Content uploaded by Bruno Annibale
Author content
All content in this area was uploaded by Bruno Annibale on Jan 21, 2014
Content may be subject to copyright.
Available via license: CC BY-NC 4.0
Content may be subject to copyright.
www.wjgnet.com
Online Submissions: wjg.wjgnet.com World J Gastroenterol 2009 November 7; 15(41): 5121-5128
wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.5121 © 2009 The WJG Press and Baishideng. All rights reserved.
ORIGINAL ARTICLES EDITORIAL
Pernicious anemia: New insights from a gastroenterological
point of view
Edith Lahner, Bruno Annibale
Edith Lahner, B runo Anni ba le , Department of Digestive
and Liver Disease, University Sapienza, 2nd Medical School,
Ospedale Sant’Andrea, Via di Grottarossa 1035, 00189 Roma,
Italy
Author contributions: Lahner E conceived and designed the
review, collected the data, performed the statistical analysis
and drafted the manuscript; Annibale B conceived the review,
revised it critically for important intellectual content and has
given nal approval of the version to be published.
Supported by Funds of the Italian Ministry for University
and Research (PRIN 2007) and by funds of the University “La
Sapienza”, Rome, Italy
Correspondence to: Bruno Annibale, Professor, Department of
Digestive and Liver Disease, University Sapienza, 2nd Medical
School, Ospedale Sant’Andrea, Via di Grottarossa 1035, 00189
Roma, Italy. bruno.annibale@uniroma1.it
Telephone: +39-6-49972369 Fax: +39-6-4455292
Received: April 27, 2009 Revised: September 22, 2009
Accepted: September 29, 2009
Published online: November 7, 2009
Abstract
Pernicious anemia (PA) is a macrocytic anemia that is
caused by vitamin B12 deciency, as a result of intrinsic
fa ctor def icie ncy. PA is a sso c iat ed wi th a tro p hic
body gastritis (ABG), whose diagnosis is based on
histological confirmation of gastric body atrophy.
Sero logical markers that sug gest oxy ntic m ucosa
damage are increased fasting gastrin and decreased
pepsinogen
Ⅰ. Without performing Schilling’s test,
intrinsic factor deficiency may not be proven, and
intrinsic factor and parietal cell antibodies are use-
ful surrogate markers of PA, with 73% sensitivity and
100% specificity. PA is mainly considered a disease
of the elderly, but younger patients represent about
15% of patients. PA patients may seek medical advice
due to symptoms related to anemia, such as weak-
ness and asthenia. Less commonly, the disease is
suspected to be caused by dyspepsia. PA is frequently
associated with autoimmune thyroid disease (40%)
and other autoimmune disorders, such as diabetes
mellitus (10%), as part of the autoimmune polyen-
docrine syndrome. PA is the end-stage of ABG. Long-
standing
Helicobacter pylori
infection probably plays
a role in many patients with PA, in whom the active
infectious process has been gradually replaced by an
autoimmune disease that terminates in a burned-out
infection and the irreversible destruction of the gastric
body mucosa. Human leucocyte antigen-DR genotypes
suggest a role for genetic susceptibility in PA. PA pa-
tients should be managed by cobalamin replacement
treatment and monitoring for onset of iron deciency.
Moreover, they should be advised about possible gas-
trointestinal long-term consequences, such as gastric
cancer and carcinoids.
© 2009 The WJG Press and Baishideng. All rights reserved.
Key words: Pernicious anemia; Autoimmune diseases;
Atrophic gastritis; Intrinsic factor; Autoantibodies; Parietal
cells; Vitamin B12 deciency;
Helicobacter pylori
Peer reviewer: Alberto Piperno, Professor, Department of
Clinical Medicine and Prevention, Clinical Medicine, San
Gerardo Hospital, Via Pergolesi 33, 20052, Monza, Italy
Lahner E, Annibale B. Pernicious anemia: New insights from a
gastroenterological point of view. World J Gastroenterol
2009;
15(41): 5121-5128 Available from: URL: http://www.wjgnet.
com/1007-9327/15/5121.asp DOI: http://dx.doi.org/10.3748/
wjg.15.5121
INTRODUCTION
Pernicious anemia (PA) (also known as Biermer’s disease[1]
and Addisonian anemia[2]) is a macrocytic anemia due to
vitamin B12 (cobalamin) deciency, which, in turn, is the
result of deciency of intrinsic factor, a protein that binds
avidly to dietary vitamin B12 and promotes its transport to
the terminal ileum for absorption[3]. The deciency of in-
trinsic factor is a consequence of the presence of atrophic
body gastritis (ABG), which results in the destruction of
the oxyntic mucosa, and thus, the loss of parietal cells,
which normally produce chlorhydric acid as well as intrin-
sic factor[4]. The term PA is sometimes used as synonym
for cobalamin deficiency or for macrocytic anemia, but
to avoid ambiguity, PA should be reserved for conditions
that result from impaired secretion of intrinsic factor
and atrophy of oxyntic mucosa[5]. However, differential
diagnosis may sometimes be challenging due to the limit
of available diagnostic tools.
PA is considered an autoimmune disorder due to
the frequent presence of gastric autoantibodies directed
against intrinsic factor, as well as against parietal cells.
PA is often considered a synonym o f au toimmune
www.wjgnet.com
gastritis, because PA is thought to be the end stage of
an autoimmune process that results in severe damage
of the oxyntic gastric mucosa[6]. Recent experimental
and clinical data strongly sug gest an involvement of
long-standing Helicobacter pylori (H pylori) infection in the
pathogenesis of ABG and PA, but it is still under debate
whether PA may be included among the long-term
consequences of H pylori gastritis[7].
The present review focuses on novel aspects regarding
the pathogenesis, clinical presentation, and diagnosis of
PA, as well as the management of PA patients from a
gastroenterological point of view.
PA: AN AUTOIMMUNE DISORDER OR AN
INFECTIOUS DISEASE?
PA is the end-stage of ABG and is generally considered
an autoimmune disease. The autoimmune origin of PA
is based on the presence of parietal cell and/or intrinsic
factor autoantibodies, and the frequent association
with other autoimmune disorders, such as autoimmune
thyroid disease (ATD), type 1 diabetes, and vitiligo[6,8].
