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Vitamin B12 (Cobalamin)

Deficiency in the
Older Adult
C. Christine Orton, PhD, FNP-BC

ABSTRACT
Vitamin B12 (cobalamin) deficiency in the older adult occurs frequently and has the
potential for serious neurological and hematological complications. Because of a myriad of
discreet clinical manifestations, this disorder is often unrecognized by providers. The pur-
pose of this article is to increase awareness of cobalamin deficiency, its causes, clinical mani-
festations, diagnostic work-up, and management. As primary providers, nurse practitioners
should have a high degree of suspicion for at-risk populations. With early identification and
treatment, cobalamin anemia has an excellent prognosis with a normal lifespan.

Keywords: autoimmune, cobalamin, megaloblastic anemia, neuropsychiatric, older


population, pernicious anemia
© 2012 American College of Nurse Practitioners

V itamin B12, also known as cobalamin, is essen-


tial for proper functioning of the neurologic
and hematologic systems. Cobalamin deficiency
in aging adults poses significant risks to their physical and
mental wellbeing. Nurse practitioners (NPs) working in
husband of 62 years. She states her primary concern is
her increased weakness and weight loss, approximately 40
pounds over the past 6 months. She states she has not
been herself, becoming more forgetful to the point of
forgetting who her son is. She was recently hospitalized
primary care settings should be aware of the wide range of for a urinary tract infection and low potassium.
neurological and hematological presentations, along with Her son confirms she has not been herself and says
subtle signs, that occur in cobalamin deficiency. Early she has had several falls (most often at night) and
detection and treatment of this deficiency can prevent increased weakness to the point she has started using a
serious and irreversible neurological injuries.1 walker, whereas she walked unaided just 1 month prior.
Although medical and nursing professionals have He says she is having episodes of extreme confusion,
published articles on cobalamin deficiency,2-5 few articles paranoia, wandering, and occasionally delusions. The
have presented case studies describing the subtle signs patient was seen 2 weeks ago by an urgent care provider
and symptoms often seen in the elderly. The purpose of after a fall, when she was diagnosed with mild dementia
this article is to present a case study of an elderly woman and acute depression. The provider encouraged the fam-
with cobalamin deficiency and to increase awareness of ily to become established with a local provider and possi-
the deficiency, including its etiologies, clinical manifesta- bly look at a “memory unit” for their mother.
tions, diagnostic work-up, and management strategies for Past medical history indicates the patient has a history
NPs in primary care settings. of chronic hypertension, hyperlipidemia, hypothyroidism,
and coronary artery disease with a “small” heart attack at
CASE STUDY age 53. She also suffers from arthritis of her knees and
Ms H, an 81-year-old woman, presents for a new patient hands. Surgeries included a total thyroidectomy while in
visit accompanied by her son. She recently moved in her 20s and a hysterectomy at age 45 without complica-
with her son and daughter in-law after the death of her tions. Current medication include donepezil 5 mg,

