strong>on</strong>g>be</str<strong>on</strong>g>cause of decreased gastric<br />

acid producti<strong>on</strong> is a more likely reas<strong>on</strong> for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency, while malabsorpti<strong>on</strong> of cobalamin <str<strong>on</strong>g>be</str<strong>on</strong>g>cause of<br />

lack of IF in pernicious anemia is a less prevalent<br />

cause.(3)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Prevalence of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

The true prevalence of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency tends to <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

underestimated for several reas<strong>on</strong>s. The comm<strong>on</strong><br />

misc<strong>on</strong>cepti<strong>on</strong> that most vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies are due<br />

to inadequate dietary intake might lead to overlooking<br />

important high-risk groups. Older adults who routinely<br />

c<strong>on</strong>sume meat and other animal proteins can still <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficient due to malabsorpti<strong>on</strong>. Clinical<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies are relatively rare. Most<br />

patients are far more likely to have mild, subclinical<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.(1)<br />

Most prevalence estimates are based solely <strong>on</strong> serum<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> results. C<strong>on</strong>fusi<strong>on</strong> can arise <str<strong>on</strong>g>be</str<strong>on</strong>g>cause<br />

cobalamin values are measured in picomoles per liter<br />

(pmol/L) in some research studies, while clinical<br />

laboratories express values in picograms per milliliter<br />

(pg/mL) or nanograms per liter (ng/L). The most<br />

frequently reported threshold value is 200 pg/mL (148<br />

pmol/L).(1, 16) Studies that have established higher<br />

cutpoints invariably have reported higher prevalence<br />

estimates. In the research literature, some investigators<br />

have used diagnostic algorithms that combine serum <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

results with <strong>on</strong>e or more additi<strong>on</strong>al laboratory findings,<br />

typically either serum Hcy or MMA.(1, 4, 17, 18)<br />

Depending <strong>on</strong> the approach used, the additi<strong>on</strong>al test<br />

findings have raised(4, 18, 19) or lowered(6, 19, 20) the<br />

observed prevalence of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency compared<br />

with findings based solely <strong>on</strong> serum vitamin B 12 levels.<br />

Unpublished data from the Nati<strong>on</strong>al Health and Nutriti<strong>on</strong><br />

Examinati<strong>on</strong> Survey (NHANES) 2001–2004 in Table 3<br />

stratified by age have estimated that 1 (3.2%) of every<br />

31 adults 51 years of age or older in the United States<br />

has a low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> serum level. Most of these people<br />

are ambulatory and do not have overt symptoms of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

18<br />

C<strong>on</strong>versi<strong>on</strong>s<br />

ng/L = pg/mL<br />

pmol/L = pg/mL x 0.738<br />

pg/mL = pmol/L ÷ 0.738<br />

Keep in mind that ng/L has<br />

the same value as pg/mL but<br />

c<strong>on</strong>versi<strong>on</strong> to pmol/L requires<br />

multiplicati<strong>on</strong> of pg/mL by<br />

0.738 (200 pg/mL<br />

x 0.738 =<br />

148 pmol/L).

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Table 3. Prevalence of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Serum Levels for<br />

the U.S. Populati<strong>on</strong> by Age, Nati<strong>on</strong>al Health and<br />

Nutriti<strong>on</strong> Examinati<strong>on</strong> Survey 2001–2004<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> 9–13 14–18 19–30 31–50 ≥ 51<br />

Serum Level years years years years years<br />

of age of age of age of age of age<br />

≤ 150 pg/mL<br />

0 0.2% 0.2% 0.5% 1.2%<br />

151–200 0.1% 0.6% 1.5% 1.0% 2.0%<br />

pg/mL<br />

201–250 0.6% 2.5% 5.2% 6.1% 5.1%<br />

pg/mL<br />

251–300 1.6% 5.4% 7.9% 6.9% 6.2%<br />

pg/mL<br />

301–350 4.2% 9.4% 11.3% 10.7% 8.9%<br />

pg/mL<br />

351–400 5.4% 9.2% 13.1% 13.5% 10.7%<br />

pg/mL<br />

> 400 pg/mL 88.0% 72.7% 60.8% 61.2% 65.8%<br />

Those prevalence figures are supported by other<br />

populati<strong>on</strong>-based studies. The Framingham study with a<br />

cohort of n<strong>on</strong>instituti<strong>on</strong>alized adults 67 through 96 years<br />

of age found that 5.3% of the participants had serum<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Risk Factors for<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

“The clinical indicati<strong>on</strong>s (for cobalamin deficiency) are of<br />

prime importance since routine screening tests, such as<br />

the blood count, are not always abnormal. The same<br />

criteria apply to both sexes and to all age groups,<br />

including preterm infants and children.” Amos, 1994<br />

Patient characteristics that increase the likelihood of a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency can <str<strong>on</strong>g>be</str<strong>on</strong>g> divided broadly into<br />

demographic and <str<strong>on</strong>g>be</str<strong>on</strong>g>havioral characteristics that increase<br />

the risk of inadequate dietary intake (malnutriti<strong>on</strong>) and<br />

physiologic factors that increase the risk of<br />

malabsorpti<strong>on</strong>. Some factors, such as advanced age,<br />

might increase the risk of both malnutriti<strong>on</strong> and<br />

malabsorpti<strong>on</strong>. In the United States, most cases of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency are due to malabsorpti<strong>on</strong> rather<br />

than inadequate intake. We will review the more obvious<br />

demographic and <str<strong>on</strong>g>be</str<strong>on</strong>g>havioral “red flags” of aging and<br />

strict vegetarianism and vegan diets and then<br />

summarize the less readily apparent but more comm<strong>on</strong><br />

physiologic factors that can affect absorpti<strong>on</strong>.<br />

Demographic and Behavioral Risk Factors<br />

The risk of developing a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency increases<br />

with age.(1, 6, 16, 21-23) The elderly, defined as<br />

individuals 65 years of age or older, are more likely to<br />

develop a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency <str<strong>on</strong>g>be</str<strong>on</strong>g>cause they are at risk<br />

for both malabsorpti<strong>on</strong> and malnutriti<strong>on</strong>. The frail<br />

elderly, especially, might have dietary insufficiency for a<br />

num<str<strong>on</strong>g>be</str<strong>on</strong>g>r of reas<strong>on</strong>s, including cognitive dysfuncti<strong>on</strong>,<br />

social isolati<strong>on</strong>, mobility limitati<strong>on</strong>s, and poverty.<br />

In c<strong>on</strong>trast to the importance of age, other demographic<br />

characteristics, including sex, race, and ethnicity, are not<br />

as important in predicting vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. While<br />

several studies have found that mild cobalamin<br />

deficiency is most comm<strong>on</strong> am<strong>on</strong>g elderly White men<br />

and least comm<strong>on</strong> am<strong>on</strong>g Black or African-American and<br />

Asian-American women, (2, 3, 16, 24) the differences<br />

20<br />

In the United<br />

States, most cases<br />

of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency are due<br />

to malabsorpti<strong>on</strong>.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

are not sufficient to support sex- or race-specific nutrient<br />

recommendati<strong>on</strong>s.(10)<br />

A patient characteristic that should always raise the<br />

index of suspici<strong>on</strong> is l<strong>on</strong>g-term adherence to a strict<br />

vegetarian or vegan diet,(10, 16, 25, 26) <str<strong>on</strong>g>be</str<strong>on</strong>g>cause vegan<br />

diets exclude all forms of animal protein, including eggs<br />

and dairy products. Thoughtfully planned vegetarian<br />

diets that include eggs, milk, and yogurt can provide<br />

adequate amounts of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. Short-term adherence<br />

to strict vegetarian and vegan diets might not cause a<br />

problem <str<strong>on</strong>g>be</str<strong>on</strong>g>cause of the large amount of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

typically stored in the liver. However, it is prudent to<br />

advise all vegetarian and vegan patients, particularly if<br />

they are elderly or anticipating a pregnancy, to c<strong>on</strong>sume<br />

synthetic cobalamin daily, either by taking a supplement<br />

c<strong>on</strong>taining vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> or eating a serving of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>–<br />

fortified grain products.(10) The requirement for vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> increases for pregnant and lactating women.(10) To<br />

review the vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> c<strong>on</strong>tent of a variety of vegetarian<br />

and vegan foods, see<br />

http://www.nal.usda.gov/fnic/foodcomp/search/.<br />

Physiologic Factors<br />

Malabsorpti<strong>on</strong> is the physiologic cause of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency and can result from a num<str<strong>on</strong>g>be</str<strong>on</strong>g>r of c<strong>on</strong>diti<strong>on</strong>s.<br />

Frequently menti<strong>on</strong>ed are pernicious anemia; (7, 24)<br />

atrophic gastritis;(3, 10, 27) gastric surgery (e.g., ileal<br />

resecti<strong>on</strong> and gastrectomy);(11, 16, 28) presence of a<br />

cobalamin-utilizing fish tapeworm such as the<br />

Diphyllobothrium latum;(2, 29) and other c<strong>on</strong>current<br />

diseases such as Crohn disease, HIV infecti<strong>on</strong>,(30-32)<br />

celiac sprue,(33, 34) and bacterial overgrowth in the<br />

small intestine.(35) Rare cases have <str<strong>on</strong>g>be</str<strong>on</strong>g>en attributed to<br />

anesthetic nitrous oxide exposure.(2, 36)<br />

Am<strong>on</strong>g the elderly, atrophic gastritis and pernicious<br />

anemia are the main causes of malabsorpti<strong>on</strong>. Atrophic<br />

gastritis often develops as people age. With resulting<br />

hypochlorhydria and achlorhydria, the body does not<br />

produce enough pepsin and hydrochloric acid to release<br />

from protein the food-bound vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. In pernicious<br />

anemia, missing IF needed to attach <str<strong>on</strong>g>B12</str<strong>on</strong>g> in the small<br />

intestine impairs the uptake of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.<br />

21<br />

Inadequate absorpti<strong>on</strong><br />

Pernicious anemia<br />

Atrophic gastritis<br />

Small intestinal bacterial<br />

overgrowth<br />

Gastrointestinal surgery<br />

(e.g., ileal resecti<strong>on</strong> or<br />

gastrectomy)<br />

Presence of a cobalaminutilizing<br />

fish tapeworm,<br />

such as Diphyllobothrium<br />

latum<br />

Crohn disease<br />

HIV infecti<strong>on</strong><br />

Celiac sprue<br />

Nitrous oxide causes the<br />

inactivati<strong>on</strong> of vitamin B 12,<br />

which might result in acute<br />

hematologic or neurologic<br />

complicati<strong>on</strong>s of vitamin B 12<br />

deficiency. Because nitrous<br />

oxide is a comm<strong>on</strong>ly used<br />

anesthetic in surgery, people<br />

at risk (e.g., the elderly)<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> m<strong>on</strong>itored for a<br />

developing symptomatic<br />

vitamin B 12 deficiency.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Undiagnosed and untreated pernicious anemia affects<br />

1%–2% of the elderly populati<strong>on</strong>.(24)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Manifestati<strong>on</strong>s of<br />

