Clinical aspects of cobalamin deficiency in elderly patients
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E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 457
7. Clinical manifestations of cobalamin deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 459
8. Classical treatment of cobalamin deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
9. Oral cobalamin therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460
10. Learning points . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Appendix A. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
1. Introduction to date, little and conflicting evidence is available about the
effectiveness of these new tests in real life clinical practice and
Cobalamin, or vitamin B12, deficiency is frequent in elderly in elderly patients .
patients , but it is often unrecognized or not investigated
because the clinical manifestations are subtle. However, 3. Epidemiology of cobalamin deficiency
because of the potential seriousness of the complications,
particularly neuropsychiatric and hematological [1–4], inves- Epidemiological studies have shown a prevalence of
tigation of all patients who present with vitamin or nutritional cobalamin deficiency of around 20% in the elderly population
deficiency is required. Classic disorders, such as pernicious of industrialized countries (between 50% and 60%, depending
anemia, are the cause of cobalamin deficiency in only a limited on the definition of cobalamin deficiency used in the study).
proportion of elderly patients . The main cause of cobalamin The Framingham study demonstrated a prevalence of 12%
deficiency is food-cobalamin malabsorption, a disorder among elderly people living in the community . Other
characterized by the inability to release vitamin B12 from studies focusing on elderly people, particularly those who are in
food or from its binding proteins . institutions or who are sick, have suggested a higher prevalence
We summarize here the current state of knowledge on of 30–40% [12,13]. Using a stringent definition (Table 1), we
clinical aspects of cobalamin deficiency in the elderly, with a have found a prevalence of 5% in a group of patients followed
special focus on food-cobalamin malabsorption and partic- or hospitalized in a tertiary reference hospital in France .
ularly on oral cobalamin therapy.
4. Cobalamin metabolism and functions
2. Definition of cobalamin deficiency
Cobalamin metabolism is complex and requires many
In the recent literature, several definitions of cobalamin processes, any one of which, if not present, may lead to
deficiency in elderly patients have emerged, depending mainly cobalamin deficiency [4,14–16]. The different stages of
on the populations studied and on the particular test assay kits cobalamin metabolism and corresponding causes of cobalamin
used [5–7]. Varying test sensitivities and specificities have deficiency are shown in Table 2 [14,16]. Once metabolized,
resulted from this lack of a precise ‘gold standard’, especially cobalamin is a cofactor and coenzyme in many biochemical
in elderly patients. The definitions of cobalamin deficiency reactions, including DNA synthesis, methionine synthesis
used in this review are shown in Table 1 [7,8]. Currently, from homocysteine, and conversion of propionyl into succinyl
cobalamin deficiency is often defined in terms of the value of coenzyme A from methyl malonate [4,9].
serum cobalamin and of homocysteine and methyl malonic A typical Western diet contributes 3–30 μg of cobalamin
acid, two components of the cobalamin metabolic pathway. In per day to the estimated daily requirement of between 2 and
the future, new serum cobalamin assay kits, such as 5 μg, according to the U.S. Food and Drug Administration
holotranscobalamin, may replace older assay kits and become . It has been estimated that there is a delay of between 5
the standard for testing for cobalamin deficiency . However, and 10 years between the onset of cobalamin deficiency and
the development of clinical illness, and this is a direct result
Table 1 of the hepatic stores (N 1.5 mg) and the enterohepatic cycle
Definitions of cobalamin (vitamin B12) deficiency [7,8] [4,14]. Between 1% and 5% of free cobalamin (or crystalline
Definitions of cobalamin deficiency cobalamin) is absorbed along the entire intestine by passive
Serum cobalamin level b150 pmol/l (b200 pg/ml) and clinical features diffusion, and this is the mechanism underlying the
and/or hematological anomalies related to cobalamin deficiency effectiveness of oral cobalamin as a treatment for cobalamin
Serum cobalamin level b150 pmol/l (b200 pg/ml) at two different times deficiencies [18,19].
