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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on Your Radar Screen
A Continuing Education Update
Course WB1349
Prepared for the
National Center on Birth Defects and Developmental Disabilities
Centers for Disease Control and Prevention
by
Marian L. Evatt, MD 1
Patricia W. Mersereau, MN, CPNP 2
Janet Kay Bobo, PhD 3
Joel Kimmons, PhD 4
Jennifer Williams, MSN, MPH, FNP-BC 5
The findings and conclusions in this report are those of the authors
and do not necessarily represent the views of the
Centers for Disease Control and Prevention.
1 Department of Neurology, Emory University, Atlanta, Georgia.
2 SciMetrika, LLC, Atlanta, Georgia.
3 Battelle Centers for Public Health Research and Evaluation, Atlanta, GA and Seattle, Washington.
4 National Center for Chronic Disease Prevention and Health Promotion, CDC, Atlanta, Georgia.
5 National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia.
i
Contents
Goal and Objectives .................................................................................1
Accreditation ...........................................................................................2
Introduction ............................................................................................3
Case Studies ............................................................................................6
Natural History and Prevalence of
Risk Factors for
Manifestations of Low
Screening Patients .................................................................................27
Detection and Diagnosis ........................................................................28
Managing Patients With Evidence of a
Prevention of
Summary ...............................................................................................42
References.............................................................................................43
References for Text in Boxes .................................................................49
Appendix A: Answers to Case Study Questions ......................................51
Appendix B: Additional Articles on
Appendix C: Evaluation Questionnaire, Pretest, and Posttest ................56
2/11/2010
ii
Figure and Tables
Figure 1. The Biochemical Role of Cobalamin........................................ 16
Table 1. Neurologic and Psychiatric Symptoms of
Table 2. Typical Stages in the Development of a
Table 3. Prevalence of
Population By Age, National Health and Nutrition Examination
Survey 2001–2004 …………………………… 19
Table 4. Prevalence of National Health and Nutrition Examination Survey
Participants With Biochemically Defined
By Age Group, United States, 2001–2004 …………………………… 31
Table 5. Tailored Diagnostic Approach for
Table 6. Examples of Treatment Regimens for
2/11/2010
Disclosure
CDC, planners, and other content experts wish to disclose
they have no financial interests or other relationships with the
manufacturers of commercial products, suppliers of commercial
services, or commercial supporters.
This module will not include any discussions of the unla
of a product or a product under investigational use.
iii
A Continuing Education Update
Goal and Objectives
The goal of this continuing education activity is to
increase the num
(physicians and midlevel providers) who prevent, detect,
and treat vitamin
patients.
After completing this continuing education material, you
should
• Descri
vitamin
age or older.
• List three neurologic effects of a vitamin
deficiency.
• List three hematologic effects of a vitamin
deficiency.
• Identify the most common presentation of a
vitamin
• Discuss the changes in absorption of vitamin
that occur with age.
• List at least two pharmacologic options for
treatment of a vitamin
2/11/2010
1
Accreditation
Continuing Medical Education (CME): This
activity for 1.5 credits is provided by the Centers
for Disease Control and Prevention (CDC),
accredited by the Accreditation Council for
Continuing Medical Education to provide category 1
credits towards the American Medical Association
(AMA) Physician’s Recognition Award.
Continuing Nursing Education (CNE): This
activity for 1.5 contact hours is provided by CDC,
which is accredited as a provider of continuing
education in nursing by the American Nurses
Credentialing Center’s Commission on
Accreditation (ANCC).
Registration
To register for the course and receive free continuing
education credit:
Go to http://www.cdc.gov/tceonline..
Log in as a participant (note: the first time you use
the online system you will need to log in as a new
participant and create a participant profile).
Find the course by searching the catalog using the
following course num
You will need to enter the verification code (
to complete the course.
Select the type of credit you wish to receive and
register for the course.
Take the examination and complete the course
evaluation.
Print your continuing education certificate.
To receive continuing education credit, you must
complete the entire course, take the post-test, and
complete the evaluation online.
During this lesson, you will find highlighted
terms. Roll your mouse over each term for
further information.
2
Introduction
radar screen for several reasons. Prevention, early
detection, and treatment of vitamin B deficiency are
important public health issues,
essential to prevent development of irreversible
neurologic damage which can impact quality of life.
Although most health care providers already recognize
the occasional person who presents with obvious signs
and symptoms, they are far less likely to screen and
diagnose the majority of patients who have a subclinical
or mildly symptomatic vitamin
many health care providers realize. Unpublished
analysis at the Centers for Disease Control and
Prevention (CDC) of laboratory data from communitybased
samples of U.S. adults 51 years of age or older
suggest about 1 (3.2%) of every 31 persons have serum
vitamin
(pg/mL).
Adequate body stores are essential for several crucial
neurologic and hematologic functions. Delays in the
diagnosis and treatment of vitamin
lead to development of severe, irreversible neurologic
damage.
The clinical importance of vitamin
over 50 years ago, when ingesting raw animal liver (the
primary storage organ for vitamin
an effective treatment for pernicious anemia. Research
has shown that the water-soluble vitamin
for the completion of several biochemical processes (see
Figure 1).
The following five top things to remem
of these and other cobalamin-related findings.
3
The top five things to remem
about vitamin
1.
age or older at a frequency of 1 (3.2%) in every 31
persons, and manifest as serum vitamin
2. All patients with unexplained hematologic or
neurologic signs or symptoms should
a vitamin
should
3. Today, megaloblastic anemia is most likely due to
vitamin
In the United States, folic acid fortification has made
folate deficient megaloblastic anemia a very rare
condition.
4. Although the body’s ability to absorb naturally
occurring vitamin
can readily use the synthetic form of cobalamin.
5. All people 51 years of age or older should get most of
their daily vitamin
containing vitamin
vitamin
4
This update has
four questions pertinent to primary health care
providers:
vitamin
o Introduction
o Case studies
o Natural history and prevalence of vitamin
deficiencies
o Manifestations of low vitamin
Which of my patients are at high risk for vitamin
deficiency?
o Risk factors for a vitamin
How do I detect and diagnose a vitamin
deficiency?
o Screening patients
o Detection and diagnosis
How should I manage a patient with evidence of
vitamin
o Managing patients with evidence of a vitamin
o Preventing vitamin
5
Case Studies
The following case studies are not actual patients. They
combine elements from different cases to emphasize
important aspects of vitamin
Case Study 1
Presentation
During a checkup for hypertension, a 65-year-old female
reports a 2-month history of tiredness, feeling faint from
“getting up too fast”, and “memory problems”.
Case Study Question 1
Do any of the presenting complaints raise your index of
suspicion about a possible vitamin
why?
History
On review of systems, she reports difficulty
concentrating, fatigue, feeling faint when she stands
quickly, and vague gastrointestinal discomfort with some
decrease in appetite.
She denies any history of previous trauma, diplopia,
dysphagia, vertigo, vision loss, loss of consciousness,
back pain, or symptoms of bowel or bladder dysfunction.
Her family history is negative for neurologic, psychiatric,
and autoimmune diseases. Her medications include an
antihypertensive, as well as an occasional antiinflammatory
drug for episodic headaches. Her social
history reveals a single woman who smokes about onehalf
pack of cigarettes per day, drinks alcohol only
socially, and denies illicit drug use. She has a high
school education and, until recently, had worked in the
office of a trucking company.
6
Case Study Question 2
What risk factors does this woman appear to have for a
vitamin
Physical Examination
Pale 65 y.o. WF who appears well-nourished, alert, and
oriented.
Vital Signs T-98.6, HR-76, R-18, B/P-130/80 supine
and 95/52 upon standing,
Height/Weight 5’4”/120 lbs.
Head Normocephalic; oropharynx clear but
pale; palpebral conjunctivae pale.
Neck Supple, full active and passive ROM
without pain, without audible bruits; no
lymphadenopathy; no thyromegaly
Back No spine tenderness
Lungs Clear to auscultation
Heart Regular rate and rhythm; no murmurs
Abdomen Soft, nontender; no organomegaly
Rectal Normal rectal tone; no fissures
Extremities No clubbing, cyanosis, or edema; FROM
Skin Pale; no rash
The general physical examination is unremarkable
except for orthostatic hypotension and a weight loss of 3
pounds since her last visit 6 months ago. She is alert
and oriented times three. Her Mini-Mental Status Exam
score is 26 out of 30. She misses one point on serial 7s
and is able to recall three of three items. There is
evidence of bilateral mildly diminished vibration and
proprioception. Her reflexes are 3+/4+ throughout, with
negative Babinski reflex.
Cranial II—Visual acuity 20/25 in both eyes
Nerves (corrected); normal fundoscopic
examination; visual fields intact with no
central scotoma
III, IV, VI—Extraocular movements
intact; pupils equal, round, and reactive
to light with no afferent pupillary defect
V, VII, XII—Intact facial sensation; intact
7
masseter motor strength, without
dysarthria; tongue protruded in midline
VIII—Hearing grossly normal
XI, X—Swallowing intact
XI—Muscle strength equal bilaterally
Motor Normal muscle bulk; muscle strength 5/5
in all muscle groups
Cere
rapid alternating movements
Case Study Questions
3. Does the fact that she appears to
indicate she is unlikely to have a vitamin deficiency?
or why not?
4. Are there any aspects of her physical examination that
suggest a vitamin
5. Given her history and physical examination findings,
what laboratory test(s) would you order?
Laboratory Studies
You order routine laboratory studies, which include
complete blood count (CBC) with smear and chemistry
screen. In addition, you order a serum vitamin
to investigate further the etiology of her fatigue and pale
mucosa. Results from the CBC and smear reveal a
borderline macrocytic anemia. The chemistry panel is
within normal limits. The serum vitamin
requested is 215 picograms per milliliter (pg/mL). This
level is considered within a “normal range” by some
laboratories, but you take into account her other signs
and symptoms and request confirmatory testing with
8
methylmalonic acid (MMA) and homocysteine (Hcy)
levels.
