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Creative Commons Attribution-Non Commercial 4.0 January 2020 • HEMATOLOGY
71
Pernicious Anaemia: Mechanisms,
Diagnosis, and Management
Abstract
Pernicious anaemia (PA) is an autoimmune disease of multifactorial aetiology involving environmental
and immunological factors. It is the most common cause of cobalamin deficiency anaemia
worldwide. The disease is a macrocytic anaemia caused by a vitamin B12 deficiency, which, in turn,
is the result of intrinsic factor deficiency, a protein that binds avidly to dietary vitamin B12 and
promotes its transport to the terminal ileum for absorption. Despite the advances in understanding
the pathogenesis and molecular biology, diagnosis of PA is still challenging for clinicians because
of its complexity, diverse clinical presentations, and the limitations of the available diagnostic tools
for the evaluation of cobalamin status and the presence of chronic autoimmune atrophic gastritis.
Asymptomatic autoimmune gastritis, a chronic inflammatory disease of the gastric mucosa, precedes
the onset of corpus atrophy by 10–20 years. Diagnostic dilemmas could occur when patients with
PA present with spuriously normal or high cobalamin levels, normocytic or microcytic anaemia,
nonanaemic macrocytosis, autoimmune haemolytic anaemia, pseudo-thrombotic microangiopathy,
hyperhomocysteinemia-associated thromboembolism, pseudoleukemia, bone marrow failure, and
neurologic manifestations without anaemia or macrocytosis. Other autoimmune disorders, especially
thyroid disease, Type 1 diabetes mellitus, and vitiligo, are also commonly associated with PA. The
present review focusses on novel aspects regarding the pathogenesis, clinical presentation, and
the diagnostic approach of PA; the true usefulness of serum vitamin B12 levels; and the risk of
adenocarcinoma and gastric carcinoids as well as their treatment and monitoring strategies.
INTRODUCTION
Pernicious anaemia (PA) (also known as
Biermer’s disease1 and Addisonian anaemia2) is a
macrocytic anaemia caused by a vitamin B12
(cobalamin) deficiency, which, in turn, is the
result of intrinsic factor (IF) deficiency. IF is a
glycoprotein that binds cobalamin and thereby
enables its absorption at the terminal ileum.3
Authors: *Wafa Ammouri,¹ Hicham Harmouche,¹ Hajar Khibri,¹ Souad
Benkirane,² Masrar Azlarab,² Zoubida Mezalek Tazi,¹ Mouna Maamar,¹
Mohamed Adnaoui¹
1. Internal medicine department, Unité d’hématologie clinique, Ibn Sina Hospital,
Mohammed V University, Rabat, Morocco
2. Laboratoire central d’hématologie, Ibn Sina Hospital, Mohammed V University,
Rabat, Morocco
*Correspondence to wafaammouri@hotmail.com
Disclosure: The authors have declared no conflicts of interest.
Received: 30.10.2019
Accepted: 05.12.2019
Keywords: Atrophic gastritis, autoantibodies, autoimmune diseases, intrinsic factor (IF), parietal
cells, pernicious anaemia (PA), vitamin B12 deficiency.
Citation: EMJ Hematol US. 2020;1[1]:71-80.
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72
Whether the stomach pathogen Helicobacter
pylori plays a causative role in PA is unclear.
The deficiency of IF is a consequence of the
presence of atrophic gastritis, which results
in the destruction of the oxyntic mucosa and
thus the loss of parietal cells, which normally
produce hydrochloric acid as well as IF.4 Acid loss
leads to iron deficiency anaemia that precedes
cobalamin-deficient PA by many years. PA
is widespread across all continents and the
prevalence of the disease ranges from 50 to
4,000 cases per 100,000 persons, depending on
the diagnostic criteria.5 However, PA prevalence
is probably underestimated as a result of the
complexity of the diagnosis. The incidence of
PA increases with age and is rare in people <30
years of age. The mean age of patients with PA
ranges from 59 to 62 years. PA is more common
in people with African or European ancestry
than in those with Asian ancestry. The highest
prevalence is seen in northern Europeans,
especially those in the UK and Scandinavian
countries.6,7 The symptomatology is dominated
by a profound megaloblastic type anaemia
and, in the most serious cases, by neurological
alterations, which can precede the diagnosis of
gastric atrophy by several decades. Furthermore,
PA correlates with other autoimmune diseases
(thyroiditis and Type 1 diabetes mellitus) as well
as a genetic disease (genotypes HLA-DRB1*03
and DRB1*04);8,9 however, dierential diagnosis
may sometimes be challenging because of the
limitations of currently available diagnostic tools.
