# Cobalamin Deficiency in Elderly Patients: A Personal View

Authors: Emmanuel Andrès; Thomas Vogel; Laure Federici; Jacques Zimmer; Ecaterina Ciobanu; Georges Kaltenbach
Journal: Current Gerontology and Geriatrics Research
 (2008)

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## Abstract

Cobalamin (vitamin B12) deficiency is particularly common in the elderly (>65 years of age) but is often unrecognized because its clinical manifestations are subtle; however, they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. In the elderly, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. Food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated toHelicobacter pylori infection, and long-term ingestion of antacids and biguanides. Management of cobalamin deficiency with cobalamin injections is currently well documented but new routes of cobalamin administration (oral and nasal) are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption.


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## Body

## 1. Introduction

Cobalamin or vitamin B12 deficiency is  common in elderly patients [1] but is often unrecognized or not
investigated because the clinical manifestations of cobalamin deficiency are
subtle. However, the complications of cobalamin deficiency, particularly the
neuropsychiatric and hematological [1–4], are
potentially serious and therefore require investigation in all patients who
present with vitamin or nutritional deficiency. Classic disorders such as
pernicious anemia are the cause of cobalamin deficiency in only a limited
number of patients, especially elderly patients [4]. A more common problem is food-cobalamin malabsorption, a
disorder characterized by the inability to release cobalamin from food or its
binding proteins [4]. This review summarizes
the current knowledge on cobalamin deficiency, with a particular focus on
food-cobalamin malabsorption and oral cobalamin therapy.


## 2. Definition of Cobalamin Deficiency

Literature of the last ten years has provided
several definitions of cobalamin deficiency [5–7]. The
definitions of cobalamin deficiency used in this review are shown in Table 1 [7, 8]. To date, cobalamin
deficiency is often defined in terms of the serum concentration of cobalamin
and of homocysteine and methyl malonic acid, two components of the cobalamin
metabolic pathway, (Figure 1) but in clinical practice, no single test has emerged as the gold standard for diagnosis of
cobalamin deficiency especially in elderly patients. Moreover, the major diagnostic challenge remains patients
who develop subtle cobalamin deficiency, often without hematological
abnormalities (usefulness of an early treatment to prevent irreversible
neurological damages) [4]. In the future, new serum cobalamin assay kits
(e.g., the holotranscobalamin assay kit) might perhaps replace older assay kits
and should become the standard for testing [6, 9].Table 1
Definitions of cobalamin (vitamin B12) deficiency [5–7].
(i) Serum cobalamin levels <150 pmol/L and
clinical features and/or hematological anomalies related to cobalamin
deficiency(ii) Serum cobalamin levels <150 pmol/L (<200 pg/mL) on 2 separate occasions(iii) Serum cobalamin levels <150 pmol/L and
total serum homocysteine levels >13μmol/L or methylmalonic acid
levels >0.4 μmol/L (in the absence of renal failure and folate and vitamin
B6 deficiencies)(iv) Low serum holotranscobalamin levels <35 pmol/LFigure 1
Cellular impact of cobalamin deficiency.


## 3. Epidemiology of Cobalamin Deficiency

Epidemiological studies show that in the general
population of industrialized countries, cobalamin  deficiency has a prevalence of
around 2 to 20%, depending on the definition of cobalamin deficiency used [4, 9].
The Framingham
study demonstrated a prevalence of 12% among elderly people living in the
community [10]. Other studies
focusing on elderly people, particularly those who are in institutions or who
are sick and malnourished, have suggested a higher prevalence of at least 30% [11, 12]. Using the definition in Table 1
(serum cobalamin levels <150 pmol/L [<200
pg/mL] on 2 separate occasions), we
found that cobalamin deficiency had a prevalence of 5% in a group of patients
followed or hospitalized in a tertiary reference hospital [8]. We also documented that around 4% of the anemia were related to
a cobalamin deficiency in a population of 300 consecutive anemia hospitalized
in our department (tertiary reference center) [8]. In the NHANES III study, 34% of all anemia in elderly patients is caused
by folate, cobalamin, or iron deficiency, alone or in combination (nutritient-deficiency anemia) [8].