Results of Confirmatory Testing
Both her MMA and Hcy levels are elevated. Her MMA is
greater than 0.5 micromoles per liter (μmol/L), and her
Hcy is greater than 17 μmol/L, confirming your suspicion
that this patient has a vitamin
You decide to investigate the cause of her vitamin
deficiency. Although she denies a history of pernicious
anemia in her family and she has had no previous
indication of autoimmune diseases, you order an antiintrinsic
factor (IF) antibody test that confirms the
presence of pernicious anemia.
Management
You explain that with the diagnosis of pernicious anemia
she will have to continue vitamin
remainder of her life, and you make a note on her chart
to assess her compliance at each visit. You also advise
her to inform her family of the diagnosis
is possibly a genetic component.
You start her on vitamin
injections. She gets IM cyanocobalamin 1,000
micrograms (µg) two times per week for 2 weeks and
then switches to oral vitamin
thereafter. Almost immediately after the initiation of
injections, she reports improved concentration. Within 2
weeks, she notes less fatigue and normal appetite.
Case Study 2
Presentation
An 85-year-old female with a 15-year history of
Parkinson disease (PD) is seen for her regularly
scheduled follow-up with her neurologist.
History
On review of systems, family mem
has
9
6 months. They also report that activities she previously
accomplished without difficulty, such as going to church,
seem to exhaust her. She acknowledges this symptom,
stating that she feels her stamina is much lower than at
the time of the last visit.
She and her family do not report an appreciable
difference in or worsening of her motor symptoms, but
they do report that she has had some hallucinations in
the form of seeing farm animals periodically in her room.
Her current medications include Stalevo(carbidopa,
levodopa, and entacapone), amantadine, Evista ®
(raloxifene hydrochloride), Effexor ® XL (venlafaxine
hydrochloride), Detrol ® LA (tolterodine tartrate),
Mirapex ® (pramipexole dihydrochloride), and Ambien ®
(zolpidem tartrate). She denies any obsessive or
compulsive
does admit having a decreased appetite and eating little
or no meat. Her family descri
as poor, stating that she is just getting by on “tea and
toast”.
Her social history reveals a widowed elderly woman who
lives with her son and daughter-in-law. She had lived
independently until 5 years ago, when completing her
activities of daily living (ADLs)
currently has a home health nurse visit once a day to
assist with ADLs and noontime medications while her
family is at work.
Physical Examination
A general examination reveals a frail, thin female with
skin irritation and slight amount of saliva evident at the
right corner of her mouth (the side where her PD
symptoms are more pronounced). She has slight
puffiness but no pitting of her ankles bilaterally.
A neurological examination reveals that she is alert and
oriented to person, place, and year. She remem
out of 3 items, but can recall only one of three items 3
minutes later. She has definite facial masking and a
decreased blink rate. Cranial nerve examination reveals
moderate hypophonia (low voice volume) and an
intermittent tremor. She is moderately stooped with a
slight tilt to the right, and she has difficulty rising from a
10
Protein intake among patients
with Parkinson disease (PD)
might interfere with levodopa’s
clinical
might inadvertently increase their
risk of vitamin B 12 deficiency by
avoiding meat, the dietary source
of vitamin
chair without assistance, even though her strength is
normal. She has a mild-to-moderate intermittent resting
tremor, worse on her right side. Sensory examination
reveals decreased vibratory thresholds in both legs up to
her ankles. Reflexes are 3+ out of 4 with crossed
adductor spread in her legs, and her plantar reflex
shows positive Babinski bilaterally.
Laboratory Studies
Her neurologist orders some routine laboratory studies,
including a CBC with smear and chemistry panel. In
addition, the neurologist decides to get a serum
deficiency, and many of the symptoms of PD also can
attributed to vitamin
Results from the CBC with smear demonstrate no
evidence of anemia. The chemistry panel is within
normal limits, with the exception of a slightly elevated
serum creatinine (1.5 milligrams per deciliter). Her
serum
normal range of 180–900 pg/mL. The neurologist
considers this value as “low-normal” and requests
confirmatory testing with MMA and HCY levels.
Results of Confirmatory Testing
Her HCY is elevated at 18 µmols/L; however, her
neurologist recognizes that this finding alone is not
considered diagnostic, given that levodopa has
known to alter HCY levels.
Her MMA is borderline at 0.38 µmol/L but, again, this
finding is not diagnostic.
Although PD can explain most of her symptoms, vitamin
age is a risk factor for atrophic gastritis, and her diet
seems to
and malnutrition could contribute to borderline vitamin
11
Slightly elevated creatinine
could indicate age-related
changes in renal function,
dehydration, or mild renal
insufficiency from other
causes.
Conversions
1,000 nmol/L* = 1 µmol/L
376 nmol/L = 0.376 µmol/L
*nanomols per liter
Management
Given the uncertain nature of the test results, her
neurologist discusses vitamin
her. She expresses disinterest in oral supplementation,
stating “If I have to take one more pill, I will scream.”
Because the laboratory findings are ambiguous, the
neurologist and she agree to monitor her status rather
than start injection therapy immediately.
On her return visit 6 months later, her serum vitamin
is 189 pg/mL, and both her Hcy and MMA levels have
increased. Her neurologist orders antiparietal cell
antibody and anti-intrinsic factor antibody tests to rule
out pernicious anemia. Both tests are negative. She is
started on 1,000 µg of IM cyanocobalamin for 5 days,
followed by monthly injections of 1,000 µg of IM
cyanocobalamin. Her neurologist makes arrangements
for the home health nurse to administer the injections.
At the next visit, the patient and her family report that
she is less fatigued, less irritable, and less withdrawn.
There is no worsening of motor symptoms; however, she
still experiences occasional hallucinations.
12
Table 1. Neurologic and Psychiatric Symptoms of
Autonomic
Impotence, urinary or fecal incontinence
Orthostatic hypotension
Cerebral
Dementia, memory loss, cognitive impairment
Depression
Psychosis
Myelopathic
Subacute combined degeneration
Ataxia
Spasticity
Lehrmitte sign (electric-shock–like sensations in the
spine)
Abnormal Gait †
Spastic
Shuffling
Constitutional
+
Fatigue
*Seen in PD or resulting from dopaminergic PD treatment), or
both
†
Note gait abnormalities do not always appear “typical” of
textbook descriptions
+
+
+
+
+
+
+
+
+
+
+
+*
+
+*
-
-
-
+
+ -
- +
13
+
Natural History and Prevalence of
“Although elderly people with low vitamin
lack the classical signs and symptoms of vitamin
e.g. megaloblastic anemia, precise evaluation and treatment in
this population is important.” Baik and Russell, 1999
The case studies illustrate two important facts about
vitamin
have profound effects on patient well-
most patients with a vitamin
subclinical stage(1-7) and do not present with symptoms
or complaints such as those of the case study patients,
some patients might
sequelae if the deficiency is not detected and the
patients followed with reassessment, prophylaxis, or
treatment, as needed. Second, treatment is safe and
remarkably effective if provided
damage occurs. Understanding the biochemistry of
vitamin
cobalamin body stores are depleted, and current
treatment strategies can help clinicians prevent
significant morbidity among their patients.
The nutritional value of vitamin
established in the first half of the 20 th century, when
ingesting raw animal liver (the primary storage organ for
this nutrient) was found to
pernicious anemia.(8) Humans cannot manufacture
cobalamin and must consume it on a regular basis.
available for human use only through ingestion of animal
proteins, such as
products. Unfortified, plant-based foods do not contain
vitamin
14
available for human use only
through ingestion of animal
proteins. Unfortified plantbased
foods do
not contain
vitamin B .
12
There are several important points about cobalamin
absorption:
It occurs primarily during the active digestion of
animal proteins in the stomach and terminal ileum,
and it depends on the availability of adequate
amounts of a num
protein (haptocorrin from saliva), gastric acid, pepsin,
and intrinsic factor (IF).(2, 3)
Gastric acid is needed to digest animal protein. When
the ability to secrete that acid is lost, a person cannot
break down the protein to release vitamin
food and can absorb only crystalline (synthetic)
vitamin
Loss of IF in pernicious anemia results in an inability
to absorb vitamin
must
high doses of oral cobalamin
(1,000 micrograms [µg] daily).(2, 11)
About 1% of large oral doses of vitamin
diffuses into the bloodstream from the small
intestine.(2, 10)
If any aspect of the digestion sequence
and malabsorption develops, the body can draw on
the large amounts of vitamin
so overt symptoms might not develop for several
years.(2, 10, 12) However, with certain conditions,
vitamin
period of time (months).
Adequate serum levels of cobalamin are crucial to
complete three enzymatic processes (Figure 1).
Methylcobalamin is a cofactor necessary to convert
homocysteine (Hcy) to methionine. Thus, vitamin
The cofactor adenosylcobalamin is required for the
conversion of methylmalonyl coenzyme A to
succinyl coenzyme A.(2, 10)
Methylcobalamin is needed to convert 5methyltetrahydrofolate
to tetrahydrofolate and is
necessary for DNA and red blood cell production.
15
Pernicious anemia is an
autoimmune disease in
which antibodies attack
gastric cells, resulting in
impaired production of
intrinsic factor that is
critical for absorption of
vitamin
Figure 1. The Biochemical Role of Cobalamin
gradually over many years and are accompanied by a
slow and varied onset of nonspecific symptoms. Carmel
descri
and subclinical.(1) Clinical deficiency manifests with
hematologic or neurologic signs and symptoms,
cobalamin levels
The first to conceptualize the natural history of a vitamin
dietary vitamin
stages: serum depletion; cell depletion; biochemical
deficiency (defined as elevated levels of Hcy and MMA);
and, finally, the classic signs and symptoms of clinical
deficiency, such as anemia (Table 2).(9, 15)
Table 2. Typical Stages in the Development of a
Stage Manifestation Comment
I
II
III
IV
Circulating serum
levels depleted
Cellular stores of
are depleted
Evidence of biochemical
deficiency via
increases in serum
homocysteine and
methylmalonic acid
Clinical signs and
symptoms apparent
Patients are typically
asymptomatic and can
remain in this stage for
several years.
Patients can remain
asymptomatic. This stage
can also continue for several
years.
the conversion of these
compounds.
