Why Vitamin B12 Deficiency Should be on your Radar Screen

cdc.gov

Why Vitamin B12 Deficiency Should be on your Radar Screen

ong>Whyong> ong>Vitaminong> ong>B12ong> ong>Deficiencyong> ong>Shouldong> Be

on Your Radar Screen

A Continuing Education Update

Course WB1349

Prepared for the

National Center on Birth Defects and Developmental Disabilities

Centers for Disease Control and Prevention

by

Marian L. Evatt, MD 1

Patricia W. Mersereau, MN, CPNP 2

Janet Kay Bobo, PhD 3

Joel Kimmons, PhD 4

Jennifer Williams, MSN, MPH, FNP-BC 5

The findings and conclusions in this report are those of the authors

and do not necessarily represent the views of the

Centers for Disease Control and Prevention.

1 Department of Neurology, Emory University, Atlanta, Georgia.

2 SciMetrika, LLC, Atlanta, Georgia.

3 Battelle Centers for Public Health Research and Evaluation, Atlanta, GA and Seattle, Washington.

4 National Center for Chronic Disease Prevention and Health Promotion, CDC, Atlanta, Georgia.

5 National Center on Birth Defects and Developmental Disabilities, CDC, Atlanta, Georgia.

i


Contents

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Goal and Objectives .................................................................................1

Accreditation ...........................................................................................2

Introduction ............................................................................................3

Case Studies ............................................................................................6

Natural History and Prevalence of ong>Vitaminong> ong>B12ong> ong>Deficiencyong>......................14

Risk Factors for ong>Vitaminong> ong>B12ong> ong>Deficiencyong> ..................................................20

Manifestations of Low ong>Vitaminong> ong>B12ong> Levels ..............................................23

Screening Patients .................................................................................27

Detection and Diagnosis ........................................................................28

Managing Patients With Evidence of a ong>Vitaminong> ong>B12ong> ong>Deficiencyong>................35

Prevention of ong>Vitaminong> ong>B12ong> Deficiencies...................................................40

Summary ...............................................................................................42

References.............................................................................................43

References for Text in Boxes .................................................................49

Appendix A: Answers to Case Study Questions ......................................51

Appendix B: Additional Articles on ong>Vitaminong> ong>B12ong> ong>Deficiencyong> .....................53

Appendix C: Evaluation Questionnaire, Pretest, and Posttest ................56

2/11/2010

ii


Figure and Tables

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Figure 1. The Biochemical Role of Cobalamin........................................ 16

Table 1. Neurologic and Psychiatric Symptoms of ong>Vitaminong> ong>B12ong>

ong>Deficiencyong> and Parkinson Disease (PD) ................................... 13

Table 2. Typical Stages in the Development of a

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>.............................................................. 17

Table 3. Prevalence of ong>Vitaminong> ong>B12ong> Serum Levels for the U.S.

Population By Age, National Health and Nutrition Examination

Survey 2001–2004 …………………………… 19

Table 4. Prevalence of National Health and Nutrition Examination Survey

Participants With Biochemically Defined ong>Vitaminong> ong>B12ong> ong>Deficiencyong>*

By Age Group, United States, 2001–2004 …………………………… 31

Table 5. Tailored Diagnostic Approach for ong>Vitaminong> ong>B12ong> ong>Deficiencyong>………34

Table 6. Examples of Treatment Regimens for ong>Vitaminong> ong>B12ong> ong>Deficiencyong>…38

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 unlaong>beong>led use

of a product or a product under investigational use.

iii


ong>Whyong> ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

ong>Shouldong> Be on Your Radar Screen:

A Continuing Education Update

Goal and Objectives

The goal of this continuing education activity is to

increase the numong>beong>r of primary care providers

(physicians and midlevel providers) who prevent, detect,

and treat vitamin ong>B12ong> deficiencies among their high-risk

patients.

After completing this continuing education material, you

should ong>beong> able to

• Descriong>beong> the prevalence in the United States of

vitamin ong>B12ong> deficiency among adults 51 years of

age or older.

• List three neurologic effects of a vitamin ong>B12ong>

deficiency.

• List three hematologic effects of a vitamin ong>B12ong>

deficiency.

• Identify the most common presentation of a

vitamin ong>B12ong> deficiency.

• Discuss the changes in absorption of vitamin ong>B12ong>

that occur with age.

• List at least two pharmacologic options for

treatment of a vitamin ong>B12ong> deficiency.

2/11/2010

1


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 numong>beong>r: WB1349.

You will need to enter the verification code (ong>B12ong>)

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Introduction

ong>Vitaminong> ong>B12ong> (cobalamin) deficiency should ong>beong> on your

radar screen for several reasons. Prevention, early

detection, and treatment of vitamin B deficiency are

important public health issues, ong>beong>cause they are

essential to prevent development of irreversible

neurologic damage which can impact quality of life.

Although most health care providers already recognize

the occasional person who presents with obvious signs

and symptoms, they are far less likely to screen and

diagnose the majority of patients who have a subclinical

or mildly symptomatic vitamin ong>B12ong> deficiency. ong>Vitaminong>

ong>B12ong> deficiency is more common among older adults than

many health care providers realize. Unpublished

analysis at the Centers for Disease Control and

Prevention (CDC) of laboratory data from communitybased

samples of U.S. adults 51 years of age or older

suggest about 1 (3.2%) of every 31 persons have serum

vitamin ong>B12ong> levels ong>beong>low 200 picograms per milliliter

(pg/mL).

ong>Vitaminong> ong>B12ong> has profound effects on human health.

Adequate body stores are essential for several crucial

neurologic and hematologic functions. Delays in the

diagnosis and treatment of vitamin ong>B12ong> deficiencies can

lead to development of severe, irreversible neurologic

damage.

The clinical importance of vitamin ong>B12ong> was established

over 50 years ago, when ingesting raw animal liver (the

primary storage organ for vitamin ong>B12ong>) was found to ong>beong>

an effective treatment for pernicious anemia. Research

has shown that the water-soluble vitamin ong>B12ong> is required

for the completion of several biochemical processes (see

Figure 1).

The following five top things to rememong>beong>r about vitamin

ong>B12ong> in primary care practice summarize the implications

of these and other cobalamin-related findings.

3


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

The top five things to rememong>beong>r

about vitamin ong>B12ong>

1. ong>Vitaminong> ong>B12ong> deficiencies occur in adults 51 years of

age or older at a frequency of 1 (3.2%) in every 31

persons, and manifest as serum vitamin ong>B12ong> levels

ong>beong>low the cutpoint of 200 picograms per milliliter.

2. All patients with unexplained hematologic or

neurologic signs or symptoms should ong>beong> evaluated for

a vitamin ong>B12ong> deficiency. If found, the cause should

should ong>beong> determined.

3. Today, megaloblastic anemia is most likely due to

vitamin ong>B12ong> deficiency and needs prompt evaluation.

In the United States, folic acid fortification has made

folate deficient megaloblastic anemia a very rare

condition.

4. Although the body’s ability to absorb naturally

occurring vitamin ong>B12ong> decreases with age, most people

can readily use the synthetic form of cobalamin.

5. All people 51 years of age or older should get most of

their daily vitamin ong>B12ong> through supplements

containing vitamin ong>B12ong> or foods fortified with

vitamin ong>B12ong>.

4


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

This update has ong>beong>en prepared and organized to address

four questions pertinent to primary health care

providers:

ong>Whyong> should I ong>beong> concerned about my patient’s

vitamin ong>B12ong> status?

o Introduction

o Case studies

o Natural history and prevalence of vitamin ong>B12ong>

deficiencies

o Manifestations of low vitamin ong>B12ong> levels

Which of my patients are at high risk for vitamin ong>B12ong>

deficiency?

o Risk factors for a vitamin ong>B12ong> deficiency

How do I detect and diagnose a vitamin ong>B12ong>

deficiency?

o Screening patients

o Detection and diagnosis

How should I manage a patient with evidence of

vitamin ong>B12ong> deficiency?

o Managing patients with evidence of a vitamin

ong>B12ong> deficiency

o Preventing vitamin ong>B12ong> deficiencies

5


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Case Studies

The following case studies are not actual patients. They

combine elements from different cases to emphasize

important aspects of vitamin ong>B12ong> deficiency.

Case Study 1

Presentation

During a checkup for hypertension, a 65-year-old female

reports a 2-month history of tiredness, feeling faint from

“getting up too fast”, and “memory problems”.

Case Study Question 1

Do any of the presenting complaints raise your index of

suspicion about a possible vitamin ong>B12ong> deficiency? If so,

why?

History

On review of systems, she reports difficulty

concentrating, fatigue, feeling faint when she stands

quickly, and vague gastrointestinal discomfort with some

decrease in appetite.

She denies any history of previous trauma, diplopia,

dysphagia, vertigo, vision loss, loss of consciousness,

back pain, or symptoms of bowel or bladder dysfunction.

Her family history is negative for neurologic, psychiatric,

and autoimmune diseases. Her medications include an

antihypertensive, as well as an occasional antiinflammatory

drug for episodic headaches. Her social

history reveals a single woman who smokes about onehalf

pack of cigarettes per day, drinks alcohol only

socially, and denies illicit drug use. She has a high

school education and, until recently, had worked in the

office of a trucking company.

6


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Case Study Question 2

What risk factors does this woman appear to have for a

vitamin ong>B12ong> deficiency?

Physical Examination

Pale 65 y.o. WF who appears well-nourished, alert, and

oriented.

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

and 95/52 upon standing,

Height/Weight 5’4”/120 lbs.

Head Normocephalic; oropharynx clear but

pale; palpebral conjunctivae pale.