Low <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Levels<br />

“Although some clinical expressi<strong>on</strong>s remain mysterious,<br />

especially the neurological dysfuncti<strong>on</strong>, our view of<br />

cobalamin deficiency has expanded <str<strong>on</strong>g>be</str<strong>on</strong>g>y<strong>on</strong>d the questi<strong>on</strong><br />

of megaloblastic anemia.”<br />

Carmel, 2000<br />

No single symptom, or cluster of symptoms, has <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

uniquely associated with inadequate levels of vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g>. Am<strong>on</strong>g older adults, the most frequently reported<br />

symptoms of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency are hematologic or<br />

neurologic in nature, but gastrointestinal and<br />

possibly vascular symptoms are also comm<strong>on</strong>. The<br />

typically n<strong>on</strong>specific manifestati<strong>on</strong>s of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency underscore the importance of encouraging all<br />

older adults to c<strong>on</strong>sume the synthetic form of the<br />

vitamin each day. Recent c<strong>on</strong>cerns have also <str<strong>on</strong>g>be</str<strong>on</strong>g>en raised<br />

about potential adverse effects <strong>on</strong> infant growth and<br />

development in exclusively breastfed babies of<br />

mothers who adhere to a strict vegan diet.(11, 16)<br />

While this situati<strong>on</strong> is rare in the United States, sequelae<br />

are often severe and irreversible in these children.<br />

Hematologic Manifestati<strong>on</strong>s<br />

Comm<strong>on</strong> symptoms associated with hematologic<br />

pathology include skin pallor, weakness, fatigue,<br />

syncope, shortness of breath, and palpitati<strong>on</strong>s.(2, 10) A<br />

classic hematologic sign of severe vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

is megaloblastic anemia.(2) Hematologic manifestati<strong>on</strong>s<br />

might also <str<strong>on</strong>g>be</str<strong>on</strong>g> due to folate deficiency. However, since<br />

1998, the U.S. Food and Drug Administrati<strong>on</strong> has<br />

required fortificati<strong>on</strong> of all enriched grain and cereal<br />

products with 140 micrograms (µg) of folic acid per 100<br />

grams of cereal grain product,(37) and that fortificati<strong>on</strong><br />

of the U.S. food supply essentially has eliminated the<br />

prevalence of folate deficiency.(21) Today, in the United<br />

States, a case of megaloblastic anemia most likely<br />

is due<br />

to<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency until proven otherwise.<br />

Although vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is not always<br />

accompanied by hematologic changes, the majority of<br />

23<br />

Today, in the United<br />

States, megaloblastic<br />

anemia is most likely<br />

due to a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency until proven<br />

otherwise.<br />

Folic acid fortificati<strong>on</strong> does not<br />

have an effect <strong>on</strong> the<br />

prevalence of megaloblastic<br />

anemia attributable to vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. Very high doses<br />

of folic acid (>5,000 µg each<br />

day) can correct the<br />

hematologic manifestati<strong>on</strong>s of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency; however,<br />

the amount of folic acid<br />

available through fortificati<strong>on</strong> as<br />

specified by the U.S. Food and<br />

Drug Administrati<strong>on</strong> (FDA) is<br />

not likely to affect a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency-induced<br />

anemia<br />

(FDA, 1996).

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

patients with clinical deficiency will have signs of<br />

megaloblastic anemia. In various studies c<strong>on</strong>ducted<br />

am<strong>on</strong>g patients with overt vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, 56%–<br />

77% of people had signs of macrocytosis or<br />

anemia.(5, 38-41) Furthermore, some researchers<br />

have found that the presence of neurologic<br />

manifestati<strong>on</strong>s of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency might even <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

correlated inversely with evidence of hematologic<br />

effects.(10, 39, 42)<br />

Neurologic Manifestati<strong>on</strong>s<br />

Comm<strong>on</strong> neurologic complaints include paresthesias<br />

(with or without objective signs of neuropathy),<br />

weakness, motor disturbances (including gait<br />

abnormalities), visi<strong>on</strong> loss, and a wide range of cognitive<br />

and <str<strong>on</strong>g>be</str<strong>on</strong>g>havioral changes (e.g., dementia, hallucinati<strong>on</strong>s,<br />

psychosis, paranoia, depressi<strong>on</strong>, violent <str<strong>on</strong>g>be</str<strong>on</strong>g>havior, and<br />

pers<strong>on</strong>ality changes). Tingling of the hands and feet is<br />

perhaps the most comm<strong>on</strong> neurologic complaint.(2, 41,<br />

42)<br />

The pathology of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency <strong>on</strong> the nervous<br />

system is unknown.(7)<br />

All patients with unexplained cognitive decline or<br />

dementia should <str<strong>on</strong>g>be</str<strong>on</strong>g> assessed for a possible vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.(41, 43-45) Several current case reports and<br />

studies support the comm<strong>on</strong> practice of assessing<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels during dementia workups.(41, 46-48)<br />

Although <strong>on</strong>ly a minority (1.5%) of all dementia cases<br />

are fully reversible following treatment,(49) many<br />

dementias from other etiologies (e.g., Parkins<strong>on</strong> or<br />

Alzheimer disease) are exacerbated when patients have<br />

a c<strong>on</strong>comitant low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> level. The American<br />

Academy of Neurology (AAN) has c<strong>on</strong>cluded that<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>cause vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is a likely comorbidity<br />

am<strong>on</strong>g the elderly, and am<strong>on</strong>g patients with suspected<br />

dementia in particular, it should <str<strong>on</strong>g>be</str<strong>on</strong>g> recognized and<br />

treated. The AAN practice guideline states that <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> included in routine assessments of dementia<br />

am<strong>on</strong>g the elderly.(44)<br />

24<br />

Many <str<strong>on</strong>g>B12</str<strong>on</strong>g>–deficient<br />

patients do have<br />

anemia or<br />

macrocytosis.<br />

All patients newly<br />

diagnosed with<br />

unexplained cognitive<br />

decline or dementia<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> assessed for a<br />

possible vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Gastrointestinal Manifestati<strong>on</strong>s<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency might also manifest with<br />

gastrointestinal complaints. Some frequently menti<strong>on</strong>ed<br />

symptoms include anorexia, flatulence, diarrhea, and<br />

c<strong>on</strong>stipati<strong>on</strong>.(7, 10, 36, 50) These symptoms can<br />

develop am<strong>on</strong>g patients with a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

without accompanying anemia, macrocytosis, or overt<br />

neurologic deficits. Glossitis, which is comm<strong>on</strong>ly thought<br />

to <str<strong>on</strong>g>be</str<strong>on</strong>g> a cardinal sign of some anemias, is actually a<br />

relatively rare manifestati<strong>on</strong> of clinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency and is completely absent in subclinical vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency according to Carmel (Carmel RA. New York<br />

Methodist Hospital [pers<strong>on</strong>al communicati<strong>on</strong>] 2006-<br />

2007).<br />

Vascular Manifestati<strong>on</strong>s<br />

Both low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels and low folate levels are<br />

associated with elevated levels of homocysteine (Hcy).<br />

Hyperhomocysteinemia increases the chance of<br />

developing a vascular occlusi<strong>on</strong>,(51) thus potentially<br />

increasing the risk of cor<strong>on</strong>ary heart disease and<br />

ischemic stroke. Although the associati<strong>on</strong> of cor<strong>on</strong>ary<br />

heart disease or ischemic stroke with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> or<br />

folate deficiency has not <str<strong>on</strong>g>be</str<strong>on</strong>g>en proven, the SEARCH<br />

(Study of the Effectiveness of Additi<strong>on</strong>al Reducti<strong>on</strong>s in<br />

Cholesterol and Homocysteine) study in the United<br />

Kingdom is seeking to obtain evidence about the effect<br />

of reducing Hcy <strong>on</strong> cardiovascular risk while treating<br />

patients with 2 milligrams (mg) of folic acid plus 1 mg of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> daily. In additi<strong>on</strong>, the SEARCH study is<br />

looking at the efficacy and safety of two different<br />

dosages of simvastatin in regard to risk reducti<strong>on</strong> for<br />

major cardiovascular events.(52) This randomized study<br />

is scheduled to end in 2008 and should provide evidence<br />

about the causal relati<strong>on</strong>ship of Hcy to cardiovascular<br />

disease and about the value of folic acid and vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

supplementati<strong>on</strong>, in additi<strong>on</strong> to answering questi<strong>on</strong>s<br />

about simvastatin therapy.<br />

Effects <strong>on</strong> Infant Growth and Development<br />

Although the previously cited hematologic, neurologic,<br />

gastrointestinal, and cardiovascular c<strong>on</strong>sequences are<br />

25<br />

Nursing infants of<br />

mothers who adhere to a<br />

strict vegetarian or vegan<br />

diet throughout their<br />

pregnancy and while<br />

breastfeeding might also<br />

experience serious <str<strong>on</strong>g>B12</str<strong>on</strong>g>related<br />

deficiency effects.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

typically observed am<strong>on</strong>g older patients, several cases of<br />

significant vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies am<strong>on</strong>g infants and<br />

young children have <str<strong>on</strong>g>be</str<strong>on</strong>g>en reported.(53-56) Low or<br />

marginal vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> status am<strong>on</strong>g pregnant women<br />

increases the risk for neural tu<str<strong>on</strong>g>be</str<strong>on</strong>g> birth defects.(57)<br />

Exclusively breastfed infants of mothers who adhere to<br />

a strict vegetarian or vegan diet that excludes all animal<br />

proteins might also experience serious effects related to<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.(50, 53, 54, 56) Clinical<br />

manifestati<strong>on</strong>s am<strong>on</strong>g infants and young children are<br />

widely varied, encompassing hematologic, neurologic,<br />

and gastrointestinal symptoms. Some potential effects<br />

include the following:<br />

Failure to thrive<br />

Hypot<strong>on</strong>ia<br />

Ataxia<br />

Developmental delays<br />

Macrocytosis or anemia<br />

General weakness<br />

Many of these effects will improve with prompt vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> administrati<strong>on</strong> but, sometimes, irreversible<br />

neurologic damage occurs <str<strong>on</strong>g>be</str<strong>on</strong>g>fore the diagnosis is made<br />

and treatment is <str<strong>on</strong>g>be</str<strong>on</strong>g>gun.(50, 53-56) Nursing infants of<br />

vegan mothers can develop significant problems even<br />

when the mother is not anemic or symptomatic in any<br />

way.(50, 53, 55) It is important for you to ask pregnant<br />

women and new mothers who breastfeed about their<br />

diets.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

<strong>Screen</strong>ing Patients<br />

“. . . It is daunting and probably unnecessary to actively<br />

seek out new asymptomatic cases [of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency] by screening . . .”<br />

Carmel, 2003<br />

Most experts do not recommend community-based mass<br />

screening programs for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, even<br />

am<strong>on</strong>g high–risk groups, such as the frail elderly. For<br />

example:<br />

The U.S. Preventive Services Task Force has not<br />

published formal recommendati<strong>on</strong>s <strong>on</strong> screening<br />

asymptomatic older adults.<br />

The major medical societies have no<br />

recommendati<strong>on</strong>s <strong>on</strong> routine cobalamin screening.<br />