The spectrum of clinical
manifestations is broad and
the sequence of symptom
development varies
markedly.
Although this model provides a useful perspective,
untreated patients will not necessarily advance through
the stages chronologically or linearly. Progression to a
later stage is not inevitable, and some patients with
evidence of an early stage deficiency might have normal
laboratory values when retested.(11) Malabsorption of
food-derived cobalamin
acid production is a more likely reason for vitamin
deficiency, while malabsorption of cobalamin
lack of IF in pernicious anemia is a less prevalent
cause.(3)
17
Prevalence of
The true prevalence of vitamin
underestimated for several reasons. The common
misconception that most vitamin
to inadequate dietary intake might lead to overlooking
important high-risk groups. Older adults who routinely
consume meat and other animal proteins can still
vitamin
vitamin
patients are far more likely to have mild, subclinical
vitamin
Most prevalence estimates are based solely on serum
vitamin
cobalamin values are measured in picomoles per liter
(pmol/L) in some research studies, while clinical
laboratories express values in picograms per milliliter
(pg/mL) or nanograms per liter (ng/L). The most
frequently reported threshold value is 200 pg/mL (148
pmol/L).(1, 16) Studies that have established higher
cutpoints invariably have reported higher prevalence
estimates. In the research literature, some investigators
have used diagnostic algorithms that combine serum
results with one or more additional laboratory findings,
typically either serum Hcy or MMA.(1, 4, 17, 18)
Depending on the approach used, the additional test
findings have raised(4, 18, 19) or lowered(6, 19, 20) the
observed prevalence of vitamin
with findings based solely on serum vitamin B 12 levels.
Unpublished data from the National Health and Nutrition
Examination Survey (NHANES) 2001–2004 in Table 3
stratified by age have estimated that 1 (3.2%) of every
31 adults 51 years of age or older in the United States
has a low vitamin
are ambulatory and do not have overt symptoms of
vitamin
18
Conversions
ng/L = pg/mL
pmol/L = pg/mL x 0.738
pg/mL = pmol/L ÷ 0.738
Keep in mind that ng/L has
the same value as pg/mL but
conversion to pmol/L requires
multiplication of pg/mL by
0.738 (200 pg/mL
x 0.738 =
148 pmol/L).
Table 3. Prevalence of
the U.S. Population by Age, National Health and
Nutrition Examination Survey 2001–2004
Serum Level years years years years years
of age of age of age of age of age
≤ 150 pg/mL
0 0.2% 0.2% 0.5% 1.2%
151–200 0.1% 0.6% 1.5% 1.0% 2.0%
pg/mL
201–250 0.6% 2.5% 5.2% 6.1% 5.1%
pg/mL
251–300 1.6% 5.4% 7.9% 6.9% 6.2%
pg/mL
301–350 4.2% 9.4% 11.3% 10.7% 8.9%
pg/mL
351–400 5.4% 9.2% 13.1% 13.5% 10.7%
pg/mL
> 400 pg/mL 88.0% 72.7% 60.8% 61.2% 65.8%
Those prevalence figures are supported by other
population-based studies. The Framingham study with a
cohort of noninstitutionalized adults 67 through 96 years
of age found that 5.3% of the participants had serum
vitamin
Risk Factors for
“The clinical indications (for cobalamin deficiency) are of
prime importance since routine screening tests, such as
the blood count, are not always abnormal. The same
criteria apply to both sexes and to all age groups,
including preterm infants and children.” Amos, 1994
Patient characteristics that increase the likelihood of a
vitamin
demographic and
the risk of inadequate dietary intake (malnutrition) and
physiologic factors that increase the risk of
malabsorption. Some factors, such as advanced age,
might increase the risk of both malnutrition and
malabsorption. In the United States, most cases of
vitamin
than inadequate intake. We will review the more obvious
demographic and
strict vegetarianism and vegan diets and then
summarize the less readily apparent but more common
physiologic factors that can affect absorption.
Demographic and Behavioral Risk Factors
The risk of developing a vitamin
with age.(1, 6, 16, 21-23) The elderly, defined as
individuals 65 years of age or older, are more likely to
develop a vitamin
for both malabsorption and malnutrition. The frail
elderly, especially, might have dietary insufficiency for a
num
social isolation, mobility limitations, and poverty.
In contrast to the importance of age, other demographic
characteristics, including sex, race, and ethnicity, are not
as important in predicting vitamin
several studies have found that mild cobalamin
deficiency is most common among elderly White men
and least common among Black or African-American and
Asian-American women, (2, 3, 16, 24) the differences
20
In the United
States, most cases
of vitamin
deficiency are due
to malabsorption.
are not sufficient to support sex- or race-specific nutrient
recommendations.(10)
A patient characteristic that should always raise the
index of suspicion is long-term adherence to a strict
vegetarian or vegan diet,(10, 16, 25, 26)
diets exclude all forms of animal protein, including eggs
and dairy products. Thoughtfully planned vegetarian
diets that include eggs, milk, and yogurt can provide
adequate amounts of vitamin
to strict vegetarian and vegan diets might not cause a
problem
typically stored in the liver. However, it is prudent to
advise all vegetarian and vegan patients, particularly if
they are elderly or anticipating a pregnancy, to consume
synthetic cobalamin daily, either by taking a supplement
containing vitamin
fortified grain products.(10) The requirement for vitamin
review the vitamin
and vegan foods, see
http://www.nal.usda.gov/fnic/foodcomp/search/.
Physiologic Factors
Malabsorption is the physiologic cause of vitamin
deficiency and can result from a num
Frequently mentioned are pernicious anemia; (7, 24)
atrophic gastritis;(3, 10, 27) gastric surgery (e.g., ileal
resection and gastrectomy);(11, 16, 28) presence of a
cobalamin-utilizing fish tapeworm such as the
Diphyllobothrium latum;(2, 29) and other concurrent
diseases such as Crohn disease, HIV infection,(30-32)
celiac sprue,(33, 34) and bacterial overgrowth in the
small intestine.(35) Rare cases have
anesthetic nitrous oxide exposure.(2, 36)
Among the elderly, atrophic gastritis and pernicious
anemia are the main causes of malabsorption. Atrophic
gastritis often develops as people age. With resulting
hypochlorhydria and achlorhydria, the body does not
produce enough pepsin and hydrochloric acid to release
from protein the food-bound vitamin
anemia, missing IF needed to attach
intestine impairs the uptake of vitamin
21
Inadequate absorption
Pernicious anemia
Atrophic gastritis
Small intestinal bacterial
overgrowth
Gastrointestinal surgery
(e.g., ileal resection or
gastrectomy)
Presence of a cobalaminutilizing
fish tapeworm,
such as Diphyllobothrium
latum
Crohn disease
HIV infection
Celiac sprue
Nitrous oxide causes the
inactivation of vitamin B 12,
which might result in acute
hematologic or neurologic
complications of vitamin B 12
deficiency. Because nitrous
oxide is a commonly used
anesthetic in surgery, people
at risk (e.g., the elderly)
should
developing symptomatic
vitamin B 12 deficiency.
Undiagnosed and untreated pernicious anemia affects
1%–2% of the elderly population.(24)
22
Manifestations of
Low
“Although some clinical expressions remain mysterious,
especially the neurological dysfunction, our view of
cobalamin deficiency has expanded
of megaloblastic anemia.”
Carmel, 2000
No single symptom, or cluster of symptoms, has
uniquely associated with inadequate levels of vitamin
symptoms of vitamin
neurologic in nature, but gastrointestinal and
possibly vascular symptoms are also common. The
typically nonspecific manifestations of a vitamin
deficiency underscore the importance of encouraging all
older adults to consume the synthetic form of the
vitamin each day. Recent concerns have also
about potential adverse effects on infant growth and
development in exclusively breastfed babies of
mothers who adhere to a strict vegan diet.(11, 16)
While this situation is rare in the United States, sequelae
are often severe and irreversible in these children.
Hematologic Manifestations
Common symptoms associated with hematologic
pathology include skin pallor, weakness, fatigue,
syncope, shortness of breath, and palpitations.(2, 10) A
classic hematologic sign of severe vitamin
is megaloblastic anemia.(2) Hematologic manifestations
might also
1998, the U.S. Food and Drug Administration has
required fortification of all enriched grain and cereal
products with 140 micrograms (µg) of folic acid per 100
grams of cereal grain product,(37) and that fortification
of the U.S. food supply essentially has eliminated the
prevalence of folate deficiency.(21) Today, in the United
States, a case of megaloblastic anemia most likely
is due
to
vitamin
Although vitamin
accompanied by hematologic changes, the majority of
23
Today, in the United
States, megaloblastic
anemia is most likely
due to a vitamin
deficiency until proven
otherwise.
Folic acid fortification does not
have an effect on the
prevalence of megaloblastic
anemia attributable to vitamin
of folic acid (>5,000 µg each
day) can correct the
hematologic manifestations of
vitamin
the amount of folic acid
available through fortification as
specified by the U.S. Food and
Drug Administration (FDA) is
not likely to affect a vitamin
anemia
(FDA, 1996).
patients with clinical deficiency will have signs of
megaloblastic anemia. In various studies conducted
among patients with overt vitamin
77% of people had signs of macrocytosis or
anemia.(5, 38-41) Furthermore, some researchers
have found that the presence of neurologic
manifestations of a vitamin
correlated inversely with evidence of hematologic
effects.(10, 39, 42)
Neurologic Manifestations
Common neurologic complaints include paresthesias
(with or without objective signs of neuropathy),
weakness, motor disturbances (including gait
abnormalities), vision loss, and a wide range of cognitive
and
psychosis, paranoia, depression, violent
personality changes). Tingling of the hands and feet is
perhaps the most common neurologic complaint.(2, 41,
42)
The pathology of vitamin
system is unknown.(7)
All patients with unexplained cognitive decline or
dementia should
deficiency.(41, 43-45) Several current case reports and
studies support the common practice of assessing
vitamin
Although only a minority (1.5%) of all dementia cases
are fully reversible following treatment,(49) many
dementias from other etiologies (e.g., Parkinson or
Alzheimer disease) are exacerbated when patients have
a concomitant low vitamin
Academy of Neurology (AAN) has concluded that
among the elderly, and among patients with suspected
dementia in particular, it should
treated. The AAN practice guideline states that
should
among the elderly.(44)
24
Many
patients do have
anemia or
macrocytosis.