## 4. Cobalamin Metabolism and Function

Cobalamin metabolism is complex and is made up of
many processes, defects in any one of which can lead
to cobalamin deficiency [4, 13–15]. The different stages of cobalamin metabolism and
corresponding causes of cobalamin deficiency are shown in Table 2. Once
metabolized, cobalamin is a cofactor and coenzyme for many biochemical
reactions, including DNA synthesis, methionine synthesis from homocysteine, and
conversion of propionyl into succinyl coenzyme A from methyl malonate [4, 9]. In a clinical setting, cobalamin
absorption is measured imperfectly by the Schilling test [4, 8]. A typical Western
diet contributes 3–30 μg of
cobalamin per day [13, 15] toward the recommended dietary allowance of
2.4 μg/day for adults and 2.6 to 2.8 μg/day during pregnancy [16]. The 5–10 year delay
between the onset of cobalamin deficiency and the development of clinical
illness is directly attributable to hepatic stores of cobalamin (>1.5 mg)
and the enterohepatic cycle [4, 13].
Between 1–5% of free
cobalamin (or crystalline cobalamin) is absorbed along the entire intestine by
passive diffusion. This absorption explains the mechanism underlying oral
treatment of cobalamin deficiencies [17, 18].Table 2
Stages of cobalamin metabolism and
corresponding causes of cobalamin deficiency [13, 15].
Stages and
factors involved in cobalamin metabolismCauses of cobalamin deficiencyIngestion
of foodStrict
vegetarianism (patients who are sick in institutions or in psychiatric
hospitals)Digestion,
which involves haptocorrin, gastric secretions (HCl and pepsin), intrinsic
factor, pancreatic and biliary secretions, and the enterohepatic cycleGastrectomy,
pernicious anemia, and food-cobalamin malabsorptionAbsorption,
which brings into play intrinsic factor and cubilinIleal
resection, malabsorption, pernicious anemia, and food-cobalamin malabsorptionTransportation
by transcobalaminsCongenital
deficiency in transcobalamin IIIntracellular
metabolism by various intracellular enzymesCongenital
deficiency in various intracellular enzymesHCl =
hydrochloric acid.


## 5. Classical Causes of Cobalamin Deficiency

In elderly patients, cobalamin deficiency is classically caused by
pernicious anemia and food-cobalamin malabsorption [1, 11, 14]. The principal characteristics of pernicious anemia have
been reported in detail in several reviews [19–21].
Diagnosis of pernicious anemia is based on the presence of (1) intrinsic factor
antibodies in serum (specificity: >98%, sensibility: around 50%) and/or (2)
autoimmune atrophic  gastritis (presence of Helicobacter pylori infection in gastric biopsies is an exclusion factor) [15, 19]. Cobalamin
deficiency caused by dietary deficiency  or malabsorption is rare. Dietary causes of deficiency are
limited to elderly people who are already malnourished. This mainly concerns
elderly patients living in institutions or in psychiatric hospitals [4, 13]. Since the 1980s, the
malabsorption of cobalamin has become rarer, owing mainly to the decreasing
frequency of gastrectomy and surgical resection of the terminal small intestine
[4, 14]. Several disorders commonly
seen in gastroenterology practice might, however, be associated with cobalamin malabsorption.
These include deficiency in the exocrine function of the pancreas after chronic
pancreatitis (usually alcoholic), lymphomas or tuberculosis (of the intestine),
Crohn’s disease, Whipple’s disease, and uncommonly celiac disease [11, 15].