The Nati<strong>on</strong>al Guideline Clearinghouse website has<br />

no guidelines calling for periodic assessment in<br />

asymptomatic patients. (However, if you provide<br />

primary care to patients with dementia or altered<br />

mental status and celiac sprue or other<br />

gastrointestinal c<strong>on</strong>diti<strong>on</strong>s, you might wish to<br />

c<strong>on</strong>sult the website (http://www.guideline.gov) for<br />

recommendati<strong>on</strong>s related to vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

m<strong>on</strong>itoring am<strong>on</strong>g these high–risk groups.)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Detecti<strong>on</strong> and Diagnosis<br />

“It is particularly important that the diagnosis of<br />

cobalamin deficiency <str<strong>on</strong>g>be</str<strong>on</strong>g> established with a high degree<br />

of certainty <str<strong>on</strong>g>be</str<strong>on</strong>g>cause cobalamin therapy almost always<br />

must <str<strong>on</strong>g>be</str<strong>on</strong>g> given for the life-time of the patient.”<br />

Stabler and Allen, 2004<br />

Keeping vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency <strong>on</strong> <strong>your</strong> radar screen<br />

means staying vigilant during <strong>your</strong> review of <strong>your</strong><br />

patient’s history and during the physical examinati<strong>on</strong>.<br />

Watch for even subtle signs of neurologic or cognitive<br />

impairment. Also, note any elements of the patient’s<br />

history that might suggest potential malabsorpti<strong>on</strong> or<br />

malnutriti<strong>on</strong>, such as previously diagnosed pernicious<br />

anemia, previous gastrointestinal surgery, vegan diet,<br />

and advanced age. Maintain an especially high index of<br />

suspici<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency in new patients who<br />

report they were treated with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> injecti<strong>on</strong>s or<br />

high doses of oral vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> supplements by a former<br />

provider, but have since disc<strong>on</strong>tinued their use. Elderly<br />

patients often fail to understand that a true<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency due to malabsorpti<strong>on</strong><br />

requires lifel<strong>on</strong>g treatment.<br />

Early detecti<strong>on</strong> and prompt treatment of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency are essential to prevent development of<br />

irreversible neurologic damage, but making an accurate<br />

and timely diagnosis can <str<strong>on</strong>g>be</str<strong>on</strong>g> challenging. The list of<br />

related signs and symptoms is l<strong>on</strong>g, varied, and n<strong>on</strong>specific.<br />

Many risk factors have <str<strong>on</strong>g>be</str<strong>on</strong>g>en identified, but<br />

there are no known necessary or sufficient causes.<br />

Complicating things further is the fact that <str<strong>on</strong>g>be</str<strong>on</strong>g>cause the<br />

liver is a very efficient storage organ for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>,<br />

even completely deficient diets in healthy adults might<br />

not result in low serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels for several<br />

years. C<strong>on</strong>versely, apparently healthy adults, especially<br />

the elderly, c<strong>on</strong>suming diets rich in naturally occurring<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> can still develop a significant deficiency<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>cause of undetected malabsorpti<strong>on</strong>. It is possible for<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency to develop in a much shorter<br />

period of time (m<strong>on</strong>ths) in some people.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

The vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> literature c<strong>on</strong>tains many articles <strong>on</strong> the<br />

relative merits and limitati<strong>on</strong>s of the various laboratory<br />

testing opti<strong>on</strong>s. Some tests are used more comm<strong>on</strong>ly for<br />

the initial assessment, while others, <str<strong>on</strong>g>be</str<strong>on</strong>g>cause of their<br />

cost, inc<strong>on</strong>venience, or difficulty of interpretati<strong>on</strong>, are<br />

reserved for c<strong>on</strong>firmatory testing in ambivalent<br />

situati<strong>on</strong>s or are used <strong>on</strong>ly in the research setting.<br />

Initial Assessment<br />

After c<strong>on</strong>ducting a thorough history and physical<br />

examinati<strong>on</strong>, if you suspect vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, you<br />

should include a complete blood count (CBC), peripheral<br />

blood smear, and serum cobalamin (<str<strong>on</strong>g>B12</str<strong>on</strong>g>) as part of the<br />

initial laboratory assessment.(58) The serum cobalamin<br />

test is readily available and generally affordable, and can<br />

detect low serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels even am<strong>on</strong>g patients<br />

who are not anemic.(59, 60) However, not all patients<br />

with a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency will have hematologic<br />

manifestati<strong>on</strong>s. As Carmel succinctly noted, “the<br />

proscripti<strong>on</strong> that cobalamin deficiency should not <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

diagnosed unless megaloblastic changes are found is<br />

akin to requiring jaundice to diagnose liver disease.”(11)<br />

While serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> c<strong>on</strong>centrati<strong>on</strong>s are generally<br />

accurate,(61) many c<strong>on</strong>diti<strong>on</strong>s can complicate the<br />

interpretati<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> laboratory values. Falsely<br />

low values have <str<strong>on</strong>g>be</str<strong>on</strong>g>en associated with multiple myeloma,<br />

oral c<strong>on</strong>traceptives,(62-64) folate deficiency,(58, 59)<br />

and pregnancy.(10) Additi<strong>on</strong>ally, a low serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level<br />

does not automatically mean a deficiency. From 20%–<br />

40% of elderly people with low serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels have<br />

normal metabolite (homocysteine [Hcy] and<br />

methylmal<strong>on</strong>ic acid [MMA]) levels and should not <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

c<strong>on</strong>sidered<br />

as having a B deficiency.(11)<br />

12<br />

Sometimes, a true cobalamin deficiency will not <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

detected by the serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> test. Some examples<br />

of falsely normal serum cobalamin results might <str<strong>on</strong>g>be</str<strong>on</strong>g> seen<br />

with (but not limited to) liver disease,(58)<br />

myeloproliferative disorders,(58) and renal<br />

insufficiency.(4, 65) If a patient has clinical e vidence of a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency and a normal<br />

serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level, it is<br />

important<br />

to evaluate further.<br />

29<br />

The complete blood<br />

count, smear, and serum<br />

cobalamin (<str<strong>on</strong>g>B12</str<strong>on</strong>g>) test<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> included in the<br />

initial laboratory<br />

assessment of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

Oral c<strong>on</strong>traceptive users generally<br />

have lower serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

than n<strong>on</strong>users; however, the<br />

evidence of tissue depleti<strong>on</strong>, as<br />

detected by high values of<br />

methylmal<strong>on</strong>ic acid and<br />

homocysteine, is lacking.<br />

“Accepted lower limits of<br />

serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels in adults<br />

range <str<strong>on</strong>g>be</str<strong>on</strong>g>tween 170 and<br />

250 pg/ml; however,<br />

higher levels (but less<br />

than 350 pg/ml) have<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>en recorded in 15% of<br />

ostensibly healthy elderly<br />

patients with other<br />

findings suggestive of a<br />

deficiency state, most<br />

notably increased levels<br />

of serum methylmal<strong>on</strong>ic<br />

acid. The true lower<br />

limits of normal serum<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> would therefore<br />

appear to <str<strong>on</strong>g>be</str<strong>on</strong>g> somewhat<br />

poorly defined.”<br />

Ward, 2002

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Opini<strong>on</strong>s differ as to the optimal laboratory cutpoint for<br />

the serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> test, due in part to the insidious<br />

<strong>on</strong>set and slow progressi<strong>on</strong> of the disorder and<br />

limitati<strong>on</strong>s of current assays. Research studies and<br />

clinical laboratories have tended to dichotomize low<br />

values at 200 picograms per milliliter(pg/mL).(18, 66,<br />

67) Stabler and Allen noted the following ranges of<br />

serum cobalamin levels am<strong>on</strong>g patients with a clinically<br />

c<strong>on</strong>firmed <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency (defined as those who “have<br />

objective clinical resp<strong>on</strong>ses to appropriate therapy”):<br />

less than 100 pg/mL, approximately 50%; 100–200<br />

pg/mL, approximately 40%; 200–350 pg/mL,<br />

approximately 10%; and more than 350 pg/mL,<br />

approximately 0.1% to 1%.(7)<br />

Adequate follow-up for suspect normal or low-normal<br />

results is needed through either additi<strong>on</strong>al c<strong>on</strong>firmatory<br />

testing or a prol<strong>on</strong>ged therapeutic trial followed by<br />

metabolic and clinical reassessment.<br />

C<strong>on</strong>firmatory Testing<br />

When the serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> results are suspect, it is<br />

helpful to obtain more informati<strong>on</strong>.(1) Several tests can<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g> used to rule out a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency either am<strong>on</strong>g<br />

patients with borderline serum cobalamin levels or<br />

am<strong>on</strong>g symptomatic patients with normal serum<br />

cobalamin levels.<br />

Homocysteine (Hcy) and Methylmal<strong>on</strong>ic Acid (MMA)<br />

By far, the most comm<strong>on</strong>, accurate, and widely used<br />

c<strong>on</strong>firmatory tests for identifying vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

are tests for Hcy and MMA.(1) Because cobalamin is<br />

necessary for the synthesis of methi<strong>on</strong>ine from Hcy, low<br />

levels of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> lead to increases in total serum<br />

Hcy. The total serum Hcy test is a sensitive indicator for<br />

a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency; however, its utility is limited as<br />

a sole c<strong>on</strong>firmatory test <str<strong>on</strong>g>be</str<strong>on</strong>g>cause elevated Hcy levels<br />

am<strong>on</strong>g patients also can <str<strong>on</strong>g>be</str<strong>on</strong>g> caused by familial<br />

hyperhomocysteinemia, levodopa therapy,(68) renal<br />

insufficiency, and folate deficiency.(1, 7, 69, 70)<br />

The serum MMA test is more specific for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels<br />

also increase in the presence of low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>cause cobalamin is required to c<strong>on</strong>vert methylmal<strong>on</strong>yl<br />

coenzyme A to succinyl coenzyme A.(2) In <strong>on</strong>e study,<br />

98.4% of people with a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> level less than 200<br />

pg/mL also had elevated MMA levels (defined as values<br />

more than 376 nanomoles per liter [nmol/L]).(70) Note<br />

that false-positive increases in serum MMA have <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

identified am<strong>on</strong>g patients with impaired renal functi<strong>on</strong>. It<br />

is necessary to rule out whether <strong>your</strong> patient has either<br />

marked intravascular volume depleti<strong>on</strong> or renal<br />

insufficiency when interpreting the MMA level, especially<br />

in the absence of a low cobalamin level.(70) Elevated<br />

MMA levels am<strong>on</strong>g most patients indicate tissue<br />

depleti<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. Data from the Nati<strong>on</strong>al Health<br />

and Nutriti<strong>on</strong> Examinati<strong>on</strong> Survey (NHANES) 2001–2004<br />

in Table 4 shows the prevalence of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

using combinati<strong>on</strong>s of serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels and MMA levels.<br />

Table 4. Prevalence of Nati<strong>on</strong>al Health and Nutriti<strong>on</strong><br />