www.npjournal.org The Journal for Nurse Practitioners - JNP 547


aspirin 81 mg, celecoxib 200 mg, chlorthalidone 50 mg, receptors in the ileum, and an intact upper gastrointesti-
potassium chloride 40 mEq, conjugated estrogen 200 mg, nal tract.8 Disorders in any of these areas can lead to
levothyroxine 112 mcg, a multivitamin, verapamil 240 cobalamin deficiency.
mg and ezetimibe/simvastatin 10-80; each medication is Cobalamin deficiency increases with age and mani-
taken once a day. Tolterodine 2 mg and omeprazole 20 fests with greater risk of sensory disturbances, neurologi-
mg are both taken twice a day. cal abnormalities, and cognitive decline.3,5,9 There are
Physical exam reveals an elderly woman who is fair several etiologies of cobalamin deficiency listed in Box 1.
skinned with slight pallor and walks slowly with use of a Pernicious anemia (PA)—the most common etiology of
walker. She is cooperative but slow to answer questions, cobalamin malabsorption9—is seen frequently in the eld-
attentive, and oriented x 1 (who). The Mini-Mental State erly population, where it is thought to result from an
Examination indicated a score of 20, suggesting moderate autoimmune attack on the gastric intrinsic factor. Fifty
dementia. Sensory exam indicated diminished sensory percent of patients with PA are found to have anti-
with pinprick/cotton distribution. Deep tendon reflexes intrinsic factor antibodies.4 This decrease of functional
were 2⫹ in the biceps, triceps, and brachioradialis and intrinsic factor leads to an overall cobalamin deficiency.
1⫹ in patellar and ankles. Pitting edema 1⫹ was noted Other autoimmune disorders, such as dysthyroidia,
bilaterally in lower extremities. Further exam findings Sjogren’s, Addison’s, and Graves disease, have been associ-
were unremarkable. ated with PA.4 Pernicious anemia has been linked to a
Although moderate dementia and acute situational hereditary component, and an increased incidence is seen
depression appear to be appropriate diagnoses, a closer in families.
assessment may reveal a very treatable and common dis- Pernicious anemia is a type of megaloblastic anemia
ease seen in the elderly. This patient presents with several where impaired synthesis of DNA results in enlarged red
classic signs of cobalamin deficiency. cells (MCV ⬎ 100 fL) related to impaired maturation
and division of the cells.10 Deficiencies of both cobal-
PATHOPHYSIOLOGY amin or folic acid can lead to a characteristic megaloblas-
Cobalamin is a cofactor for 2 significant reactions in tic anemia that results in ineffective erythropoiesis.5 The
human cells. It is necessary for DNA synthesis and red blood cells (RBCs) are hyperplasic with excess cyto-
nuclear maturation, which leads to normal red cell matu- plasm and immature nuclei. The cells are oval, rather than
ration and division, as well as other rapidly dividing the usual concave shape, with flimsy membranes. Rather
cells.2 A second function of cobalamin is the reaction than living for approximately 4 months, these mega-
that prevents the development of abnormal fatty acids loblastic cells live only a few weeks, resulting in moderate
from being incorporated into neuronal lipids, which has to severe anemia.10 Both folic acid and cobalamin defi-
been associated with myelin breakdown and linked to ciency lead to megaloblastic characteristics, but neuropa-
neurologic complications.6 Cobalamin is a coenzyme thy occurs only with cobalamin deficiency.11
needed for the metabolism of methylmalonic acid Malaborption disorders from gastrectomy, gastritis,
(MMA) and homocysteine (HC).3,6,7 Deficiency leads to pancreatic disease, and several intestinal disorders may
elevated levels of MMA and HC levels. Animal protein lead to low cobalamin levels.4 Ileal resection, inflamma-
through meat, fish, dairy products, and eggs provides the tion, or neoplasm can also bring about cobalamin defi-
only natural dietary source of cobalamin. ciency.9 A possible link between susceptibility to
Through a complex cascade of events, pepsin, Helicobacter pylori infection, atrophic gastritis, and low
transcobalamin, and pancreatic proteases help cobalamin serum cobalamin levels has been suggested by Kaptan.12
bind to intrinsic factor, which is secreted from the pari- Decreased dietary intake, as seen in strict vegans and veg-
etal cells of the stomach.8 At this point the Cobalamin– etarians, is an additional cause of cobalamin deficiency.
Intrinsic Factor (CIF) complex is absorbed in the distal Several drugs also have been associated with lower
ileum, and the cobalamin is released into the plasma. cobalamin levels, including long-term use of proton pump
Adequate absorption of cobalamin requires adequate inhibitors (eg, omeprazole) and colchicine, chlorampheni-
dietary intake, acid-pepsin in the stomach, pancreatic col, cholestyramine, H2 receptor antagonists, and met-
proteases, functional intrinsic factor, functioning CIF formin.2,13 Additionally, folate, potassium supplements, and