All patients newly
diagnosed with
unexplained cognitive
decline or dementia
should
possible vitamin
deficiency.
Gastrointestinal Manifestations
gastrointestinal complaints. Some frequently mentioned
symptoms include anorexia, flatulence, diarrhea, and
constipation.(7, 10, 36, 50) These symptoms can
develop among patients with a vitamin
without accompanying anemia, macrocytosis, or overt
neurologic deficits. Glossitis, which is commonly thought
to
relatively rare manifestation of clinical vitamin
deficiency and is completely absent in subclinical vitamin
Methodist Hospital [personal communication] 2006-
2007).
Vascular Manifestations
Both low vitamin
associated with elevated levels of homocysteine (Hcy).
Hyperhomocysteinemia increases the chance of
developing a vascular occlusion,(51) thus potentially
increasing the risk of coronary heart disease and
ischemic stroke. Although the association of coronary
heart disease or ischemic stroke with vitamin
folate deficiency has not
(Study of the Effectiveness of Additional Reductions in
Cholesterol and Homocysteine) study in the United
Kingdom is seeking to obtain evidence about the effect
of reducing Hcy on cardiovascular risk while treating
patients with 2 milligrams (mg) of folic acid plus 1 mg of
vitamin
looking at the efficacy and safety of two different
dosages of simvastatin in regard to risk reduction for
major cardiovascular events.(52) This randomized study
is scheduled to end in 2008 and should provide evidence
about the causal relationship of Hcy to cardiovascular
disease and about the value of folic acid and vitamin
supplementation, in addition to answering questions
about simvastatin therapy.
Effects on Infant Growth and Development
Although the previously cited hematologic, neurologic,
gastrointestinal, and cardiovascular consequences are
25
Nursing infants of
mothers who adhere to a
strict vegetarian or vegan
diet throughout their
pregnancy and while
breastfeeding might also
experience serious
deficiency effects.
typically observed among older patients, several cases of
significant vitamin
young children have
marginal vitamin
increases the risk for neural tu
Exclusively breastfed infants of mothers who adhere to
a strict vegetarian or vegan diet that excludes all animal
proteins might also experience serious effects related to
vitamin
manifestations among infants and young children are
widely varied, encompassing hematologic, neurologic,
and gastrointestinal symptoms. Some potential effects
include the following:
Failure to thrive
Hypotonia
Ataxia
Developmental delays
Macrocytosis or anemia
General weakness
Many of these effects will improve with prompt vitamin
neurologic damage occurs
and treatment is
vegan mothers can develop significant problems even
when the mother is not anemic or symptomatic in any
way.(50, 53, 55) It is important for you to ask pregnant
women and new mothers who breastfeed about their
diets.
26
Screening Patients
“. . . It is daunting and probably unnecessary to actively
seek out new asymptomatic cases [of vitamin
deficiency] by screening . . .”
Carmel, 2003
Most experts do not recommend community-based mass
screening programs for vitamin
among high–risk groups, such as the frail elderly. For
example:
The U.S. Preventive Services Task Force has not
published formal recommendations on screening
asymptomatic older adults.
The major medical societies have no
recommendations on routine cobalamin screening.
The National Guideline Clearinghouse website has
no guidelines calling for periodic assessment in
asymptomatic patients. (However, if you provide
primary care to patients with dementia or altered
mental status and celiac sprue or other
gastrointestinal conditions, you might wish to
consult the website (http://www.guideline.gov) for
recommendations related to vitamin
monitoring among these high–risk groups.)
27
Detection and Diagnosis
“It is particularly important that the diagnosis of
cobalamin deficiency
of certainty
must
Stabler and Allen, 2004
Keeping vitamin
means staying vigilant during your review of your
patient’s history and during the physical examination.
Watch for even subtle signs of neurologic or cognitive
impairment. Also, note any elements of the patient’s
history that might suggest potential malabsorption or
malnutrition, such as previously diagnosed pernicious
anemia, previous gastrointestinal surgery, vegan diet,
and advanced age. Maintain an especially high index of
suspicion of vitamin
report they were treated with vitamin
high doses of oral vitamin
provider, but have since discontinued their use. Elderly
patients often fail to understand that a true
vitamin
requires lifelong treatment.
Early detection and prompt treatment of a vitamin
deficiency are essential to prevent development of
irreversible neurologic damage, but making an accurate
and timely diagnosis can
related signs and symptoms is long, varied, and nonspecific.
Many risk factors have
there are no known necessary or sufficient causes.
Complicating things further is the fact that
liver is a very efficient storage organ for vitamin
even completely deficient diets in healthy adults might
not result in low serum vitamin
years. Conversely, apparently healthy adults, especially
the elderly, consuming diets rich in naturally occurring
vitamin
vitamin
period of time (months) in some people.
28
The vitamin
relative merits and limitations of the various laboratory
testing options. Some tests are used more commonly for
the initial assessment, while others,
cost, inconvenience, or difficulty of interpretation, are
reserved for confirmatory testing in ambivalent
situations or are used only in the research setting.
Initial Assessment
After conducting a thorough history and physical
examination, if you suspect vitamin
should include a complete blood count (CBC), peripheral
blood smear, and serum cobalamin (
initial laboratory assessment.(58) The serum cobalamin
test is readily available and generally affordable, and can
detect low serum vitamin
who are not anemic.(59, 60) However, not all patients
with a vitamin
manifestations. As Carmel succinctly noted, “the
proscription that cobalamin deficiency should not
diagnosed unless megaloblastic changes are found is
akin to requiring jaundice to diagnose liver disease.”(11)
While serum vitamin
accurate,(61) many conditions can complicate the
interpretation of vitamin
low values have
oral contraceptives,(62-64) folate deficiency,(58, 59)
and pregnancy.(10) Additionally, a low serum
does not automatically mean a deficiency. From 20%–
40% of elderly people with low serum
normal metabolite (homocysteine [Hcy] and
methylmalonic acid [MMA]) levels and should not
considered
as having a B deficiency.(11)
12
Sometimes, a true cobalamin deficiency will not
detected by the serum vitamin
of falsely normal serum cobalamin results might
with (but not limited to) liver disease,(58)
myeloproliferative disorders,(58) and renal
insufficiency.(4, 65) If a patient has clinical e vidence of a
vitamin
serum
important
to evaluate further.
29
The complete blood
count, smear, and serum
cobalamin (
should
initial laboratory
assessment of vitamin
Oral contraceptive users generally
have lower serum vitamin
than nonusers; however, the
evidence of tissue depletion, as
detected by high values of
methylmalonic acid and
homocysteine, is lacking.
“Accepted lower limits of
serum
range
250 pg/ml; however,
higher levels (but less
than 350 pg/ml) have
ostensibly healthy elderly
patients with other
findings suggestive of a
deficiency state, most
notably increased levels
of serum methylmalonic
acid. The true lower
limits of normal serum
appear to
poorly defined.”
Ward, 2002
Opinions differ as to the optimal laboratory cutpoint for
the serum vitamin
onset and slow progression of the disorder and
limitations of current assays. Research studies and
clinical laboratories have tended to dichotomize low
values at 200 picograms per milliliter(pg/mL).(18, 66,
67) Stabler and Allen noted the following ranges of
serum cobalamin levels among patients with a clinically
confirmed
objective clinical responses to appropriate therapy”):
less than 100 pg/mL, approximately 50%; 100–200
pg/mL, approximately 40%; 200–350 pg/mL,
approximately 10%; and more than 350 pg/mL,
approximately 0.1% to 1%.(7)
Adequate follow-up for suspect normal or low-normal
results is needed through either additional confirmatory
testing or a prolonged therapeutic trial followed by
metabolic and clinical reassessment.
Confirmatory Testing
When the serum vitamin
helpful to obtain more information.(1) Several tests can
patients with borderline serum cobalamin levels or
among symptomatic patients with normal serum
cobalamin levels.
Homocysteine (Hcy) and Methylmalonic Acid (MMA)
By far, the most common, accurate, and widely used
confirmatory tests for identifying vitamin
are tests for Hcy and MMA.(1) Because cobalamin is
necessary for the synthesis of methionine from Hcy, low
levels of vitamin
Hcy. The total serum Hcy test is a sensitive indicator for
a vitamin
a sole confirmatory test
among patients also can
hyperhomocysteinemia, levodopa therapy,(68) renal
insufficiency, and folate deficiency.(1, 7, 69, 70)
The serum MMA test is more specific for vitamin
deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels
also increase in the presence of low vitamin
30
coenzyme A to succinyl coenzyme A.(2) In one study,
98.4% of people with a vitamin
pg/mL also had elevated MMA levels (defined as values
more than 376 nanomoles per liter [nmol/L]).(70) Note
that false-positive increases in serum MMA have
identified among patients with impaired renal function. It
is necessary to rule out whether your patient has either
marked intravascular volume depletion or renal
insufficiency when interpreting the MMA level, especially
in the absence of a low cobalamin level.(70) Elevated
MMA levels among most patients indicate tissue
depletion of vitamin
and Nutrition Examination Survey (NHANES) 2001–2004
in Table 4 shows the prevalence of vitamin
using combinations of serum
Table 4. Prevalence of National Health and Nutrition
Examination Survery Participants With Biochemically
Defined
States, 2001–2004
Age Group
(Years of Age) pg/mL and MMA and MMA ≥ 270
≥ 270 nmol/L nmol/L
9–13 years of age 0.1% 2.5%
14–18 years of age 0.2% 3.7%
19–30 years of age 0.4% 3.5%
31–50 years of age 0.6% 3.6%
≥ 51 years of age 1.6%
7.9%
*Biochemically defined vitamin
picograms per milliliter (pg/mL) and methylmalonic acid (MMA) ≥
270 nanomoles per liter (nmol/L) or serum
MMA ≥ 270 nmol/L
Two popular methods for interpreting diagnostic
thresholds for MMA and Hcy elevations are the use of
cutpoints determined by laboratory norms (e.g., 3
standard deviations above the mean) and specific values
(e.g., MMA greater than 0.26 micromole per liter
31
Conversions
1,000 nmol/L* = 1 µmol/L†
376 nmol/L = 0.376 µmol/L
*nanomols per liter
†micromols per liter
[µmol/L](69) or greater than 0.4 µmol/L;(59) Hcy
greater than 15 µmol/L(71, 72)). Many clinicians rely on
ranges specified by the clinical laboratories they use.