ABG associated with PA is often called autoimmune
gastritis or type A gastritis, which is defined as a type
of chronic atrophic gastritis restricted to the body mu-
cosa, characterized by a severe, diffuse atrophy of the
oxyntic glands and hypochlorhydria, and a normal antral
mucosa[4]. Another classical histological feature of ABG
is the absence of H pylori on gastric mucosal biopsies[4].
It is now accepted that long-standing H pylori infection
is able to induce atrophy of the gastric mucosa, and
H pylori is considered the main causative agent of mul-
tifocal atrophic gastritis, in which the antrum is almost
invariably involved[9]. Thus, ABG is generally considered
a separate entity from H pylori-related atrophic gastritis,
mainly because the prevalence of H pylori infection in
patients with severe ABG and PA has been found to be
low[10,11]. However, in the past few years, the question
has been raised whether H pylori may be implicated in
the pathogenesis of ABG, and, as a basic mechanism
for the induction of gastric autoimmunity by H pylori
infection, molecular mimicry has been proposed[7,12,13].
Molecular mimicry is dened as the possibility that se-
quence similarities between foreign and self-peptides are
sufcient to result in the cross-activation of autoreactive
T or B cells by pathogen-derived peptides. It is a phe-
nomenon associated with some pathogens in which the
antigens that evoke an immune response have enough
similarity to the body’s own proteins to cause an autoim-
mune reaction, such as in rheumatoid arthritis, mediated
by cross-reactive T cells and/or circulating antibodies.
In fact, gastric H+/K+-ATPase has been recognized
as the major autoantigen in experimental and human
ABG[14-16], and autoreactive gastric CD4+ T cells that
recognize H+/K+-ATPase and H pylori antigens have
been recently described in ABG[17,18]. Thus, PA and ABG
seem to be an example of pathogen-induced, organ-
specific autoimmunity, in which genetic susceptibility
plays an important role in relation to the loss of immu-
nological tolerance[18]. In fact, the immunological basis
of molecular mimicry lies in the recognition by T-cell
antigen receptors of antigenic peptides bound to hu-
man leucocyte antigen (HLA) molecules on the surface
of antigen-presenting cells, and inappropriate activation
of T cells may occur as a result of the upregulation
of HLA molecules in genetically susceptible individu-
als[19]. A specic HLA-DR pattern was suggested in PA
patients several years ago[20], and more recently, block-
ing experiments with anti-DR and anti-DQ antibodies
have shown that DR antigen probably represents the
HLA restriction element in ABG[17]. By using a DNA-
based, sequence-specic oligonucleotide technology, we
observed in our series of PA patients that the genotypes
HLA-DRB1*03 and DRB1*04, which are known to be
associated with other autoimmune disease (such as type
1 diabetes and ATD)[21], were significantly associated
with PA, compared to a control group (unpublished
data), which supports the idea that genetic susceptibility
for autoimmunity may play a role in PA.
Tabl e 1 shows the lite ratu re r egard ing H pylori
infection and related gastric histological features in
some PA patients[10,22-24]. T he p rese nce of H p ylor i
infection was diagnosed by histology in up to 30%
(median 11%), but by serology (IgG) in up to 51%
(median 20.5%) of PA patients. It is well known that
the diagnosis of H pylori infection may be difficult in
patients with ABG. H pylori may disappear over time
due to the hostile gastric microenvironment, and past
infection may be demonstrated by serological positivity
to H pylori in a large majority of patients with ABG or
PA[10,25-27]. A recent study has reported that seropositivity
against H pylori antigens may be demonstrated in a
very high percentage of patients with ABG by using
ad hoc immunoblotting[28]: in this study 47.8% of ABG
patients had PA and all but two of them presented with
seropositivity against H pylori antigens, including CagA
and VacA. As far as regards histological features of the
gastric body, in the vast majority of PA patients (> 70%)
this disorder is associated with severe body atrophy and
the presence of intestinal metaplasia. From data reported
in Table 1, another interesting obser vation emerges:
irrespective of the presence of H pylori infection, in
about half of PA patients, the gastric antrum is involved,
and about one-third have antral atrophic gastritis, whose
presence is strongly related to H pylori infection[9]. This
observation challenges the widely accepted notion that
PA occurs exclusively in association with the classical
histological feature of corpus-restricted atrophic gastritis.
All these data taken together support the idea that long-
standing H pylori infection probably plays an important
role in many genetically susceptible PA patients. In
these patients, the active infectious process has been
gradually replaced by an autoimmune process directed
by autoreactive gastric CD4+ T cells that recognize
H+/K+-ATPase and H pylori antigens, which ends in a
burned-out infection and the irreversible destruction
of the gastric body mucosa. The failure to demonstrate
H pylori infection in some of these individuals does not
necessarily argue against the role of the bacterium in
5122 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
these patients, but more likely indicates that a point of
no return may be reached beyond which the autoimmune
process may no longer require the continued presence
of the inducing pathogen[29].
PA is frequently described as a disease of adults >
60 years of age[8,30,31]. Among our unpublished series of
177 PA patients, about one half were < 60 years of age;
in particular, 4% of patients were < 30 years and 10%
were 30-40 years of age (Figure 1). Table 1 shows that
the mean age of PA patients in published studies ranges
from 59 to 62 years. These data challenge the common
notion that PA is an exclusive disease of the elderly,
and suggest that, in clinical practice, PA is probably
under-diagnosed in elderly and younger patients[32].
Stratication by age cohorts (< 20 years to > 60 years)
of ABG patients identified by hypergastrinemia and
positive parietal cell antibodies has shown a regular and
progressive increase in mean corpuscular volume and
levels of ferritin and gastrin, and a decrease in vitamin
B12 levels. However, the prevalence of H pylori infection
has decreased from > 80% at age < 20 years to 12.5%
at > 60 years[32]. This reminds us that: (1) iron deciency
is a complication of achlorhydria and may precede the
development of PA[4]; (2) ABG patients frequently
present with iron deficiency anemia[33-35]; and (3) iron
deficiency may be present concomitantly with PA[36].