Neck Supple, full active and passive ROM

without pain, without audible bruits; no

lymphadenopathy; no thyromegaly

Back No spine tenderness

Lungs Clear to auscultation

Heart Regular rate and rhythm; no murmurs

Abdomen Soft, nontender; no organomegaly

Rectal Normal rectal tone; no fissures

Extremities No clubbing, cyanosis, or edema; FROM

Skin Pale; no rash

The general physical examination is unremarkable

except for orthostatic hypotension and a weight loss of 3

pounds since her last visit 6 months ago. She is alert

and oriented times three. Her Mini-Mental Status Exam

score is 26 out of 30. She misses one point on serial 7s

and is able to recall three of three items. There is

evidence of bilateral mildly diminished vibration and

proprioception. Her reflexes are 3+/4+ throughout, with

negative Babinski reflex.

Cranial 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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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

Cereong>beong>llar Normal finger-to-nose, heel-to-shin, and

rapid alternating movements

Case Study Questions

3. Does the fact that she appears to ong>beong> “well-nourished”

indicate she is unlikely to have a vitamin deficiency? ong>Whyong>

or why not?

4. Are there any aspects of her physical examination that

suggest a vitamin ong>B12ong> deficiency?

5. Given her history and physical examination findings,

what laboratory test(s) would you order?

Laboratory Studies

You order routine laboratory studies, which include

complete blood count (CBC) with smear and chemistry

screen. In addition, you order a serum vitamin ong>B12ong> level

to investigate further the etiology of her fatigue and pale

mucosa. Results from the CBC and smear reveal a

borderline macrocytic anemia. The chemistry panel is

within normal limits. The serum vitamin ong>B12ong> level you

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

level is considered within a “normal range” by some

laboratories, but you take into account her other signs

and symptoms and request confirmatory testing with

8


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> deficiency.

You decide to investigate the cause of her vitamin ong>B12ong>

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 ong>B12ong> therapy for the

remainder of her life, and you make a note on her chart

to assess her compliance at each visit. You also advise

her to inform her family of the diagnosis ong>beong>cause there

is possibly a genetic component.

You start her on vitamin ong>B12ong> intramuscular (IM)

injections. She gets IM cyanocobalamin 1,000

micrograms (µg) two times per week for 2 weeks and

then switches to oral vitamin ong>B12ong> 1,000 µg daily

thereafter. Almost immediately after the initiation of

injections, she reports improved concentration. Within 2

weeks, she notes less fatigue and normal appetite.

Case Study 2

Presentation

An 85-year-old female with a 15-year history of

Parkinson disease (PD) is seen for her regularly

scheduled follow-up with her neurologist.

History

On review of systems, family memong>beong>rs report that she

has ong>beong>come more withdrawn and irritable during the last

9


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>beong>haviors or any recent trauma, but she

does admit having a decreased appetite and eating little

or no meat. Her family descriong>beong>s her nutritional intake

as poor, stating that she is just getting by on “tea and

toast”.

Her social history reveals a widowed elderly woman who

lives with her son and daughter-in-law. She had lived

independently until 5 years ago, when completing her

activities of daily living (ADLs) ong>beong>came too difficult. She

currently has a home health nurse visit once a day to

assist with ADLs and noontime medications while her

family is at work.

Physical Examination

A general examination reveals a frail, thin female with

skin irritation and slight amount of saliva evident at the

right corner of her mouth (the side where her PD

symptoms are more pronounced). She has slight

puffiness but no pitting of her ankles bilaterally.

A neurological examination reveals that she is alert and

oriented to person, place, and year. She rememong>beong>rs 3

out of 3 items, but can recall only one of three items 3

minutes later. She has definite facial masking and a

decreased blink rate. Cranial nerve examination reveals

moderate hypophonia (low voice volume) and an

intermittent tremor. She is moderately stooped with a

slight tilt to the right, and she has difficulty rising from a

10

Protein intake among patients

with Parkinson disease (PD)

might interfere with levodopa’s

clinical ong>beong>nefit. Thus, PD patients

might inadvertently increase their

risk of vitamin B 12 deficiency by

avoiding meat, the dietary source

of vitamin ong>B12ong>.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> level

ong>beong>cause she is considered at high risk for a vitamin ong>B12ong>

deficiency, and many of the symptoms of PD also can ong>beong>

attributed to vitamin ong>B12ong> deficiency.

Results from the CBC with smear demonstrate no

evidence of anemia. The chemistry panel is within

normal limits, with the exception of a slightly elevated

serum creatinine (1.5 milligrams per deciliter). Her

serum ong>B12ong> level is 225 pg/mL, within the laboratory’s

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

considers this value as “low-normal” and requests

confirmatory testing with MMA and HCY levels.

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 ong>beong>en

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

ong>B12ong> deficiency can also account for some of them. Her

age is a risk factor for atrophic gastritis, and her diet

seems to ong>beong> deficient in protein so both malabsorption

and malnutrition could contribute to borderline vitamin

ong>B12ong> deficiency.

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Management

Given the uncertain nature of the test results, her

neurologist discusses vitamin ong>B12ong> supplementation with

her. She expresses disinterest in oral supplementation,

stating “If I have to take one more pill, I will scream.”

Because the laboratory findings are ambiguous, the

neurologist and she agree to monitor her status rather

than start injection therapy immediately.

On her return visit 6 months later, her serum vitamin ong>B12ong>

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Table 1. Neurologic and Psychiatric Symptoms of ong>Vitaminong> ong>B12ong>

ong>Deficiencyong> and Parkinson Disease (PD)

ong>Vitaminong> PD

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

ong>B12ong>

ong>Deficiencyong>

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

+


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Natural History and Prevalence of

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

“Although elderly people with low vitamin ong>B12ong> status frequently

lack the classical signs and symptoms of vitamin ong>B12ong> deficiency,

e.g. megaloblastic anemia, precise evaluation and treatment in

this population is important.” Baik and Russell, 1999

The case studies illustrate two important facts about

vitamin ong>B12ong> (cobalamin). First, low vitamin ong>B12ong> levels can

have profound effects on patient well-ong>beong>ing. Although

most patients with a vitamin ong>B12ong> deficiency are in a

subclinical stage(1-7) and do not present with symptoms

or complaints such as those of the case study patients,

some patients might ong>beong> at risk for developing serious

sequelae if the deficiency is not detected and the

patients followed with reassessment, prophylaxis, or

treatment, as needed. Second, treatment is safe and

remarkably effective if provided ong>beong>fore permanent

damage occurs. Understanding the biochemistry of

vitamin ong>B12ong>, the problems that might develop when

cobalamin body stores are depleted, and current

treatment strategies can help clinicians prevent

significant morbidity among their patients.

The nutritional value of vitamin ong>B12ong> was initially

established in the first half of the 20 th century, when

ingesting raw animal liver (the primary storage organ for

this nutrient) was found to ong>beong> an effective treatment for

pernicious anemia.(8) Humans cannot manufacture

cobalamin and must consume it on a regular basis.

ong>Vitaminong> ong>B12ong> is a water-soluble compound that is naturally

available for human use only through ingestion of animal

proteins, such as ong>beong>ef, poultry, fish, eggs, and dairy

products. Unfortified, plant-based foods do not contain

vitamin ong>B12ong>.(2, 9, 10)

14

ong>Vitaminong> ong>B12ong> is naturally

available for human use only

through ingestion of animal

proteins. Unfortified plantbased

foods do

not contain

vitamin B .

12


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 numong>beong>r of compounds, including the R

protein (haptocorrin from saliva), gastric acid, pepsin,

and intrinsic factor (IF).(2, 3)

Gastric acid is needed to digest animal protein. When

the ability to secrete that acid is lost, a person cannot

break down the protein to release vitamin ong>B12ong> from

food and can absorb only crystalline (synthetic)

vitamin ong>B12ong>.(2)

Loss of IF in pernicious anemia results in an inability

to absorb vitamin ong>B12ong>. People with pernicious anemia

must ong>beong> treated with parenteral cyanocobalamin or

high doses of oral cobalamin

(1,000 micrograms [µg] daily).(2, 11)

About 1% of large oral doses of vitamin ong>B12ong> passively

diffuses into the bloodstream from the small

intestine.(2, 10)

If any aspect of the digestion sequence ong>beong>gins to fail

and malabsorption develops, the body can draw on

the large amounts of vitamin ong>B12ong> stored in the liver,

so overt symptoms might not develop for several

years.(2, 10, 12) However, with certain conditions,

vitamin ong>B12ong> deficiency might develop over a shorter

period of time (months).

Adequate serum levels of cobalamin are crucial to

complete three enzymatic processes (Figure 1).

Methylcobalamin is a cofactor necessary to convert

homocysteine (Hcy) to methionine. Thus, vitamin

ong>B12ong> deficiency increases Hcy.(1, 12, 13)

The cofactor adenosylcobalamin is required for the

conversion of methylmalonyl coenzyme A to

succinyl coenzyme A.(2, 10)

Methylcobalamin is needed to convert 5methyltetrahydrofolate

to tetrahydrofolate and is

necessary for DNA and red blood cell production.

15

Pernicious anemia is an

autoimmune disease in

which antibodies attack

gastric cells, resulting in

impaired production of

intrinsic factor that is

critical for absorption of

vitamin ong>B12ong>.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Figure 1. The Biochemical Role of Cobalamin

ong>Vitaminong> ong>B12ong> deficiencies often, but not always, develop

gradually over many years and are accompanied by a

slow and varied onset of nonspecific symptoms. Carmel

descriong>beong>s vitamin ong>B12ong> deficiency in two states: clinical

and subclinical.(1) Clinical deficiency manifests with

hematologic or neurologic signs and symptoms,

cobalamin levels


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

The first to conceptualize the natural history of a vitamin

ong>B12ong> deficiency, Herong>beong>rt noted that vegetarians with

dietary vitamin ong>B12ong> insufficiency progressed through four

stages: serum depletion; cell depletion; biochemical

deficiency (defined as elevated levels of Hcy and MMA);

and, finally, the classic signs and symptoms of clinical

deficiency, such as anemia (Table 2).(9, 15)

Table 2. Typical Stages in the Development of a ong>Vitaminong>

ong>B12ong> ong>Deficiencyong>. Herong>beong>rt, 1994

Stage Manifestation Comment

I

II

III

IV

Circulating serum ong>B12ong>

levels depleted

Cellular stores of ong>B12ong>

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.

ong>Vitaminong> ong>B12ong> is required for

the conversion of these

compounds.