Examinati<strong>on</strong> Survery Participants With Biochemically<br />

Defined <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g>* By Age Group, United<br />

States, 2001–2004<br />

Age Group <str<strong>on</strong>g>B12</str<strong>on</strong>g> ≤ 200 <str<strong>on</strong>g>B12</str<strong>on</strong>g> > 200 pg/mL<br />

(Years of Age) pg/mL and MMA and MMA ≥ 270<br />

≥ 270 nmol/L nmol/L<br />

9–13 years of age 0.1% 2.5%<br />

14–18 years of age 0.2% 3.7%<br />

19–30 years of age 0.4% 3.5%<br />

31–50 years of age 0.6% 3.6%<br />

≥ 51 years of age 1.6%<br />

7.9%<br />

*Biochemically defined vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> ≤ 200<br />

picograms per milliliter (pg/mL) and methylmal<strong>on</strong>ic acid (MMA) ≥<br />

270 nanomoles per liter (nmol/L) or serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> > 200 pg/mL and<br />

MMA ≥ 270 nmol/L<br />

Two popular methods for interpreting diagnostic<br />

thresholds for MMA and Hcy elevati<strong>on</strong>s are the use of<br />

cutpoints determined by laboratory norms (e.g., 3<br />

standard deviati<strong>on</strong>s above the mean) and specific values<br />

(e.g., MMA greater than 0.26 micromole per liter<br />

31<br />

C<strong>on</strong>versi<strong>on</strong>s<br />

1,000 nmol/L* = 1 µmol/L†<br />

376 nmol/L = 0.376 µmol/L<br />

*nanomols per liter<br />

†micromols per liter

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

[µmol/L](69) or greater than 0.4 µmol/L;(59) Hcy<br />

greater than 15 µmol/L(71, 72)). Many clinicians rely <strong>on</strong><br />

ranges specified by the clinical laboratories they use.<br />

The cost of testing for MMA or Hcy might <str<strong>on</strong>g>be</str<strong>on</strong>g> a c<strong>on</strong>cern.<br />

Quotes from Quest Laboratories (Atlanta, Georgia, May<br />

2006) state that the direct patient (no insurance) cost<br />

for a serum MMA is $212 and for a serum Hcy is $191.<br />

Other metabolites, serum propi<strong>on</strong>ate and serum 2methylcitrate,<br />

are also present in vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

However, measuring either of these metabolites has no<br />

advantage over measuring MMA to diagnose a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency,(2) and they are not available routinely in<br />

many clinical laboratories.<br />

Again, it is important to remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r that abnormal<br />

metabolite levels might <str<strong>on</strong>g>be</str<strong>on</strong>g> due to c<strong>on</strong>diti<strong>on</strong>s other than<br />

a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, such as renal insufficiency. In<br />

<strong>on</strong>e study of the elderly, renal insufficiency was<br />

associated with 20% or greater of all abnormal<br />

metabolite levels.(11)<br />

Other Tests<br />

If the root cause of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is not obvious,<br />

you should c<strong>on</strong>sider ordering additi<strong>on</strong>al tests to<br />

determine it. Antibodies to intrinsic factor and gastrin or<br />

pentagastrin I levels are often used to diagnose<br />

pernicious anemia.(10, 36, 60)<br />

Serum holotranscobalamin II measures <strong>on</strong>e of the bloodbinding<br />

proteins used to transport vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.(60) Some<br />

investigators recommend it;(73) others are c<strong>on</strong>cerned<br />

about the lack of c<strong>on</strong>vincing evidence of its value.(2, 9,<br />

10, 60) Theoretically, it is attractive, but early claims of<br />

its value have <str<strong>on</strong>g>be</str<strong>on</strong>g>en poorly documented. While<br />

immunoassays have replaced the older crude methods, it<br />

is too early to determine whether measurement of<br />

holotranscobalamin II is <str<strong>on</strong>g>be</str<strong>on</strong>g>tter than measurement of<br />

serum cobalamin. (1)<br />

The deoxyuridine suppressi<strong>on</strong> test ( or “DUST”) has <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

descri<str<strong>on</strong>g>be</str<strong>on</strong>g>d as a sensitive indicator of impaired thymidine<br />

synthesis due to either deficiency or metabolic<br />

inactivati<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> or folate.(58) However, DUST<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

is used rarely in the clinical setting <str<strong>on</strong>g>be</str<strong>on</strong>g>cause it is not<br />

necessary in the evaluati<strong>on</strong> of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

DUST is also a complicated, expensive, and timec<strong>on</strong>suming<br />

test.(58)<br />

The Schilling test is included in most lists of possible<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency c<strong>on</strong>firmatory tests, but it is not<br />

available in U.S. clinical practices at this time. The<br />

Shilling test is the classic test for determining whether a<br />

pers<strong>on</strong> can absorb vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. However, a pers<strong>on</strong>’s<br />

ability to absorb crystalline vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> can differ from<br />

his or her ability to absorb the naturally occurring<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.(59) While, it is not an accurate test for<br />

identifying cobalamin deficiency, it can <str<strong>on</strong>g>be</str<strong>on</strong>g> a helpful tool<br />

in determining the root cause of an identified deficiency.<br />

It reveals cobalamin malabsorpti<strong>on</strong> such as that found in<br />

pernicious anemia and ileal disease. A normal Schilling<br />

test cannot rule out vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.(29, 36)<br />

There is no gold standard for determining cobalamin<br />

deficiency. Part of the problem is related not to the tests<br />

used, but to “an uncertain boundary <str<strong>on</strong>g>be</str<strong>on</strong>g>tween cobalamin<br />

depleti<strong>on</strong> and disease.”(1, 20)<br />

A diagnostic approach to tailor testing to the nature of a<br />

patient’s clinical problem is suggested by Carmel and<br />

summarized in Table 5(1)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Table 5. Tailored Diagnostic Approach for<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Problem Goal Suggested Tests<br />

Patient with mild to<br />

severe hematologic<br />

or neurologic signs<br />

or symptoms, or<br />

both<br />

Patient with<br />

hematologic or<br />

neurologic signs or<br />

symptoms, or<br />

both, unlikely due<br />

to vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency<br />

C<strong>on</strong>firm suspected<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency<br />

Ensure if vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

exists, it is not<br />

missed<br />

Serum <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

Serum <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

MMA* and Hcy †<br />

Asymptomatic Determine if MMA (metabolic<br />

patient with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> changes often<br />

c<strong>on</strong>diti<strong>on</strong> known to deficiency has precede low<br />

cause vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> developed yet cobalamin levels)<br />

deficiency<br />

Asymptomatic<br />

patient accidentally<br />

found to have low<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> level or high<br />

Hcy †<br />

*MMA–methylmal<strong>on</strong>ic acid<br />

† Hcy–homocysteine<br />

Determine if<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency exists<br />

MMA<br />

Flagging the patient’s chart will help you remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r to<br />

follow-up if choosing to “watch and wait” with an<br />

asymptomatic patient.<br />

Experienced clinicians differ <strong>on</strong> the importance of<br />

tracking down the root cause of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>fore initiating treatment; however, determining the<br />

cause of the deficiency is important ultimately in<br />

individualizing the treatment approach.(1)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Managing Patients With Evidence of a<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

“A caregiver must manage a subclinically deficient<br />

patient with pernicious anemia as a cause quite<br />

differently and pay closer attenti<strong>on</strong> than to a similar<br />

patient without it.”<br />

Carmel, 2006<br />

Clinical <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Opti<strong>on</strong>s available for treating a clinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency include oral and parenteral (intramuscular or<br />

subcutaneous) preparati<strong>on</strong>s. Intravenous dosing is not<br />

recommended <str<strong>on</strong>g>be</str<strong>on</strong>g>cause this will result in most of the<br />

vitamin <str<strong>on</strong>g>be</str<strong>on</strong>g>ing lost in the urine.(74)<br />

The resp<strong>on</strong>se of a patient with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

anemia to treatment is usually rapid, with reticulocytosis<br />

occurring within 2–5 days, and the hematocrit<br />

normalizing within weeks.(10) Treatment with cobalamin<br />

effectively halts progressi<strong>on</strong> of the deficiency process,<br />

but might not fully reverse more advanced neurologic<br />

effects.(39, 42) If the underlying cause of the vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is treatable (e.g., fish tapeworm infecti<strong>on</strong><br />

or bacterial overgrowth), then treatment should include<br />

addressing the underlying etiology.(7)<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> is c<strong>on</strong>sidered safe, even at levels much<br />

higher than the recommended dose. It has not <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

shown to <str<strong>on</strong>g>be</str<strong>on</strong>g> toxic or cause cancer, birth defects, or<br />

mutati<strong>on</strong>s.(10, 75) Be aware, however, that patients<br />

who have a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency with associated<br />

megaloblastic anemia might experience hypokalemia and<br />

fluid overload early in treatment due to increased<br />

erythropoiesis, cellular uptake of potassium, and<br />

increased blood volume.(76, 77)<br />

While the route, dosage, treatment timing, and follow-up<br />

might vary somewhat, there is no questi<strong>on</strong> about the<br />

decisi<strong>on</strong> to treat patients with pernicious anemia or with<br />

a low serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level and hematologic or neurologic<br />

signs or symptoms without pernicious anemia (clinical<br />

35<br />

Cobalamin replacement is<br />

effective <str<strong>on</strong>g>be</str<strong>on</strong>g>cause<br />

crystalline forms of <str<strong>on</strong>g>B12</str<strong>on</strong>g> can<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g> absor<str<strong>on</strong>g>be</str<strong>on</strong>g>d even when<br />

animal protein-bound<br />

forms cannot <str<strong>on</strong>g>be</str<strong>on</strong>g> digested.<br />

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> is not<br />

carcinogenic, teratogenic,<br />

or mutagenic. It is<br />

c<strong>on</strong>sidered safe even at<br />

1,000 times the RDA.<br />

Baik and Russell, 1999

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency). Once treated for a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency due to pernicious anemia or other<br />

irreversible severe problems with absorpti<strong>on</strong>,<br />

patients need to c<strong>on</strong>tinue some form of cobalamin<br />

therapy for life.(7)<br />

Parenteral (Intramuscular or Subcutaneous)<br />

Administrati<strong>on</strong> of parenteral crystalline cobalamin has<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>en the standard treatment protocol for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency for decades.(78, 79) Few side effects have<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>en reported, and patient acceptance is generally high.<br />

Anecdotally, the subcutaneous route causes less burning<br />

than does the intramuscular route (Carmel RA. New York<br />

Methodist Hospital [pers<strong>on</strong>al communicati<strong>on</strong>] 2006-<br />

2007). Regimens for parenteral administrati<strong>on</strong> vary. An<br />

approach suggested by Stabler and Allen is 1<br />

milligram (mg) (or 1,000 micrograms [µg]) of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> given weekly for 8 weeks, then <strong>on</strong>ce<br />

m<strong>on</strong>thly for life.(7)<br />

Some providers have used quarterly injecti<strong>on</strong>s after the<br />

initial dosing protocol. However, experts state that in<br />

pernicious anemia or severe malabsorptive deficiency<br />

quarterly injecti<strong>on</strong>s are not sufficient, noting that<br />

cobalamin levels start to fall prior to the 1 m<strong>on</strong>th followup<br />