548 The Journal for Nurse Practitioners - JNP Volume 8, Issue 7, July/August 2012
vitamin C may inhibit absorption and lead to a deficiency
of cobalamin. 14 Increased risk of developing either cobal- Box 1. Etiologies of Vitamin B12 Deficiency
amin deficiency or folic acid anemia is seen in certain Malabsorption of Vitamin B12
populations; these include adults older than 50, elderly, • Pernicious anemiaa
alcoholics, and those with malabsorption/malnutrition • Atrophic gastritis
disorders. • Pancreatic insufficiency
Prevalence of cobalamin deficiency is difficult to • Partial or total gastrectomy
ascertain because of the diverse etiologies and different • Ileal resection
assays used to determine serum levels.6 However, using a • Bacterial overgrowth
serum radioassay cutoff level of 200 pg/mL, the preva- • Helicobacter pyloris
lence rate for the older (⬎ 51 years) population was • Intestinal disorders
reported to be 5%-16%.2,3,15,16 Assessing for elevated HC • Tapeworm
and MMA levels along with serum cobalamin, the preva-
lence increased to 21% in the same population.6 Congenital Intrinsic Factor or
Increased age is the primary risk factor for the devel- Transcobalamin II Deficiency
opment of cobalamin deficiency, primarily because of the Nutritional Deficiency
higher risk of malabsorption and malnutrition.3 • Vegan diet
Interestingly, the Framingham Offspring Study found little • Vegetarian diet in pregnancy
differences between age groups (26-49, 50-64, and 65-83)
and low levels of cobalamain.17 Other demographic factors Human Immunodeficiency Virus
such as sex, race, and ethnicity are not seen as significant in Hereditary Factors
predicting cobalamin deficiency.3,6 Pernicious anemia has
Drugs
been noted to be more widespread in people of Celtic,
• Biguanides (metformin)
Scandinavian, and African origins.11,13,18 Although cobal-
• Colchicine
amin deficiency is common in the elderly, the megaloblas-
• Neomycin
tic anemia related to it is uncommon.
• Nitrous oxide
• Proton pump inhibitors (omeparzole)
EVALUATION
aSignifies
Manifestations the most common etiology.
Cobalamin deficiency may take 3-4 years to develop
because of the small daily requirement (1 mcg) needed
and the large body stores (1000 mcg) of cobalamin found rhea, glossitis, and cheilosis. Fifty percent of patients
in the liver and throughout the body. The patient usually present with Hunter’s glossitis, in which the lingual
presents with subtle manifestations of moderate to severe papillae atrophy, leaving the tongue smooth and shiny.19
anemia, but as a result of the slow onset of cobalamin, The tongue may be painful, beefy red, or have red
patients are often severely anemic at the time of presenta- patches on the dorsum edges. These symptoms may lead
tion.9 Frequently, health care is sought for symptoms of to unwanted weight loss. Constipation or having several
cardiac, renal, genitourinary, gastrointestinal, infectious, semisolid bowel movements daily may be reported. On
mental, or neurological disorders.13 General manifesta- rare occasions patients may present with abdominal
tions of anemia such as fatigue, pallor, dizziness, dyspnea, rigidity and severe abdominal pain, which suggests
and muscle weakness may be seen. Patients with more spinal cord pathology.13
severe anemia may present with tachycardia, heart mur- Most patients with cobalamin deficiency exhibit
murs, and chest pain. Patients with pre-existing heart dis- some degree of neurologic symptoms, including sym-
ease are at risk for developing congestive heart failure metric paresthesias of the legs and arms, progressive
and coronary insufficiency. weakness, and eventually spastic ataxia with a loss of
Gastrointestinal intestinal symptoms seen in cobal- vibratory and position sense. Other neurologic symp-
amin anemia include anorexia, nausea, vomiting diar- toms are weakness, clumsiness, and an unsteady gait,