The spectrum of clinical

manifestations is broad and

the sequence of symptom

development varies

markedly.

Although this model provides a useful perspective,

untreated patients will not necessarily advance through

the stages chronologically or linearly. Progression to a

later stage is not inevitable, and some patients with

evidence of an early stage deficiency might have normal

laboratory values when retested.(11) Malabsorption of

food-derived cobalamin ong>beong>cause of decreased gastric

acid production is a more likely reason for vitamin ong>B12ong>

deficiency, while malabsorption of cobalamin ong>beong>cause of

lack of IF in pernicious anemia is a less prevalent

cause.(3)

17


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Prevalence of ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

The true prevalence of vitamin ong>B12ong> deficiency tends to ong>beong>

underestimated for several reasons. The common

misconception that most vitamin ong>B12ong> deficiencies are due

to inadequate dietary intake might lead to overlooking

important high-risk groups. Older adults who routinely

consume meat and other animal proteins can still ong>beong>

vitamin ong>B12ong> deficient due to malabsorption. Clinical

vitamin ong>B12ong> deficiencies are relatively rare. Most

patients are far more likely to have mild, subclinical

vitamin ong>B12ong> deficiency.(1)

Most prevalence estimates are based solely on serum

vitamin ong>B12ong> results. Confusion can arise ong>beong>cause

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 ong>B12ong>

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 ong>B12ong> deficiency compared

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 ong>B12ong> serum level. Most of these people

are ambulatory and do not have overt symptoms of

vitamin ong>B12ong> deficiency.

18

Conversions

ng/L = pg/mL

pmol/L = pg/mL x 0.738

pg/mL = pmol/L ÷ 0.738

Keep in mind that ng/L has

the same value as pg/mL but

conversion to pmol/L requires

multiplication of pg/mL by

0.738 (200 pg/mL

x 0.738 =

148 pmol/L).


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Table 3. Prevalence of ong>Vitaminong> ong>B12ong> Serum Levels for

the U.S. Population by Age, National Health and

Nutrition Examination Survey 2001–2004

ong>Vitaminong> ong>B12ong> 9–13 14–18 19–30 31–50 ≥ 51

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 ong>B12ong> levels


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Risk Factors for

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

“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 ong>B12ong> deficiency can ong>beong> divided broadly into

demographic and ong>beong>havioral characteristics that increase

the risk of inadequate dietary intake (malnutrition) and

physiologic factors that increase the risk of

malabsorption. Some factors, such as advanced age,

might increase the risk of both malnutrition and

malabsorption. In the United States, most cases of

vitamin ong>B12ong> deficiency are due to malabsorption rather

than inadequate intake. We will review the more obvious

demographic and ong>beong>havioral “red flags” of aging and

strict vegetarianism and vegan diets and then

summarize the less readily apparent but more common

physiologic factors that can affect absorption.

Demographic and Behavioral Risk Factors

The risk of developing a vitamin ong>B12ong> deficiency increases

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

individuals 65 years of age or older, are more likely to

develop a vitamin ong>B12ong> deficiency ong>beong>cause they are at risk

for both malabsorption and malnutrition. The frail

elderly, especially, might have dietary insufficiency for a

numong>beong>r of reasons, including cognitive dysfunction,

social isolation, mobility limitations, and poverty.

In contrast to the importance of age, other demographic

characteristics, including sex, race, and ethnicity, are not

as important in predicting vitamin ong>B12ong> deficiency. While

several studies have found that mild cobalamin

deficiency is most common among elderly White men

and least common among Black or African-American and

Asian-American women, (2, 3, 16, 24) the differences

20

In the United

States, most cases

of vitamin ong>B12ong>

deficiency are due

to malabsorption.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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) ong>beong>cause vegan

diets exclude all forms of animal protein, including eggs

and dairy products. Thoughtfully planned vegetarian

diets that include eggs, milk, and yogurt can provide

adequate amounts of vitamin ong>B12ong>. Short-term adherence

to strict vegetarian and vegan diets might not cause a

problem ong>beong>cause of the large amount of vitamin ong>B12ong>

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 ong>B12ong> or eating a serving of vitamin ong>B12ong>–

fortified grain products.(10) The requirement for vitamin

ong>B12ong> increases for pregnant and lactating women.(10) To

review the vitamin ong>B12ong> content of a variety of vegetarian

and vegan foods, see

http://www.nal.usda.gov/fnic/foodcomp/search/.

Physiologic Factors

Malabsorption is the physiologic cause of vitamin ong>B12ong>

deficiency and can result from a numong>beong>r of conditions.

Frequently mentioned are pernicious anemia; (7, 24)

atrophic gastritis;(3, 10, 27) gastric surgery (e.g., ileal

resection and gastrectomy);(11, 16, 28) presence of a

cobalamin-utilizing fish tapeworm such as the

Diphyllobothrium latum;(2, 29) and other concurrent

diseases such as Crohn disease, HIV infection,(30-32)

celiac sprue,(33, 34) and bacterial overgrowth in the

small intestine.(35) Rare cases have ong>beong>en attributed to

anesthetic nitrous oxide exposure.(2, 36)

Among the elderly, atrophic gastritis and pernicious

anemia are the main causes of malabsorption. Atrophic

gastritis often develops as people age. With resulting

hypochlorhydria and achlorhydria, the body does not

produce enough pepsin and hydrochloric acid to release

from protein the food-bound vitamin ong>B12ong>. In pernicious

anemia, missing IF needed to attach ong>B12ong> in the small

intestine impairs the uptake of vitamin ong>B12ong>.

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 ong>beong> monitored for a

developing symptomatic

vitamin B 12 deficiency.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Undiagnosed and untreated pernicious anemia affects

1%–2% of the elderly population.(24)

22


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Manifestations of

Low ong>Vitaminong> ong>B12ong> Levels

“Although some clinical expressions remain mysterious,

especially the neurological dysfunction, our view of

cobalamin deficiency has expanded ong>beong>yond the question

of megaloblastic anemia.”

Carmel, 2000

No single symptom, or cluster of symptoms, has ong>beong>en

uniquely associated with inadequate levels of vitamin

ong>B12ong>. Among older adults, the most frequently reported

symptoms of vitamin ong>B12ong> deficiency are hematologic or

neurologic in nature, but gastrointestinal and

possibly vascular symptoms are also common. The

typically nonspecific manifestations of a vitamin ong>B12ong>

deficiency underscore the importance of encouraging all

older adults to consume the synthetic form of the

vitamin each day. Recent concerns have also ong>beong>en raised

about potential adverse effects on infant growth and

development in exclusively breastfed babies of

mothers who adhere to a strict vegan diet.(11, 16)

While this situation is rare in the United States, sequelae

are often severe and irreversible in these children.

Hematologic Manifestations

Common symptoms associated with hematologic

pathology include skin pallor, weakness, fatigue,

syncope, shortness of breath, and palpitations.(2, 10) A

classic hematologic sign of severe vitamin ong>B12ong> deficiency

is megaloblastic anemia.(2) Hematologic manifestations

might also ong>beong> due to folate deficiency. However, since

1998, the U.S. Food and Drug Administration has

required fortification of all enriched grain and cereal

products with 140 micrograms (µg) of folic acid per 100

grams of cereal grain product,(37) and that fortification

of the U.S. food supply essentially has eliminated the

prevalence of folate deficiency.(21) Today, in the United

States, a case of megaloblastic anemia most likely

is due

to

vitamin ong>B12ong> deficiency until proven otherwise.

Although vitamin ong>B12ong> deficiency is not always

accompanied by hematologic changes, the majority of

23

Today, in the United

States, megaloblastic

anemia is most likely

due to a vitamin ong>B12ong>

deficiency until proven

otherwise.

Folic acid fortification does not

have an effect on the

prevalence of megaloblastic

anemia attributable to vitamin

ong>B12ong> deficiency. Very high doses

of folic acid (>5,000 µg each

day) can correct the

hematologic manifestations of

vitamin ong>B12ong> deficiency; however,

the amount of folic acid

available through fortification as

specified by the U.S. Food and

Drug Administration (FDA) is

not likely to affect a vitamin

ong>B12ong> deficiency-induced

anemia

(FDA, 1996).


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

patients with clinical deficiency will have signs of

megaloblastic anemia. In various studies conducted

among patients with overt vitamin ong>B12ong> deficiency, 56%–

77% of people had signs of macrocytosis or

anemia.(5, 38-41) Furthermore, some researchers

have found that the presence of neurologic

manifestations of a vitamin ong>B12ong> deficiency might even ong>beong>

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 ong>beong>havioral changes (e.g., dementia, hallucinations,

psychosis, paranoia, depression, violent ong>beong>havior, and

personality changes). Tingling of the hands and feet is

perhaps the most common neurologic complaint.(2, 41,

42)

The pathology of vitamin ong>B12ong> deficiency on the nervous

system is unknown.(7)

All patients with unexplained cognitive decline or

dementia should ong>beong> assessed for a possible vitamin ong>B12ong>

deficiency.(41, 43-45) Several current case reports and

studies support the common practice of assessing

vitamin ong>B12ong> levels during dementia workups.(41, 46-48)

Although only a minority (1.5%) of all dementia cases

are fully reversible following treatment,(49) many

dementias from other etiologies (e.g., Parkinson or

Alzheimer disease) are exacerbated when patients have

a concomitant low vitamin ong>B12ong> level. The American

Academy of Neurology (AAN) has concluded that

ong>beong>cause vitamin ong>B12ong> deficiency is a likely comorbidity

among the elderly, and among patients with suspected

dementia in particular, it should ong>beong> recognized and

treated. The AAN practice guideline states that ong>B12ong> levels

should ong>beong> included in routine assessments of dementia

among the elderly.(44)

24

Many ong>B12ong>–deficient

patients do have

anemia or

macrocytosis.