## 6. Food-Cobalamin Malabsorption

First, well-described by Carmel
in 1995 [22], the food-cobalamin
malabsorption is a syndrome characterized by the inability to release cobalamin
from food or intestinal transport proteins, particularly in the presence of
hypochlorhydria, in which the absorption of “unbound” cobalamin is normal. As
various studies have shown [14, 22, 23],
this syndrome is defined by cobalamin deficiency in the presence of sufficient
food-cobalamin intake and normal Schilling test results, which rules out
malabsorption or pernicious anemia. The principal characteristics of this
syndrome are listed in  Table 3. In theory, indisputable evidence of
food-cobalamin malabsorption comes from using 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, 14, 23].Table 3
Food-cobalamin
malabsorption syndrome [4, 14, 15].
Criteria
for food-cobalamin malabsorptionAssociated
conditions or agents–  Low-serum cobalamin (vitamin B12)
levels– Gastric disease: atrophic
gastritis, type A atrophic gastritis, gastric disease associated withHelicobacter pylori infection, partial gastrectomy, gastric by-pass, and vagotomy–  Normal results of Schilling test
using free cyanocobalamin labeled with cobalt-58, or abnormal results of
derived Schilling test‡– Pancreatic insufficiency: alcohol
abuse– No anti-intrinsic factor
antibodies– Gastric or intestinal bacterial
overgrowth: achlorhydria, tropical sprue, Ogylvie’s syndrome, and HIV– No
dietary cobalamin deficiency– Drugs: antacids (H2-receptor
antagonists and proton-pump inhibitors) or biguanides (metformin)– Alcohol abuse– Sjögren’s syndrome, systemic
sclerosis– Haptocorrine deficiency– Ageing or
idiopathic‡Derived
Schilling tests use food-bound cobalamin (e.g., egg yolk, chicken, and fish
proteins).Food-cobalamin malabsorption has been found to be the leading cause of
cobalamin malabsorption, especially in elderly patients [4, 11, 22]. In our experience (300 patients with a documented
cobalamin deficiency), food-cobalamin malabsorption accounts for about 60–70% of the cases
of cobalamin deficiency in elderly patients, whereas pernicious anemia
accounted for only 15–25% [14, 23].
Some authors have speculated about the reality and significance of cobalamin
deficiency related to food-cobalamin malabsorption [4], because many patients have only mild clinical or hematological
features. Several of our patients, however, [14] had significant features classically associated with pernicious
anemia, including polyneuropathy, confusion, dementia, medullar-combined
sclerosis, anemia, and a pancytopenia. Nevertheless, the partial nature of this
form of malabsorption might produce a more slowly progressive depletion of
cobalamin than does the more complete malabsorption engendered by disruption of
intrinsic factor-mediated absorption. The slower progression of depletion
probably explains why mild preclinical deficiency is associated with
food-cobalamin malabsorption more often than with pernicious anemia [4, 14].Food-cobalamin malabsorption is caused primarily by atrophic gastritis [14]. Achlorhydria hampers the
extraction of cobalamin from protein food sources. Over 40% of patients older
than 80 years of age have gastric atrophy that might or might not be related to Helicobacter pylori infection [11, 24]. Other factors that contribute
to food-cobalamin malabsorption in elderly people include chronic carriage of H. pylori and intestinal microbial
proliferation (in which case cobalamin deficiency can be corrected by
antibiotic treatment) [24, 25];
long-term ingestion of antiacids, including H2-receptor antagonists and
proton-pump inhibitors [26, 27],
particularly among patients with Zollinger-Ellison syndrome [28, 29], and biguanides (metformin) [30–32]; chronic
alcoholism; surgery or gastric reconstruction (e.g., bypass surgery for
obesity); partial pancreatic exocrine failure [4, 14], and Sjögren’s syndrome or systemic sclerosis [33] (Table 3). In a series of 92
elderly patients (mean age: 76 years) with food-cobalamin malabsorption [14], we have reported at least one of
these associated conditions or agents in 60% of the patients. These conditions
mainly include atrophic gastritis (±H.
pylori infection) in 30% of the patients and long-term metformin or antacid
intake in 20% of the elderly patients.