PATHOPHYSIOLOGY
Physiological Roles of Vitamin B12
Vitamin B12, or cobalamin, is an hydrosoluble
vitamin synthesised by micro-organisms and
detected in trace amounts mostly in foods
of animal origin. The normal daily
cobalamin requirement for an adult
corresponds to 1–2 nmol/L. The absorption and
transport mecchanisms are dependent on
three key proteins: haptocorrin (HC), IF, and
transcobalamin (TC).
In the stomach, vitamin B12 released from food
protein by peptic action is bound to HC and
travels to the duodenum, where pancreatic
proteases digest HC, releasing vitamin B12 to
bind to IF. The IF–vitamin B12 complex binds
to a specific receptor called cubilin in the distal
ileum and is internalised. Eventually it is released
by lysosomes, and transported into the blood.
Both HC and TC bind circulating vitamin B12 and
although the latter is the cellular delivery protein,
it is transported together with TC I, II, or III to
finally be stored in the hepatocyte.4,5
Cobalamin acts as a fundamental enzymatic
cofactor in myelopoiesis (role in nucleotide
synthesis) and myelination of the central and
peripheral nervous system. The two enzymes
through which vitamin B12 serve this function are
methionine synthase and methylmalonyl-CoA
mutase. Thus, cobalamin serves as a cofactor
for methionine synthesis through the transfer
of a methyl group to homocysteine which is an
atherogenic and potential endothelial toxin. This
conversion of homocysteine to methionine forms
demethylated tetrahydrofolate which is required
for DNA synthesis. Further metabolism of
methionine to S-Adenosyl methionine is essential
for myelin synthesis and the maintenance of
neuronal integrity, as well as for neurotransmitter
regulation. Thus, a lack of cobalamin leads to
either the destruction of myelin sheaths or the
incorporation of abnormal fatty acids into myelin
sheaths, thereby leading to impaired neural
function and/or transmissions which may be the
underlying cause of the neurological symptoms
seen in vitamin B12 deficiency.
The resulting anaemia may be macrocytic with
bone marrow promegaloblastosis, reflecting
ineective erythropoiesis, or normocytic
reflecting concomitant iron deficiency
from achlorhydria.
Dyssynchrony between the maturation of
the cytoplasm and that of the nuclei leads
to macrocytosis, immature nuclei, and
hypersegmentation in granulocytes in the
peripheral blood. The ineective erythropoiesis
results in intramedullary haemolysis and the
release of lactate dehydrogenase (LDH).4,8
Inhibition of DNA synthesis as a result of vitamin
B12 deficiency causes megaloblastic changes
not only in bone marrow but also in other rapidly
dividing cells, such as gastrointestinal epithelial
tissue, explaining gastrointestinal disorders in
patients with PA.
Creative Commons Attribution-Non Commercial 4.0 January 2020 • HEMATOLOGY
73
Physiopathology of
Pernicious Anaemia
PA is a complex, autoimmune, multifactorial
disease. The environment appears to play a
crucial, independent role in the pathogenesis of
PA. Even though PA associated with gastric
atrophy is now considered an outcome of chronic
H. pylori infection, the relationships between
PA and H. pylori is still not clear with conflicting
views.10-14 H. pylori are ubiquitous organisms
invading the gastric mucosa and are a global
burden. They cause superficial gastritis, destruction
of gastric parietal cells, and atrophic gastritis,
resulting in reduced availability of IF for vitamin
B12 transport. This causes an interference with
vitamin B12 absorption, thus leading to vitamin
B12 deficiency and its clinical manifestations.