All patients newly

diagnosed with

unexplained cognitive

decline or dementia

should ong>beong> assessed for a

possible vitamin ong>B12ong>

deficiency.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Gastrointestinal Manifestations

ong>Vitaminong> ong>B12ong> deficiency might also manifest with

gastrointestinal complaints. Some frequently mentioned

symptoms include anorexia, flatulence, diarrhea, and

constipation.(7, 10, 36, 50) These symptoms can

develop among patients with a vitamin ong>B12ong> deficiency

without accompanying anemia, macrocytosis, or overt

neurologic deficits. Glossitis, which is commonly thought

to ong>beong> a cardinal sign of some anemias, is actually a

relatively rare manifestation of clinical vitamin ong>B12ong>

deficiency and is completely absent in subclinical vitamin

ong>B12ong> deficiency according to Carmel (Carmel RA. New York

Methodist Hospital [personal communication] 2006-

2007).

Vascular Manifestations

Both low vitamin ong>B12ong> levels and low folate levels are

associated with elevated levels of homocysteine (Hcy).

Hyperhomocysteinemia increases the chance of

developing a vascular occlusion,(51) thus potentially

increasing the risk of coronary heart disease and

ischemic stroke. Although the association of coronary

heart disease or ischemic stroke with vitamin ong>B12ong> or

folate deficiency has not ong>beong>en proven, the SEARCH

(Study of the Effectiveness of Additional Reductions in

Cholesterol and Homocysteine) study in the United

Kingdom is seeking to obtain evidence about the effect

of reducing Hcy on cardiovascular risk while treating

patients with 2 milligrams (mg) of folic acid plus 1 mg of

vitamin ong>B12ong> daily. In addition, the SEARCH study is

looking at the efficacy and safety of two different

dosages of simvastatin in regard to risk reduction for

major cardiovascular events.(52) This randomized study

is scheduled to end in 2008 and should provide evidence

about the causal relationship of Hcy to cardiovascular

disease and about the value of folic acid and vitamin ong>B12ong>

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 ong>B12ong>related

deficiency effects.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

typically observed among older patients, several cases of

significant vitamin ong>B12ong> deficiencies among infants and

young children have ong>beong>en reported.(53-56) Low or

marginal vitamin ong>B12ong> status among pregnant women

increases the risk for neural tuong>beong> birth defects.(57)

Exclusively breastfed infants of mothers who adhere to

a strict vegetarian or vegan diet that excludes all animal

proteins might also experience serious effects related to

vitamin ong>B12ong> deficiency.(50, 53, 54, 56) Clinical

manifestations among infants and young children are

widely varied, encompassing hematologic, neurologic,

and gastrointestinal symptoms. Some potential effects

include the following:

Failure to thrive

Hypotonia

Ataxia

Developmental delays

Macrocytosis or anemia

General weakness

Many of these effects will improve with prompt vitamin

ong>B12ong> administration but, sometimes, irreversible

neurologic damage occurs ong>beong>fore the diagnosis is made

and treatment is ong>beong>gun.(50, 53-56) Nursing infants of

vegan mothers can develop significant problems even

when the mother is not anemic or symptomatic in any

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

women and new mothers who breastfeed about their

diets.

26


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Screening Patients

“. . . It is daunting and probably unnecessary to actively

seek out new asymptomatic cases [of vitamin ong>B12ong>

deficiency] by screening . . .”

Carmel, 2003

Most experts do not recommend community-based mass

screening programs for vitamin ong>B12ong> deficiency, even

among high–risk groups, such as the frail elderly. For

example:

The U.S. Preventive Services Task Force has not

published formal recommendations on screening

asymptomatic older adults.

The major medical societies have no

recommendations on routine cobalamin screening.

The National Guideline Clearinghouse website has

no guidelines calling for periodic assessment in

asymptomatic patients. (However, if you provide

primary care to patients with dementia or altered

mental status and celiac sprue or other

gastrointestinal conditions, you might wish to

consult the website (http://www.guideline.gov) for

recommendations related to vitamin ong>B12ong>

monitoring among these high–risk groups.)

27


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Detection and Diagnosis

“It is particularly important that the diagnosis of

cobalamin deficiency ong>beong> established with a high degree

of certainty ong>beong>cause cobalamin therapy almost always

must ong>beong> given for the life-time of the patient.”

Stabler and Allen, 2004

Keeping vitamin ong>B12ong> deficiency on your radar screen

means staying vigilant during your review of your

patient’s history and during the physical examination.

Watch for even subtle signs of neurologic or cognitive

impairment. Also, note any elements of the patient’s

history that might suggest potential malabsorption or

malnutrition, such as previously diagnosed pernicious

anemia, previous gastrointestinal surgery, vegan diet,

and advanced age. Maintain an especially high index of

suspicion of vitamin ong>B12ong> deficiency in new patients who

report they were treated with vitamin ong>B12ong> injections or

high doses of oral vitamin ong>B12ong> supplements by a former

provider, but have since discontinued their use. Elderly

patients often fail to understand that a true

vitamin ong>B12ong> deficiency due to malabsorption

requires lifelong treatment.

Early detection and prompt treatment of a vitamin ong>B12ong>

deficiency are essential to prevent development of

irreversible neurologic damage, but making an accurate

and timely diagnosis can ong>beong> challenging. The list of

related signs and symptoms is long, varied, and nonspecific.

Many risk factors have ong>beong>en identified, but

there are no known necessary or sufficient causes.

Complicating things further is the fact that ong>beong>cause the

liver is a very efficient storage organ for vitamin ong>B12ong>,

even completely deficient diets in healthy adults might

not result in low serum vitamin ong>B12ong> levels for several

years. Conversely, apparently healthy adults, especially

the elderly, consuming diets rich in naturally occurring

vitamin ong>B12ong> can still develop a significant deficiency

ong>beong>cause of undetected malabsorption. It is possible for

vitamin ong>B12ong> deficiency to develop in a much shorter

period of time (months) in some people.

28


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

The vitamin ong>B12ong> literature contains many articles on the

relative merits and limitations of the various laboratory

testing options. Some tests are used more commonly for

the initial assessment, while others, ong>beong>cause of their

cost, inconvenience, or difficulty of interpretation, are

reserved for confirmatory testing in ambivalent

situations or are used only in the research setting.

Initial Assessment

After conducting a thorough history and physical

examination, if you suspect vitamin ong>B12ong> deficiency, you

should include a complete blood count (CBC), peripheral

blood smear, and serum cobalamin (ong>B12ong>) as part of the

initial laboratory assessment.(58) The serum cobalamin

test is readily available and generally affordable, and can

detect low serum vitamin ong>B12ong> levels even among patients

who are not anemic.(59, 60) However, not all patients

with a vitamin ong>B12ong> deficiency will have hematologic

manifestations. As Carmel succinctly noted, “the

proscription that cobalamin deficiency should not ong>beong>

diagnosed unless megaloblastic changes are found is

akin to requiring jaundice to diagnose liver disease.”(11)

While serum vitamin ong>B12ong> concentrations are generally

accurate,(61) many conditions can complicate the

interpretation of vitamin ong>B12ong> laboratory values. Falsely

low values have ong>beong>en associated with multiple myeloma,

oral contraceptives,(62-64) folate deficiency,(58, 59)

and pregnancy.(10) Additionally, a low serum ong>B12ong> level

does not automatically mean a deficiency. From 20%–

40% of elderly people with low serum ong>B12ong> levels have

normal metabolite (homocysteine [Hcy] and

methylmalonic acid [MMA]) levels and should not ong>beong>

considered

as having a B deficiency.(11)

12

Sometimes, a true cobalamin deficiency will not ong>beong>

detected by the serum vitamin ong>B12ong> test. Some examples

of falsely normal serum cobalamin results might ong>beong> seen

with (but not limited to) liver disease,(58)

myeloproliferative disorders,(58) and renal

insufficiency.(4, 65) If a patient has clinical e vidence of a

vitamin ong>B12ong> deficiency and a normal

serum ong>B12ong> level, it is

important

to evaluate further.

29

The complete blood

count, smear, and serum

cobalamin (ong>B12ong>) test

should ong>beong> included in the

initial laboratory

assessment of vitamin ong>B12ong>

Oral contraceptive users generally

have lower serum vitamin ong>B12ong> levels

than nonusers; however, the

evidence of tissue depletion, as

detected by high values of

methylmalonic acid and

homocysteine, is lacking.

“Accepted lower limits of

serum ong>B12ong> levels in adults

range ong>beong>tween 170 and

250 pg/ml; however,

higher levels (but less

than 350 pg/ml) have

ong>beong>en recorded in 15% of

ostensibly healthy elderly

patients with other

findings suggestive of a

deficiency state, most

notably increased levels

of serum methylmalonic

acid. The true lower

limits of normal serum

ong>B12ong> would therefore

appear to ong>beong> somewhat

poorly defined.”

Ward, 2002


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Opinions differ as to the optimal laboratory cutpoint for

the serum vitamin ong>B12ong> test, due in part to the insidious

onset and slow progression of the disorder and

limitations of current assays. Research studies and

clinical laboratories have tended to dichotomize low

values at 200 picograms per milliliter(pg/mL).(18, 66,

67) Stabler and Allen noted the following ranges of

serum cobalamin levels among patients with a clinically

confirmed ong>B12ong> deficiency (defined as those who “have

objective clinical responses to appropriate therapy”):

less than 100 pg/mL, approximately 50%; 100–200

pg/mL, approximately 40%; 200–350 pg/mL,

approximately 10%; and more than 350 pg/mL,

approximately 0.1% to 1%.(7)

Adequate follow-up for suspect normal or low-normal

results is needed through either additional confirmatory

testing or a prolonged therapeutic trial followed by

metabolic and clinical reassessment.