These ndings further support the idea that PA seems
to be a long-duration disease that is related to H pylori,
gastric achlorhydria and atrophy, which begins many
years before the establishment of clinical vitamin B12
deciency.
CLINICAL PRESENTATION OF PA
The clinical presentation of PA is often insidious for
various reasons. The onset and progression of PA are
very slow. As a consequence, patients often are not aware
of their symptoms related to anemia, because over time
they have become used to them. In many such cases, the
underlying disease may not be suspected until a complete
red blood count has been performed. However, patients
with PA may seek medical advice due to non-specific
symptoms related to the presence of anemia per se, such
as weakness, asthenia, decreased mental concentration,
headache, and especially, in elderly patients, cardiological
symptoms such as palpitations and chest pain[3,6]. Less
frequently, patients with PA may present only with
neurological symptoms, such as paresthesia, unsteady
gait, clumsiness, and in some cases, spasticity. Indeed,
vitamin B12 deciency may cause peripheral neuropathy
and lesions in the posterior and lateral columns of
the spinal cord (subacute combined degeneration)
and in the cerebrum, and these lesions progress from
demyelinization to axonal degeneration and eventual
neuronal death. It is particularly important to recognize
these symptoms early, because the neurological lesions
may not be reversed after replacement therapy with
vitamin B12[3,5]. Finally, the onset of PA may be observed
in patients undergoing medical treatment for other
autoimmune conditions frequently associated with PA,
such as ATD, type 1 diabetes, and vitiligo, as part of the
autoimmune polyendocrine syndromes[37].
Although the primary cause of PA is ABG, rarely the
disease may result from gastrointestinal tract symptoms.
The reason for the apparent paradox may lie in the
fact that ABG is associated with hypochlorhydria, and
symptoms of the upper gastrointestinal tract are often
related to the presence of chlorhydric acid. However,
hypochlorhydria itself may cause impaired gastric
emptying, which eventually leads to dyspeptic symptoms
such as epigastric discomfort, postprandial bloating and
fullness, and early satiety[38]. In our experience, awareness
and concern about upper gastrointestinal or neurological
symptoms often are not sufficient to s eek medi cal
advice, since patients over time become used to these
slowly and insidiously presenting complaints. Only 3%
of PA patients presented directly to our gastroenterology
unit for long-standing dyspepsia, and only 3% were
referred from a neurologist. At the time of diagnosis of
Table 1
H pylori
infection and related gastric histological features in a series of PA patients
n
(%)
First author/
publication
year[Ref.]
No. of
patients
Mean
age (yr)
F:M
ratio
Geographical
origin
Severe
body
atrophy
Body
intestinal
metaplasia
Antral
inammation
Antral
atrophic
gastritis
Positive
H pylori
histology
Positive
H pylori
serology
Fong TL/1991[22] 28 59 1.2:0.8 USA1ND 18 (64) 14 (50) 2 (7) 3 (11) 2 (7)
Haruma K/1995[23] 24 65 0.9:1.1 Japan 24 (100) 18 (75) 22 (92) 17 (71) 0 (0) 0 (0)
Sari R/2000[24] 30 60 0.9:1.1 Turkey 15 (50) 13 (43) 14 (47) 8 (27) 12 (30) ND
Annibale B/2000[10] 81 62 0.9:1.1 Italy 56 (69) 70 (86) 43 (53) 27 (30) 8 (10) 41 (51)
Annibale B/
2009[unpublished data]
177 60 1:1 Italy 124 (70) 161 (91) 81 (46) 40 (23) 19 (11) 61 (34)
1Hispanic, n = 20; white, n = 3; black, n = 5. ND: Not done.
50
40
30
20
10
0
% of patients with pernicious
anemia
< 30 30-40 40-50 50-60 60-70 70-80 > 80
t
/yr
Figure 1 Age cohorts of a series of patients with PA (n = 177) consecutively
diagnosed between 1992 and 2005 at an academic gastroenterology unit.
Lahner E
et al
. Pernicious anemia 5123
www.wjgnet.com
PA, dyspeptic symptoms were complained of by 28%
of patients, and neurological symptoms were present in
19% (unpublished data).
An increased association of PA with other autoim-
mune diseases, such as type 1 diabetes (3%-4%)[39], vi-
tiligo (2%-8%)[3], and in particular, ATD (3%-32%)[40]
has been reported. Among our unpublished series of
177 PA patients, 41% had associated ATD and 10%
presented with vitiligo or alopecia, which indicates that
a subgroup of PA patients can be considered as having
a type Ⅱ autoimmune polyendocrine syndrome. In a
recent study, we have observed that ABG and ATD oc-
cur in a closely linked fashion, with ATD being present
in about 40% of ABG patients[41]. These data suggest
that, in patients with autoimmune disorders, in particular
ATD, a possible association with PA should be suspect-
ed and excluded. The diagnosis of concomitant autoim-
mune thyroiditis and PA may have an important clinical
implication, in particular, in those patients who require
replacement therapy with thyroxine. Recently, it has been
reported that patients with impaired acid secretion may
present with thyroxine malabsorption that requires an
increased dose of the drug[42], and in patients with PA,
associated hypochlorhydria is always present, due to the
loss of oxyntic mucosa[4].
Useful information about which patients may have PA
can be derived also from epidemiological data. According
to the older literature, PA is thought to be particularly
common among individuals of Scandinavian, English or
Irish ancestry, whereas it appears to be much less common
in Caucasians of Italian or Greek origin[43]. However,
more recently, the disease have been reported in black and
Latin American subjects[30,44], and as shown in Table 1,
series of PA patients have been diagnosed in the United
States, Turkey and Italy, and even in Japan. The reason
for the different distribution of PA among different
ethnical groups is not known yet, but probably lies in their
different genetic background, and in different awareness
and diagnostic accuracy for this often overseen disorder.
In the so-called high-risk groups, about nine new cases are
detected per 100 000 population per year, and about 0.13%
of the population is affected[31]. A more recent population
survey has reported that 1.9% of persons aged > 60 years
have undiagnosed PA[30].