In genetically susceptible individuals, H. pylori
infection triggers autoantibodies by a mechanism
of molecular mimicry;12,13 however, studies
showed that only a minority of patients with PA
are infected with H. pylori.12,13 The eect of H. pylori
treatment on the potential reversal of atrophic
gastritis is also controversial.14,15
Studies to understand the genetic component of
PA are long overdue and may provide important
insights into its mechanism. Furthermore, rapid
progress has been made in the understanding
of susceptibility to a spectrum of other
autoimmune diseases through genome wide
association studies.
There are two key facts that confirm the
existence of a genetic basis. Firsty, PA has a
familial link with ≤19% of the patients having a
family member with PA. On the other hand, it
has been observed that the genotypes HLA-
DRB1*03 and DRB1*04 were significantly
associated with PA. These genotypes were
seen in other autoimmune diseases and
support the concept that autoimmunity may
play a role in PA.16-18
Patients with PA have been shown to have two
types of antibodies: one to parietal cells and the
other to IF (IFA) or its binding site in the small
bowel. The immune response is directed against
the gastric H+/K+-ATPase, which accounts for
the associated achlorhydria. This proton pump is
responsible for acid secretion in the stomach and
is the major protein of the secretory canaliculi of
gastric parietal cells. It produces acid by secreting
H+ ions in exchange with K+. The gastric H+/
K+-ATPase is formed by a catalytic 100 kDa α
subunit and a 60–90 kDa β subunit. The highly
conserved catalytic α subunit is phosphorylated
during its reaction cycles and the β subunit
comprises a heavily glycosylated 35 kDa core
protein. The atrophic gastritis is caused by the
action of autoreactive CD4+ T cells that recognise
H+/K+-ATP ase, which leads to their immune
destruction.19-21 The β subunit is considered the
causal antigen and the source of the autoimmune
response responsible for the damage to the
gastric mucosa. Parietal cells are present at a
high frequency in PA (80–90%), especially in
early stages of the disease and bind to both the
α and β subunits of gastric H+/K+-ATPase. In
the later stages of the disease, the incidence of
parietal cells decreases due to the progression
of autoimmune gastritis and a loss of gastric
parietal cell mass, the result of the decrease in
antigenic rate.
Studies have reported IFA positivity in 40–60%
of patients with PA. These antibodies lead to
cobalamin malabsorption in the terminal ileum
that leads to cobalamin deficient megaloblastic
PA.22,23 However, iron deficiency anaemia, a
known complication of achlorhydria, occurs
predominantly in women and precedes the onset
of cobalamin-deficient PA by approximately
20 years.19,24 So, the patients with unexplained
iron deficiency anaemia should be checked for
autoimmune gastritis and PA.
CLINICAL FEATURES
PA usually manifests itself in people >30 years
old (usually adults >60 years) and aects both
sexes equally. The clinical presentation proceeds
gradually, and patients usually exhibit symptoms
of anaemia with pallor, fatigue, lightheadedness,
or tachycardia and decreased mental
concentration. Involvement of small-bowel
epithelium may result in malabsorption and
diarrhoea, with weight loss and anorexia being
additional common complaints. Glossitis is a
frequent sign of megaloblastic anaemia, with the
patient displaying a painful, smooth, red tongue.
Other symptoms reported include dyspeptic
symptoms, epigastric discomfort, postprandial
bloating and fullness, and early satiety.
HEMATOLOGY • January 2020 EMJ
74
The elevation in bilirubin levels, caused by
ineective erythropoiesis, manifests as jaundice.
Patients may develop neurological symptoms or
may be associated with autoimmune diseases
such as autoimmune thyroid disease, Type 1
diabetes mellitus, and vitiligo, as part of the
autoimmune polyendocrine syndromes.3,4,23,25,26
NEUROLOGIC ABNORMALITIES
Neurologic abnormalities are seen in PA as
a result of vitamin B12 deficiency. It could be
isolated or be the first manifestation of vitamin
deficiency and occur without any haematological
or gastrointestinal context. Demyelination is the
initial finding, which progresses to axonal
degeneration and neuronal death if left untreated.