(Allen RH. University of Colorado [pers<strong>on</strong>al<br />

communicati<strong>on</strong>] 2006 -2007).<br />

Oral<br />

Large, daily oral replacement doses might <str<strong>on</strong>g>be</str<strong>on</strong>g> an<br />

acceptable alternative if patients are compliant.(7)<br />

Sufficient amounts of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> are absor<str<strong>on</strong>g>be</str<strong>on</strong>g>d via<br />

passive diffusi<strong>on</strong> in the small intestine.(2, 11) A study by<br />

Eussen et al. dem<strong>on</strong>strated a linear resp<strong>on</strong>se in the<br />

reducti<strong>on</strong> of metabolites and increased serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

with increasing dosages of oral cyanocobalamin.(80) A<br />

comm<strong>on</strong> therapy is 1 mg (1,000 µg) of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

to <str<strong>on</strong>g>be</str<strong>on</strong>g> c<strong>on</strong>sumed daily.(2, 11, 14)<br />

Intranasal<br />

A relatively new vehicle for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> therapy is a<br />

cyanocobalamin gel for intranasal use. Some experts<br />

are not c<strong>on</strong>vinced of its efficacy, and the cost is $30 for<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

500 µg (Carmel RA. New York Methodist Hospital<br />

[pers<strong>on</strong>al communicati<strong>on</strong>] 2006-2007). If chosen, the<br />

intranasal gel should <str<strong>on</strong>g>be</str<strong>on</strong>g> used for maintenance <strong>on</strong>ly after<br />

treatment with parenteral or oral vitamin therapy has<br />

established adequate metabolic status am<strong>on</strong>g patients<br />

with no nervous system involvement.(74) The<br />

recommended dose for therapy is 500 µg<br />

intranasally <strong>on</strong>ce a week.(74) Absorpti<strong>on</strong> can <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

inc<strong>on</strong>sistent.<br />

Treatment approaches vary somewhat in the initial<br />

treatment and the route used.(7, 77, 81) Given the<br />

l<strong>on</strong>g-term nature of cobalamin therapy, c<strong>on</strong>siderati<strong>on</strong> of<br />

the patient’s c<strong>on</strong>diti<strong>on</strong> (e.g., cognitive impairment),<br />

c<strong>on</strong>venience of getting the treatment, and ease of<br />

administrati<strong>on</strong> should heavily influence the method and<br />

dosage selected.(7, 11) For example, oral therapy is less<br />

painful and can <str<strong>on</strong>g>be</str<strong>on</strong>g> self-administered. However, <str<strong>on</strong>g>be</str<strong>on</strong>g>cause<br />

cognitive impairment is a frequent reas<strong>on</strong> for<br />

n<strong>on</strong>compliance, patients might <str<strong>on</strong>g>be</str<strong>on</strong>g> more compliant with<br />

clinic or home health nurse-administered injecti<strong>on</strong>s.<br />

Additi<strong>on</strong>ally, Carmel observed that many patients prefer<br />

the c<strong>on</strong>venience of m<strong>on</strong>thly injecti<strong>on</strong>s to daily<br />

c<strong>on</strong>sumpti<strong>on</strong> of pills.(11)<br />

Examples of treatment regimens from different sources<br />

for clinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency are listed in Table 6.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Table 6. Examples of Treatment Regimens<br />

for Clinical <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Due to Initial<br />

Maintenance<br />

Cyanocobalamin Cyanocobalamin<br />

Pernicious Varies, not limited 1 mg IM or SQ q<br />

anemia to:<br />

m<strong>on</strong>th for life<br />

1 mg<br />

OR<br />

intramuscularly 1 mg–2 mg<br />

(IM) or<br />

orally (PO)<br />

subcutaneously every day (QD)<br />

(SQ) every (q)<br />

week x 8<br />

OR<br />

for life<br />

1 mg IM or SQ x<br />

7 in 1 m<strong>on</strong>th<br />

Other food- Varies, not limited 1 mg IM or SQ q<br />

bound <str<strong>on</strong>g>B12</str<strong>on</strong>g> to: m<strong>on</strong>th possibly<br />

malabsorpti<strong>on</strong> 1 mg IM or SQ q for life<br />

problems week x 8 OR<br />

OR<br />

650 µg–1 mg PO<br />

1 mg IM or SQ x QD possibly for<br />

7 in 1 m<strong>on</strong>th life<br />

OR<br />

1 mg–2 mg PO<br />

QD<br />

Rarer Treat underlying 1 mg IM or SQ q<br />

malabsorpti<strong>on</strong> c<strong>on</strong>diti<strong>on</strong> m<strong>on</strong>th<br />

problems AND OR<br />

(tape worms, Cyanocobalamin 650 µg–1 mg PO<br />

bacterial varies, not limited QD<br />

overgrowth) to:<br />

Treating underlying<br />

1 mg IM or SQ q c<strong>on</strong>diti<strong>on</strong> might<br />

week x 8 resolve <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

OR<br />

deficiency. If<br />

1 mg IM or SQ x cyanocobalamin is<br />

7 in 1 m<strong>on</strong>th d/c’d, follow up<br />

with regular<br />

assessment of<br />

metabolites.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Subclinical <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

The far more prevalent patient presentati<strong>on</strong> is by an<br />

asymptomatic individual with borderline serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels<br />

and elevated homocysteine or methylmal<strong>on</strong>ic acid levels,<br />

or both. These patients pose a dilemma for providers<br />

<str<strong>on</strong>g>be</str<strong>on</strong>g>cause there are no guidelines for the treatment of<br />

patients with subclinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

Some providers prefer to treat these patients and check<br />

to see that metabolite markers have normalized, while<br />

others prefer to “wait and watch”. For patients in the<br />

subclinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency category, taking a<br />

vitamin with <str<strong>on</strong>g>B12</str<strong>on</strong>g> (usual dosages are 6–25 µg) is not<br />

sufficient to correct the metabolites. Two recent studies<br />

have suggested that the lowest dose of oral<br />

cyanocobalamin needed to normalize metabolites in<br />

subclinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is 500–1,000 µg<br />

daily.(80, 82) The providers who test for and treat<br />

patients with subclinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, especially<br />

those patients with possible pernicious anemia or<br />

elevated metabolites, or both, can prevent potential<br />

subsequent hematologic and neurologic manifestati<strong>on</strong>s.<br />

Whether treating or “waiting and watching”, you should<br />

remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r that routine m<strong>on</strong>itoring of and educating the<br />

patient are important.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Preventi<strong>on</strong> of <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> Deficiencies<br />

“The . . . Recommended Dietary Allowance (RDA) (2.4<br />

mcg/day) for <str<strong>on</strong>g>B12</str<strong>on</strong>g> for adults ages 51 and older are the<br />

same as for younger adults but with the<br />

recommendati<strong>on</strong> that <str<strong>on</strong>g>B12</str<strong>on</strong>g>–fortified foods (such as<br />

fortified ready-to-eat cereals) or <str<strong>on</strong>g>B12</str<strong>on</strong>g>–c<strong>on</strong>taining<br />

supplements <str<strong>on</strong>g>be</str<strong>on</strong>g> used to meet much of the<br />

requirements.” Institute of Medicine, 1999<br />

The irreversible nature of the late-stage neurologic<br />

effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency provides str<strong>on</strong>g<br />

support for the value of preventi<strong>on</strong>.(44, 50, 83)<br />

Fortunately, a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is easily treated and<br />

prevented. Because of the high prevalence of mild,<br />

subclinical cobalamin deficiency am<strong>on</strong>g asymptomatic<br />

individuals, it is important to remain vigilant, especially<br />

with individuals at high risk for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

If “watch and wait” is the selected plan of care, periodic<br />

reassessment of untreated asymptomatic patients is<br />

important to identify progressive depleti<strong>on</strong> of vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g>.<br />

The Institute of Medicine (IOM) recommends that all<br />

adults 18 years of age or older c<strong>on</strong>sume 2.4 micrograms<br />

(µg) per day of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>.(10) Subclinical vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency, often undiagnosed and untreated, has <str<strong>on</strong>g>be</str<strong>on</strong>g>en<br />

estimated to occur am<strong>on</strong>g 5%–15% of the elderly<br />

populati<strong>on</strong>.(4, 6, 16, 19, 65) However, a recent clinical<br />

study dem<strong>on</strong>strates that it takes 650–1,000 µg of<br />

cyanocobalamin daily to provide 80%–90% of the<br />

estimated maximum reducti<strong>on</strong> in methylmal<strong>on</strong>ic<br />

acid.(80)<br />

Given the high prevalence of atrophic gastritis (loss of<br />

acid secreti<strong>on</strong>) am<strong>on</strong>g older adults, the IOM suggests<br />

that adults older than 50 years of age use vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>–<br />

fortified foods and supplements (e.g., multivitamins or<br />

single supplements) as the primary means to meet this<br />

requirement <str<strong>on</strong>g>be</str<strong>on</strong>g>cause crystalline formulati<strong>on</strong>s are much<br />

more readily absor<str<strong>on</strong>g>be</str<strong>on</strong>g>d and used than naturally occurring<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>. Most multivitamins c<strong>on</strong>tain 6–25 µg<br />

cyanocobalamin; some c<strong>on</strong>tain more. Single<br />

40<br />

The irreversible nature of<br />

the late-stage neurologic<br />

effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency provides<br />

str<strong>on</strong>g support for the<br />

value of preventi<strong>on</strong>.