Confirmatory Testing

When the serum vitamin ong>B12ong> results are suspect, it is

helpful to obtain more information.(1) Several tests can

ong>beong> used to rule out a vitamin ong>B12ong> deficiency either among

patients with borderline serum cobalamin levels or

among symptomatic patients with normal serum

cobalamin levels.

Homocysteine (Hcy) and Methylmalonic Acid (MMA)

By far, the most common, accurate, and widely used

confirmatory tests for identifying vitamin ong>B12ong> deficiency

are tests for Hcy and MMA.(1) Because cobalamin is

necessary for the synthesis of methionine from Hcy, low

levels of vitamin ong>B12ong> lead to increases in total serum

Hcy. The total serum Hcy test is a sensitive indicator for

a vitamin ong>B12ong> deficiency; however, its utility is limited as

a sole confirmatory test ong>beong>cause elevated Hcy levels

among patients also can ong>beong> caused by familial

hyperhomocysteinemia, levodopa therapy,(68) renal

insufficiency, and folate deficiency.(1, 7, 69, 70)

The serum MMA test is more specific for vitamin ong>B12ong>

deficiency than the Hcy test.(1, 2, 7, 69, 70) MMA levels

also increase in the presence of low vitamin ong>B12ong> levels

30


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

ong>beong>cause cobalamin is required to convert methylmalonyl

coenzyme A to succinyl coenzyme A.(2) In one study,

98.4% of people with a vitamin ong>B12ong> level less than 200

pg/mL also had elevated MMA levels (defined as values

more than 376 nanomoles per liter [nmol/L]).(70) Note

that false-positive increases in serum MMA have ong>beong>en

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 ong>B12ong>. Data from the National Health

and Nutrition Examination Survey (NHANES) 2001–2004

in Table 4 shows the prevalence of vitamin ong>B12ong> deficiency

using combinations of serum ong>B12ong> levels and MMA levels.

Table 4. Prevalence of National Health and Nutrition

Examination Survery Participants With Biochemically

Defined ong>Vitaminong> ong>B12ong> ong>Deficiencyong>* By Age Group, United

States, 2001–2004

Age Group ong>B12ong> ≤ 200 ong>B12ong> > 200 pg/mL

(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 ong>B12ong> deficiency is serum ong>B12ong> ≤ 200

picograms per milliliter (pg/mL) and methylmalonic acid (MMA) ≥

270 nanomoles per liter (nmol/L) or serum ong>B12ong> > 200 pg/mL and

MMA ≥ 270 nmol/L

Two popular methods for interpreting diagnostic

thresholds for MMA and Hcy elevations are the use of

cutpoints determined by laboratory norms (e.g., 3

standard deviations above the mean) and specific values

(e.g., MMA greater than 0.26 micromole per liter

31

Conversions

1,000 nmol/L* = 1 µmol/L†

376 nmol/L = 0.376 µmol/L

*nanomols per liter

†micromols per liter


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

[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 ong>beong> a concern.

Quotes from Quest Laboratories (Atlanta, Georgia, May

2006) state that the direct patient (no insurance) cost

for a serum MMA is $212 and for a serum Hcy is $191.

Other metabolites, serum propionate and serum 2methylcitrate,

are also present in vitamin ong>B12ong> deficiency.

However, measuring either of these metabolites has no

advantage over measuring MMA to diagnose a vitamin

ong>B12ong> deficiency,(2) and they are not available routinely in

many clinical laboratories.

Again, it is important to rememong>beong>r that abnormal

metabolite levels might ong>beong> due to conditions other than

a vitamin ong>B12ong> deficiency, such as renal insufficiency. In

one study of the elderly, renal insufficiency was

associated with 20% or greater of all abnormal

metabolite levels.(11)

Other Tests

If the root cause of vitamin ong>B12ong> deficiency is not obvious,

you should consider ordering additional tests to

determine it. Antibodies to intrinsic factor and gastrin or

pentagastrin I levels are often used to diagnose

pernicious anemia.(10, 36, 60)

Serum holotranscobalamin II measures one of the bloodbinding

proteins used to transport vitamin ong>B12ong>.(60) Some

investigators recommend it;(73) others are concerned

about the lack of convincing evidence of its value.(2, 9,

10, 60) Theoretically, it is attractive, but early claims of

its value have ong>beong>en poorly documented. While

immunoassays have replaced the older crude methods, it

is too early to determine whether measurement of

holotranscobalamin II is ong>beong>tter than measurement of

serum cobalamin. (1)

The deoxyuridine suppression test ( or “DUST”) has ong>beong>en

descriong>beong>d as a sensitive indicator of impaired thymidine

synthesis due to either deficiency or metabolic

inactivation of vitamin ong>B12ong> or folate.(58) However, DUST

32


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

is used rarely in the clinical setting ong>beong>cause it is not

necessary in the evaluation of a vitamin ong>B12ong> deficiency.

DUST is also a complicated, expensive, and timeconsuming

test.(58)

The Schilling test is included in most lists of possible

vitamin ong>B12ong> deficiency confirmatory tests, but it is not

available in U.S. clinical practices at this time. The

Shilling test is the classic test for determining whether a

person can absorb vitamin ong>B12ong>. However, a person’s

ability to absorb crystalline vitamin ong>B12ong> can differ from

his or her ability to absorb the naturally occurring

vitamin ong>B12ong>.(59) While, it is not an accurate test for

identifying cobalamin deficiency, it can ong>beong> a helpful tool

in determining the root cause of an identified deficiency.

It reveals cobalamin malabsorption such as that found in

pernicious anemia and ileal disease. A normal Schilling

test cannot rule out vitamin ong>B12ong> deficiency.(29, 36)

There is no gold standard for determining cobalamin

deficiency. Part of the problem is related not to the tests

used, but to “an uncertain boundary ong>beong>tween cobalamin

depletion and disease.”(1, 20)

A diagnostic approach to tailor testing to the nature of a

patient’s clinical problem is suggested by Carmel and

summarized in Table 5(1)

33


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Table 5. Tailored Diagnostic Approach for

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong>

deficiency

Confirm suspected

vitamin ong>B12ong>

deficiency

Ensure if vitamin

ong>B12ong> deficiency

exists, it is not

missed

Serum ong>B12ong>

Serum ong>B12ong>

MMA* and Hcy †

Asymptomatic Determine if MMA (metabolic

patient with vitamin ong>B12ong> changes often

condition known to deficiency has precede low

cause vitamin ong>B12ong> developed yet cobalamin levels)

deficiency

Asymptomatic

patient accidentally

found to have low

ong>B12ong> level or high

Hcy †

*MMA–methylmalonic acid

† Hcy–homocysteine

Determine if

vitamin ong>B12ong>

deficiency exists

MMA

Flagging the patient’s chart will help you rememong>beong>r to

follow-up if choosing to “watch and wait” with an

asymptomatic patient.

Experienced clinicians differ on the importance of

tracking down the root cause of a vitamin ong>B12ong> deficiency

ong>beong>fore initiating treatment; however, determining the

cause of the deficiency is important ultimately in

individualizing the treatment approach.(1)

34


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Managing Patients With Evidence of a

ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

“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 ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Options available for treating a clinical vitamin ong>B12ong>

deficiency include oral and parenteral (intramuscular or

subcutaneous) preparations. Intravenous dosing is not

recommended ong>beong>cause this will result in most of the

vitamin ong>beong>ing lost in the urine.(74)

The response of a patient with vitamin ong>B12ong> deficiency

anemia to treatment is usually rapid, with reticulocytosis

occurring within 2–5 days, and the hematocrit

normalizing within weeks.(10) Treatment with cobalamin

effectively halts progression of the deficiency process,

but might not fully reverse more advanced neurologic

effects.(39, 42) If the underlying cause of the vitamin

ong>B12ong> deficiency is treatable (e.g., fish tapeworm infection

or bacterial overgrowth), then treatment should include

addressing the underlying etiology.(7)

ong>Vitaminong> ong>B12ong> is considered safe, even at levels much

higher than the recommended dose. It has not ong>beong>en

shown to ong>beong> toxic or cause cancer, birth defects, or

mutations.(10, 75) Be aware, however, that patients

who have a vitamin ong>B12ong> deficiency with associated

megaloblastic anemia might experience hypokalemia and

fluid overload early in treatment due to increased

erythropoiesis, cellular uptake of potassium, and

increased blood volume.(76, 77)

While the route, dosage, treatment timing, and follow-up

might vary somewhat, there is no question about the

decision to treat patients with pernicious anemia or with

a low serum ong>B12ong> level and hematologic or neurologic

signs or symptoms without pernicious anemia (clinical

35

Cobalamin replacement is

effective ong>beong>cause

crystalline forms of ong>B12ong> can

ong>beong> absorong>beong>d even when

animal protein-bound

forms cannot ong>beong> digested.

ong>Vitaminong> ong>B12ong> is not

carcinogenic, teratogenic,

or mutagenic. It is

considered safe even at

1,000 times the RDA.

Baik and Russell, 1999


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

vitamin ong>B12ong> deficiency). Once treated for a vitamin

ong>B12ong> deficiency due to pernicious anemia or other

irreversible severe problems with absorption,

patients need to continue some form of cobalamin

therapy for life.(7)

Parenteral (Intramuscular or Subcutaneous)

Administration of parenteral crystalline cobalamin has

ong>beong>en the standard treatment protocol for vitamin ong>B12ong>

deficiency for decades.(78, 79) Few side effects have

ong>beong>en reported, and patient acceptance is generally high.