www.npjournal.org The Journal for Nurse Practitioners - JNP 549


which is often worse in a dark room because of the loss are elevated in cobalamin deficiency, whereas in folate
of proprioception. deficiency only HC is elevated.21
Urinary and fecal incontinence are rare manifesta- Because of various lab methods for measuring cobal-
tions. These symptoms are a result of myelin degenera- amin and the uncertainty between cobalamin depletion
tion and loss of nerve fibers in the dorsal and lateral and the onset of disease, there is no universal gold stan-
columns of the spinal cord.13,19 Older patients and dard to diagnose cobalamin deficiency.3,21 However, cli-
those with more severe cobalamin anemia may be at nicians can use the following guidelines in interpreting
increased risk for frank dementia and neuropsychiatric cobalamin levels:21
disease. The neuropsychiatric manifestations may • ⬎ 300 pg/ml, deficiency is unlikely
include paranoia, cognitive dysfunction, delusions, and • 200-300 pg/ml, deficiency possible
hallucinations. The term megaloblastic madness has been • ⬍ 200 pg/ml, deficiency is positive
used to describe this disorder.13 Symptoms often mimic Cobalamin and folate deficiency are often found to
dementia or Alzheimer’s disease. Irritability, memory coexist, and each patient should be evaluated for both
impairment, and somnolence, along with visual, taste, deficiencies. Folate levels may be done using serum
and smell changes are other cerebral signs manifested in folate, which varies significantly after meals or by using
cobalamin anemia.9 RBC folate levels, reportedly a more reliable indicator of
Some patients are found to have Lhermitte’s syn- tissue folate. Because of its cost, RBC folate levels may be
drome, a shock-like sensation that radiates to the feet reserved for patients with borderline values of serum
during neck flexion. Interestingly 20%-25% of patients folate or those who may have a combined folate and
with cobalamin deficiency, even those who present with cobalamin deficiency.21
neurologic manifestations, do not have anemia or macro- The Shilling test, a traditional test for diagnosing
cytosis.9 However, if left untreated their symptoms can pernicious anemia using radioactive tracers, is rarely
become irreversible.1 used at this time in the United Sates. Other methods
Other manifestations that may occur with B12 defi- can reliably diagnose pernicious anemia and cobalamin
ciency include hepatomegaly, splenomegaly, arthralgias, deficiency. Autoimmune attacks on gastric intrinsic fac-
and arthritis. Urinary retention and impaired micturition, tor are thought to be a factor in cobalamin deficiency
which predisposes patients to urinary tract infections, in pernicious anemia. Anti-intrinsic factor antibodies
may also occur. Spinothalamic involvement is seen with present in the serum are highly positive for the diagno-
nocturnal pain and upper or lower extremity cramps.13 sis of pernicious anemia.21

Diagnostics Differential
In addition to a thorough history and physical examina- The differential is lengthy and includes neurologic, gas-
tion, an analysis of laboratory findings is indicated to trointestinal, hepatic, and thyroid diagnoses, as well as
diagnose deficiency. A peripheral smear to evaluate red other possible anemias. Box 2 outlines other possibilities
cell indices will show a macrocytic anemia, with an that should be considered with patients presenting with
increased mean cell volume and mean cell hemoglobin. manifestations of megaloblastic anemia.
Other findings are hypersegmented neutrophils, large
platelets, and anisopoikilocytosis (erythrocytes of varying PUTTING IT ALL TOGETHER
sizes and abnormal shapes). Mild leukopenia, thrombocy- It has been suggested that all patients over 65 who are
topenia, or pancytopenia may be present.19,20 malnourished, present with cognitive impairment,
Other lab findings center on measurement of serum myelopathy, neuropathy, or reside in institutions should
cobalamin, RBC (or serum) folate concentrations; be screened for cobalamin (B12) deficiency.4,16,22,23 Both
metabolites, MMA, and HC levels; and intrinsic factor folate and cobalamin levels should be evaluated since
antibodies. Adding serum MMA and HC levels, which cobalamin and folate deficiencies often coexist.21 If both
are more sensitive and more reliable than the vitamin are within normal range, additional testing is not
levels, aids the provider in an accurate diagnosis of cobal- required. If the folate or cobalamin are less than the nor-
amin deficiency. Serum concentrations of HC and MMA mal range, providers should then check the MMA and