A female preponderance ranging from 1.7 to 2.0:1 has
been reported in white subjects[3]. This sex distribution
has been confir med in the more recent population
survey of persons > 60 years old that was conducted
in California, in which the prevalence of PA was 2.7%
in women and 1.4% in men[30]. However, data reported
in Table 1 concerning United States, Japanese, Turkish
and Italian PA patients seem not to conrm the female
preponderance described in older studies.
DIAGNOSIS OF PA
PA is dened as the presence of a hemoglobin concentra-
tion < 13 g/dL for men and < 12 g/dL for women[45],
mean corpuscular volume ≥ 100 fL[5], low levels of co-
balamin (vitamin B12)[5], together with the concomitant
presence of ABG and intrinsic factor deciency (Figure 2).
By definition, PA is associated with ABG, and strict
diagnostic criteria for ABG are based on the histologi-
cal confirmation of gastric body mucosal atrophy and
enterochromafn-like (ECL) cell hyperplasia, associated
with hypochlorhydria to pentagastrin stimulation[4]. In-
creased levels of fasting gastrin and decreased levels of
pepsinogen
Ⅰ are well accepted serological markers[46,47],
which suggest the presence of oxyntic mucosa damage,
which should be confir med, however, by appropriate
histological sampling of gastric body mucosa to diag-
nose ABG denitively.
As far as regards gastric mucosa histology, classical
ndings associated with PA are the presence of corpus-
restricted atrophy with a spared antrum, as well as the
presence of hyperplasia of ECL cells[4,6]. As shown in
Table 1, in about 50% of PA patients, antral mucosa is not
spared, and in about 27% of PA patients, a concomitant
antral atrophic gastritis may be obser ved. These data
strongly suggest that an extension of gastritis to the
gastric antrum does not necessarily exclude the diagnosis
of PA and the presence of gastric autoimmunity. The
determination of ECL cell hyperplasia is helpful in the
histological diagnosis of ABG, because the presence of
this histological change may be considered an indirect
confirmation of the presence of hypochlorhydria. This
leads to hypergastrinemia, which in turn, is a trophic
factor for ECL cells that leads to their hyperplasia, and
eventually, to the development of gastric carcinoids[48].
Intrinsic factor deciency can be proven by the now
obsolete Schilling test. To confirm that the cobalamin
deficiency is the result of intestinal malabsorption due
to intrinsic factor deciency, urinary excretion of orally
administered vitamin B12 is low, and is increased by ad-
ministration of vitamin B12 and intrinsic factor. Unfor-
tunately, the availability of this test is vanishing due to
problems related to its radioactive reagents. Therefore,
in clinical practice, the presence of intrinsic factor de-
ficiency may not be proven, and increasing reliance is
placed on the detection of intrinsic factor antibodies for
the diagnosis of PA, which are viewed as useful markers
of this disease[49]. Earlier studies have reported positivity
for intrinsic factor antibodies in 40%-60% of patients
with PA[50,51], which rises to 60%-80% with increasing
duration of disease[52].
Diagnosis of pernicious anemia
Blood tests:
Complete blood count
Serum cobalamin levels
Cobalamin deciency +
macrocytic anemia
Intrinsic factor
deciency
Atrophic body
gastritis
Serological markers:
Increased fasting gastrin
Reduced levels of pepsinogen
Ⅰ
Histological conrmation
by bioptic sampling of
gastric body mucosa
Schilling test (obsolete) or serological
markers for pernicious anemia:
Intrinsic factor antibodies
Parietal cell antibodies
Figure 2 Diagnostic ow-chart for PA.
5124 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
Recently, we reassessed the diagnostic performance
of intrinsic factor and parietal cell antibodies in PA
patients by using a novel ELISA[48], which yielded for
intrinsic factor antibodies, a sensitivity and specific-
ity of 37% and 100%, respectively, and for parietal cell
antibodies, a sensitivity and specificity of 81.5% and
90.3%, respectively. The combined assessment of both
autoantibodies significantly increased their diagnostic
performance, which yielded 73% sensitivity for PA,
while maintaining 100% specicity. Thus, our data show
that, by combining the assessment of intrinsic factor and
parietal cell autoantibodies, the diagnostic performance
of these surrogate markers for PA may be notably im-
proved. Beyond being a specific hallmark of PA, the
positivity for intrinsic factor and parietal cell antibodies
may be interpreted as an expression of oxyntic mucosal
damage, because a positive correlation between the in-
creasing histological score of body mucosa atrophy and
the titer of both antibodies can be observed[27,35].
Accurate differential diagnosis of other causes of
cobalamin deciency is mandatory. As shown in Table 2,
cobalamin deficiency may result from other causes of
impaired absorption in the stomach or intestine, or by
decreased intake due to vegetarianism. Among cases of
mal-digestion, there are very rare cases related to severe
pancreatic insufficiency, but more interesting is the
recent evidence of mal-digestion of dietary cobalamin
in patients with corpus-predominant H pylori gastritis,
which leads to impaired acid secretion and consequent
increased intragastric pH[53,54]. In fact, dietary cobalamin is
bound to salivary proteins, which needs to be cleaved in
the presence of chlorhydric acid before it can be bound
to intrinsic factor and be absorbed in the terminal ileum[4].
In these cases of mal-digestion of dietary cobalamin,
the Schilling test would be normal, which indicates
that cobalamin deficiency is not due to intrinsic factor
deciency. Without performing a Schilling test, it may be
challenging to discriminate between the presence of PA
and mal-digestion of dietary cobalamin. However, from a
practical point of view, the clinical management of these
two groups of patients is similar. As observed[54,55], when
atrophy of the gastric body mucosa is mild and active
H pylori infection is present, in patients with mal-digestion
of dietary cobalamin, a reversal of body mucosal atrophy,
anemia and cobalamin deficiency following eradication
treatment may be achieved. An accurate differential
diagnosis should be carried out also for macrocytic anemia,
which may underlie other causes such as folate deciency
and myelodysplastic syndrome (Table 2).