<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

supplements typically come in doses of 100 µg, 250 µg,<br />

500 µg, 1,000 µg, and 2,000 µg. For more informati<strong>on</strong><br />

<strong>on</strong> vitamin supplements for adults, see the Nati<strong>on</strong>al<br />

Institutes of Health Office of Dietary Supplements<br />

website at<br />

http://ods.od.nih.gov/factsheets/cc/vitb12.html.<br />

Vegans, or strict vegetarians, must obtain their per-day<br />

dose of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> by c<strong>on</strong>suming a vitamin supplement<br />

or eating a fortified cereal product. Currently available<br />

data do not support the suggesti<strong>on</strong> that vegans can<br />

meet their minimum daily requirements for vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

by c<strong>on</strong>suming unfortified plant-based foods, nutriti<strong>on</strong>al<br />

yeast, algae, or seaweed products.<br />

For more informati<strong>on</strong> <strong>on</strong> the vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels of over<br />

1,100 comm<strong>on</strong> food items, visit the U.S. Department of<br />

Agriculture and Agricultural Research website at<br />

http://www.ars.usda.gov/ba/bhnrc/ndl.<br />

Several experts in the field find that even higher doses<br />

of oral cobalamin are necessary for the preventi<strong>on</strong> of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency am<strong>on</strong>g the elderly and have stated<br />

that the amount in the IOM recommendati<strong>on</strong> is<br />

insufficient.(80)(Carmel RA. New York Methodist Hospital<br />

[pers<strong>on</strong>al communicati<strong>on</strong>] 2006-2007; Allen RH.<br />

University of Colorado [pers<strong>on</strong>al communicati<strong>on</strong>] 2006-<br />

2007) Lindenbaum’s findings of the prevalence of<br />

cobalamin deficiency am<strong>on</strong>g the elderly survivors from<br />

the Framingham study suggests “deficiencies can, at<br />

least in part, <str<strong>on</strong>g>be</str<strong>on</strong>g> prevented by oral supplementati<strong>on</strong>,<br />

although . . . the dose of cobalamin administered may<br />

have to <str<strong>on</strong>g>be</str<strong>on</strong>g> much larger than that usually given in routine<br />

multivitamin preparati<strong>on</strong>s.”(4)<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Summary<br />

Low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels occur am<strong>on</strong>g 1 in 31 adults 51<br />

years of age or older am<strong>on</strong>g the U.S. populati<strong>on</strong>. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g><br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency is simple to prevent and simple to treat,<br />

but the diagnosis is easy to miss and is often overlooked<br />

in the outpatient setting.<br />

All patients with unexplained hematologic or neurologic<br />

symptoms should <str<strong>on</strong>g>be</str<strong>on</strong>g> evaluated for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency. If such a deficiency is found, the cause<br />

should <str<strong>on</strong>g>be</str<strong>on</strong>g> determined.(7, 44) Irreversible neurologic<br />

damage can occur if diagnosis and treatment are<br />

delayed.<br />

A complete blood count, peripheral blood smear, and<br />

serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> level are the tests of choice for initial<br />

assessment of cobalamin deficiency. Keep in mind that<br />

megaloblastic anemia and changes in mean corpuscular<br />

value are not always present when there is a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency. Homcysteine and methylmal<strong>on</strong>ic acid can <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

used to c<strong>on</strong>firm a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency for cases with<br />

ambiguous initial results <str<strong>on</strong>g>be</str<strong>on</strong>g>cause metabolic changes<br />

often precede low cobalamin levels.<br />

You have inexpensive treatment opti<strong>on</strong>s available to<br />

treat a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. Remem<str<strong>on</strong>g>be</str<strong>on</strong>g>r that treatment<br />

is safe, effective, and has no known toxicity level.<br />

To prevent a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, you should advise<br />

all patients 51 years of age or older to c<strong>on</strong>sume<br />

synthetic vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> daily. Dosage recommendati<strong>on</strong>s<br />

vary.<br />

Acknowledgements: The authors thank Christine Pfeiffer, PhD, for<br />

assistance with laboratory interpretati<strong>on</strong>, and Quanhe Yang,<br />

PhD,and Heather Carter Hamner, MS, MPH, for statistical support.<br />

We also appreciate the comments and suggesti<strong>on</strong>s from our panel<br />

of reviewers S<strong>on</strong>ja Rasmussen, MD; Joe Mulinare, MD; R.J. Berry,<br />

MD; Lorraine Yeung, MD; Shar<strong>on</strong> Roy, MD; Mary Dott, MD; John<br />

Mersereau, MD; Jennifer Zreloff, MD; Jas<strong>on</strong> Bell, MD; Pauline<br />

Terebuh, MD; Dan Watkins, PA; Gail Walls, MSN; Sally Lehr, MSN;<br />

Darla Ura, MSN; Sue Ann Bell, MSN; Christa Purnell, MSN; Molly<br />

Cogswell, RN, PhD, and Malissa Perritt, MSN.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

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vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. Clin Lab Med. 2002 Jun;22(2):435-<br />

45.<br />

61. Mas<strong>on</strong> JB. C<strong>on</strong>sequences of altered micr<strong>on</strong>utrients<br />

status. In: Goldman L, Bennett JC, editors. Cecil Textbook of<br />

Medicine. Philadelphia: W. B. Saunders, Inc.; 2000. p. 170-8.<br />

62. Riedel B, Bjorke M<strong>on</strong>sen AL, Ueland PM, Schneede J.<br />

Effects of oral c<strong>on</strong>traceptives and horm<strong>on</strong>e replacement<br />

therapy <strong>on</strong> markers of cobalamin status. Clin Chem. 2005<br />

Apr;51(4):778-81.<br />

63. Shojania AM. Oral c<strong>on</strong>traceptives: effect of folate and<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> metabolism. Can Med Assoc J. 1982 Feb<br />

1;126(3):244-7.<br />

64. Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T.<br />

Serum folate and vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels in women using modern<br />

oral c<strong>on</strong>ceptives (OC) c<strong>on</strong>taining 20 mcg ethinyl estradiol. Eur<br />

J Obstet Gynecol Reprod Biol 2003 Mar 107(1):57-61.<br />

65. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea<br />

M, Azen C. Serum cobalamin, homocysteine, and<br />

methylmal<strong>on</strong>ic acid c<strong>on</strong>centrati<strong>on</strong>s in a multiethnic elderly<br />

populati<strong>on</strong>: ethnic and sex differences in cobalamin and<br />

metabolite abnormalities. Am J Clin Nutr. 1999<br />

Nov;70(5):904-10.<br />

66. <str<strong>on</strong>g>Why</str<strong>on</strong>g>te EM, Mulsant BH, Butters MA, Qayyum M, Towers<br />

A, Sweet RA, et al. Cognitive and <str<strong>on</strong>g>be</str<strong>on</strong>g>havioral correlates of low<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels in elderly patients with progressive<br />

dementia. Am J Geriatr Psychiatry. 2002 May-Jun;10(3):321-<br />

7.<br />

67. Stabler SP. <strong>Screen</strong>ing the older populati<strong>on</strong> for<br />

cobalamin (vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>) deficiency. J Am Geriatr Soc. 1995<br />

Nov;43(11):1290-7.<br />

68. O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L,<br />

Dewey RB, Jr., Bottiglieri T, et al. Elevated plasma<br />

homocysteine level in patients with Parkins<strong>on</strong> disease: motor,<br />

affective, and cognitive associati<strong>on</strong>s. Arch Neurol. 2004<br />

Jun;61(6):865-8.<br />

69. Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A,<br />

Stokkeland M, et al. Evaluati<strong>on</strong> of indicators of cobalamin<br />

deficiency defined as cobalamin-induced reducti<strong>on</strong> in<br />

increased serum methylmal<strong>on</strong>ic acid. Clin Chem. 2000<br />

Nov;46(11):1744-50.<br />

70. Savage DG, Lindenbaum J, Stabler SP, Allen RH.<br />

Sensitivity of serum methylmal<strong>on</strong>ic acid and total<br />

homocysteine determinati<strong>on</strong>s for diagnosing cobalamin and<br />

folate deficiencies. Am J Med. 1994 Mar;96(3):239-46.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

71. Ray JG, Cole DE, Boss SC. An Ontario-wide study of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>, serum folate, and red cell folate levels in relati<strong>on</strong><br />

to plasma homocysteine: is a preventable public health issue<br />

<strong>on</strong> the rise? Clin Biochem. 2000 Jul;33(5):337-43.<br />

72. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum<br />

H, Sand<str<strong>on</strong>g>be</str<strong>on</strong>g>rg S. Cobalamin deficiency in general practice.<br />

Assessment of the diagnostic utility and cost-<str<strong>on</strong>g>be</str<strong>on</strong>g>nefit analysis<br />

of methylmal<strong>on</strong>ic acid determinati<strong>on</strong> in relati<strong>on</strong> to current<br />

diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98.<br />

73. Her<str<strong>on</strong>g>be</str<strong>on</strong>g>rt V. The elderly need oral vitamin B-12. Am J<br />

Clin Nutr. 1998 Apr;67(4):739-40.<br />

74. RXList I. Cyanocobalamin. WebMD; 2008.<br />

75. Schauss AG. Recommended optimum nutrient intakes.<br />

In: Pizzorno, editor. Textbook of Natural Medicine. 2nd ed:<br />

Churchill Livingst<strong>on</strong>e, Inc.; 1999. p. 909-27.<br />

76. Hoffman R, Benz E, Shattil S, Furie B, Cohen H,<br />

Sil<str<strong>on</strong>g>be</str<strong>on</strong>g>rstein L, et al. Hematology: Basic Principles and Practice.<br />

4th ed. Philadelphia: Elsevier Churchill Livingst<strong>on</strong>e; 2005.<br />

77. Marks PW, Zuker<str<strong>on</strong>g>be</str<strong>on</strong>g>rg LR. Case records of the<br />

Massachusetts General Hospital. Weekly clinicopathological<br />

exercises. Case 30-2004. A 37-year-old woman with<br />

paresthesias of the arms and legs. N Engl J Med. 2004 Sep<br />

23;351(13):1333-41.<br />

78. Lawhorne LW, Wright H, Cragen D. Characteristics of<br />

n<strong>on</strong>-cobalamin deficient patients who receive regular<br />

cyanocobalamin injecti<strong>on</strong>s. Fam Med. 1991 Sep-<br />

Oct;23(7):506-9.<br />

79. Hughes D, Elwood PC, Shint<strong>on</strong> NK, Wright<strong>on</strong> RJ. Clinical<br />

trial of the effect of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> in elderly subjects with low<br />

serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels. Br Med Journal. 1970;2:458-60.<br />

80. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland<br />

PM, Hoefnagels WH, et al. Oral cyanocobalamin<br />

supplementati<strong>on</strong> in older people with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency:<br />

a dose-finding trial. Arch Intern Med. 2005 May<br />

23;165(10):1167-72.<br />

81. Solom<strong>on</strong> LR. Cobalamin-resp<strong>on</strong>sive disorders in the<br />

ambulatory care setting: unreliability of cobalamin,<br />

methylmal<strong>on</strong>ic acid, and homocysteine testing. Blood. 2005<br />

Feb 1;105(3):978-85.<br />

82. Stabler SP, Allen RH, Dolce ET, Johns<strong>on</strong> MA. Elevated<br />

serum S-adenosylhomocysteine in cobalamin-deficient elderly<br />

and resp<strong>on</strong>se to treatment. Am J Clin Nutr. 2006<br />

Dec;84(6):1422-9.<br />

83. Wolters M, Strohle A, Hahn A. Cobalamin: a critical<br />

vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

References for Text in Boxes<br />

Amos R, Daws<strong>on</strong> D, Fish D, Leeming R, Linnell J.<br />

Guidelines <strong>on</strong> the investigati<strong>on</strong> and diagnosis of<br />

cobalamin and folate deficiencies. A publicati<strong>on</strong> of the<br />

British Committee for Standards in Haematology. BCSH<br />

General Haematology Test Force. Clin Lab Haematol.<br />

1994 Jun;16(2):101–15.<br />

Baik H, Russell R. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency in the elderly.<br />

Annual Rev Nutr.1999(19):357–77.<br />

Bernard MA, Nak<strong>on</strong>ezny PA, Kashner TM. The effect of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency <strong>on</strong> older veterans and its<br />

relati<strong>on</strong>ship to health. J Am Geriatr Soc. 1998<br />

Oct;46(10):1199–206.<br />

Carmel R. Current c<strong>on</strong>cepts in cobalamin deficiency.<br />

Annu Rev Med. 2000;51:357–75.<br />

Carmel R, Green R, Rosenblatt DS, Watkins D. Update<br />

<strong>on</strong> cobalamin, folate, and homocysteine. Hematology<br />

(Am Soc Hematol Educ Program). 2003:62–81.<br />

U.S. Food and Drug Administrati<strong>on</strong> (FDA). Food<br />

standards: amendment of standards of identity for<br />

enriched grain products to require additi<strong>on</strong> of folic acid. .<br />