The widely known major manifestations
described include peripheral neuropathy,
subacute combined degeneration of spinal
cord, dementia, ataxia, optic atrophy, psychosis,
and mood disturbance. Further neurological
disorders described include cerebellar ataxia,
abnormalities of cranial nerves, parkinsonism, and
movement disorders.26-31
Isolated cases of nominal dysphasia or amnesic
aphasia were reported.32,33 A minority of patients
exhibit mental or psychiatric disturbances
(psychosis) or autonomic signs (bladder, erectile
dysfunction, and orthostatic hypotension).
Additionally, patients with PA must be closely
observed for hypotension and it is also advisable
to screen patients with chronic postural
hypotension for vitamin B12 deficiency.34 Epilepsy
is rarely seen in adult cases. The appearance
of motor symptoms is indicative of subacute
combined degeneration involving the dorsal
and lateral spinal columns. Imaging of the spinal
cord in cases of severe myelopathy that are not
initially recognised as the result of vitamin B12
deficiency, had characteristic hyperintensity on
T2-weighted imaging, described as an inverted
V-shaped pattern in the cervical and thoracic
spinal cord.28,29 It is particularly important to
recognise these symptoms early because the
neurological lesions may not be reversed after
replacement therapy with vitamin B12.
GASTRIC CANCER AND
PERNICIOUS ANAEMIA
Patients with PA may also be at a higher risk for
developing gastric cancer (GC) (adenocarcinoma
and gastric carcinoid Type I) as an end-stage
evolution of atrophic gastritis. Hypergastrinaemia,
secondary to hypochlorhydria in PA patients, is
a well-known risk factor for enterochroman-
like cell hyperplasia and gastric carcinoids.
Hypochlorhydria leads to overgrowth of
nitrosamine producing bacteria with potential
carcinogen activity.35 However, more extensive
atrophy of the gastric mucosa (multifocal
atrophic gastritis) seems to be associated
with an increased risk of progression to gastric
neoplastic lesions.35
The meta-analysis presented by Vannella et al.36
reported that PA is associated with a nearly 7-fold
relative risk of GC and the incidence-rate of GC
in PA is 0.27% per person-years. Furthermore, a
recent meta-analysis by Lahner et al.37 showed
an overall lower relative risk of cancers other
than GC in PA patients, but an increased relative
risk of biliary tract cancers and haematological
malignancies was observed. The increased risk
for the development of gastric neuroendocrine
tumours in patients with PA represent an
additional potential rationale for endoscopic
surveillance in these patients.38 The management
of patients with PA remains controversial
and the need for endoscopic and histological
surveillance strategies to prevent GC in these
patients is not universally accepted. However, in
young patients, and when endoscopy detects
any preneoplastic characteristic lesions, most
experts agree that it is convenient to perform
an endoscopic evaluation at the diagnosis of PA
and then every 2–5 years. Additionally, the British
Society of Gastroenterology (BSG) guidelines
recommended a follow-up with endoscopic
surveillance every 3 years to patients with
extensive GA. PA patients should be monitored
regularly using gastroscopy with antral and
corporal biopsies.39
Creative Commons Attribution-Non Commercial 4.0 January 2020 • HEMATOLOGY
75
PERNICIOUS ANAEMIAPRESENTING
WITH HYPERHOMOCYSTEINEMIA
ASSOCIATED THROMBOEMBOLISM
Several case-control studies and even a meta-
analysis have confirmed a link between venous
thrombosis and hyperhomocysteinemia.
Homocysteine is due to genetic and acquired
factors (poor diet in folate and vitamin B12,
older age, renal impairment, thyroid diseases,
and malignancies) induced by the intake and
the concentrations of vitamin B9 or B12 in
the majority of cases.40,41 However, the most
common cause of vitamin B12 deficiency with
hyperhomocysteinemia is PA.