## 7. Clinical Manifestations of Cobalamin Deficiency

The primary clinical manifestations of cobalamin deficiency are
described in  Table4. They are highly polymorphic and of varying
severity ranging from common sensory neuropathy and isolated anomalies of
macrocytosis and hypersegmentation of neutrophils, to severe disorders,
including combined sclerosis of the spinal cord, hemolytic anemia, and even pancytopenia
[2, 14, 34–36]. In the
aforementioned series of 92 patients with food-cobalamin malabsorption [14], we have found at least one
clinical feature or hematological abnormalities in, respectively, 70% and 76%
of the patients. Cobalamin deficiency appears to be more common among patients
who have a variety of chronic neurologic conditions such as dementia,
Alzheimer’s disease, stroke, Parkinson’s disease, and depression, although it
is unclear if these are causal relationships [4, 37]. In our own studies in which we administered cobalamin to
patients with dementia, improvement was not observed [8, 14]. Other studies have had similar results [1, 2, 9]. At this time, a causal role of cobalamin in these
conditions remains speculative.Table 4
Main
clinical features of cobalamin deficiency [2, 4, 14, 15, 34–36].
Hematological
manifestationsNeuro-psychiatric
manifestationsDigestive manifestationsOther manifestations– Frequent: macrocytosis, hypersegmentation of the neutrophils, aregenerative macrocytary anemia, LDH and bilirubin elevation, medullary megaloblastosis (“blue spinal cord”)– Frequent:
polyneurites (especially sensitive ones), ataxia, Babinski’s phenomenon– Classic:
Hunter’s glossitis, jaundice, LDH and bilirubin elevation (“intramedullary
destruction”)– Under
study: atrophy of the vaginal mucosa and chronic vaginal and urinary
infections (especially mycosis), hypofertility and repeated miscarriages
(connection with cobalamin deficiency under study), venous thromboembolic
disease, angina (hyperhomocysteinemia), osteoporosis– Rare:
isolated thrombocytopenia and neutropenia, pancytopenia– Classic:
combined sclerosis of the spinal cord– Debatable:
abdominal pain, dyspepsia, nausea, vomiting, diarrhea, disturbances in
intestinal functioning– Very rare: hemolytic anemia,
thrombotic microangiopathy (presence of schistocytes)– Rare: cerebellar syndromes affecting the cranial nerves including optic neuritis,
optic atrophy, urinary, and/or
fecal incontinence– Rare:
resistant and recurring mucocutaneous ulcers cobalamin
deficiency– Under study: changes in the
higher functions, even dementia, stroke and atherosclerosis
(hyperhomocysteinemia), parkinsonian syndromes, depression, multiple
sclerosis


## 8. Classical Treatment of Cobalamin Deficiency

The classic treatment for cobalamin
deficiency, particularly when the cause is not dietary deficiency, is
parenteral administration—in most countries
intramuscular injection—of this vitamin
(in the form of cyanocobalamin and, more rarely, hydroxy or methyl cobalamin) [1, 17, 18, 34]. However, traditions
concerning both dose and schedule of administration vary considerably. In France, the
recommended practice is to build up the tissue stores of the vitamin quickly
and correct serum cobalamin hypovitaminosis, particularly in the case of
pernicious anemia. The treatment involves the administration of 1000 μg of
cyanocobalamin per day for 1 week, followed by 1000 μg per week for 1 month,
followed by 1000 μg per month, normally for the rest of the patient’s life [11, 19]. In USA and UK,
dosages ranging from 100 to 1000 μg per month [or every 2-3 months when
hydroxocobalamin is given] are used during the rest of the patient’s life [4, 17]. Hydroxocobalamin may have
several advantages due to a better tissular retention and storage.
Additionally, recent works concern oral cobalamin therapy through food
fortification [3, 11].