Fed Regist, 1996; 61(44): 8781-97.<br />

Her<str<strong>on</strong>g>be</str<strong>on</strong>g>rt V. Staging vitamin B-12 (cobalamin) status in<br />

vegetarians. Am J Clin Nutr. 1994 May;59(5<br />

Suppl):1213S–22S.<br />

Institute of Medicine (IOM). Dietary reference intakes for<br />

thiamin, riboflavin, niacin, vitamin B6, folate, vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g>, pantothenic acid, biotin and choline. Washingt<strong>on</strong>,<br />

D.C.: Nati<strong>on</strong>al Academy Press; 1998.<br />

Matchar DB, McCrory DC, Millingt<strong>on</strong> DS, Feussner JR.<br />

Performance of the serum cobalamin assay for diagnosis<br />

of cobalamin deficiency. Am J Med Sci. 1994<br />

Nov;308(5):276–83.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Pennypacker LC, Allen RH, Kelly JP, Matthews LM,<br />

Grigsby J, Kaye K, et al. High prevalence of cobalamin<br />

deficiency in elderly outpatients. J Am Geriatr Soc. 1992<br />

Dec;40(12):1197–204.<br />

Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA,<br />

Stabler SP. <strong>Screen</strong>ing for cobalamin deficiency in<br />

geriatric outpatients: prevalence and influence of<br />

synthetic cobalamin intake. J Am Geriatr Soc. 2002<br />

Apr;50(4):624–30.<br />

Stabler SP, Allen RH. Megoblastic anemias. In: Goldman,<br />

ed. Cecil Textbook of Medicine, 22nd ed. Philadelphia:<br />

W. B. Saunders Company; 2004. p. 1050–7.<br />

Ward PC. Modern approaches to the investigati<strong>on</strong> of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. Clin Lab Med. 2002<br />

Jun;22(2):435–45.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Appendix A<br />

Answers to Case Study Questi<strong>on</strong>s<br />

1. Do any of the presenting complaints raise<br />

<strong>your</strong> index of suspici<strong>on</strong> about a possible<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency? If so, why? Yes.<br />

Complaints of tiredness for 2 m<strong>on</strong>ths and memory<br />

problems in a woman 65 years of age might<br />

indicate a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

2. What risk factors does this woman appear to<br />

have for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency? The <strong>on</strong>ly<br />

immediately apparent risk factor is her age. Risk<br />

of developing a deficiency <str<strong>on</strong>g>be</str<strong>on</strong>g>gins to increase at 51<br />

years of age. Sex is not an important predictor.<br />

The patient’s nutriti<strong>on</strong>al status is unclear at this<br />

stage. Future questi<strong>on</strong>s might usefully pro<str<strong>on</strong>g>be</str<strong>on</strong>g> the<br />

patient for regular sources of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>, including<br />

meat and dairy products as well as fortified foods<br />

and nutriti<strong>on</strong>al supplements.<br />

3. Does the fact that she appears to <str<strong>on</strong>g>be</str<strong>on</strong>g> “wellnourished”<br />

indicate she is unlikely to have a<br />

vitamin deficiency? <str<strong>on</strong>g>Why</str<strong>on</strong>g> or why not? No. The<br />

fact that she is well-nourished does not rule out a<br />

potential deficiency. Weight, or body mass index,<br />

is not a useful predictor. Normal and overweight<br />

individuals might still have a significant vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency <str<strong>on</strong>g>be</str<strong>on</strong>g>cause most deficiencies are due to<br />

malabsorpti<strong>on</strong> rather than malnutriti<strong>on</strong>. Markedly<br />

underweight patients, who might truly <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

malnourished, are at increased risk for a vitamin<br />

<str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency, particularly if they are elderly or<br />

have <str<strong>on</strong>g>be</str<strong>on</strong>g>en adhering to a vegetarian or vegan diet<br />

for several years.<br />

4. Are there any aspects of her physical<br />

examinati<strong>on</strong> that suggest a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency? Mucosal and skin pallor are subtle<br />

signs.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

5. Given her history and physical examinati<strong>on</strong><br />

findings, what laboratory test(s) would you<br />

order? In additi<strong>on</strong> to the usual chemistry panel<br />

and complete blood count with smear to check for<br />

anemia, a serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> test should <str<strong>on</strong>g>be</str<strong>on</strong>g> ordered. Lownormal<br />

levels indicate a need for further<br />

assessment <str<strong>on</strong>g>be</str<strong>on</strong>g>cause serum levels can <str<strong>on</strong>g>be</str<strong>on</strong>g><br />

maintained at the expense of liver stores even in<br />

the presence of <strong>on</strong>going malabsorpti<strong>on</strong>.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Appendix B<br />

Additi<strong>on</strong>al Articles <strong>on</strong> <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

<str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Allen R, Lindenbaum J, Stabler S. High prevalence<br />

of cobalamin deficiency in the elderly. Trans Am<br />

Clin Climatol Assoc. 1995;107:37–45.<br />

Carmel R, Melnyk S, James J. Cobalamin deficiency<br />

with and without neurologic abnormalities:<br />

differences in homocysteine and methi<strong>on</strong>ine<br />

metabolism. Blood. 2003;101:3302–8.<br />

Carmel R. Pernicious anemia: the expected<br />

findings of very low cobalamin levels, anemia, and<br />

macrocytosis are often lacking. Arch Intern Med.<br />

1988;148:1712–4.<br />

Clarke R. Preventi<strong>on</strong> of vitamin B-12 deficiency in<br />

old age. Am J Clin Nutr. 2001;73:151–2.<br />

Fairfield K, Fletcher R. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g>s for chr<strong>on</strong>ic disease<br />

preventi<strong>on</strong> in adults - Scientific Review. JAMA.<br />

2002;287:3116–26.<br />

Fletcher R, Fairfield K. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g>s for chr<strong>on</strong>ic disease<br />

preventi<strong>on</strong> in adults - clinical applicati<strong>on</strong>s. JAMA.<br />

2002;287:3127–9.<br />

Her<str<strong>on</strong>g>be</str<strong>on</strong>g>rt V. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> and folic acid<br />

supplementati<strong>on</strong>. Am J Clin Nutr. 1997;66:1479–<br />

80.<br />

Herrmann W, Schorr H, Bodis M, Knaapp J, Muller<br />

A, Stein G, et al. Role of homocysteine,<br />

cystathi<strong>on</strong>ine and methylmal<strong>on</strong>ic acid<br />

measurement for the diagnosis of vitamin<br />

deficiency in high-aged subjects. Eur J Clin Invest.<br />

2000;30:1083–9.<br />

Ho G, Kauwell G, Bailey L. Practiti<strong>on</strong>ers’ guide to<br />

meeting the vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> recommended dietary<br />

allowances for people aged 51 years and older. J<br />

Am Diet Assoc. 1999;99:725–7.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Holleland G, Schneede J, Ueland P, Lund P, Refsum<br />

H, Sand<str<strong>on</strong>g>be</str<strong>on</strong>g>rg S, et al. Cobalamin deficiency in<br />

general practice: assessment of the diagnostic<br />

utility and cost-<str<strong>on</strong>g>be</str<strong>on</strong>g>nefit analysis of methylmal<strong>on</strong>ic<br />

acid determinati<strong>on</strong> in relati<strong>on</strong> to current diagnostic<br />

strategies. Clin Chem. 1999;45:189–98.<br />

Hvas A, Ellegaard J, Nexo E. Increased plasma<br />

methylmal<strong>on</strong>ic acid level does not predict clinical<br />

manifestati<strong>on</strong>s of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency. Arch<br />

Intern Med. 2001;161:1535–41.<br />

Johns<strong>on</strong> M, Hawthorne N, Brackett W, Fischer J,<br />

Gunter E, Allen R, et al. Hyperhomocysteinemia<br />

and vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency in elderly using title<br />

IIIC nutriti<strong>on</strong> services. Am J Clin Nutr.<br />

2003;77:211–20.<br />

Lokk J, Nilss<strong>on</strong> M, Nor<str<strong>on</strong>g>be</str<strong>on</strong>g>rg B, Hultdin J, Sandstrom<br />

H, Westman G. Shifts in <str<strong>on</strong>g>B12</str<strong>on</strong>g> opini<strong>on</strong>s in primary<br />

health care of Sweden. Scand J Public Health.<br />

2001;29:122–8.<br />

Malouf R, Areosa S. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> for cogniti<strong>on</strong>.<br />

Cochrane Database Syst Rev. 2003:3.<br />

Meins W, Muller-Thomsen T, Meier-Baumgartner<br />

H. Subnormal serum vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> and <str<strong>on</strong>g>be</str<strong>on</strong>g>havioral<br />

and psychological symptoms in Alzheimer’s<br />

disease. Int J Geriatr Psychiatry. 2000;15:415–8.<br />

Misra U, Kalita J, Das A. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

neurological syndromes: a clinical, MRI, and<br />

electrodiagnostic study. Electromyogr Clin<br />

Neurophysiol. 2003;43:57–64.<br />

Mitchell S, Rockwood K. The associati<strong>on</strong> <str<strong>on</strong>g>be</str<strong>on</strong>g>tween<br />

antiulcer medicati<strong>on</strong> and initiati<strong>on</strong> of cobalamin<br />

replacement in older pers<strong>on</strong>s. J Clin Epidemiol.<br />

2001;54:531–4.<br />

Naurath H, Joosten E, Riezler R, Stabler S, Allen R,<br />

Lindenbaum J. Effects of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g>, folate, and<br />

vitamin B6 supplements in elderly people with<br />

normal serum vitamin c<strong>on</strong>centrati<strong>on</strong>s. Lancet.<br />

1995;346:85–9.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Penninx BW, Guralnick JM, Ferrucci L. Fried LP,<br />

Allen R, Stabler S. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> B(12) deficiency and<br />

depressi<strong>on</strong> in physically disabled older women:<br />

epidemiologic evidence from the Women’s Health<br />

and Aging Study. Am J Psychiatry.<br />

2000;157:715–21.<br />

Stopeck A. Links <str<strong>on</strong>g>be</str<strong>on</strong>g>tween helicobacter pylori<br />

infecti<strong>on</strong>, cobalamin deficiency, and pernicious<br />

anemia. Arch Intern Med. 2000;160:1229–30.<br />

Tiemeier H, van Tuiji H, Hoffman A, Meijer J,<br />

Kilaan A, Breteler M. <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g>, folate, and<br />

homocysteine in depressi<strong>on</strong>: the Rotterdam Study.<br />

Am J Psychiatry. 2002;159:2099–101.<br />

van Asselt D, Blom H, Zuiderent R, Wevers R,<br />

Jakobs C, van den Broek W, et al. Clinical<br />

significance of low cobalamin levels in older<br />

hospital patients. Neth J Med. 2000;57:41–9.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Appendix C<br />