It was thought that the main pathophysiological
link among these vitamins and venous thrombosis
is the accumulation of homocysteine as a result
of decreased concentrations of these B group
vitamins. However, all of these vitamins have
a homocysteine-independent role related to
the development of venous thrombosis. In
addition, hyperhomocysteinemia inhibits the
inactivation of factor Va by activated protein
C and could increase the eect of factor V
Leiden. Many hypotheses have been suggested
to explain how hyperhomocysteinemia may
lead to venous thrombosis. One hypothesis
is that homocysteinemia has a toxic eect on
the vascular endothelium and on the dotting
cascade.40 Addittionally, homocysteine has
several procoagulant properties including the
decrease of antithrombin III binding to endothelial
heparan sulfate, increase of anity between
lipoprotein(a) and fibrin, induction of tissue
factor activity in endothelial cells, and inhibition
of inactivation of factor V by activated protein
C.42,43 Understanding the molecular pathogenesis
of the development of thrombosis in patients
with hyperhomocysteinemia related to Biermer’s
disease would help us identify patients at risk and
treat them accordingly. Thus, these conditions
should remain in the clinician’s mind, especially
when thrombosis occurs along with biological
abnormalities such as anaemia, megaloblastosis,
or haemolysis.44
DIAGNOSIS OF PERNICIOUS ANAEMIA
The diagnosis of PA relies on the presentation
of megaloblastic anaemia, low serum vitamin
B12 levels, gastric atrophy, and the presence of
antibodies to gastric parietal cell or IF (Figure 1).
Figure 1: Diagnostic algorithm for pernicious anaemia.8,50
Diagnosis of pericious anaemia
Intrinsic factor deficiency Cobalamin deficiency
Macrocytic anaemia
Atrophic body gastritis
Increased fasting gastrin
Reduced level of pepsinogen 1
Intrinsic factor antibodies
Parietal cell antibodies
Serum cobalamin level
Complete blood count
Neurological disorders
Serum methyl malonic
acid/Homocysteine
Histological confirmation by
gastric biopsy
HEMATOLOGY • January 2020 EMJ
76
The anaemia is macrocytic and normochromic
with a reduction in the absolute number of
reticulocytes. The patient’s red blood cells exhibit
marked anisopoikilocytosis and numerous oval
macrocytes. Although the hypersegmented
neutrophils support the diagnosis of
megaloblastic anaemia, they are not specific. The
variation in the size and shape of red blood cells
could lead to a misdiagnosis of microangiopathic
haemolytic anaemia instead of megaloblastic
anaemia. Some patients may present with
nonanaemic macrocytosis for several months
before the diagnosis of PA is made. Additionally,
macrocytosis is absent in 30% of PA patients if
iron deficiency is associated. Moreover, there may
be masking of macrocytosis by α-thalassemia
in PA patients with African origins who might
present with microcytosis. Pancytopenia is often
present with rates ranging from 5 to 37%.45
Schistocytes may be seen in megaloblastic
anaemias as a reult of erythroblast
cytoskeletal fragility, reflecting the severity of
dyserythropoiesis. Several cases of PA presenting
with pseudothrombotic microangiopathy are
reported in the literature and treated with plasma
transfusions and exchange. These cases are
characterised by haemolysis, thrombocytopenia,
and schistocytosis with higher mean LDH
levels.46 Very high LDH levels, mild-moderate
thrombocytopenia, and a low reticulocyte count
are strongly suggestive of pseudothrombotic
microangioapthy and should prompt the
physician to screen for cobalamin deficiency.47
Bone marrow biopsy and aspiration are not
necessary for the diagnosis of megaloblastic
anaemia (Figure 2) and may be misleading in cases
of severe pancytopenia with hypercellularity,
increased erythroblasts, and even cytogenetic
abnormalities, confusing the diagnosis with acute
leukaemia. It shows a hypercellular bone marrow
with a shift toward immaturity and abnormal
maturation of erythroid and myeloid cell lines.
The immature neutrophil series exhibits nuclear-
cytoplasmic asynchrony with numerous giant
metamyelocytes. The ineective erythropoiesis
and myelopoiesis are responsible for the
pancytopenia in megaloblastic anaemia, despite
marrow hypercellularity.3,4
Serum vitamin B12 and serum folate levels should
be determined concurrently to correctly identify
patients deficient in either or both; however,
there exists limited sensitivity and specificity.
Figure 2: Bone marrow biopsy displaying megablastosis.