Serum cobalamin level b150 pmol/l (b200 pg/ml) and total serum
homocysteine level N13 μmol/l or methylmalonic acid
levels N0.4 μmol/l a 5. Causes of cobalamin deficiency
Low serum holotranscobalamin level
This definition is useful only in the absence of renal failure and folate Fig. 1 presents the principal causes of cobalamin deficiency
and vitamin B6 deficiency because homocysteine and methylmalonic acid in 172 elderly patients (median age 70 years) hospitalized in the
levels are dependent on these factors. University Hospital of Strasbourg, France . Historically, in
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458 E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462
Table 2 Table 3
Stages of cobalamin metabolism and corresponding causes of cobalamin Food-cobalamin malabsorption syndrome [4,15,16]
Criteria for food-cobalamin Associated conditions or agents
Stages and factors in Causes of malabsorption
cobalamin metabolism cobalamin deficiency
– Low serum cobalamin – Gastric disease: atrophic gastritis,
Intake solely through food Strict vegetarianism (patients (vitamin B12) levels type A atrophic gastritis, gastric disease
who are sick in institutions associated with Helicobacter pylori
or in psychiatric hospitals) infection, partial gastrectomy,
Digestion brings into play Gastrectomies; pernicious gastric by-pass, vagotomy
haptocorrin, gastric secretions anemia; food-cobalamin – Normal results of Schilling test – Pancreatic insufficiency: alcohol
(HCl and pepsin), intrinsic factor, malabsorption using free cyanocobalamin abuse
pancreatic and biliary secretions, labeled with cobalt-58 or
the enterohepatic cycle abnormal results of derived
Absorption brings into play intrinsic Ileal resections; malabsorption; Schilling test a
factors and cubilin pernicious anemia; – No anti-intrinsic factor – Gastric or intestinal bacterial
food-cobalamin malabsorption antibodies overgrowth: achlorhydria, tropical
Transport by transcobalamins Congenital deficiency in sprue, Ogylvie's syndrome, HIV
transcobalamin II – No dietary cobalamin – Drugs: antacids (H2-receptor
Intracellular metabolism based on various Congenital deficiency in deficiency antagonists and proton pump
intracellular enzymes various intracellular enzymes inhibitors) or biguanides (metformin)
– Sjögren's syndrome, systemic
HCl = hydrochloric acid.
– Haptocorrine deficiency
– Aging or idiopathic disorder
elderly patients, cobalamin deficiency was associated with Derived Schilling tests use food-bound cobalamin (e.g., egg yolk,
pernicious anemia (or Biermer's or Addison's disease) [1,12]. chicken, and fish proteins).
The principal characteristics of pernicious anemia have been
reported in detail in several recent reviews [20–22]. Cobalamin malabsorption, especially in elderly patients [4,8,12,23]. In our
deficiency caused by dietary deficiency or surgical resection is experience [15,24], food-cobalamin malabsorption has
rare in the elderly. Dietary deficiency is limited to elderly accounted for 60–70% of cases of cobalamin deficiency in
people who are already malnourished, such as elderly patients elderly patients, with pernicious anemia accounting for just
living in institutions or in psychiatric hospitals [4,14]. Since the 15–25%.
1980s, malabsorption of cobalamin caused by surgery has
become uncommon, owing mainly to the decreasing frequency 6. Food-cobalamin malabsorption syndrome
of gastrectomy and surgical resection of the ileum [4,8,15].