In this context, it should be kept in mind that, in or-
der to diagnose vitamin B12 deciency, total vitamin B12
measurement is used cost-effectively as the parameter
of choice, but it has limited sensitivity and specificity,
especially in persons with vitamin B12 concentrations in
the lower reference range (< 400 pmol/L). As an alter-
native, modern biomarkers for early diagnosis of vitamin
B12 deciency, such as holotranscobalamin, also known
as active B12 , and methyl malonic acid as a functional
B12 marker, have been proposed[56]. Figure 2 shows a
proposed diagnostic work-up when the presence of PA
is suspected.
CLINICAL MANAGEMENT OF PATIENTS
WITH PA
The clinical management of patients with PA has two
different aspects: firstly, the treatment of cobalamin
deciency and the monitoring of onset of iron deciency;
and secondly, the surveillance of these patients, to detect
early the long-term consequences of PA, such as gastric
cancer and carcinoids.
Treatment of cobalamin deciency and monitoring of
iron deciency
Cobalamin replacement treatment is able to correct the
anemia, whereas the neurological complications may
be corrected only if the replacement treatment is given
soon after their onset. The therapeutic recommendations
for PA with regard to dosage and administration of
vitamin B12 substitution treatment are divergent[57]. In the
United States, patients usually receive vitamin B12 injections
of 1 mg/d in their rst week of treatment; in the following
month, they receive weekly injections and then monthly
injections[58]. In Denmark, patients receive injections of
1 mg/wk cyanocobalamin during the first month and
every 3 mo subsequently, or 1 mg hydroxycobalamin
every other month[59]. According to our protocol, a higher
dosage of cobalamin is used to prevent early relapse of
cobalamin deciency: rstly patients receive intramuscular
injection of 5 mg/d cyanocobalamin for 5 d, which
replenishes the cobalamin body stores; then, vitamin B12
stores are maintained by intramuscular injection of 5 mg
cyanocobalamin every 3 mo.
Table 2 Differential diagnosis of PA: other causes of macrocytic anemia and cobalamin deciency
Other causes of macrocytic anemia Other causes of cobalamin deciency
Folate deciency due to decreased intake, impaired absorption or increased requirements Gastric causes of impaired absorption/mal-digestion:
Drugs (e.g. methotrexate, azathioprine, 6-mercaptopurine, acyclovir, 5-uorouracil, phenobarbital) Gastrectomy
Accelerated erythropoiesis: hemolytic anemia, response to hemorrhage Corpus-predominant H pylori gastritis
Liver disease (alcoholic, advance cirrhosis, poor dietary intake) Long-term proton pump inhibitor therapy
Hypoplastic anemia, myelodysplastic syndrome Intestinal causes of impaired absorption:
Chronic obstructive pulmonary disease Ileal disease or resection
Blind loop syndrome
Fish tapeworm
Severe pancreatic insufciency
Decreased intake due to vegetarianism
Lahner E
et al
. Pernicious anemia 5125
www.wjgnet.com
Furthermore, according to our protocol, PA patients
are monitored at least yearly by complete blood count,
and serum cobalamin and ferritin levels, to monitor the
replacement treatment and to detect early the eventual
onset of iron deciency. Also patients with ABG with iron
deciency anemia or without hematological alterations are
monitored in the same way, to detect early the eventual
onset of cobalamin deficiency. Finally, PA patients are
monitored by at least a yearly clinical interview, to verify
the onset of new symptoms that are suspicious of long-
term consequences of PA, such as dysphagia, epigastric
pain, dyspeptic symptoms, loss of body weight, and/or
iron-deficiency, which require immediate gastroscopic
investigation.
Long-term consequences of PA
Although PA is substantially a benign disorder for a large
number of patients, it is epidemiologically and biologi-
cally linked to the development of intestinal-type gas-
tric adenocarcinoma and gastric carcinoid type
Ⅰ[60,61].
Hypergastrinemia, secondary to hypochlorhydria in PA
patients, is a well-known risk factor for ECL cell hyper-
plasia and gastric carcinoids[62,63], and it has been reported
that one in 25 patients with PA develops gastric carci-
noids[64]. Moreover, the crucial role of hypochlorhydria, as
a consequence of atrophy of the oxyntic mucosa, in the
development of gastric cancer, has been highlighted[65].
Hypochlorhydria leads to overgrowth of nitrosamine-
producing bacteria with potential carcinogen activity[66].
Also ascorbic acid, the main redox agent in the gastric
juice with protective action against reactive oxygen spe-
cies, is reduced in the presence of atrophy of the oxyntic
mucosa. It has been described previously that the level
of ascorbic acid in the gastric juice is reduced in patients
with ABG, with an indirect correlation between ascorbic
acid level and intragastric pH[67].
In the literature, the annual incidence of gastric cancer
in PA patients ranges from 0.1% to 0.5%[62,64,68]. A recent
follow-up study of patients with ABG has reported an
annual incidence risk of 0.14% for developing gastric
cancer, during an observation period of 6.7 years[69]. To
date, the need and cost-effectiveness of endoscopic/
histological surveillance in patients with PA have not
been established denitively[4]. One previous study[64] that
has considered the relatively benign nature of gastric
carcinoids in patients with PA has concluded that follow-
up is indicated at 5-year intervals only in patients with
ECL hyperplasia. As for gastric cancer, the same authors
have concluded that the rst gastroscopic follow-up after
diagnosis of PA should be performed relatively soon,
and that only PA patients with preneoplastic lesions and
those with gastrointestinal symptoms should undergo
endoscopic surveillance[64]. Another study has concluded
that follow-up should be performed at 3-year intervals
only in PA patients aged < 60 years[70]. A more recent
study has compared the usefulness of 2- and 4-year
follow-up in patients with ABG, and has shown that
the rst follow-up performed 4 years after the diagnosis
seems to be safe and convenient for early detection of
potentially neoplastic lesions[71]. As a result of the lack
of other prospective data, and considering the risk for
developing neoplastic lesions over time in some PA
patients, in our unit, PA patients are monitored regularly
by gastroscopy with antral and corporal biopsies at 4-year
intervals.