A bone marrow aspirate shows megaloblastic features. Large erythroblasts and other red-cell precursors are
characterised by an open, immature nuclear chromatin pattern. There is dyssynchrony between the maturation of the
cytoplasm and that of the nuclei in later red-cell and granulocyte precursors.
Photographs courtesy of Dr Benkirane.
Creative Commons Attribution-Non Commercial 4.0 January 2020 • HEMATOLOGY
77
Dierentiating between vitamin B12 deficiency
and folate deficiency is essential to patient
management because treatment of vitamin
B12 deficient patients with folate alone may
reverse the megaloblastic blood picture,
although the associated neurologic damage
may worsen. Cobalamin level is measured
by an automated competitive-binding
immunoenzymatic luminescence method, the
results of which may not always accurately reflect
actual vitamin B12 stores. Low levels (<100 pg/
mL) are usually associated with clinical deficiency,
however both false-negative and false-positive
values are common (occurring in up to 50% of the
tests), attributable to the fact that only 20% of
the total measured vitamin B12 is on the cellular
delivery protein TC; the remainder is bound to
haptocorrin, a protein of unknown function. IF
antibodies may bind the test IF reagent and if
there is a failure in the denaturation step intended
to denature IF-blocking antibodies, spuriously
normal or increased vitamin B12 levels can be
measured.48,49 In this situation, measurement of
serum methylmalonic acid and total homocysteine
is useful in making the diagnosis of vitamin B12
(markedly elevated levels) deficiency in patients
who have not received treatment, including
those who have only neurologic manifestations
of deficiency.
ELEVATED LEVELS OF
TOTAL HOMOCYSTEINE AND
METHYLMALONIC ACID
Methylmalonic acids have been proven as markers
for insucient intracellular vitamin B12 because
the levels can be remeasured to document
adequate vitamin B12 replacement. An elevated
level of methylmalonic acid is reasonably specific
for vitamin B12 deficiency, and the level always
decreases with vitamin B12 therapy. The level of
serum total homocysteine is less specific because
it is also elevated in folate deficiency, classic
homocystinuria, and renal failure.
A deficit of IF may be demonstrated using the
Schilling test, a dynamic multistep investigatory
test which involves the ingestion of isotope-
labelled vitamin B12, followed by an injection
of unlabelled vitamin B12. Given its complexity
and problems related to the use of radioactive
agents, the Schiling test is now being replaced by
other diagnostic strategies such as the detection
of IFA.
A positive test for anti-IFA or anti-parietal-cell
antibodies (by immunoblotting, ELISA, and
chemiluminescent immunoassay methods)
identifies an autoimmune basis for the gastric
atrophy in PA. Anti-parietal-cell antibodies are
found in 90% of patients with PA, but have low
specificity and are seen in atrophic gastritis
without megaloblastic anaemia as well as in
various autoimmune disorders. IFA are less
sensitive as a result of only being found in 60%
of patients with PA, but are considered highly
specific for PA. However, a positive correlation
between the increasing histological score of body
mucosa atrophy and the titer of both antibodies
can be observed.18,39 Surveillance for autoimmune
thyroid disease is reasonable in patients with
positive antibody tests. A diagnostic workup
of megaloblastic anaemia should also include
evaluation of iron because the bone marrow
is overloaded with iron that cannot be utilised
during the megaloblastic state. Therefore, iron
supplementation may be warranted even though
the patient has an initial normal serum iron value.
Chronic atrophic gastritis can be diagnosed on
the basis of an elevated fasting serum gastrin
level and a low level of serum pepsinogen I.
Some experts recommend endoscopy to confirm
gastritis and rule out gastric carcinoid and other
GC because patients with pernicious anaemia are
at increased risk for such cancers. In PA patients,
the mucosa of the cardia and fundus is thinned
and atrophied, with shrunken glands and
containing few principal and parietal cells, while
usually the mucosa of the antrum is spared.
However, a concomitant antral atrophic gastritis
may be observed in 25% of PA patients.50
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.
Dierential Diagnosis
Accurate dierential diagnosis of other causes of
macrocytic anaemia and cobalamin deficiency is
mandatory (Table 1).