Anecdotally, the subcutaneous route causes less burning

than does the intramuscular route (Carmel RA. New York

Methodist Hospital [personal communication] 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 ong>B12ong> given weekly for 8 weeks, then once

monthly for life.(7)

Some providers have used quarterly injections after the

initial dosing protocol. However, experts state that in

pernicious anemia or severe malabsorptive deficiency

quarterly injections are not sufficient, noting that

cobalamin levels start to fall prior to the 1 month followup

(Allen RH. University of Colorado [personal

communication] 2006 -2007).

Oral

Large, daily oral replacement doses might ong>beong> an

acceptable alternative if patients are compliant.(7)

Sufficient amounts of vitamin ong>B12ong> are absorong>beong>d via

passive diffusion in the small intestine.(2, 11) A study by

Eussen et al. demonstrated a linear response in the

reduction of metabolites and increased serum ong>B12ong> levels

with increasing dosages of oral cyanocobalamin.(80) A

common therapy is 1 mg (1,000 µg) of vitamin ong>B12ong>

to ong>beong> consumed daily.(2, 11, 14)

Intranasal

A relatively new vehicle for vitamin ong>B12ong> therapy is a

cyanocobalamin gel for intranasal use. Some experts

are not convinced of its efficacy, and the cost is $30 for

36


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

500 µg (Carmel RA. New York Methodist Hospital

[personal communication] 2006-2007). If chosen, the

intranasal gel should ong>beong> used for maintenance only after

treatment with parenteral or oral vitamin therapy has

established adequate metabolic status among patients

with no nervous system involvement.(74) The

recommended dose for therapy is 500 µg

intranasally once a week.(74) Absorption can ong>beong>

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 ong>beong> self-administered. However, ong>beong>cause

cognitive impairment is a frequent reason for

noncompliance, patients might ong>beong> more compliant with

clinic or home health nurse-administered injections.

Additionally, Carmel observed that many patients prefer

the convenience of monthly injections to daily

consumption of pills.(11)

Examples of treatment regimens from different sources

for clinical vitamin ong>B12ong> deficiency are listed in Table 6.

37


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Table 6. Examples of Treatment Regimens

for Clinical ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> to: month possibly

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 ong>B12ong>

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Subclinical ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

The far more prevalent patient presentation is by an

asymptomatic individual with borderline serum ong>B12ong> levels

and elevated homocysteine or methylmalonic acid levels,

or both. These patients pose a dilemma for providers

ong>beong>cause there are no guidelines for the treatment of

patients with subclinical vitamin ong>B12ong> deficiency.

Some providers prefer to treat these patients and check

to see that metabolite markers have normalized, while

others prefer to “wait and watch”. For patients in the

subclinical vitamin ong>B12ong> deficiency category, taking a

vitamin with ong>B12ong> (usual dosages are 6–25 µg) is not

sufficient to correct the metabolites. Two recent studies

have suggested that the lowest dose of oral

cyanocobalamin needed to normalize metabolites in

subclinical vitamin ong>B12ong> deficiency is 500–1,000 µg

daily.(80, 82) The providers who test for and treat

patients with subclinical vitamin ong>B12ong> deficiency, especially

those patients with possible pernicious anemia or

elevated metabolites, or both, can prevent potential

subsequent hematologic and neurologic manifestations.

Whether treating or “waiting and watching”, you should

rememong>beong>r that routine monitoring of and educating the

patient are important.

39


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Prevention of ong>Vitaminong> ong>B12ong> Deficiencies

“The . . . Recommended Dietary Allowance (RDA) (2.4

mcg/day) for ong>B12ong> for adults ages 51 and older are the

same as for younger adults but with the

recommendation that ong>B12ong>–fortified foods (such as

fortified ready-to-eat cereals) or ong>B12ong>–containing

supplements ong>beong> used to meet much of the

requirements.” Institute of Medicine, 1999

The irreversible nature of the late-stage neurologic

effects of a vitamin ong>B12ong> deficiency provides strong

support for the value of prevention.(44, 50, 83)

Fortunately, a vitamin ong>B12ong> deficiency is easily treated and

prevented. Because of the high prevalence of mild,

subclinical cobalamin deficiency among asymptomatic

individuals, it is important to remain vigilant, especially

with individuals at high risk for a vitamin ong>B12ong> deficiency.

If “watch and wait” is the selected plan of care, periodic

reassessment of untreated asymptomatic patients is

important to identify progressive depletion of vitamin

ong>B12ong>.

The Institute of Medicine (IOM) recommends that all

adults 18 years of age or older consume 2.4 micrograms

(µg) per day of vitamin ong>B12ong>.(10) Subclinical vitamin ong>B12ong>

deficiency, often undiagnosed and untreated, has ong>beong>en

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 ong>B12ong>–

fortified foods and supplements (e.g., multivitamins or

single supplements) as the primary means to meet this

requirement ong>beong>cause crystalline formulations are much

more readily absorong>beong>d and used than naturally occurring

vitamin ong>B12ong>. Most multivitamins contain 6–25 µg

cyanocobalamin; some contain more. Single

40

The irreversible nature of

the late-stage neurologic

effects of a vitamin ong>B12ong>

deficiency provides

strong support for the

value of prevention.


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> by consuming a vitamin supplement

or eating a fortified cereal product. Currently available

data do not support the suggestion that vegans can

meet their minimum daily requirements for vitamin ong>B12ong>

by consuming unfortified plant-based foods, nutritional

yeast, algae, or seaweed products.

For more information on the vitamin ong>B12ong> levels of over

1,100 common food items, visit the U.S. Department of

Agriculture and Agricultural Research website at

http://www.ars.usda.gov/ba/bhnrc/ndl.

Several experts in the field find that even higher doses

of oral cobalamin are necessary for the prevention of

vitamin ong>B12ong> deficiency among the elderly and have stated

that the amount in the IOM recommendation is

insufficient.(80)(Carmel RA. New York Methodist Hospital

[personal communication] 2006-2007; Allen RH.

University of Colorado [personal communication] 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, ong>beong> prevented by oral supplementation,

although . . . the dose of cobalamin administered may

have to ong>beong> much larger than that usually given in routine

multivitamin preparations.”(4)

41


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Summary

Low vitamin ong>B12ong> levels occur among 1 in 31 adults 51

years of age or older among the U.S. population. ong>Vitaminong>

ong>B12ong> deficiency is simple to prevent and simple to treat,

but the diagnosis is easy to miss and is often overlooked

in the outpatient setting.

All patients with unexplained hematologic or neurologic

symptoms should ong>beong> evaluated for a vitamin ong>B12ong>

deficiency. If such a deficiency is found, the cause

should ong>beong> determined.(7, 44) Irreversible neurologic

damage can occur if diagnosis and treatment are

delayed.

A complete blood count, peripheral blood smear, and

serum vitamin ong>B12ong> level are the tests of choice for initial

assessment of cobalamin deficiency. Keep in mind that

megaloblastic anemia and changes in mean corpuscular

value are not always present when there is a vitamin ong>B12ong>

deficiency. Homcysteine and methylmalonic acid can ong>beong>

used to confirm a vitamin ong>B12ong> deficiency for cases with

ambiguous initial results ong>beong>cause metabolic changes

often precede low cobalamin levels.

You have inexpensive treatment options available to

treat a vitamin ong>B12ong> deficiency. Rememong>beong>r that treatment

is safe, effective, and has no known toxicity level.

To prevent a vitamin ong>B12ong> deficiency, you should advise

all patients 51 years of age or older to consume

synthetic vitamin ong>B12ong> daily. Dosage recommendations

vary.

Acknowledgements: The authors thank Christine Pfeiffer, PhD, for

assistance with laboratory interpretation, and Quanhe Yang,

PhD,and Heather Carter Hamner, MS, MPH, for statistical support.

We also appreciate the comments and suggestions from our panel

of reviewers Sonja Rasmussen, MD; Joe Mulinare, MD; R.J. Berry,

MD; Lorraine Yeung, MD; Sharon Roy, MD; Mary Dott, MD; John

Mersereau, MD; Jennifer Zreloff, MD; Jason Bell, MD; Pauline

Terebuh, MD; Dan Watkins, PA; Gail Walls, MSN; Sally Lehr, MSN;

Darla Ura, MSN; Sue Ann Bell, MSN; Christa Purnell, MSN; Molly

Cogswell, RN, PhD, and Malissa Perritt, MSN.

42


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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40. Lindenbaum J, Healton EB, Savage DG, Brust JC,

Garrett TJ, Podell ER, et al. Neuropsychiatric disorders caused

by cobalamin deficiency in the absence of anemia or

macrocytosis. Nutrition. 1995 Mar-Apr;11(2):180-2.

41. Stabler SP, Allen RH, Savage DG, Lindenbaum J.

Clinical spectrum and diagnosis of cobalamin deficiency.

Blood. 1990 Sep 1;76(5):871-81.

42. Savage DG, Lindenbaum J. Neurological complications

of acquired cobalamin deficiency: clinical aspects. Baillieres

Clin Haematol. 1995 Sep;8(3):657-78.

43. Adelman AM, Daly MP. Initial evaluation of the patient

with suspected dementia. Am Fam Physician. 2005 May

1;71(9):1745-50.

44. Knopman DS, DeKosky ST, Cummings JL, Chui H,

Corey-Bloom J, Relkin N, et al. Practice parameter: diagnosis

of dementia (an evidence-based review). Report of the

Quality Standards Subcommittee of the American Academy of

Neurology. Neurology. 2001 May 8;56(9):1143-53.

45. Wynn M, Wynn A. The danger of ong>B12ong> deficiency in the

elderly. Nutr Health. 1998;12(4):215-26.

45


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

46. Eastley R, Wilcock GK, Bucks RS. ong>Vitaminong> ong>B12ong>

deficiency in dementia and cognitive impairment: the effects

of treatment on neuropsychological function. Int J Geriatr

Psychiatry. 2000 Mar;15(3):226-33.

47. Goeong>beong>ls N, Soyka M. Dementia associated with vitamin

B(12) deficiency: presentation of two cases and review of the

literature. J Neuropsychiatry Clin Neurosci. 2000

Summer;12(3):389-94.