CONCLUSION
PA is an often silent and under-diagnosed autoimmune
disease, because its onset and progression are very slow
and patients may become used to their complaints.
Nevertheless, the clinical consequences of undiagnosed
PA may be serious, including gastric neoplastic lesions.
Thus, gastroenterologists should increase their awareness
of this disorder, whose definite histological diagnosis
may be preceded by reliable noninvasive serological
screening.
REFERENCES
1 Zittoun J. [Biermer's disease] Rev Prat 2001; 51: 1542-1546
2 Meecham J, Jones EW. Addison's disease and Addisonian
anaemia. Lancet 1967; 1: 535-538
3 Wintrobe MM, Lee GR, Boggs DR, Bithell TC, Foerster J,
Athens JW, Lukens JN. Megaloblastic and nonmegaloblastic
macrocy ti c an emias. In: Wi nt robe MM, Lee GR , Bo gg s
DR, Bithell TC, Foerster J, Athens JW, Lukens JN, editors.
Clinical hematology. 8th ed. Philadelphia: Lea & Febiger,
1981: 559-604
4 Lee EL, Feldman M. Gastritis and other gastropathies.
In: Fe ld man M, Friedman LS, Sleis en ge r MH, editors.
Sleisenger & Fordtran's gastrointestinal and liver disease:
pathophysiology, diagnosis, management. 7th ed.
Philadelphia: Saunders, 2002: 810-827
5 Babior BM. Erythrocyte disorders: Anemias related to
disturbance of DNA synthesis (megaloblastic anemias). In:
Williams JW, Beutler E, Erslev AJ, Lichtman MA, editors.
Hematology. 4th ed. New York: McGraw-Hill, 1998: 453-481
6 To h B H, Glee son PA, Whi tti ngha m S, va n Drie l I R.
Autoimmune gastritis and pernicious anemia. In: Rose NR,
Mackay IR, editors. The autoimmune diseases. 3rd ed. St.
Louis, MO: Academic Press, 1998: 459-476
7 D'Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del
Prete G. Gastric autoimmunity: the role of Helicobacter
pylori and molecular mimicry. Trends Mol Med 2004; 10:
316-323
8 Toh BH, van Driel IR, Gleeson PA. Pernicious anemia. N
Engl J Med 1997; 337: 1441-1448
9 Peterson WL, Graham DY. Helicobacter pylori. In: Feldman
M, Friedman LS, Sleisenger MH, editors. Sleisenger &
Fordtran’s gastrointestinal and liver disease: pathophysiology,
diagnosis, management. 7th ed. Philadelphia: Saunders, 2002:
732-746
10 Annibale B, Lahner E, Bordi C, Martino G, Caruana P,
Grossi C, Negrini R, Delle Fave G. Role of Helicobacter
pylori infection in pernicious anaemia. Dig Liver Dis 2000;
32: 756-762
11 Varis O, Valle J, Siurala M. Is Helicobacter pylori involved in
the pathogenesis of the gastritis characteristic of pernicious
anaemia? Comparison between pernicious anaemia relatives
and duodenal ulcer relatives. Scand J Gastroenterol 1993; 28:
705-708
12 Appelmelk BJ, Faller G, Claeys D, Kirchner T, Vandenbroucke-
Grauls CM. Bugs on trial: the case of Helicobacter pylori
and autoimmunity. Immunol Today 1998; 19: 296-299
13 Field J, Biondo MA, Murphy K, Alderuccio F, Toh BH.
Experimental autoimmune gastritis: mouse models of
human organ-specic autoimmune disease. Int Rev Immunol
5126 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
www.wjgnet.com
2005; 24: 93-110
14 Toh BH, van Driel IR, Gleeson PA. Autoimmune gastritis:
tolerance and autoimmunity to the gastric H+/K+ ATPase
(proton pump). Autoimmunity 1992; 13: 165-172
15 Ma JY, Borch K, Mårdh S. Human gastric H,K-adenosine
triphosphatase beta-subunit is a major autoantigen in
atrophic corpus gastritis. Expression of the recombinant
human glycoprotein in insect cells. Scand J Gastroenterol
1994; 29: 790-794
16 Claeys D, Faller G, Appelmelk BJ, Negrini R, Kirchner T.
The gastric H+,K+-ATPase is a major autoantigen in chronic
Helicobacter pylori gastritis with body mucosa atrophy.
Gastroenterology 1998; 115: 340-347
17 Amedei A, Bergman MP, Appelmelk BJ, Azzurri A,
Benag iano M, Tamburin i C, van der Ze e R, Telfor d JL ,
Vandenbroucke-Grauls CM, D'Elios MM, Del Prete G.
Molecular mimicry between Helicobacter pylori antigens
and H+, K+ --adenosine triphosphatase in human gastric
autoimmunity. J Exp Med 2003; 198: 1147-1156
18 D'Elios MM, Amedei A, Azzurri A, Benagiano M, Del Prete
G, Bergman MP, Vandenbroucke-Grauls CM, Appelmelk
BJ. Molecular specificity and functional properties of
autoreactive T-cell response in human gastric autoimmunity.