HEMATOLOGY • January 2020 EMJ
78
TREATMENT
The clinical management of patients with PA
has two dierent aspects: the treatment of
cobalamin deficiency and the monitoring of iron
deficiency onset. PA is caused by inadequate
secretion of gastric IF, which is necessary for
vitamin B12 absorption and thus cannot be
treated with oral vitamin B12 supplements.
The therapeutic recommendations for PA, with
regard to dosage and administration of vitamin
B12 substitution treatment, are divergent.
Vitamin B12 must be administered parenterally
and patients generally receive an intramuscular
injection of 1,000 µg B12 every day or every
other day during the first week of treatment. The
next month, they receive injections every week,
subsequently followed by monthly injections.
The alternative to intramuscular B12 injection is
high-dose oral B12, to which a 1,000–2,000 µg/
day dose has been demonstrated to be eective.51
However, despite many studies suggesting oral
administration of vitamin B12 to be easy, eective,
and less costly than intramuscular administration,
debate surrounds the eectiveness of the oral
route. Patients should be oered this alternative
after an informed discussion on the advantages
and disadvantages of both treatment options.
The eect of oral cobalamin treatment in
patients presenting with severe neurological
manifestations has not yet been adequately
documented. Although, recommendations
are to always use the parenteral route in
severe neurological manifestations. Approved
sublingual and intranasal formulations of B12 are
also available.52,53
PA requires lifelong treatment and the percentage
of vitamin B12 absorption improves with
supplementation, but symptoms of vitamin B12
deficiency may be improved after just a few days
of medical treatment. Gastric atrophy, however, is
not cured by cobalamin.
MONITORING
The earliest sign of treatment response is an
increase in reticulocyte count, usually within
3 days of treatment. Following changes in
the decrease of biochemical markers such as
methylmalonic acid and plasma homocysteine
levels have been observed in the first 5 days of
treatment.4,8 Sustained normalisation of serum
cobalamin usually occurs following 2 weeks
of therapy.
The macrocytosis correction takes place during
the first month of treatment. The surveillance
of these patients is mandatory to detect
early long-term consequences of PA, such
as GC and carcinoids.50 A clinical interview
should be considered every year to attest the
Table 1: Other causes of macrocytic anaemia and cobalamin deficiency.3,4
Causes of macrocytic anaemia Causes of cobalamin deficiency
Hypoplastic anaemia, myelodysplastic syndrome
Folate deficiency
Liver disease (alcoholic, advance cirrhosis, poor
dietary intake)
Haemolytic anaemia, response to haemorrhage
Drugs (e.g., methotrexate, azathioprine,
6-mercaptopurine, acyclovir, 5-florouracil,
phenobarbital)
Chronic obstructive pulmonary disease
Total or partial gastrectomy
Gastric bypass or other bariatric surgery
Ileal resection or organ reconstructive surgery
Corpus-predominant Helicobacter pylori gastritis
Inflammatory bowel disease, tropical sprue
Imerslund–Gräsbeck and other syndromes
Protein-bound vitamin B12 malabsorption
Mild atrophic gastritis
Use of metformin or drugs that block stomach acid
Vegan of vegetarian diet, or diet low in meat and dairy
products
Creative Commons Attribution-Non Commercial 4.0 January 2020 • HEMATOLOGY
79
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commencement of new symptoms. These may
include epigastric pain, dysphagia, iron deficiency,
and/or others that require gastroscopic
investigation. The key management principle is
the importance of routine follow-up.
CONCLUSION
PA is an underdiagnosed autoimmune
disease. It is a complex disorder consisting of
haematological, gastric, and immunological
alterations. Macrocytic anaemia is the result of
vitamin B12 deficiency, which, in turn, is the result
of deficiency of IF corpus atrophy. The diagnosis
of PA remains challenging in many circumstances
for many clinicians because of its diverse clinical
manifestations and the limitations of currently
available diagnostic tools. Early detection and
treatment have led to a lower percentage of
vitamin B12 deficiency patients with PA.
HEMATOLOGY • January 2020 EMJ
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