48. Hutto BR. Folate and cobalamin in psychiatric illness.

Compr Psychiatry. 1997 Nov-Dec;38(6):305-14.

49. Boustani M, Peterson B, Hanson L, Harris R, Lohr KN.

Screening for dementia in primary care: a summary of the

evidence for the U.S. Preventive Services Task Force. Ann

Intern Med. 2003 Jun 3;138(11):927-37.

50. Rasmussen SA, Fernhoff PM, Scanlon KS. ong>Vitaminong> ong>B12ong>

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 ong>B12ong> deficiency. Clin Lab

Haematol. 1997 Mar;19(1):23-5.

54. Muhammad R, Fernhoff P, Rasmussen G, Bowman B,

Scalon K. Neurologic impairment in children associated with

maternal dietary deficiency of cobalamin--Georgia, 2001.

JAMA. 2003 Feb 26;289(8):979-80.

55. Turner RJ, Scott-Jupp R, Kohler JA. Infantile

megaloblastosis secondary to acquired vitamin ong>B12ong>

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 ong>B12ong> status increases the risk of offspring with spina

bifida. Am J Obstet Gynecol. 2004;191:11-7.

58. Amos R, Dawson D, Fish D, Leeming R, Linnell J.

Guidelines on the investigation and diagnosis of cobalamin

and folate deficiencies. A publication of the British Committee

for Standards in Haematology. BCSH General Haematology

Test Force. Clin Lab Haematol. 1994 Jun;16(2):101-15.

46


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> deficiency. Clin Lab Med. 2002 Jun;22(2):435-

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 ong>B12ong> metabolism. Can Med Assoc J. 1982 Feb

1;126(3):244-7.

64. Sutterlin MW, Bussen SS, Rieger L, Dietl J, Steck T.

Serum folate and vitamin ong>B12ong> levels in women using modern

oral conceptives (OC) containing 20 mcg ethinyl estradiol. Eur

J Obstet Gynecol Reprod Biol 2003 Mar 107(1):57-61.

65. Carmel R, Green R, Jacobsen DW, Rasmussen K, Florea

M, Azen C. Serum cobalamin, homocysteine, and

methylmalonic acid concentrations in a multiethnic elderly

population: ethnic and sex differences in cobalamin and

metabolite abnormalities. Am J Clin Nutr. 1999

Nov;70(5):904-10.

66. ong>Whyong>te EM, Mulsant BH, Butters MA, Qayyum M, Towers

A, Sweet RA, et al. Cognitive and ong>beong>havioral correlates of low

vitamin ong>B12ong> levels in elderly patients with progressive

dementia. Am J Geriatr Psychiatry. 2002 May-Jun;10(3):321-

7.

67. Stabler SP. Screening the older population for

cobalamin (vitamin ong>B12ong>) deficiency. J Am Geriatr Soc. 1995

Nov;43(11):1290-7.

68. O'Suilleabhain PE, Sung V, Hernandez C, Lacritz L,

Dewey RB, Jr., Bottiglieri T, et al. Elevated plasma

homocysteine level in patients with Parkinson disease: motor,

affective, and cognitive associations. Arch Neurol. 2004

Jun;61(6):865-8.

69. Bolann BJ, Solli JD, Schneede J, Grottum KA, Loraas A,

Stokkeland M, et al. Evaluation of indicators of cobalamin

deficiency defined as cobalamin-induced reduction in

increased serum methylmalonic acid. Clin Chem. 2000

Nov;46(11):1744-50.

70. Savage DG, Lindenbaum J, Stabler SP, Allen RH.

Sensitivity of serum methylmalonic acid and total

homocysteine determinations for diagnosing cobalamin and

folate deficiencies. Am J Med. 1994 Mar;96(3):239-46.

47


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

71. Ray JG, Cole DE, Boss SC. An Ontario-wide study of

vitamin ong>B12ong>, serum folate, and red cell folate levels in relation

to plasma homocysteine: is a preventable public health issue

on the rise? Clin Biochem. 2000 Jul;33(5):337-43.

72. Holleland G, Schneede J, Ueland PM, Lund PK, Refsum

H, Sandong>beong>rg S. Cobalamin deficiency in general practice.

Assessment of the diagnostic utility and cost-ong>beong>nefit analysis

of methylmalonic acid determination in relation to current

diagnostic strategies. Clin Chem. 1999 Feb;45(2):189-98.

73. Herong>beong>rt V. The elderly need oral vitamin B-12. Am J

Clin Nutr. 1998 Apr;67(4):739-40.

74. RXList I. Cyanocobalamin. WebMD; 2008.

75. Schauss AG. Recommended optimum nutrient intakes.

In: Pizzorno, editor. Textbook of Natural Medicine. 2nd ed:

Churchill Livingstone, Inc.; 1999. p. 909-27.

76. Hoffman R, Benz E, Shattil S, Furie B, Cohen H,

Silong>beong>rstein L, et al. Hematology: Basic Principles and Practice.

4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005.

77. Marks PW, Zukerong>beong>rg LR. Case records of the

Massachusetts General Hospital. Weekly clinicopathological

exercises. Case 30-2004. A 37-year-old woman with

paresthesias of the arms and legs. N Engl J Med. 2004 Sep

23;351(13):1333-41.

78. Lawhorne LW, Wright H, Cragen D. Characteristics of

non-cobalamin deficient patients who receive regular

cyanocobalamin injections. Fam Med. 1991 Sep-

Oct;23(7):506-9.

79. Hughes D, Elwood PC, Shinton NK, Wrighton RJ. Clinical

trial of the effect of vitamin ong>B12ong> in elderly subjects with low

serum ong>B12ong> levels. Br Med Journal. 1970;2:458-60.

80. Eussen SJ, de Groot LC, Clarke R, Schneede J, Ueland

PM, Hoefnagels WH, et al. Oral cyanocobalamin

supplementation in older people with vitamin ong>B12ong> deficiency:

a dose-finding trial. Arch Intern Med. 2005 May

23;165(10):1167-72.

81. Solomon LR. Cobalamin-responsive disorders in the

ambulatory care setting: unreliability of cobalamin,

methylmalonic acid, and homocysteine testing. Blood. 2005

Feb 1;105(3):978-85.

82. Stabler SP, Allen RH, Dolce ET, Johnson MA. Elevated

serum S-adenosylhomocysteine in cobalamin-deficient elderly

and response to treatment. Am J Clin Nutr. 2006

Dec;84(6):1422-9.

83. Wolters M, Strohle A, Hahn A. Cobalamin: a critical

vitamin in the elderly. Prev Med. 2004 Dec;39(6):1256-66.

48


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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. ong>Vitaminong> ong>B12ong> deficiency in the elderly.

Annual Rev Nutr.1999(19):357–77.

Bernard MA, Nakonezny PA, Kashner TM. The effect of

vitamin ong>B12ong> deficiency on older veterans and its

relationship to health. J Am Geriatr Soc. 1998

Oct;46(10):1199–206.

Carmel R. Current concepts in cobalamin deficiency.

Annu Rev Med. 2000;51:357–75.

Carmel R, Green R, Rosenblatt DS, Watkins D. Update

on cobalamin, folate, and homocysteine. Hematology

(Am Soc Hematol Educ Program). 2003:62–81.

U.S. Food and Drug Administration (FDA). Food

standards: amendment of standards of identity for

enriched grain products to require addition of folic acid. .

Fed Regist, 1996; 61(44): 8781-97.

Herong>beong>rt V. Staging vitamin B-12 (cobalamin) status in

vegetarians. Am J Clin Nutr. 1994 May;59(5

Suppl):1213S–22S.

Institute of Medicine (IOM). Dietary reference intakes for

thiamin, riboflavin, niacin, vitamin B6, folate, vitamin

ong>B12ong>, pantothenic acid, biotin and choline. Washington,

D.C.: National Academy Press; 1998.

Matchar DB, McCrory DC, Millington DS, Feussner JR.

Performance of the serum cobalamin assay for diagnosis

of cobalamin deficiency. Am J Med Sci. 1994

Nov;308(5):276–83.

49


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> deficiency. Clin Lab Med. 2002

Jun;22(2):435–45.

50


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Appendix A

Answers to Case Study Questions

1. Do any of the presenting complaints raise

your index of suspicion about a possible

vitamin ong>B12ong> deficiency? If so, why? Yes.

Complaints of tiredness for 2 months and memory

problems in a woman 65 years of age might

indicate a vitamin ong>B12ong> deficiency.

2. What risk factors does this woman appear to

have for a vitamin ong>B12ong> deficiency? The only

immediately apparent risk factor is her age. Risk

of developing a deficiency ong>beong>gins to increase at 51

years of age. Sex is not an important predictor.

The patient’s nutritional status is unclear at this

stage. Future questions might usefully proong>beong> the

patient for regular sources of vitamin ong>B12ong>, including

meat and dairy products as well as fortified foods

and nutritional supplements.

3. Does the fact that she appears to ong>beong> “wellnourished”

indicate she is unlikely to have a

vitamin deficiency? ong>Whyong> or why not? No. The

fact that she is well-nourished does not rule out a

potential deficiency. Weight, or body mass index,

is not a useful predictor. Normal and overweight

individuals might still have a significant vitamin ong>B12ong>

deficiency ong>beong>cause most deficiencies are due to

malabsorption rather than malnutrition. Markedly

underweight patients, who might truly ong>beong>

malnourished, are at increased risk for a vitamin

ong>B12ong> deficiency, particularly if they are elderly or

have ong>beong>en adhering to a vegetarian or vegan diet

for several years.

4. Are there any aspects of her physical

examination that suggest a vitamin ong>B12ong>

deficiency? Mucosal and skin pallor are subtle

signs.