The cost of testing for MMA or Hcy might
Quotes from Quest Laboratories (Atlanta, Georgia, May
2006) state that the direct patient (no insurance) cost
for a serum MMA is $212 and for a serum Hcy is $191.
Other metabolites, serum propionate and serum 2methylcitrate,
are also present in vitamin
However, measuring either of these metabolites has no
advantage over measuring MMA to diagnose a vitamin
many clinical laboratories.
Again, it is important to remem
metabolite levels might
a vitamin
one study of the elderly, renal insufficiency was
associated with 20% or greater of all abnormal
metabolite levels.(11)
Other Tests
If the root cause of vitamin
you should consider ordering additional tests to
determine it. Antibodies to intrinsic factor and gastrin or
pentagastrin I levels are often used to diagnose
pernicious anemia.(10, 36, 60)
Serum holotranscobalamin II measures one of the bloodbinding
proteins used to transport vitamin
investigators recommend it;(73) others are concerned
about the lack of convincing evidence of its value.(2, 9,
10, 60) Theoretically, it is attractive, but early claims of
its value have
immunoassays have replaced the older crude methods, it
is too early to determine whether measurement of
holotranscobalamin II is
serum cobalamin. (1)
The deoxyuridine suppression test ( or “DUST”) has
descri
synthesis due to either deficiency or metabolic
inactivation of vitamin
32
is used rarely in the clinical setting
necessary in the evaluation of a vitamin
DUST is also a complicated, expensive, and timeconsuming
test.(58)
The Schilling test is included in most lists of possible
vitamin
available in U.S. clinical practices at this time. The
Shilling test is the classic test for determining whether a
person can absorb vitamin
ability to absorb crystalline vitamin
his or her ability to absorb the naturally occurring
vitamin
identifying cobalamin deficiency, it can
in determining the root cause of an identified deficiency.
It reveals cobalamin malabsorption such as that found in
pernicious anemia and ileal disease. A normal Schilling
test cannot rule out vitamin
There is no gold standard for determining cobalamin
deficiency. Part of the problem is related not to the tests
used, but to “an uncertain boundary
depletion and disease.”(1, 20)
A diagnostic approach to tailor testing to the nature of a
patient’s clinical problem is suggested by Carmel and
summarized in Table 5(1)
33
Table 5. Tailored Diagnostic Approach for
Problem Goal Suggested Tests
Patient with mild to
severe hematologic
or neurologic signs
or symptoms, or
both
Patient with
hematologic or
neurologic signs or
symptoms, or
both, unlikely due
to vitamin
deficiency
Confirm suspected
vitamin
deficiency
Ensure if vitamin
exists, it is not
missed
Serum
Serum
MMA* and Hcy †
Asymptomatic Determine if MMA (metabolic
patient with vitamin
condition known to deficiency has precede low
cause vitamin
deficiency
Asymptomatic
patient accidentally
found to have low
Hcy †
*MMA–methylmalonic acid
† Hcy–homocysteine
Determine if
vitamin
deficiency exists
MMA
Flagging the patient’s chart will help you remem
follow-up if choosing to “watch and wait” with an
asymptomatic patient.
Experienced clinicians differ on the importance of
tracking down the root cause of a vitamin
cause of the deficiency is important ultimately in
individualizing the treatment approach.(1)
34
Managing Patients With Evidence of a
“A caregiver must manage a subclinically deficient
patient with pernicious anemia as a cause quite
differently and pay closer attention than to a similar
patient without it.”
Carmel, 2006
Clinical
Options available for treating a clinical vitamin
deficiency include oral and parenteral (intramuscular or
subcutaneous) preparations. Intravenous dosing is not
recommended
vitamin
The response of a patient with vitamin
anemia to treatment is usually rapid, with reticulocytosis
occurring within 2–5 days, and the hematocrit
normalizing within weeks.(10) Treatment with cobalamin
effectively halts progression of the deficiency process,
but might not fully reverse more advanced neurologic
effects.(39, 42) If the underlying cause of the vitamin
or bacterial overgrowth), then treatment should include
addressing the underlying etiology.(7)
higher than the recommended dose. It has not
shown to
mutations.(10, 75) Be aware, however, that patients
who have a vitamin
megaloblastic anemia might experience hypokalemia and
fluid overload early in treatment due to increased
erythropoiesis, cellular uptake of potassium, and
increased blood volume.(76, 77)
While the route, dosage, treatment timing, and follow-up
might vary somewhat, there is no question about the
decision to treat patients with pernicious anemia or with
a low serum
signs or symptoms without pernicious anemia (clinical
35
Cobalamin replacement is
effective
crystalline forms of
animal protein-bound
forms cannot
carcinogenic, teratogenic,
or mutagenic. It is
considered safe even at
1,000 times the RDA.
Baik and Russell, 1999
vitamin
irreversible severe problems with absorption,
patients need to continue some form of cobalamin
therapy for life.(7)
Parenteral (Intramuscular or Subcutaneous)
Administration of parenteral crystalline cobalamin has
deficiency for decades.(78, 79) Few side effects have
Anecdotally, the subcutaneous route causes less burning
than does the intramuscular route (Carmel RA. New York
Methodist Hospital [personal communication] 2006-
2007). Regimens for parenteral administration vary. An
approach suggested by Stabler and Allen is 1
milligram (mg) (or 1,000 micrograms [µg]) of
vitamin
monthly for life.(7)
Some providers have used quarterly injections after the
initial dosing protocol. However, experts state that in
pernicious anemia or severe malabsorptive deficiency
quarterly injections are not sufficient, noting that
cobalamin levels start to fall prior to the 1 month followup
(Allen RH. University of Colorado [personal
communication] 2006 -2007).
Oral
Large, daily oral replacement doses might
acceptable alternative if patients are compliant.(7)
Sufficient amounts of vitamin
passive diffusion in the small intestine.(2, 11) A study by
Eussen et al. demonstrated a linear response in the
reduction of metabolites and increased serum
with increasing dosages of oral cyanocobalamin.(80) A
common therapy is 1 mg (1,000 µg) of vitamin
to
Intranasal
A relatively new vehicle for vitamin
cyanocobalamin gel for intranasal use. Some experts
are not convinced of its efficacy, and the cost is $30 for
36
500 µg (Carmel RA. New York Methodist Hospital
[personal communication] 2006-2007). If chosen, the
intranasal gel should
treatment with parenteral or oral vitamin therapy has
established adequate metabolic status among patients
with no nervous system involvement.(74) The
recommended dose for therapy is 500 µg
intranasally once a week.(74) Absorption can
inconsistent.
Treatment approaches vary somewhat in the initial
treatment and the route used.(7, 77, 81) Given the
long-term nature of cobalamin therapy, consideration of
the patient’s condition (e.g., cognitive impairment),
convenience of getting the treatment, and ease of
administration should heavily influence the method and
dosage selected.(7, 11) For example, oral therapy is less
painful and can
cognitive impairment is a frequent reason for
noncompliance, patients might
clinic or home health nurse-administered injections.
Additionally, Carmel observed that many patients prefer
the convenience of monthly injections to daily
consumption of pills.(11)
Examples of treatment regimens from different sources
for clinical vitamin
37
Table 6. Examples of Treatment Regimens
for Clinical
Due to Initial
Maintenance
Cyanocobalamin Cyanocobalamin
Pernicious Varies, not limited 1 mg IM or SQ q
anemia to:
month for life
1 mg
OR
intramuscularly 1 mg–2 mg
(IM) or
orally (PO)
subcutaneously every day (QD)
(SQ) every (q)
week x 8
OR
for life
1 mg IM or SQ x
7 in 1 month
Other food- Varies, not limited 1 mg IM or SQ q
bound
malabsorption 1 mg IM or SQ q for life
problems week x 8 OR
OR
650 µg–1 mg PO
1 mg IM or SQ x QD possibly for
7 in 1 month life
OR
1 mg–2 mg PO
QD
Rarer Treat underlying 1 mg IM or SQ q
malabsorption condition month
problems AND OR
(tape worms, Cyanocobalamin 650 µg–1 mg PO
bacterial varies, not limited QD
overgrowth) to:
Treating underlying
1 mg IM or SQ q condition might
week x 8 resolve
OR
deficiency. If
1 mg IM or SQ x cyanocobalamin is
7 in 1 month d/c’d, follow up
with regular
assessment of
metabolites.
38
Subclinical
The far more prevalent patient presentation is by an
asymptomatic individual with borderline serum
and elevated homocysteine or methylmalonic acid levels,
or both. These patients pose a dilemma for providers
patients with subclinical vitamin
Some providers prefer to treat these patients and check
to see that metabolite markers have normalized, while
others prefer to “wait and watch”. For patients in the
subclinical vitamin
vitamin with
sufficient to correct the metabolites. Two recent studies
have suggested that the lowest dose of oral
cyanocobalamin needed to normalize metabolites in
subclinical vitamin
daily.(80, 82) The providers who test for and treat
patients with subclinical vitamin
those patients with possible pernicious anemia or
elevated metabolites, or both, can prevent potential
subsequent hematologic and neurologic manifestations.
Whether treating or “waiting and watching”, you should
remem
patient are important.