Int Rev Immunol 2005; 24: 111-122
19 Albert LJ, Inman RD. Molecular mimicry and autoimmunity.
N Engl J Med 1999; 341: 2068-2074
20 Ungar B, Mathews JD, Tait BD, Cowling DC. HLA-DR
patterns in pernicious anaemia. Br Med J (Clin Res Ed) 1981;
282: 768-770
21 Fernando MM, Stevens CR, Walsh EC, De Jager PL, Goyette
P, Plenge RM, Vyse TJ, Rioux JD. Dening the role of the
MHC in autoimmunity: a review and pooled analysis. PLoS
Genet 2008; 4: e1000024
22 Fong TL, Dool ey CP, De hes a M, Co hen H, Car me l R,
Fitzgibbons PL, Perez-Perez GI, Blaser MJ. Helicobacter
pylori infection in pernicious anemia: a prospective controlled
study. Gastroenterology 1991; 100: 328-332
23 Haruma K, Komoto K, Kawaguchi H, Okamoto S, Yoshihara
M, Sumii K, Kajiyama G. Pernicious anemia and Helicobacter
pylori infection in Japan: evaluation in a country with a high
prevalence of infection. Am J Gastroenterol 1995; 90: 1107-1110
24 Sar i R, Ozen S, Aydogdu I, Yildirim B, Sevinc A. The
pathological examinations of gastric mucosa in patients
with Helicobacter pylori-positive and -negative pernicious
anemia. Helicobacter 2000; 5: 215-221
25 Valle J, Kekki M, Sipponen P, Ihamäki T, Siurala M. Long-
te rm cou rse and con se quenc es of Helic ob acter pyl ori
gastritis. Results of a 32-year follow-up study. Scan d J
Gastroenterol 1996; 31: 546-550
26 Karnes WE Jr, Samloff IM, Siurala M, Kekki M, Sipponen P,
Kim SW, Walsh JH. Positive serum antibody and negative
tissue staining for Helicobacter pylori in subjects with
atrophic body gastritis. Gastroenterology 1991; 101: 167-174
27 Annibale B, Negrini R, Caruana P, Lahner E, Grossi C,
Bordi C, Delle Fave G. Two-thirds of atrophic body gastritis
patients have evidence of Helicobacter pylori infection.
Helicobacter 2001; 6: 225-233
28 Annibale B, Lahner E, Santucci A, Vaira D, Pasquali A,
Severi C, Mini R, Figura N, Delle Fave G. CagA and VacA are
immunoblot markers of past Helicobacter pylori infection in
atrophic body gastritis. Helicobacter 2007; 12: 23-30
29 Rose NR , Bon a C. Def ini ng cri ter ia for auto imm une
diseases (Witebsky's postulates revisited). Immunol Today
1993; 14: 426-430
30 Carmel R. Prevalence of undiagnosed pernicious anemia in
the elderly. Arch Intern Med 1996; 156: 1097-1100
31 Pedersen AB, Mosbech J. Morbidity of pernicious anaemia.
Incidence, prevalence, and treatment in a Danish county.
Acta Med Scand 1969; 185: 449-452
32 Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J,
Patz J. Variable hematologic presentation of autoimmune
gastritis: age-related progression from iron deficiency to
cobalamin depletion. Blood 2006; 107: 1673-1679
33 Annibale B, Capurso G, Chistolini A, D'Ambra G, DiGiulio E,
Monarca B, DelleFave G. Gastrointestinal causes of refractory
iron deficiency anemia in patients without gastrointestinal
symptoms. Am J Med 2001; 111: 439-445
34 Marignani M, Delle Fave G, Mecarocci S, Bordi C, Angeletti
S, D'Ambra G, Aprile MR, Corleto VD, Monarca B, Annibale
B. High prevalence of atrophic body gastritis in patients
with unexplained microcytic and macrocytic anemia: a
prospective screening study. Am J Gastroenterol 1999; 94:
766-772
35 Anniba le B, Lah ne r E, Ne grini R, Bacci ni F, Bor di C,
Monarca B, Delle Fave G. Lack of specic association between
gastric autoimmunity hallmarks and clinical presentations
of atrophic body gastritis. World J Gastroenterol 2005; 11:
5351-5357
36 Carmel R, Weiner JM, Johnson CS. Iron deciency occurs
frequently in patients with pernicious anemia. JAMA 1987;
257: 1081-1083
37 Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine
syndromes. N Engl J Med 2004; 350: 2068-2079
38 Tosetti C, Stanghellini V, Tucci A, Poli L, Salvioli B, Biasco
G, Paparo GF, Levorato M, Corinaldesi R. Gastric emptying
and dyspeptic symptoms in patients with nonautoimmune
fundic atrophic gastritis. Dig Dis Sci 2000; 45: 252-257
39 De Block CE, De Leeuw IH, Van Gaal LF. Autoimmune
gastritis in type 1 diabetes: a clinically oriented review. J
Clin Endocrinol Metab 2008; 93: 363-371
40 Feldt-Rasmussen U, Bech K, Bliddal H, Høier-Madsen M,
Jørgensen F, Kappelgaard E, Nielsen H, Lanng Nielsen J,
Ryder LP, Thomsen M. Autoantibodies, immune complexes
and HLA-D in thyrogastric autoimmunity. Tissue Antigens
1983; 22: 342-347
41 Lahner E, Centanni M, Agnello G, Gargano L, Vannella L,
Iannoni C, Delle Fave G, Annibale B. Occurrence and risk
factors for autoimmune thyroid disease in patients with
atrophic body gastritis. Am J Med 2008; 121: 136-141
42 Centanni M, Gargano L, Canettieri G, Viceconti N, Franchi A,
Delle Fave G, Annibale B. Thyroxine in goiter, Helicobacter
pylori infection, and chronic gastritis. N Engl J Med 2006; 354:
1787-1795
43 Friedlander RD. Racial factor in pernicious anaemia. Am J
Med Sci 1934; 187: 634
44 Carmel R, Johnson CS. Racial patterns in pernicious anemia.
Early age at onset and increased frequency of intrinsic-
factor antibody in black women. N Engl J Med 1978; 298:
647-650
45 WHO/UNICEF/UNU. Iron deficiency anaemia: assesment,
prevention, and control. Geneva: World Health Organization,
2001 (WHO/NHD/01.3)
46 Kekki M, Samloff IM, Varis K, Ihamäki T. Serum
pepsinogen I and serum gastrin in the screening of severe
atrophic corpus gastritis. Scand J Gastroenterol Suppl 1991;
186: 109-116
47 Väänänen H, Vauhkonen M, Helske T, Kääriäinen I,
Rasmussen M, Tunturi-Hihnala H, Koskenpato J, Sotka
M, Turunen M, Sandström R, Ristikankare M, Jussila A,
Sipponen P. Non-endoscopic diagnosis of atrophic gastritis
with a blood test. Correlation between gastric histology and
serum levels of gastrin-17 and pepsinogen I: a multicentre
study. Eur J Gastroenterol Hepatol 2003; 15: 885-891
48 Lahner E, Norma n GL, Sev eri C, Encab o S, Sh ums Z,
Vannella L, Fave GD, Annibale B. Reassessment of intrinsic
factor and parietal cell autoantibodies in atrophic gastritis
with respect to cobalamin deficiency. Am J Gastroenterol
2009; 104: 2071-2079
49 Toh BH, Alderuccio F. Parietal cell and intrinsic factor
autoantibodies. In: Shoenfeld Y, Gershwin ME, Meroni PL,
editors. Autoantibodies. 2nd ed. Amsterdam: Elsevier, 2007:
479-486
50 Ungar B, Whittingham S, Francis CM. Pernicious anaemia:
incidence and significance of circulating antibodies to
Lahner E
et al
. Pernicious anemia 5127
www.wjgnet.com
intrinsic factor and to parietal cells. Australas Ann Med 1967;
16: 226-229
51 Davidson RJ, Atrah HI, Sewell HF. Longitudinal study of
circulating gastric antibodies in pernicious anaemia. J Clin
Pathol 1989; 42: 1092-1095
52 Carmel R. Reassessment of the relative prevalences of
antibodies to gastric parietal cell and to intrinsic factor in
patients with pernicious anaemia: inuence of patient age
and race. Clin Exp Immunol 1992; 89: 74-77
53 Carmel R, Perez-Perez GI, Blaser MJ. Helicobacter pylori
infection and food-cobalamin malabsorption. Dig Dis Sci
1994; 39: 309-314
54 Cohen H, Weinstein WM, Carmel R. Heterogeneity of gastric
histology and function in food cobalamin malabsorption:
absence of atrophic gastritis and achlorhydria in some
patients with severe malabsorption. Gut 2000; 47: 638-645
55 Annibale B, Capurso G, Delle Fave G. Consequences
of Helicobacter pylori infection on the absorption of
micronutrients. Dig Liver Dis 2002; 34 Suppl 2: S72-S77
56 Her rm an n W, Obeid R. Causes and early diagnosis of
vitamin B12 deciency. Dtsch Arztebl Int 2008; 105: 680-685
57 Hvas AM, Nexo E. Diagnosis and treatment of vitamin B12
deciency--an update. Haematologica 2006; 91: 1506-1512
58 Pruthi RK, Tefferi A. Pernicious anemia revisited. Mayo Clin
Proc 1994; 69: 144-150
59 Bastrup-Madsen P, Helleberg-Rasmussen I, Nørregaard
S, Halver B, Hansen T. Long term therapy of pernicious
anaemia with the depot cobalamin preparation betolvex.
Scand J Haematol 1983; 31: 57-62
60 Correa P. Human gastric carcinogenesis: a multistep and
multifactorial process--First American Cancer Society
Award Lecture on Cancer Epidemiology and Prevention.
Cancer Res 1992; 52: 6735-6740
61 Wu MS, Chen CJ, Lin JT. Host-environment interactions:
their impact on progression from gastric inflammation to
carcinogenesis and on development of new approaches to
prevent and treat gastric cancer. Cancer Epidemiol Biomarkers
Prev 2005; 14: 1878-1882
62 Sjöblom SM, Sipponen P, Miettinen M, Karonen SL, Jrvinen
HJ. Gastroscopic screening for gastric carcinoids and
carcinoma in pernicious anemia. Endoscopy 1988; 20: 52-56
63 Annibale B, Azzoni C, Corleto VD, di Giulio E, Caruana
P, D'Ambra G, Bordi C, Delle Fave G. Atrophic body
gastritis patients with enterochromafn-like cell dysplasia
are at increased risk for the development of type I gastric
carcinoid. Eur J Gastroenterol Hepatol 2001; 13: 1449-1456
64 Kokkola A, Sjöblom SM, Haapiainen R, Sipponen P,
Puolakkainen P, Järvinen H. The risk of gastric carcinoma
and carcinoid tumours in patients with pernicious anaemia.
A prospective follow-up study. Scand J Gastroenterol 1998;
33: 88-92
65 Uemu ra N, Oka mot o S, Yam amo to S, Mat su mur a N,
Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper
RJ. Helicobacter pylori infection and the development of
gastric cancer. N Engl J Med 2001; 345: 784-789
66 Eisenbrand G, Adam B, Peter M, Malfertheiner P, Schlag P.
Formation of nitrite in gastric juice of patients with various
gastric disorders after ingestion of a standard dose of
nitrate--a possible risk factor in gastric carcinogenesis. IARC
Sci Publ 1984; 963-968
67 Annibale B, Capurso G, Lahner E, Passi S, Ricci R, Maggio
F, Delle Fave G. Concomitant alterations in intragastric pH
and ascorbic acid concentration in patients with Helicobacter
pylori gastritis and associated iron deciency anaemia. Gut
2003; 52: 496-501
68 Scha fer LW , L ars on DE, Me lto n L J 3rd, Hi ggi ns JA,
Zinsmeister AR. Risk of development of gastric carcinoma
in patients with pernicious anemia: a population-based
study in Rochester, Minnesota. Mayo Clin Proc 1985; 60:
444-448
69 Lahner E, Bordi C, Cattaruzza MS, Iannoni C, Milione M,
Delle Fave G, Annibale B. Long-term follow-up in atrophic
body gastritis patients: atrophy and intestinal metaplasia
are persistent lesions irrespective of Helicobacter pylori
infection. Aliment Pharmacol Ther 2005; 22: 471-481
70 Sjöblom SM, Sipponen P, Järvinen H. Gastroscopic follow
up of pernicious anaemia patients. Gut 1993; 34: 28-32
71 Lahner E, Caruana P, D'Ambra G, Ferraro G, Di Giulio E,
Delle Fave G, Bordi C, Annibale B. First endoscopic-histologic
follow-up in patients with body-predominant atrophic
gastritis: when should it be done? Gastrointest Endosc 2001; 53:
443-448
S- Editor Li LF L- Editor Kerr C E- Editor Zheng XM
5128 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol November 7, 2009 Volume 15 Number 41