550 The Journal for Nurse Practitioners - JNP Volume 8, Issue 7, July/August 2012
total HC levels, both of which are sensitive indicators of
vitamin B12 deficiency.18 If both metabolites are normal, Box 2. Differentials
again, both deficiencies are ruled out. If both metabolites Alzheimer’s
are increased, cobalamin deficiency is confirmed (Table Achlorhydra
1).22 However, folate deficiency cannot be ruled out, and Alcoholic hepatitis
a serum folate level or RBC folate would be in order. If Aplastic anemia, toxic or idiopathic
methyimalonic acid is normal and the HC level is Bone marrow failure
increased, folate deficiency is likely. To aid in determining Celiac sprue
cause of cobalamin deficiency, intrinsic factor should be Cirrhosis
completed to diagnose pernicious anemia. Folate deficiency
Hemolytic anemia
MANAGEMENT Thyroid disorders
Prevention Immune thrombocytopenic purpura
Given the potential for serious neurological and hemato- Inflammatory bowel disease
logical side effects, the primary provider needs to be vig- Iron deficiency anemia
ilant and have a high degree of suspicion in certain Macrocytosis
populations at risk for cobalamin deficiency. This group Malabsorption disorders
includes all older adults over 50 who are not consuming Medications
fortified foods or supplements and patients with malab- Megaloblastic anemia
sorption disorders (eg, atrophic gastritis, chronic alco- Myelodysplastic syndrome
holism, gastric surgery, pancreatic insufficiency, or Multiple myeloma
chronic inflammatory disease of the ileum).1,19,23 All Neoplasm (gastric and colorectal)
patients who present with cognitive impairment should Neutropenia
be investigated for B12 deficiency.4,16,23,24 Other groups Pancreatic insufficiency
who should be screened include patients presenting with Psychiatric disorders: schizophrenia, dementia,
unexplained neurologic or hematologic signs or symp- senility, alzheimer’s
toms and pure vegans or strict vegetarians.3,21 Sprue, tropical
Thalassemia
Treatment Zollinger-Ellison syndrome
After establishing that the patient does indeed have a
cobalamin deficiency, treatment should be initiated imme-
diately. Determining the cause of the deficiency is still needed.3,5,21 Lower doses, such as 100 mcg, have been
somewhat controversial, and many clinicians treat patients recommended as an alternative to the 1000 mcg.1
if a diagnosis of low cobalamin is established.1 Adequate However, use of lower dose formulas may result in a
replacement of cobalamin is the goal of therapy. B12 is slower response, which may be critical when neurologic
available for parenteral use as cyanocobalamin or hydroxo- disease is present.17
cobalamin—the latter is thought to be retained better in Alternative treatment includes oral therapy after ini-
the body and therefore is more available to cells. A num- tial parenteral loading doses by ingestion of 1000-2000
ber of drug regimens have been suggested; the standard mcg every day. Because of the variable absorption of oral
protocol is to initially restore body stores by giving large B12, large daily doses are needed.2,3,6 Oral B12 replace-
daily doses of cobalamin administered parenterally, either ment for compliant patients has been shown to be safe,
intramuscular or deep subcutaneous. effective, and well tolerated. Serial cobalamin measure-
Cobalamin therapy is initiated by administering either ments at periodic intervals are suggested to ensure ade-
of the cobalamin formulas at 1000 mcg intramuscularly quate cobalamin levels have been obtained. New
(IM) every day for 1 or 2 weeks, followed by 1000 mcg therapies of cobalamin treatment include sublingual and
IM every week for 4-6 weeks. Afterward, a maintenance nasal spray or gel. These formulas are expensive and have
dose of 1000 mcg IM every month for life will be not been extensively studied.21