39
Prevention of
“The . . . Recommended Dietary Allowance (RDA) (2.4
mcg/day) for
same as for younger adults but with the
recommendation that
fortified ready-to-eat cereals) or
supplements
requirements.” Institute of Medicine, 1999
The irreversible nature of the late-stage neurologic
effects of a vitamin
support for the value of prevention.(44, 50, 83)
Fortunately, a vitamin
prevented. Because of the high prevalence of mild,
subclinical cobalamin deficiency among asymptomatic
individuals, it is important to remain vigilant, especially
with individuals at high risk for a vitamin
If “watch and wait” is the selected plan of care, periodic
reassessment of untreated asymptomatic patients is
important to identify progressive depletion of vitamin
The Institute of Medicine (IOM) recommends that all
adults 18 years of age or older consume 2.4 micrograms
(µg) per day of vitamin
deficiency, often undiagnosed and untreated, has
estimated to occur among 5%–15% of the elderly
population.(4, 6, 16, 19, 65) However, a recent clinical
study demonstrates that it takes 650–1,000 µg of
cyanocobalamin daily to provide 80%–90% of the
estimated maximum reduction in methylmalonic
acid.(80)
Given the high prevalence of atrophic gastritis (loss of
acid secretion) among older adults, the IOM suggests
that adults older than 50 years of age use vitamin
fortified foods and supplements (e.g., multivitamins or
single supplements) as the primary means to meet this
requirement
more readily absor
vitamin
cyanocobalamin; some contain more. Single
40
The irreversible nature of
the late-stage neurologic
effects of a vitamin
deficiency provides
strong support for the
value of prevention.
supplements typically come in doses of 100 µg, 250 µg,
500 µg, 1,000 µg, and 2,000 µg. For more information
on vitamin supplements for adults, see the National
Institutes of Health Office of Dietary Supplements
website at
http://ods.od.nih.gov/factsheets/cc/vitb12.html.
Vegans, or strict vegetarians, must obtain their per-day
dose of vitamin
or eating a fortified cereal product. Currently available
data do not support the suggestion that vegans can
meet their minimum daily requirements for vitamin
by consuming unfortified plant-based foods, nutritional
yeast, algae, or seaweed products.
For more information on the vitamin
1,100 common food items, visit the U.S. Department of
Agriculture and Agricultural Research website at
http://www.ars.usda.gov/ba/bhnrc/ndl.
Several experts in the field find that even higher doses
of oral cobalamin are necessary for the prevention of
vitamin
that the amount in the IOM recommendation is
insufficient.(80)(Carmel RA. New York Methodist Hospital
[personal communication] 2006-2007; Allen RH.
University of Colorado [personal communication] 2006-
2007) Lindenbaum’s findings of the prevalence of
cobalamin deficiency among the elderly survivors from
the Framingham study suggests “deficiencies can, at
least in part,
although . . . the dose of cobalamin administered may
have to
multivitamin preparations.”(4)
41
Summary
Low vitamin
years of age or older among the U.S. population.
but the diagnosis is easy to miss and is often overlooked
in the outpatient setting.
All patients with unexplained hematologic or neurologic
symptoms should
deficiency. If such a deficiency is found, the cause
should
damage can occur if diagnosis and treatment are
delayed.
A complete blood count, peripheral blood smear, and
serum vitamin
assessment of cobalamin deficiency. Keep in mind that
megaloblastic anemia and changes in mean corpuscular
value are not always present when there is a vitamin
deficiency. Homcysteine and methylmalonic acid can
used to confirm a vitamin
ambiguous initial results
often precede low cobalamin levels.
You have inexpensive treatment options available to
treat a vitamin
is safe, effective, and has no known toxicity level.
To prevent a vitamin
all patients 51 years of age or older to consume
synthetic vitamin
vary.
Acknowledgements: The authors thank Christine Pfeiffer, PhD, for
assistance with laboratory interpretation, and Quanhe Yang,
PhD,and Heather Carter Hamner, MS, MPH, for statistical support.
We also appreciate the comments and suggestions from our panel
of reviewers Sonja Rasmussen, MD; Joe Mulinare, MD; R.J. Berry,
MD; Lorraine Yeung, MD; Sharon Roy, MD; Mary Dott, MD; John
Mersereau, MD; Jennifer Zreloff, MD; Jason Bell, MD; Pauline
Terebuh, MD; Dan Watkins, PA; Gail Walls, MSN; Sally Lehr, MSN;
Darla Ura, MSN; Sue Ann Bell, MSN; Christa Purnell, MSN; Molly
Cogswell, RN, PhD, and Malissa Perritt, MSN.
42
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on cobalamin, folate, and homocysteine. Hematology (Am Soc
Hematol Educ Program). 2003:62-81.
2. Baik H RR.
1999(19):357-77.
3. Carmel R. Cobalamin, the stomach, and aging. Am J
Clin Nutr. 1997 Oct;66(4):750-9.
4. Lindenbaum J, Rosen
Allen RH. Prevalence of cobalamin deficiency in the
Framingham elderly population. Am J Clin Nutr. 1994
Jul;60(1):2-11.
5. Mills JL, Von Kohorn I, Conley MR, Zeller JA, Cox C,
Williamson RE, et al. Low vitamin B-12 concentrations in
patients without anemia: the effect of folic acid fortification of
grain. Am J Clin Nutr. 2003 Jun;77(6):1474-7.
6. Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA,
Stabler SP. Screening for cobalamin deficiency in geriatric
outpatients: prevalence and influence of synthetic cobalamin
intake. J Am Geriatr Soc. 2002 Apr;50(4):624-30.
7. Stabler SP, Allen RH. Megoblastic anemias. In:
Goldman L, Ausiello D, editors. Cecil Textbook of Medicine.
22nd ed. Philadelphia: W. B. Saunders Company; 2004. p.
1050-7.
8. Hoffbrand AV, Her
Hematol. 1999 Oct;36(4 Suppl 7):13-23.
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10. Institute of Medicine (IOM). Dietary reference intakes
for thiamin, riboflavin, niacin, vitamin B6, folate, vitamin
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11. Carmel R. Current concepts in cobalamin deficiency.
Annu Rev Med. 2000;51:357-75.
12. Her
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15. Her
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16. Stabler S, Allen R.
Worldwide Problem. Annu Rev Nutr. 2004;24:299-326.
43
17. Allen RH, Stabler SP, Savage DG, Lindenbaum J.
Diagnosis of cobalamin deficiency I: usefulness of serum
methylmalonic acid and total homocysteine concentrations.
Am J Hematol. 1990 Jun;34(2):90-8.
18. Bernard MA, Nakonezny PA, Kashner TM. The effect of
vitamin
to health. J Am Geriatr Soc. 1998 Oct;46(10):1199-206.
19. Pennypacker LC, Allen RH, Kelly JP, Matthews LM,
Grigsby J, Kaye K, et al. High prevalence of cobalamin
deficiency in elderly outpatients. J Am Geriatr Soc. 1992
Dec;40(12):1197-204.
20. Matchar DB, McCrory DC, Millington DS, Feussner JR.
Performance of the serum cobalamin assay for diagnosis of
cobalamin deficiency. Am J Med Sci. 1994 Nov;308(5):276-
83.
21. Pfeiffer C, Caudill S, Gunter E, Osterloh J, Sampson E.
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22. Clarke R, Refsum H, Birks J, Evans JG, Johnston C,
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23. Wright JD, Bialostosky K, Gunter EW, Carroll MD, Najjar
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28. Sumner AE, Chin MM, Abrahm JL, Berry GT, Gracely EJ,
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29. Beck WS. Diagnosis of megaloblastic anemia. Annu Rev
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30. Burkes RL, Cohen H, Krailo M, Sinow RM, Carmel R.
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44
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31. Harriman GR, Smith PD, Horne MK, Fox CH, Koenig S,
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32. Remacha AF, Cadafalch J. Cobalamin deficiency in
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35. Oh R, Brown DL.
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36. Green R, Kinsella LJ. Current concepts in the diagnosis
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37. U. S. Food and Drug Administration (FDA). Food
standards: amendment of standards of identity for enriched
grain products to require addition of folic acid. Fed Regist,
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38. Carmel R. Pernicious anemia. The expected findings of
very low serum cobalamin levels, anemia, and macrocytosis
are often lacking. Arch Intern Med. 1988 Aug;148(8):1712-4.
39. Healton EB, Savage DG, Brust JC, Garrett TJ,
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Medicine (Baltimore). 1991 Jul;70(4):229-45.
40. Lindenbaum J, Healton EB, Savage DG, Brust JC,
Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused
by cobalamin deficiency in the absence of anemia or
macrocytosis. Nutrition. 1995 Mar-Apr;11(2):180-2.
41. Stabler SP, Allen RH, Savage DG, Lindenbaum J.
Clinical spectrum and diagnosis of cobalamin deficiency.
Blood. 1990 Sep 1;76(5):871-81.
42. Savage DG, Lindenbaum J. Neurological complications
of acquired cobalamin deficiency: clinical aspects. Baillieres
Clin Haematol. 1995 Sep;8(3):657-78.
43. Adelman AM, Daly MP. Initial evaluation of the patient
with suspected dementia. Am Fam Physician. 2005 May
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44. Knopman DS, DeKosky ST, Cummings JL, Chui H,
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of dementia (an evidence-based review). Report of the
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45. Wynn M, Wynn A. The danger of
elderly. Nutr Health. 1998;12(4):215-26.
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46. Eastley R, Wilcock GK, Bucks RS.
deficiency in dementia and cognitive impairment: the effects
of treatment on neuropsychological function. Int J Geriatr
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47. Goe
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literature. J Neuropsychiatry Clin Neurosci. 2000
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48. Hutto BR. Folate and cobalamin in psychiatric illness.
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49. Boustani M, Peterson B, Hanson L, Harris R, Lohr KN.
Screening for dementia in primary care: a summary of the
evidence for the U.S. Preventive Services Task Force. Ann
Intern Med. 2003 Jun 3;138(11):927-37.
50. Rasmussen SA, Fernhoff PM, Scanlon KS.
deficiency in children and adolescents. J Pediatr. 2001
Jan;138(1):10-7.
51. Refsum H, Ueland PM, Nygard O, Vollset SE.
Homocysteine and cardiovascular disease. Annu Rev Med.
1998;49:31-62.
52. Bowman L, Armitage J, Bulbulia R, Parish S, Collins R.
Study of the effectiveness of additional reductions in
cholesterol and homocysteine (SEARCH): characteristics of a
randomized trial among 12064 myocardial infarction
survivors. Am Heart J. 2007 Nov;154(5):815-23, 23 e1-6.