Several other uncommon disorders in elderly people have been First described by Carmel in 1995 , food-cobalamin
associated with cobalamin malabsorption: deficiency in the malabsorption is a syndrome characterized by the inability of
exocrine function of the pancreas following chronic pancrea- the body to release cobalamin from food or intestinal transport
titis (usually alcoholic), lymphomas or tuberculosis (intestine), proteins, particularly in the presence of hypochlorhydria,
Crohn's disease, Whipple's disease, and celiac disease [12,16]. where the absorption of “unbound” cobalamin is normal. This
The past 15 years have been marked by the recognition of food- syndrome is characterized by cobalamin deficiency in the
cobalamin malabsorption as the leading cause of cobalamin presence of sufficient food-cobalamin intake and a normal
Schilling test, ruling out malabsorption or pernicious anemia
[15,23,24]. The principal characteristics of this syndrome are
listed in Table 3. Authors supporting the existence of this
syndrome have employed a modified Schilling test, which uses
radioactive cobalamin bound to animal proteins (e.g., salmon,
trout) and reveals malabsorption when the results of a standard
Schilling test are normal [4,15,24]. Some authors have
questioned the existence and significance of cobalamin
deficiency related to food-cobalamin malabsorption 
because many patients experience only mild clinical or
hematological features. However, several of the patients we
have described in a recently published study  had serious
features classically associated with pernicious anemia, includ-
ing polyneuropathy, confusion, dementia, medullar-combined
sclerosis, anemia, and pancytopenia. Table 4 lists the principal
features in the aforementioned series of 92 elderly patients with
Fig. 1. Causes of cobalamin deficiency in 172 elderly patients . food-cobalamin malabsorption . Nevertheless, the partial
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E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 459
Table 4 pump inhibitors [27,28], particularly among patients with
Clinical manifestations in 92 elderly patients with food-cobalamin Zollinger–Ellison syndrome , and biguanides (metfor-
min) [30,31]; chronic alcoholism; surgery or gastric recon-
Clinical manifestations struction (e.g., bypass surgery for obesity); partial pancreatic
Epidemiological data The median (±SD) patient age is 76 ± 8 years; the exocrine failure [4,15]; and Sjögren's syndrome or systemic
female/male ratio is 2. sclerosis  (Table 3). In a series of 92 elderly patients
Clinical data – Clinical features are reported in 70% of all
(mean age 76 years) with food-cobalamin malabsorption
patients, with mild sensory polyneuropathy (45%),
confusion or impaired mental functioning (23%), , we have reported at least one of these associated
and physical asthenia (21%). conditions or agents in 60% of the patients. These conditions
Biological and – The mean (±SD) serum cobalamin level is mainly include atrophic gastritis (± H. pylori infection) in
hematological data 131 ± 38 pg/mL and the mean total 30% of the patients and long-term metformin or antacid
serum homocysteine level is 22.1 ± 9.3 μmol/L.
intake in 20% of the patients.
–Hematological abnormalities are reported in 76%
of all patients, with macrocytosis (mean erythrocyte
cell volume N100 fL; 53%), anemia (hemoglobin 7. Clinical manifestations of cobalamin deficiency
level b10 g:dL; 21%), leukopenia (white cells count
b4 × 109/L; 11%), thrombopenia (platelets count The primary clinical manifestations of cobalamin deficiency
b100 × 109/L; 9%), and pancytopenia (6.5%).
in elderly patients are described in Table 5. They are highly
– The mean (± SD) hemoglobin level is 10.9 ± 2.5 g/
dL and the mean erythrocyte cell volume is 95.7 ± polymorphic and of varying severity, ranging from milder
12.7 fL. conditions such as tiredness, common sensory neuropathy, and
isolated anomalies of macrocytosis or hypersegmentation of
neutrophils, to severe disorders, including combined sclerosis
nature of this form of malabsorption may produce a more of the spinal cord, hemolytic anemia, and even pancytopenia
slowly progressive depletion of cobalamin than does the more [2,15,33–35]. In the aforementioned series of 92 patients with
complete malabsorption engendered by disruption of the food-cobalamin malabsorption , we found at least one
intrinsic factor-mediated absorption. The slower progression of clinical or hematological abnormality in 70% and 76% of the
depletion probably explains why mild, preclinical deficiency is patients, respectively (Table 4). Cobalamin deficiency appears
more frequently associated with food-cobalamin malabsorp- to be more common among patients who have a variety of
tion than with pernicious anemia [4,15]. chronic neurological conditions, such as dementia, Alzheimer's
Food-cobalamin malabsorption is caused primarily by disease, stroke, Parkinson's disease, and depression, although it
atrophic gastritis . Over 40% of patients older than is unclear if there is a causal relationship [4,36]. In these
80 years have gastric atrophy, related or not to Helicobacter conditions, it is important to keep in mind that malnutrition is
pylori infection [12,25]. Other factors that contribute to food- often an important factor. In our personal experience, the
cobalamin malabsorption in the elderly include: intestinal administration of cobalamin to patients with dementia did not
microbial proliferation (cobalamin deficiency that can be improve their neurological condition [8,15]. Other reported
addressed by antibiotic treatment) [5,26]; long-term ingestion studies found similar results [19,37]. To date, the causal role of
of antacids, including H2-receptor antagonists and proton cobalamin in these conditions remains unclear.