51


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> test should ong>beong> ordered. Lownormal

levels indicate a need for further

assessment ong>beong>cause serum levels can ong>beong>

maintained at the expense of liver stores even in

the presence of ongoing malabsorption.

52


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Appendix B

Additional Articles on ong>Vitaminong> ong>B12ong>

ong>Deficiencyong>

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. ong>Vitaminong>s for chronic disease

prevention in adults - Scientific Review. JAMA.

2002;287:3116–26.

Fletcher R, Fairfield K. ong>Vitaminong>s for chronic disease

prevention in adults - clinical applications. JAMA.

2002;287:3127–9.

Herong>beong>rt V. ong>Vitaminong> ong>B12ong> and folic acid

supplementation. Am J Clin Nutr. 1997;66:1479–

80.

Herrmann W, Schorr H, Bodis M, Knaapp J, Muller

A, Stein G, et al. Role of homocysteine,

cystathionine and methylmalonic acid

measurement for the diagnosis of vitamin

deficiency in high-aged subjects. Eur J Clin Invest.

2000;30:1083–9.

Ho G, Kauwell G, Bailey L. Practitioners’ guide to

meeting the vitamin ong>B12ong> recommended dietary

allowances for people aged 51 years and older. J

Am Diet Assoc. 1999;99:725–7.

53


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Holleland G, Schneede J, Ueland P, Lund P, Refsum

H, Sandong>beong>rg S, et al. Cobalamin deficiency in

general practice: assessment of the diagnostic

utility and cost-ong>beong>nefit analysis of methylmalonic

acid determination in relation to current diagnostic

strategies. Clin Chem. 1999;45:189–98.

Hvas A, Ellegaard J, Nexo E. Increased plasma

methylmalonic acid level does not predict clinical

manifestations of vitamin ong>B12ong> deficiency. Arch

Intern Med. 2001;161:1535–41.

Johnson M, Hawthorne N, Brackett W, Fischer J,

Gunter E, Allen R, et al. Hyperhomocysteinemia

and vitamin ong>B12ong> deficiency in elderly using title

IIIC nutrition services. Am J Clin Nutr.

2003;77:211–20.

Lokk J, Nilsson M, Norong>beong>rg B, Hultdin J, Sandstrom

H, Westman G. Shifts in ong>B12ong> opinions in primary

health care of Sweden. Scand J Public Health.

2001;29:122–8.

Malouf R, Areosa S. ong>Vitaminong> ong>B12ong> for cognition.

Cochrane Database Syst Rev. 2003:3.

Meins W, Muller-Thomsen T, Meier-Baumgartner

H. Subnormal serum vitamin ong>B12ong> and ong>beong>havioral

and psychological symptoms in Alzheimer’s

disease. Int J Geriatr Psychiatry. 2000;15:415–8.

Misra U, Kalita J, Das A. ong>Vitaminong> ong>B12ong> deficiency

neurological syndromes: a clinical, MRI, and

electrodiagnostic study. Electromyogr Clin

Neurophysiol. 2003;43:57–64.

Mitchell S, Rockwood K. The association ong>beong>tween

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 ong>B12ong>, folate, and

vitamin B6 supplements in elderly people with

normal serum vitamin concentrations. Lancet.

1995;346:85–9.

54


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Penninx BW, Guralnick JM, Ferrucci L. Fried LP,

Allen R, Stabler S. ong>Vitaminong> B(12) deficiency and

depression in physically disabled older women:

epidemiologic evidence from the Women’s Health

and Aging Study. Am J Psychiatry.

2000;157:715–21.

Stopeck A. Links ong>beong>tween helicobacter pylori

infection, cobalamin deficiency, and pernicious

anemia. Arch Intern Med. 2000;160:1229–30.

Tiemeier H, van Tuiji H, Hoffman A, Meijer J,

Kilaan A, Breteler M. ong>Vitaminong> ong>B12ong>, folate, and

homocysteine in depression: the Rotterdam Study.

Am J Psychiatry. 2002;159:2099–101.

van Asselt D, Blom H, Zuiderent R, Wevers R,

Jakobs C, van den Broek W, et al. Clinical

significance of low cobalamin levels in older

hospital patients. Neth J Med. 2000;57:41–9.

55


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

Appendix C

ong>Whyong> ong>Vitaminong> ong>B12ong> ong>Deficiencyong> ong>Shouldong> Be

on Your Radar Screen

Evaluation Questionnaire and

Posttest

Course Goal: To increase the numong>beong>r of primary care

providers (physicians and midlevel providers) who

prevent, detect, and treat vitamin ong>B12ong> deficiencies

among their high-risk patients.

Objectives:

• Descriong>beong> the prevalence in the United States of

vitamin ong>B12ong> deficiency among adults 51 years of

age or older.

• List three neurologic effects of a vitamin ong>B12ong>

deficiency.

• List three hematologic effects of a vitamin ong>B12ong>

deficiency.

• Identify the most common presentation of a

vitamin ong>B12ong> deficiency.

• Discuss the changes in absorption of vitamin ong>B12ong>

that occur with age.

• List at least two pharmacologic options for

treatment of a vitamin ong>B12ong> deficiency.

1. The learning outcomes (objectives) were relevant to

the goal of this course.

a. Strongly agree

b.Agree

c. Undecided

d. Disagree

e. Strongly disagree

2. The content was appropriate given the stated

objectives of the course.

a. Strongly agree

b. Agree

56


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 descriong>beong> the prevalence in the

United States of vitamin ong>B12ong> deficiency among adults 51

years of age or older.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

13. I am confident I can list three neurologic effects of a

vitamin ong>B12ong> deficiency.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

58


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

14. I am confident I can list three hematologic effects of

a vitamin ong>B12ong> deficiency.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

15. I am confident that I can identify the most common

presentation of vitamin ong>B12ong> deficiency.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

16. I am confident that I can discuss the changes in

absorption of vitamin ong>B12ong> that occur with age.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

17. I am confident I can list at least two pharmacologic

options for treatment of a vitamin ong>B12ong> deficiency.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

18. The content expert(s) for this document

demonstrated expertise in the subject matter.

a. Strongly agree

b. Agree

c. Undecided

d. Disagree

e. Strongly disagree

19. Do you feel this course was commercially biased?

Yes or No

If yes, please explain

59


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

20. Please descriong>beong> in the following space any technical

difficulties you experienced with the course.

21. What could ong>beong> done to improve future course

offerings?

22. Do you have any further comments?

60


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>beong>en following a

vegetarian diet for the past 5 years to try to lose weight.

During the physical examination, she is alert and

oriented x 3, but tearful at one point during the

interview with an MMSE score of 28 out of 30. There are

no abnormal physical findings.

Her CBC results:

RBC 4.6 (4.2–5.8) 10^6/µL

MCV 90 (78–102) fL

Hgb 15 (12.0–16.0) g/dL

WBC 6.4 (4.3–11.0) 10^3/µL (normal differential)

Plts 312 (144–440) 10^3/µL

Smear shows normocytic, normochromic RBCs

Chemistry results:

Na 139 (136–148) mEq/L

K 4.7 (3.5–5.5) mEq/L

Cl 103 (98–110) mmol/L

BUN 20.0 (9.34–23.35)mg/dL

Cr 1.0 (0.4–1.5) mg/dL

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

1. Which of the following presenting symptoms

suggest this patient might have a vitamin ong>B12ong>

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 ong>B12ong> deficiency

except:

a. Being 51 years of age or older

b. Being female sex

c. Having hypothyroidism

d. Following a vegetarian diet

3. You might find ______ patients with evidence

of low vitamin ong>B12ong> levels in every 100 patients

you see. (Hint: Use prevalence data from the

research literature to determine your answer.)

a. 0–1

b. 2–4

c. 8–10

d. 15 or more

4. What can you conclude from the CBC with

smear results about the likelihood that this

patient has a vitamin ong>B12ong> deficiency?

a. Her CBC and smear are abnormal so she must

have a ong>B12ong> deficiency.

b. Her CBC and smear are normal so she does not

have a ong>B12ong> deficiency.

c. A normal CBC and smear do not rule out a ong>B12ong>

deficiency.

d. Nothing; it was a mistake to order a CBC and

smear in the first place.

You obtain a serum ong>B12ong> level. Her results are:

Serum ong>B12ong> 211 (211-911) pg/mL

5. What does this patient’s serum ong>B12ong> result

suggest?

a. Her result is within normal limits so she does

not have a vitamin ong>B12ong> deficiency.

62


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

b. She might have a vitamin ong>B12ong> deficiency;

further testing could ong>beong> useful.

c. None of the above.

6. A serum ong>B12ong> result might ong>beong> misleading for

patients who:

a. Are on oral contraceptives

b. Are fasting

c. Have liver disease or renal disease

d. Answers (a) and (c)

7. Setting aside issues of cost and patient

convenience, which one of the following

additional tests would you consider the most

informative at this time?

a. Serum homocysteine

b. Serum methylmalonic acid

c. Serum holotranscobalamin

d. Schilling test

You order additional tests during the workup for this

patient.

Other laboratory results:

TSH 2.3 (0.34–5.6) µ units/mL

ESR 23 (0–30) mm/Hr

CRP 3.1 (0–4.9) mg/L

Hcy 20 (4–17) µmol/L

MMA 0.71 (0.08–0.56) µmol/L

8. Considering all of the evidence presented for

this patient, what would you do next?

a. Ask the patient to increase consumption of

animal food products and recheck her in 6

months

b. Ask the patient to take a multivitamin with ong>B12ong>

and recheck her in 6 months

c. Check for intrinsic factor antibodies and ong>beong>gin

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


ong>Vitaminong> ong>B12ong> ong>Deficiencyong>

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 ong>B12ong> will cure her.

b. You advise her that she must continue

treatment with vitamin ong>B12ong> for life.

c. You tell her that seaweed, nutritional yeast, and

algae will help prevent signs and symptoms

from occurring later.

d. A and C

e. None of the above

64

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