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Table 1. Differentiating Between Cobalamin and Folic mends all adults over 50 include B12-fortified foods (eg,
Acid Deficiency breakfast cereals, which may contain 25%-100% of the
Methlmalonic RDA) or B12 supplements in their diet.25 Vegans and
Patient Condition Acid Homocysteine strict vegetarians are encouraged to follow these guide-
No Deficiency Normal Normal lines as well, especially those who are pregnant or breast
Cobalamin Elevated Elevated feeding.6 Some experts feel higher doses of B12 supple-
Deficiency ments than those currently recommended by the IOM
Folate Normal Elevated may be needed for elderly patients to prevent deficiency.3
Deficiency As a consequence of increased familial incidence of
Adapted from Conrad ME. Pernicious anemia: differential diagnosis and
workup. http://emedicine.medscape.com/article/204930-differential. Updated
pernicious anemia, family members should be made
May 26, 2011. Accessed February 20, 2011. aware they are at a greater risk for developing this dis-
ease.1 Usually, no restrictions on activity are needed
If the deficiency is reversed and the cause eliminated, unless severe gait ataxia or weakness is noted.
cobalamin replacement can be stopped.
Blood transfusions are rarely needed for cobalamin Referral
deficiencies and must be weighed against the risk of the Referral to a neurologist, may be helpful if the patient
elderly patient developing congestive failure. If indeed presents or develops unusual neurological manifestations.1
the patient presents with severe anemia and is critically To help improve gait, balance, and arm function, physical
ill, 1 unit of blood may be transfused with caution, along therapy and occupational therapy may be used.
with low-dose diuretic therapy.1 Consultations with a gastroenterologist and a hematolo-
Follow-up care and repeat labs are required of all gist should be considered.6
patients to ensure they are responding to therapy and to
support their lifetime compliance with therapy. Cobalamin CONCLUSION
deficiency has been associated with gastric and colorectal After analyzing Ms H’s risk factors and presenting symp-
cancers; therefore, routine screening for these disorders toms (age, sudden onset of neuropsychiatric changes,
should be included in the plan of care for these patients.6 weight loss, falls at night, history of urinary tract infec-
tions, tachycardia, extreme weakness, decreased deep ten-
Education don reflexes in extremities, med history), her provider
Other management considerations include patient/family decided to assess for cobalamin deficiency. A serum B12
education, which should include information on the dis- level of 281 pg/ml indicated she had low levels, and she
ease process and possible need for lifelong cobalamin began treatment immediately. She received 1000 mcg IM
replacement, as well as monitoring for malignancy. every week for 6 weeks and then started on a mainte-
Patients may be taught to self-administer cobalamin sub- nance dose of 1000 mcg/month for life.
cutaneously, which helps give them a sense of control in Within a few days of starting treatment, the family
managing their disorder. The Institute of Medicine noticed a significant change in Ms H’s cognitive level,
(IOM) suggests the recommended dietary allowance overall strength, and bouts with incontinence She also
(RDA) for vitamin B12 is 2.4 mcg/day for those 14 and received physical therapy for 8 weeks for gait and
older, except for pregnant (2.6 mcg) and lactating strength training. Grief counseling was provided by hos-
women (2.8 mcg).14,25 Diet education should include pice, and her weight stabilized. She is now active in her
foods high in vitamin B12 such as beef liver, clams, forti- assisted living facility, where she walks unaided, serves on
fied breakfast cereals, fish (trout, salmon, haddock), several committees, and has resumed writing prose and
yogurt, meats, and eggs for those with low-intake cobal- poetry.
amin deficiency.6,14 The Framingham Offspring study Cobalamin plays a crucial role in several neurologic
noted B12 is absorbed better from dairy products than and hematologic functions, and deficiency of this essen-
meats and fish, for unknown reasons. tial vitamin can have profound effects on these systems.
Given that up to 30% of older adults may have diffi- With early identification and treatment, cobalamin defi-
culty absorbing natural B12, the IOM further recom- ciency anemia has an excellent prognosis with a normal

552 The Journal for Nurse Practitioners - JNP Volume 8, Issue 7, July/August 2012
21. Schrier SL. Diagnosis and treatment of vitamin B12 and folic acid.
lifespan. However, if not treated early, neurological com- http://www.uptodate.com/contents/diagnosis-and-treatment-of-vitamin-b12-
plications can become permanent. With the advent of the and-folic-acid-deficiency?source⫽search_result&selectedTitle⫽1%7E145.
Updated February 2, 2010. Accessed February 17, 2011.
Boomers turning 60 at a rate of 7-10,000/day,26 NPs 22. Aaron S, Kumar S, Vijayan J, et al. Clinical and laboratory features and
response to treatment in patients presenting with vitamin B12 deficiency-
have an extraordinary opportunity to use their assessment related neurological syndromes. Neurology India. 2005;53(1):55-58.
and detective skills in screening and uncovering a myriad 23. Eastley R, Wilcock GK, Bucks BS. Vitamin B12 deficiency in dementia and
cognitive impairment: the effects of treatment on neuropsychological
of disorders, including megaloblastic anemia.24 As pri- function. Int J Geriatr Psychiatry. 2000;15:226-233.
24. Knopman DS, DeKosky ST, Cmmings JL, et al. Practice parameter: diagnosis
mary providers NPs should have a high degree of suspi- of dementia (an evidence-based review). Report of the Quality Standards
cion for at-risk populations. Additionally, NPs should be Subcommittee of the American Academy of Neurology. Neurology.
2001;56(9):1143-1153.
aware that patients with certain medications, alcoholism, 25. Institute of Medicine. Dietary reference intakes for thiamin, riboflavin, niacin,
vitamin B6, folate, vitamin B12, pantothenic acid, biotin and choline.
vegan practices, and malabsoprtion/malnutrition syn- Washington, DC: National Academy Press; 2000.
26. US Securities and Exchange Commission. Oldest baby boomers turn 65.
dromes are at risk for cobalamin deficiency and should http://www.sec.gov/spotlight/seniors/oldestboomers2007.htm. Updated
be screened routinely. September 10, 2007. Accessed June 15, 2011.

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