Main clinical features of cobalamin deficiency in elderly patients [2,4,15,16,33–35]
Hematological manifestations Neuro-psychiatric manifestations Digestive manifestations Other manifestations
– Frequent: macrocytosis, neutrophil – Frequent: polyneuritis (especially – Classic: Hunter's glossitis, – Frequent: tiredness, loss of appetite
hypersegmentation, aregenerative sensitive), ataxia, Babinski's phenomenon jaundice, LDH and bilirubin
macrocytary anemia, medullar elevation (“intramedullary
megaloblastosis (“blue spinal cord”) destruction”)
– Rare: isolated thrombocytopenia and – Classic: combined sclerosis of the – Debatable: abdominal pain, – Under study: atrophy of the vaginal
neutropenia, pancytopenia spinal cord dyspepsia, nausea, vomiting, mucosa and chronic vaginal and
diarrhea, disturbances in urinary infections (especially mycosis),
intestinal functioning venous thromboembolic disease,
– Very rare: hemolytic anemia, – Rare: cerebellar syndromes affecting the – Rare: resistant and recurring
thrombotic microangiopathy cranial nerves including optic neuritis, optic mucocutaneous ulcers
(presence of schistocytes) atrophy, urinary and/or fecal incontinence
– Under study: changes in the higher
functions, dementia, stroke, angina and
parkinsonian syndromes, depression,
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8. Classical treatment of cobalamin deficiency both food-cobalamin malabsorption [41–44] and pernicious
anemia  using a crystalline cobalamin (cyanocobalamin).
The standard treatment of cobalamin deficiency, particular- The main results of our oral cobalamin treatment studies (open,
ly when the cause is not dietary deficiency, is parenteral not randomized) are summarized in Table 6 [41–44,47]. These
administration – usually by intramuscular injection – of data confirmed the previously reported efficacy of oral
cyanocobalamin or hydroxocobalamin [1,18,19,33]. In France, crystalline cyanocobalamin, especially in food-cobalamin
the recommended practice to build up the body stores of the therapy [19,35,39]. All patients treated orally corrected their
vitamin quickly and to correct serum cobalamin hypovitami- vitamin B12 levels and at least two-thirds their hematological
nosis, particularly in the case of pernicious anemia, involves abnormalities [41–44,47]. Moreover, one-third experienced
the administration of 1000 μg of cyanocobalamin per day for clinical improvement upon oral treatment. In most cases of
1 week, followed by 1000 μg/week for 1 month, and then by 1 food-cobalamin malabsorption, “low” cobalamin doses (i.e.,
injection of the same dose once a month, normally for the rest between 125 to 1000 μg of oral crystalline cyanocobalamin per
of the patient's life [8,12,20]. In the UK, the regimen involves day) were used. These findings are consistent with the results
the administration of intramuscular hydroxocobalamin, initial- of two prospective, randomized, controlled studies comparing
ly 1000 μg 3 times a week for 2 weeks and then every 3 months oral cobalamin versus intramuscular cobalamin therapy
in cases where there is no neurological involvement and [18,40]. Kuzminski et al. , in a prospective, randomized
1000 μg on alternate days until no further clinical improvement trial including 38 patients, reported improvement in hemato-
and then every 2 months for the rest of the patient's life when logical parameters and cobalamin levels (mean value 907 pg/
there is neurological involvement . mL) after 4 months of oral cobalamin therapy using a much
higher dose (i.e., 2000 μg/day). Bolaman et al. , in a
9. Oral cobalamin therapy prospective randomized trial of 60 patients, also reported
significant improvement in hematological parameters and
In the absence of nutritional deficiency etiology, two cobalamin levels (mean improvement +140.9 pg/mL) after