53. Monagle PT, Tauro GP. Infantile megaloblastosis
secondary to maternal vitamin
Haematol. 1997 Mar;19(1):23-5.
54. Muhammad R, Fernhoff P, Rasmussen G, Bowman B,
Scalon K. Neurologic impairment in children associated with
maternal dietary deficiency of cobalamin--Georgia, 2001.
JAMA. 2003 Feb 26;289(8):979-80.
55. Turner RJ, Scott-Jupp R, Kohler JA. Infantile
megaloblastosis secondary to acquired vitamin
deficiency. Pediatr Hematol Oncol. 1999 Jan-Feb;16(1):79-
81.
56. von Schenck U, Bender-Gotze C, Koletzko B.
Persistence of neurological damage induced by dietary
vitamin B-12 deficiency in infancy. Arch Dis Child. 1997
Aug;77(2):137-9.
57. Groenen PM, van Rooij IA, Peer PG, Gooskens RH,
Zielhuis GA, Steegers-Theunissen RP. Marginal maternal
vitamin
bifida. Am J Obstet Gynecol. 2004;191:11-7.
58. Amos R, Dawson D, Fish D, Leeming R, Linnell J.
Guidelines on the investigation and diagnosis of cobalamin
and folate deficiencies. A publication of the British Committee
for Standards in Haematology. BCSH General Haematology
Test Force. Clin Lab Haematol. 1994 Jun;16(2):101-15.
46
59. Klee GG. Cobalamin and folate evaluation:
measurement of methylmalonic acid and homocysteine vs
vitamin B(12) and folate. Clin Chem. 2000 Aug;46(8 Pt
2):1277-83.
60. Ward PC. Modern approaches to the investigation of
vitamin
45.
61. Mason JB. Consequences of altered micronutrients
status. In: Goldman L, Bennett JC, editors. Cecil Textbook of
Medicine. Philadelphia: W. B. Saunders, Inc.; 2000. p. 170-8.
62. Riedel B, Bjorke Monsen AL, Ueland PM, Schneede J.
Effects of oral contraceptives and hormone replacement
therapy on markers of cobalamin status. Clin Chem. 2005
Apr;51(4):778-81.
63. Shojania AM. Oral contraceptives: effect of folate and
vitamin
1;126(3):244-7.
64. Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T.
Serum folate and vitamin
oral conceptives (OC) containing 20 mcg ethinyl estradiol. Eur
J Obstet Gynecol Reprod Biol 2003 Mar 107(1):57-61.
65. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea
M, Azen C. Serum cobalamin, homocysteine, and
methylmalonic acid concentrations in a multiethnic elderly
population: ethnic and sex differences in cobalamin and
metabolite abnormalities. Am J Clin Nutr. 1999
Nov;70(5):904-10.
66.
A, Sweet RA, et al. Cognitive and
vitamin
dementia. Am J Geriatr Psychiatry. 2002 May-Jun;10(3):321-
7.
67. Stabler SP. Screening the older population for
cobalamin (vitamin
Nov;43(11):1290-7.
68. O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L,
Dewey RB, Jr., Bottiglieri T, et al. Elevated plasma
homocysteine level in patients with Parkinson disease: motor,
affective, and cognitive associations. Arch Neurol. 2004
Jun;61(6):865-8.
69. Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A,
Stokkeland M, et al. Evaluation of indicators of cobalamin
deficiency defined as cobalamin-induced reduction in
increased serum methylmalonic acid. Clin Chem. 2000
Nov;46(11):1744-50.
70. Savage DG, Lindenbaum J, Stabler SP, Allen RH.
Sensitivity of serum methylmalonic acid and total
homocysteine determinations for diagnosing cobalamin and
folate deficiencies. Am J Med. 1994 Mar;96(3):239-46.
47
71. Ray JG, Cole DE, Boss SC. An Ontario-wide study of
vitamin
to plasma homocysteine: is a preventable public health issue
on the rise? Clin Biochem. 2000 Jul;33(5):337-43.
72. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum
H, Sand
Assessment of the diagnostic utility and cost-
of methylmalonic acid determination in relation to current
diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98.
73. Her
Clin Nutr. 1998 Apr;67(4):739-40.
74. RXList I. Cyanocobalamin. WebMD; 2008.
75. Schauss AG. Recommended optimum nutrient intakes.
In: Pizzorno, editor. Textbook of Natural Medicine. 2nd ed:
Churchill Livingstone, Inc.; 1999. p. 909-27.
76. Hoffman R, Benz E, Shattil S, Furie B, Cohen H,
Sil
4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005.
77. Marks PW, Zuker
Massachusetts General Hospital. Weekly clinicopathological
exercises. Case 30-2004. A 37-year-old woman with
paresthesias of the arms and legs. N Engl J Med. 2004 Sep
23;351(13):1333-41.
78. Lawhorne LW, Wright H, Cragen D. Characteristics of
non-cobalamin deficient patients who receive regular
cyanocobalamin injections. Fam Med. 1991 Sep-
Oct;23(7):506-9.
79. Hughes D, Elwood PC, Shinton NK, Wrighton RJ. Clinical
trial of the effect of vitamin
serum
80. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland
PM, Hoefnagels WH, et al. Oral cyanocobalamin
supplementation in older people with vitamin
a dose-finding trial. Arch Intern Med. 2005 May
23;165(10):1167-72.
81. Solomon LR. Cobalamin-responsive disorders in the
ambulatory care setting: unreliability of cobalamin,
methylmalonic acid, and homocysteine testing. Blood. 2005
Feb 1;105(3):978-85.
82. Stabler SP, Allen RH, Dolce ET, Johnson MA. Elevated
serum S-adenosylhomocysteine in cobalamin-deficient elderly
and response to treatment. Am J Clin Nutr. 2006
Dec;84(6):1422-9.
83. Wolters M, Strohle A, Hahn A. Cobalamin: a critical
vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66.
48
References for Text in Boxes
Amos R, Dawson D, Fish D, Leeming R, Linnell J.
Guidelines on the investigation and diagnosis of
cobalamin and folate deficiencies. A publication of the
British Committee for Standards in Haematology. BCSH
General Haematology Test Force. Clin Lab Haematol.
1994 Jun;16(2):101–15.
Baik H, Russell R.
Annual Rev Nutr.1999(19):357–77.
Bernard MA, Nakonezny PA, Kashner TM. The effect of
vitamin
relationship to health. J Am Geriatr Soc. 1998
Oct;46(10):1199–206.
Carmel R. Current concepts in cobalamin deficiency.
Annu Rev Med. 2000;51:357–75.
Carmel R, Green R, Rosenblatt DS, Watkins D. Update
on cobalamin, folate, and homocysteine. Hematology
(Am Soc Hematol Educ Program). 2003:62–81.
U.S. Food and Drug Administration (FDA). Food
standards: amendment of standards of identity for
enriched grain products to require addition of folic acid. .
Fed Regist, 1996; 61(44): 8781-97.
Her
vegetarians. Am J Clin Nutr. 1994 May;59(5
Suppl):1213S–22S.
Institute of Medicine (IOM). Dietary reference intakes for
thiamin, riboflavin, niacin, vitamin B6, folate, vitamin
D.C.: National Academy Press; 1998.
Matchar DB, McCrory DC, Millington DS, Feussner JR.
Performance of the serum cobalamin assay for diagnosis
of cobalamin deficiency. Am J Med Sci. 1994
Nov;308(5):276–83.
49
Pennypacker LC, Allen RH, Kelly JP, Matthews LM,
Grigsby J, Kaye K, et al. High prevalence of cobalamin
deficiency in elderly outpatients. J Am Geriatr Soc. 1992
Dec;40(12):1197–204.
Rajan S, Wallace JI, Beresford SA, Brodkin KI, Allen RA,
Stabler SP. Screening for cobalamin deficiency in
geriatric outpatients: prevalence and influence of
synthetic cobalamin intake. J Am Geriatr Soc. 2002
Apr;50(4):624–30.
Stabler SP, Allen RH. Megoblastic anemias. In: Goldman,
ed. Cecil Textbook of Medicine, 22nd ed. Philadelphia:
W. B. Saunders Company; 2004. p. 1050–7.
Ward PC. Modern approaches to the investigation of
vitamin
Jun;22(2):435–45.
50
Appendix A
Answers to Case Study Questions
1. Do any of the presenting complaints raise
your index of suspicion about a possible
vitamin
Complaints of tiredness for 2 months and memory
problems in a woman 65 years of age might
indicate a vitamin
2. What risk factors does this woman appear to
have for a vitamin
immediately apparent risk factor is her age. Risk
of developing a deficiency
years of age. Sex is not an important predictor.
The patient’s nutritional status is unclear at this
stage. Future questions might usefully pro
patient for regular sources of vitamin
meat and dairy products as well as fortified foods
and nutritional supplements.
3. Does the fact that she appears to
indicate she is unlikely to have a
vitamin deficiency?
fact that she is well-nourished does not rule out a
potential deficiency. Weight, or body mass index,
is not a useful predictor. Normal and overweight
individuals might still have a significant vitamin
deficiency
malabsorption rather than malnutrition. Markedly
underweight patients, who might truly
malnourished, are at increased risk for a vitamin
have
for several years.
4. Are there any aspects of her physical
examination that suggest a vitamin
deficiency? Mucosal and skin pallor are subtle
signs.
51
5. Given her history and physical examination
findings, what laboratory test(s) would you
order? In addition to the usual chemistry panel
and complete blood count with smear to check for
anemia, a serum
levels indicate a need for further
assessment
maintained at the expense of liver stores even in
the presence of ongoing malabsorption.
52
Appendix B
Additional Articles on
Allen R, Lindenbaum J, Stabler S. High prevalence
of cobalamin deficiency in the elderly. Trans Am
Clin Climatol Assoc. 1995;107:37–45.
Carmel R, Melnyk S, James J. Cobalamin deficiency
with and without neurologic abnormalities:
differences in homocysteine and methionine
metabolism. Blood. 2003;101:3302–8.