<str<strong>on</strong>g>Why</str<strong>on</strong>g> <str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g> <str<strong>on</strong>g>Should</str<strong>on</strong>g> Be<br />

<strong>on</strong> Your <strong>Radar</strong> <strong>Screen</strong><br />

Evaluati<strong>on</strong> Questi<strong>on</strong>naire and<br />

Posttest<br />

Course Goal: To increase the num<str<strong>on</strong>g>be</str<strong>on</strong>g>r of primary care<br />

providers (physicians and midlevel providers) who<br />

prevent, detect, and treat vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiencies<br />

am<strong>on</strong>g their high-risk patients.<br />

Objectives:<br />

• Descri<str<strong>on</strong>g>be</str<strong>on</strong>g> the prevalence in the United States of<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency am<strong>on</strong>g adults 51 years of<br />

age or older.<br />

• List three neurologic effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.<br />

• List three hematologic effects of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.<br />

• Identify the most comm<strong>on</strong> presentati<strong>on</strong> of a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

• Discuss the changes in absorpti<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

that occur with age.<br />

• List at least two pharmacologic opti<strong>on</strong>s for<br />

treatment of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

1. The learning outcomes (objectives) were relevant to<br />

the goal of this course.<br />

a. Str<strong>on</strong>gly agree<br />

b.Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

2. The c<strong>on</strong>tent was appropriate given the stated<br />

objectives of the course.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

3. The c<strong>on</strong>tent was presented clearly.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

4. The learning envir<strong>on</strong>ment was c<strong>on</strong>ducive to learning.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

5. The delivery method (i.e., Web) helped me learn the<br />

material more easily.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

6. The instructi<strong>on</strong>al strategies helped me learn the<br />

material.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

7. Overall, the quality of the course materials was<br />

excellent.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

8. The course was<br />

a. Much too difficult<br />

b. A little too difficult<br />

c. Just right<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

d. A little too easy<br />

e. Much too easy<br />

9. Overall, the course was<br />

a. Much too l<strong>on</strong>g<br />

b. A little too l<strong>on</strong>g<br />

c. Just right<br />

d. A little too short<br />

e. Much too short<br />

10. The availability of c<strong>on</strong>tinuing educati<strong>on</strong> credit<br />

influenced my decisi<strong>on</strong> to participate in this activity.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

f. Not applicable<br />

11. As a result of my completing this educati<strong>on</strong>al<br />

activity, it is likely that I will make changes in my<br />

practice.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

f. Not applicable<br />

12. I am c<strong>on</strong>fident I can descri<str<strong>on</strong>g>be</str<strong>on</strong>g> the prevalence in the<br />

United States of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency am<strong>on</strong>g adults 51<br />

years of age or older.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

13. I am c<strong>on</strong>fident I can list three neurologic effects of a<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

14. I am c<strong>on</strong>fident I can list three hematologic effects of<br />

a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

15. I am c<strong>on</strong>fident that I can identify the most comm<strong>on</strong><br />

presentati<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

16. I am c<strong>on</strong>fident that I can discuss the changes in<br />

absorpti<strong>on</strong> of vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> that occur with age.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

17. I am c<strong>on</strong>fident I can list at least two pharmacologic<br />

opti<strong>on</strong>s for treatment of a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

18. The c<strong>on</strong>tent expert(s) for this document<br />

dem<strong>on</strong>strated expertise in the subject matter.<br />

a. Str<strong>on</strong>gly agree<br />

b. Agree<br />

c. Undecided<br />

d. Disagree<br />

e. Str<strong>on</strong>gly disagree<br />

19. Do you feel this course was commercially biased?<br />

Yes or No<br />

If yes, please explain<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

20. Please descri<str<strong>on</strong>g>be</str<strong>on</strong>g> in the following space any technical<br />

difficulties you experienced with the course.<br />

21. What could <str<strong>on</strong>g>be</str<strong>on</strong>g> d<strong>on</strong>e to improve future course<br />

offerings?<br />

22. Do you have any further comments?<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

Pretest and Posttest<br />

If you want to receive c<strong>on</strong>tinuing educati<strong>on</strong> credit for<br />

this program, complete this posttest. Please read the<br />

case history and then answer the questi<strong>on</strong>s that follow.<br />

Choose the answer that is most correct for each<br />

questi<strong>on</strong>.<br />

Case<br />

A 60-year-old teacher with a history of hypothyroidism<br />

and gastroesophageal reflux disease (GERD) reports<br />

significant fatigue, hot flashes, and memory difficulty<br />

since her last annual visit. On detailed review of<br />

symptoms, she also admits to irritability, emoti<strong>on</strong>al<br />

lability, decreased appetite, difficulty sleeping, and<br />

occasi<strong>on</strong>al tingling of her fingertips. Her last m<strong>on</strong>thly<br />

period was 2 years ago. She has <str<strong>on</strong>g>be</str<strong>on</strong>g>en following a<br />

vegetarian diet for the past 5 years to try to lose weight.<br />

During the physical examinati<strong>on</strong>, she is alert and<br />

oriented x 3, but tearful at <strong>on</strong>e point during the<br />

interview with an MMSE score of 28 out of 30. There are<br />

no abnormal physical findings.<br />

Her CBC results:<br />

RBC 4.6 (4.2–5.8) 10^6/µL<br />

MCV 90 (78–102) fL<br />

Hgb 15 (12.0–16.0) g/dL<br />

WBC 6.4 (4.3–11.0) 10^3/µL (normal differential)<br />

Plts 312 (144–440) 10^3/µL<br />

Smear shows normocytic, normochromic RBCs<br />

Chemistry results:<br />

Na 139 (136–148) mEq/L<br />

K 4.7 (3.5–5.5) mEq/L<br />

Cl 103 (98–110) mmol/L<br />

BUN 20.0 (9.34–23.35)mg/dL<br />

Cr 1.0 (0.4–1.5) mg/dL<br />

CO2 25 (21–33) mmol/L<br />

Gluc 80 (60–140) mg/dL<br />

GOT 26 (1–32) U/L<br />

GPT 14 (1–30) U/L<br />

AlkPhos 115 (31–121) U/L<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

1. Which of the following presenting symptoms<br />

suggest this patient might have a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency?<br />

a. Fatigue<br />

b. Difficulty sleeping<br />

c. Hot flashes<br />

d. Emoti<strong>on</strong>al lability<br />

e. All of the above<br />

2. All of the following factors might place this<br />

patient at high risk for a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency<br />

except:<br />

a. Being 51 years of age or older<br />

b. Being female sex<br />

c. Having hypothyroidism<br />

d. Following a vegetarian diet<br />

3. You might find ______ patients with evidence<br />

of low vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> levels in every 100 patients<br />

you see. (Hint: Use prevalence data from the<br />

research literature to determine <strong>your</strong> answer.)<br />

a. 0–1<br />

b. 2–4<br />

c. 8–10<br />

d. 15 or more<br />

4. What can you c<strong>on</strong>clude from the CBC with<br />

smear results about the likelihood that this<br />

patient has a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency?<br />

a. Her CBC and smear are abnormal so she must<br />

have a <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

b. Her CBC and smear are normal so she does not<br />

have a <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />

c. A normal CBC and smear do not rule out a <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

deficiency.<br />

d. Nothing; it was a mistake to order a CBC and<br />

smear in the first place.<br />

You obtain a serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> level. Her results are:<br />

Serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> 211 (211-911) pg/mL<br />

5. What does this patient’s serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> result<br />

suggest?<br />

a. Her result is within normal limits so she does<br />

not have a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency.<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

b. She might have a vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> deficiency;<br />

further testing could <str<strong>on</strong>g>be</str<strong>on</strong>g> useful.<br />

c. N<strong>on</strong>e of the above.<br />

6. A serum <str<strong>on</strong>g>B12</str<strong>on</strong>g> result might <str<strong>on</strong>g>be</str<strong>on</strong>g> misleading for<br />

patients who:<br />

a. Are <strong>on</strong> oral c<strong>on</strong>traceptives<br />

b. Are fasting<br />

c. Have liver disease or renal disease<br />

d. Answers (a) and (c)<br />

7. Setting aside issues of cost and patient<br />

c<strong>on</strong>venience, which <strong>on</strong>e of the following<br />

additi<strong>on</strong>al tests would you c<strong>on</strong>sider the most<br />

informative at this time?<br />

a. Serum homocysteine<br />

b. Serum methylmal<strong>on</strong>ic acid<br />

c. Serum holotranscobalamin<br />

d. Schilling test<br />

You order additi<strong>on</strong>al tests during the workup for this<br />

patient.<br />

Other laboratory results:<br />

TSH 2.3 (0.34–5.6) µ units/mL<br />

ESR 23 (0–30) mm/Hr<br />

CRP 3.1 (0–4.9) mg/L<br />

Hcy 20 (4–17) µmol/L<br />

MMA 0.71 (0.08–0.56) µmol/L<br />

8. C<strong>on</strong>sidering all of the evidence presented for<br />

this patient, what would you do next?<br />

a. Ask the patient to increase c<strong>on</strong>sumpti<strong>on</strong> of<br />

animal food products and recheck her in 6<br />

m<strong>on</strong>ths<br />

b. Ask the patient to take a multivitamin with <str<strong>on</strong>g>B12</str<strong>on</strong>g><br />

and recheck her in 6 m<strong>on</strong>ths<br />

c. Check for intrinsic factor antibodies and <str<strong>on</strong>g>be</str<strong>on</strong>g>gin<br />

treatment<br />

d. Nothing<br />

9. Which of the following treatment opti<strong>on</strong>s<br />

would you select for this patient?<br />

a. Intramuscular injecti<strong>on</strong>s, starting with frequent<br />

injecti<strong>on</strong>s that are gradually tapered to m<strong>on</strong>thly<br />

injecti<strong>on</strong>s<br />


<str<strong>on</strong>g>Vitamin</str<strong>on</strong>g> <str<strong>on</strong>g>B12</str<strong>on</strong>g> <str<strong>on</strong>g>Deficiency</str<strong>on</strong>g><br />

b. Oral formulati<strong>on</strong>, same dosage throughout<br />

c. Intramuscular injecti<strong>on</strong>s initially, switching to<br />

an oral formulati<strong>on</strong> later<br />

d. One of the above, depending <strong>on</strong> issues of cost,<br />

c<strong>on</strong>venience, and likely patient compliance<br />

10. Pernicious anemia was c<strong>on</strong>firmed. How do<br />

you advise this patient about her prognosis?<br />

a. You tell her that a course of treatment with<br />

vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> will cure her.<br />

b. You advise her that she must c<strong>on</strong>tinue<br />

treatment with vitamin <str<strong>on</strong>g>B12</str<strong>on</strong>g> for life.<br />

c. You tell her that seaweed, nutriti<strong>on</strong>al yeast, and<br />

algae will help prevent signs and symptoms<br />

from occurring later.<br />

d. A and C<br />

e. N<strong>on</strong>e of the above<br />


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