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 />
i
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 />
ii
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 />
iii
<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 />
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<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 />
2
<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 />
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<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 />
4
<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 />
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<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 />
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<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 />
7
<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 />
8
<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 />
9
<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 />
12
<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 />
12
<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 />
17
<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 />
22
<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 />
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 />
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 />
26
<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 />
27
<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 />
28
<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 />
30
<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 />
32
<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 />
33
<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 />
34
<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 />
36
<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 />
37
<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 />
38
<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 />
39
<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 />
41
<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 />
42
<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> status increases the risk of offspring with spina<br />
bifida. Am J Obstet Gynecol. 2004;191:11-7.<br />
58. 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 cobalamin<br />
and folate deficiencies. A publicati<strong>on</strong> of the British Committee<br />
for Standards in Haematology. BCSH General Haematology<br />
Test Force. Clin Lab Haematol. 1994 Jun;16(2):101-15.<br />
46
<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 />
59. Klee GG. Cobalamin and folate evaluati<strong>on</strong>:<br />
measurement of methylmal<strong>on</strong>ic acid and homocysteine vs<br />
vitamin B(12) and folate. Clin Chem. 2000 Aug;46(8 Pt<br />
2):1277-83.<br />
60. 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 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 />
47
<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 />
48
<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 />
49
<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 />
50
<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 />
51
<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 />
52
<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 />
53
<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 />
54
<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 />
55
<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 />
56
<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 />
57
<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 />
58
<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 />
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<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 />
60
<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 />
61
<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 />
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<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 />
63
<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 />
64