Carmel R. Pernicious anemia: the expected
findings of very low cobalamin levels, anemia, and
macrocytosis are often lacking. Arch Intern Med.
1988;148:1712–4.
Clarke R. Prevention of vitamin B-12 deficiency in
old age. Am J Clin Nutr. 2001;73:151–2.
Fairfield K, Fletcher R.
prevention in adults - Scientific Review. JAMA.
2002;287:3116–26.
Fletcher R, Fairfield K.
prevention in adults - clinical applications. JAMA.
2002;287:3127–9.
Her
supplementation. Am J Clin Nutr. 1997;66:1479–
80.
Herrmann W, Schorr H, Bodis M, Knaapp J, Muller
A, Stein G, et al. Role of homocysteine,
cystathionine and methylmalonic acid
measurement for the diagnosis of vitamin
deficiency in high-aged subjects. Eur J Clin Invest.
2000;30:1083–9.
Ho G, Kauwell G, Bailey L. Practitioners’ guide to
meeting the vitamin
allowances for people aged 51 years and older. J
Am Diet Assoc. 1999;99:725–7.
53
Holleland G, Schneede J, Ueland P, Lund P, Refsum
H, Sand
general practice: assessment of the diagnostic
utility and cost-
acid determination in relation to current diagnostic
strategies. Clin Chem. 1999;45:189–98.
Hvas A, Ellegaard J, Nexo E. Increased plasma
methylmalonic acid level does not predict clinical
manifestations of vitamin
Intern Med. 2001;161:1535–41.
Johnson M, Hawthorne N, Brackett W, Fischer J,
Gunter E, Allen R, et al. Hyperhomocysteinemia
and vitamin
IIIC nutrition services. Am J Clin Nutr.
2003;77:211–20.
Lokk J, Nilsson M, Nor
H, Westman G. Shifts in
health care of Sweden. Scand J Public Health.
2001;29:122–8.
Malouf R, Areosa S.
Cochrane Database Syst Rev. 2003:3.
Meins W, Muller-Thomsen T, Meier-Baumgartner
H. Subnormal serum vitamin
and psychological symptoms in Alzheimer’s
disease. Int J Geriatr Psychiatry. 2000;15:415–8.
Misra U, Kalita J, Das A.
neurological syndromes: a clinical, MRI, and
electrodiagnostic study. Electromyogr Clin
Neurophysiol. 2003;43:57–64.
Mitchell S, Rockwood K. The association
antiulcer medication and initiation of cobalamin
replacement in older persons. J Clin Epidemiol.
2001;54:531–4.
Naurath H, Joosten E, Riezler R, Stabler S, Allen R,
Lindenbaum J. Effects of vitamin
vitamin B6 supplements in elderly people with
normal serum vitamin concentrations. Lancet.
1995;346:85–9.
54
Penninx BW, Guralnick JM, Ferrucci L. Fried LP,
Allen R, Stabler S.
depression in physically disabled older women:
epidemiologic evidence from the Women’s Health
and Aging Study. Am J Psychiatry.
2000;157:715–21.
Stopeck A. Links
infection, cobalamin deficiency, and pernicious
anemia. Arch Intern Med. 2000;160:1229–30.
Tiemeier H, van Tuiji H, Hoffman A, Meijer J,
Kilaan A, Breteler M.
homocysteine in depression: the Rotterdam Study.
Am J Psychiatry. 2002;159:2099–101.
van Asselt D, Blom H, Zuiderent R, Wevers R,
Jakobs C, van den Broek W, et al. Clinical
significance of low cobalamin levels in older
hospital patients. Neth J Med. 2000;57:41–9.
55
Appendix C
on Your Radar Screen
Evaluation Questionnaire and
Posttest
Course Goal: To increase the num
providers (physicians and midlevel providers) who
prevent, detect, and treat vitamin
among their high-risk patients.
Objectives:
• Descri
vitamin
age or older.
• List three neurologic effects of a vitamin
deficiency.
• List three hematologic effects of a vitamin
deficiency.
• Identify the most common presentation of a
vitamin
• Discuss the changes in absorption of vitamin
that occur with age.
• List at least two pharmacologic options for
treatment of a vitamin
1. The learning outcomes (objectives) were relevant to
the goal of this course.
a. Strongly agree
b.Agree
c. Undecided
d. Disagree
e. Strongly disagree
2. The content was appropriate given the stated
objectives of the course.
a. Strongly agree
b. Agree
56
c. Undecided
d. Disagree
e. Strongly disagree
3. The content was presented clearly.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
4. The learning environment was conducive to learning.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
5. The delivery method (i.e., Web) helped me learn the
material more easily.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
6. The instructional strategies helped me learn the
material.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
7. Overall, the quality of the course materials was
excellent.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
8. The course was
a. Much too difficult
b. A little too difficult
c. Just right
57
d. A little too easy
e. Much too easy
9. Overall, the course was
a. Much too long
b. A little too long
c. Just right
d. A little too short
e. Much too short
10. The availability of continuing education credit
influenced my decision to participate in this activity.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
f. Not applicable
11. As a result of my completing this educational
activity, it is likely that I will make changes in my
practice.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
f. Not applicable
12. I am confident I can descri
United States of vitamin
years of age or older.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
13. I am confident I can list three neurologic effects of a
vitamin
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
58
14. I am confident I can list three hematologic effects of
a vitamin
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
15. I am confident that I can identify the most common
presentation of vitamin
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
16. I am confident that I can discuss the changes in
absorption of vitamin
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
17. I am confident I can list at least two pharmacologic
options for treatment of a vitamin
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
18. The content expert(s) for this document
demonstrated expertise in the subject matter.
a. Strongly agree
b. Agree
c. Undecided
d. Disagree
e. Strongly disagree
19. Do you feel this course was commercially biased?
Yes or No
If yes, please explain
59
20. Please descri
difficulties you experienced with the course.
21. What could
offerings?
22. Do you have any further comments?
60
Pretest and Posttest
If you want to receive continuing education credit for
this program, complete this posttest. Please read the
case history and then answer the questions that follow.
Choose the answer that is most correct for each
question.
Case
A 60-year-old teacher with a history of hypothyroidism
and gastroesophageal reflux disease (GERD) reports
significant fatigue, hot flashes, and memory difficulty
since her last annual visit. On detailed review of
symptoms, she also admits to irritability, emotional
lability, decreased appetite, difficulty sleeping, and
occasional tingling of her fingertips. Her last monthly
period was 2 years ago. She has
vegetarian diet for the past 5 years to try to lose weight.
During the physical examination, she is alert and
oriented x 3, but tearful at one point during the
interview with an MMSE score of 28 out of 30. There are
no abnormal physical findings.
Her CBC results:
RBC 4.6 (4.2–5.8) 10^6/µL
MCV 90 (78–102) fL
Hgb 15 (12.0–16.0) g/dL
WBC 6.4 (4.3–11.0) 10^3/µL (normal differential)
Plts 312 (144–440) 10^3/µL
Smear shows normocytic, normochromic RBCs
Chemistry results:
Na 139 (136–148) mEq/L
K 4.7 (3.5–5.5) mEq/L
Cl 103 (98–110) mmol/L
BUN 20.0 (9.34–23.35)mg/dL
Cr 1.0 (0.4–1.5) mg/dL
CO2 25 (21–33) mmol/L
Gluc 80 (60–140) mg/dL
GOT 26 (1–32) U/L
GPT 14 (1–30) U/L
AlkPhos 115 (31–121) U/L
61
1. Which of the following presenting symptoms
suggest this patient might have a vitamin
deficiency?
a. Fatigue
b. Difficulty sleeping
c. Hot flashes
d. Emotional lability
e. All of the above
2. All of the following factors might place this
patient at high risk for a vitamin
except:
a. Being 51 years of age or older
b. Being female sex
c. Having hypothyroidism
d. Following a vegetarian diet
3. You might find ______ patients with evidence
of low vitamin
you see. (Hint: Use prevalence data from the
research literature to determine your answer.)
a. 0–1
b. 2–4
c. 8–10
d. 15 or more
4. What can you conclude from the CBC with
smear results about the likelihood that this
patient has a vitamin
a. Her CBC and smear are abnormal so she must
have a
b. Her CBC and smear are normal so she does not
have a
c. A normal CBC and smear do not rule out a
deficiency.
d. Nothing; it was a mistake to order a CBC and
smear in the first place.
You obtain a serum
Serum
5. What does this patient’s serum
suggest?
a. Her result is within normal limits so she does
not have a vitamin
62
b. She might have a vitamin
further testing could
c. None of the above.
6. A serum
patients who:
a. Are on oral contraceptives
b. Are fasting
c. Have liver disease or renal disease
d. Answers (a) and (c)
7. Setting aside issues of cost and patient
convenience, which one of the following
additional tests would you consider the most
informative at this time?
a. Serum homocysteine
b. Serum methylmalonic acid
c. Serum holotranscobalamin
d. Schilling test
You order additional tests during the workup for this
patient.
Other laboratory results:
TSH 2.3 (0.34–5.6) µ units/mL
ESR 23 (0–30) mm/Hr
CRP 3.1 (0–4.9) mg/L
Hcy 20 (4–17) µmol/L
MMA 0.71 (0.08–0.56) µmol/L
8. Considering all of the evidence presented for
this patient, what would you do next?
a. Ask the patient to increase consumption of
animal food products and recheck her in 6
months
b. Ask the patient to take a multivitamin with
and recheck her in 6 months
c. Check for intrinsic factor antibodies and
treatment
d. Nothing
9. Which of the following treatment options
would you select for this patient?
a. Intramuscular injections, starting with frequent
injections that are gradually tapered to monthly
injections
63
b. Oral formulation, same dosage throughout
c. Intramuscular injections initially, switching to
an oral formulation later
d. One of the above, depending on issues of cost,
convenience, and likely patient compliance
10. Pernicious anemia was confirmed. How do
you advise this patient about her prognosis?
a. You tell her that a course of treatment with
vitamin
b. You advise her that she must continue
treatment with vitamin
c. You tell her that seaweed, nutritional yeast, and
algae will help prevent signs and symptoms
from occurring later.
d. A and C
e. None of the above
64
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