## 9. Oral Cobalamin Therapy

Since cobalamin is absorbed by
intrinsic factor-independent passive diffusion (1% of oral cobalamin), daily
high-dose oral cyanocobalamin can induce and maintain remissions in patients
with megaloblastic anemia [15]. In cases of cobalamin deficiency other
than those caused by nutritional deficiency, alternative routes of cobalamin
administration have been used: oral [17, 18, 38–44]
and nasal [45, 46]. These other
routes of administration have been proposed as a way of avoiding the
discomfort, inconvenience, and cost of monthly injections. Our working group
has developed an effective oral treatment of food-cobalamin malabsorption [40–43] and for
pernicious anemia [47] using
crystalline cobalamin (cyanocobalamin). Our principal studies of oral cobalamin
treatment (open, not randomized studies) are described in  Table 5 [40–43, 47]. These
data confirm the previously reported efficacy of oral crystalline
cyanocobalamin, especially in food-cobalamin therapy [18, 36, 38]. All of our patients who were treated orally corrected
their cobalamin levels and at least two-thirds corrected their hematological
abnormalities [40–43, 47]. Moreover,
one-third of patients experienced a clinical improvement on oral treatment. In
most cases of food-cobalamin malabsorption,
“low” cobalamin doses (i.e., 125–1000 μg of oral
crystalline cyanocobalamin per day) were used. These data is in accordance with
the results of the two prospective randomized-controlled studies comparing
oral cobalamin with intramuscular cobalamin therapy [17, 39]. A systematic review of randomized-controlled trials by the Vitamin B12 Cochrane Group supports the
efficacy of oral cobalamin therapy, with a dose between 1000 and 2000 μg given
initially daily and then weekly [48].
In this analysis, serum cobalamin levels increased significantly in patients
receiving oral cobalamin and both groups of patients (receiving oral and intramuscular
treatment) had neurological improvement. The Cochrane
group concludes that daily oral therapy “may be as effective as intramuscular
administration in obtaining short term haematological and neurological
responses in cobalamin deficient patients” [48]. Nevertheless to our knowledge, the effect of oral cobalamin treatment in
patients presenting severe neurological manifestations has not yet been
adequately documented. Thus until this has been done parenteral cobalamin
therapy is still to be recommended for such patients. In a randomized,
parallel-group, double-blind, dose-finding trial, Eussen et al. showed that the lowest dose of
oral cyanocobalamin required to normalize mild cobalamin deficiency is more
than 200 times the recommended dietary allowance of approximately 3 μg daily
(i.e., >500 μg per day) [49]. The
procedure for oral cobalamin treatment has, however, not been completely
validated yet in real life, particularly the long-term efficacy [50]. To date, as several authors
suggest, oral cobalamin therapy remains one of “medicine’s best kept secrets” [51]. Since loading doses of cobalamin
far exceed physiologic requirements, clinical responses may result from
pharmacologic effects on either cobalamin-related processes or on cellular
functions completely unrelated to the known biochemical actions of cobalamin [52]. As a result, blood cobalamin,
methylmalonic acid and homocysteine values often fail to predict whether or not
a patient will respond to cobalamin therapy [53]. Nevertheless, the following
can be proposed: ongoing supplementation until associated disorders are
corrected (e.g., by halting the ingestion of the offending medication or
exogenosis, or by treating H. pylori infection or pancreatic exocrine failure), lifelong administration or, when
applicable, sequential administration [54].Table 5
Experience of oral cobalamin therapy for food-cobalamin malabsorption in the
university hospital of Strasbourg, France.
Study characteristics (number of patients)Therapeutic modalitiesResultsOpen prospective study of well-documented cobalamin deficiency related to food-cobalamin malabsorption(n=10)Oral crystalline cyanocobalamin: 650μg per day
during at least 3 months– Normalization
of serum cobalamin levels in 80% of the patients[41]– Significant
increase of hemoglobin (Hb) levels (mean of 1.9 g/dL) and decrease of mean
erythrocyte cell volume (ECV) (mean of 7.8 fL)– Improvement of clinical abnormalities in 20% of the patients– No
adverse effectOpen
prospective study of low-cobalamin levels not related to pernicious anemia(n=20)Oral crystalline cyanocobalamin: between 1000μg per
day during at least 1 week– Normalization
of serum cobalamin levels in 85% of the patients[42]– No
adverse effectOpen
prospective study of well-documented cobalamin deficiency related to
food-cobalamin malabsorption(n=30)Oral crystalline cyanocobalamin: between 1000 and
250μg per day during 1 month–
Normalization
of serum cobalamin levels in 87% of the patients[40]– Significant
increase of Hb levels (mean of 0.6 g/dL) and decrease of ECV (mean of 3 fL);
normalization of Hb levels and ECV in 54% and 100% of the patients,
respectively– Dose
effect: effectiveness dose of cobalamin ≥500μg per day– No
adverse effectOpen
prospective study of low-cobalamin levels not related to pernicious anemia(n=30)Oral crystalline cyanocobalamin: between 1000 and
125μg per day during at least 1 week– Normalization
of serum cobalamin levels in all patients with at least a dose of vitamin ≥250μg per day[43]– Dose
effect: effectiveness dose of cobalamin ≥500μg per day– No
adverse effectOpen
prospective study of low cobalamin levels related to pernicious anemia(n=10)Oral crystalline cyanocobalamin: 1000μg per day
during at least 3 months– Significant
increase of serum cobalamin levels in 90% of the patients (mean of 117.4 pg/mL)[47]– Significant
increase of Hb levels (mean of 2.45 g/dL) and decrease of ECV (mean of 10.4 fL)– Improvement
of clinical abnormalities in 30% of the patients



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