alternative routes of cobalamin administration have recently 3 months of 1000 μg daily of oral cyanocobalamin therapy. A
been proposed: oral [18,19,39–44] and nasal [45,46]. Our systematic review conducted under the auspices of the
working group has developed an effective oral treatment for Cochrane Metabolic and Endocrine Disorders Review Group
Oral cobalamin therapy for food-cobalamin malabsorption: main results of studies conducted mainly in the University Hospital of Strasbourg, France
Study characteristics (number of patients) Therapeutic modalities Results
Open prospective study of well-documented Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in 
vitamin B12 deficiency related to 650 μg/ day for at least 3 months 80% of the patients
food-cobalamin malabsorption (n = 10) – Significant increase in hemoglobin (Hb) levels (mean of
1.97 g/dL) and decrease in mean erythrocyte cell volume
(ECV) (mean of 7.8 fL)
– Improvement of clinical abnormalities in 20% of
– No adverse effect
Open prospective study of low vitamin B12 Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in 85% 
levels not related to pernicious anemia (n = 20) 1000 μg/day for at least 1 week of patients
– No adverse effect
Open prospective study of well-documented Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in 87% 
vitamin B12 deficiency related to between 1000 and 250 μg/day of patients
food-cobalamin malabsorption (n = 30) for 1 month – Significant increase in Hb levels (mean of 0.6 g/dL) and
decrease in ECV (mean of 3 fL); normalization of Hb
levels and ECV in 54% and 100% of patients, respectively
– Dose effect — effectiveness dose of vitamin
B12 ≥500 μg/day
– No adverse effect
Open prospective study of low vitamin B12 levels Oral crystalline cyanocobalamin: – Normalization of serum vitamin B12 levels in all patients 
not related to pernicious anemia (n = 30) between 1000 and 125 μg/day for with a dose of at least ≥250 μg/day
at least 1 week – Dose effect — effectiveness dose of vitamin B12 ≥500 μg/
– No adverse effect
Open prospective study of low vitamin B12 levels Oral crystalline cyanocobalamin: – Significant increase in serum vitamin B12 levels in 90% of 
related to pernicious anemia (n = 10) 1000 μg/day for at least 3 months patients (mean of 117.4 pg/mL
– Significant increase in Hb levels (mean of 2.45 g/dL) and
decrease in ECV (mean of 10.4 fL)
– Improvement of clinical abnormalities in 30% of patients
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E. Andrès et al. / European Journal of Internal Medicine 18 (2007) 456–462 461
supports the efficacy of oral cobalamin therapy, with a daily the search to human data, elderly patients (N65 years old),
dose of 2000 and 1000 μg initially, and thereafter weekly, of clinical trial, review, and guidelines, and English and French
vitamin B12 . Vidal-Alaball et al. reported that serum languages. Additional references were localized through a
vitamin B12 levels increased significantly in patients on oral review of textbooks on hematology and internal medicine, as
vitamin B12, and both groups of patients receiving oral or well as information gleaned from international meetings.
intramuscular treatment had neurological improvement. In a Additional unpublished data from our cohort with cobalamin
recent randomized, parallel-group, double blind, dose-finding deficiency at the University Hospital of Strasbourg were also
trial, Eussen et al. demonstrated that the lowest dose of oral considered. All of the papers and abstracts were reviewed by
cyanocobalamin required to normalize mild cobalamin at least two senior researchers who selected the data used in
deficiency (N 500 μg per day) is more than 200 times greater the study.
than the recommended dietary allowance, which is approxi-
mately 3 μg daily . However, a standardized oral References
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