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Autoimmune Gastritis in Type 1 Diabetes: A Clinically Oriented Review

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Autoimmune gastritis and pernicious anemia are common autoimmune disorders, being present in up to 2% of the general population. In patients with type 1 diabetes or autoimmune thyroid disease, the prevalence is 3- to 5-fold increased. This review addresses the epidemiology, pathogenesis, diagnosis, clinical consequences, and management of autoimmune gastritis in type 1 diabetic patients. Autoimmune gastritis is characterized by: 1) atrophy of the corpus and fundus; 2) autoantibodies to the parietal cell and to intrinsic factor; 3) achlorhydria; 4) iron deficiency anemia; 5) hypergastrinemia; 6) pernicious anemia may result from vitamin B12 deficiency; and 7) in up to 10% of patients, autoimmune gastritis may predispose to gastric carcinoid tumors or adenocarcinomas. This provides a strong rationale for screening, early diagnosis, and treatment. The management of patients with autoimmune gastritis implies yearly determination of gastrin, iron, vitamin B12 levels, and a complete blood count. Iron or vitamin B12 should be supplemented in patients with iron deficiency or pernicious anemia. Whether regular gastroscopic surveillance, including biopsies, is needed in patients with autoimmune gastritis/pernicious anemia is controversial. The gastric carcinoids that occur in these patients generally do not pose a great threat to life, whereas the danger of developing carcinoma is controversial. Nevertheless, awaiting a consensus statement, we suggest performing gastroscopy and biopsy at least once in patients with autoantibodies to the parietal cell, iron-, or vitamin B12-deficiency anemia, or high gastrin levels. The high prevalence of autoimmune gastritis in type 1 diabetic patients and its possible adverse impact on the health of the patient provide a strong rationale for screening, early diagnosis, periodic surveillance by gastroscopy, and treatment.
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Autoimmune Gastritis in Type 1 Diabetes: A Clinically
Oriented Review
Christophe E. M. De Block, Ivo H. De Leeuw, and Luc F. Van Gaal
Department of Diabetology-Endocrinology, Antwerp University Hospital and University of Antwerp, B-2650 Edegem, Belgium
Context: Autoimmune gastritis and pernicious anemia are common autoimmune disorders, being
present in up to 2% of the general population. In patients with type 1 diabetes or autoimmune
thyroid disease, the prevalence is 3- to 5-fold increased. This review addresses the epidemiology,
pathogenesis, diagnosis, clinical consequences, and management of autoimmune gastritis in type
1 diabetic patients.
Synthesis: Autoimmune gastritis is characterized by: 1) atrophy of the corpus and fundus; 2) autoan-
tibodies to the parietal cell and to intrinsic factor; 3) achlorhydria; 4) iron deficiency anemia; 5) hyper-
gastrinemia; 6) pernicious anemia may result from vitamin B12 deficiency; and 7) in up to 10% of
patients, autoimmune gastritis may predispose to gastric carcinoid tumors or adenocarcinomas. This
provides a strong rationale for screening, early diagnosis, and treatment. The management of patients
with autoimmune gastritis implies yearly determination of gastrin, iron, vitamin B12 levels, and a
complete blood count. Iron or vitamin B12 should be supplemented in patients with iron deficiency or
pernicious anemia. Whether regular gastroscopic surveillance, including biopsies, is needed in patients
with autoimmune gastritis/pernicious anemia is controversial. The gastric carcinoids that occur in these
patients generally do not pose a great threat to life, whereas the danger of developing carcinoma is
controversial. Nevertheless, awaiting a consensus statement, we suggest performing gastroscopy and
biopsy at least once in patients with autoantibodies to the parietal cell, iron-, or vitamin B12-deficiency
anemia, or high gastrin levels.
Conclusion: The high prevalence of autoimmune gastritis in type 1 diabetic patients and its possible
adverse impact on the health of the patient provide a strong rationale for screening, early diagnosis,
periodic surveillance by gastroscopy, and treatment. (J Clin Endocrinol Metab 93: 363–371, 2008)
A
utoimmune gastritis and pernicious anemia are common
autoimmune diseases with respective prevalences of 2 and
0.15–1% in the general population, increasing with age (1–3). In
patients with type 1 diabetes (4, 5) or autoimmune thyroid dis-
ease (6, 7), the prevalence is 3- to 5-fold increased.
Autoimmune gastritis is characterized by atrophy of the cor-
pus and fundus, and the presence of circulating autoantibodies to
the parietal cell (PCA) and to their secretory product, intrinsic
factor (AIF) (8). Chronic autoaggression to the gastric proton
pump, H
/K
ATPase, may result in decreased gastric acid se
-
cretion, hypergastrinemia, and iron deficiency anemia (9, 10). In
a later stage of the disease, pernicious anemia may result from
vitamin B12 deficiency, which is 10 times more common in type
1 diabetic than nondiabetic subjects (5). Finally, in up to 10% of
patients, autoimmune gastritis may predispose to gastric carci-
noid tumors or adenocarcinomas (11). Determining demo-
graphic, immunological, and genetic risk factors, and early di-
agnosis of autoimmune gastritis are important to prevent and
treat iron deficiency anemia, pernicious anemia, and (pre)ma-
lignant gastric lesions [intestinal metaplasia and enterochromaf-
fin-like (ECL) hyper/dysplasia].
History
Thomas Addison was the first to report a patient with autoim-
mune atrophic gastritis in 1849 (12). He described a “very re-
0021-972X/08/$15.00/0
Printed in U.S.A.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2007-2134 Received September 21, 2007. Accepted November 13, 2007.
First Published Online November 20, 2007
Abbreviations: AIF, Autoantibodies to the intrinsic factor; CgA, chromogranin A; ECL,
enterochromaffin-like; HLA, human leukocyte antigen; PCA, autoantibodies to the parietal
cell.
SPECIAL FEATURE
Clinical Review
J Clin Endocrinol Metab, February 2008, 93(2):363–371 jcem.endojournals.org 363
markable form of anemia,” which was later called pernicious
anemia that was linked to atrophy of the gastric mucosa by Flint
in 1860 (13). Successful treatment with raw liver suggested that
this megaloblastic anemia was caused by insufficiency of an ex-
trinsic factor (vitamin B12) and an intrinsic factor in gastric juice
(14). The discovery of AIF by Schwartz in 1960 (15) and PCA by
Irvine et al. in 1962 (16) constituted the immunological expla-
nation of the underlying atrophic gastritis that causes pernicious
anemia (17).
Definition and Diagnosis of Autoimmune
Gastritis
(Table 1)
Autoimmune gastritis affects the parietal cell-containing gastric
corpus and fundus with sparing of the antrum (8, 18). PCA,
targeted against gastric H
/K
ATPase, are detected in 60 85%
and intrinsic factor antibodies in 30–50% of patients with au-
toimmune gastritis (5, 19).
Besides pernicious anemia, iron deficiency anemia is fre-
quently observed (9, 10). Furthermore, autoimmune gastritis is
characterized by hypo- or achlorhydria, high serum gastrin, and
low pepsinogen I concentrations (20, 21). Chronic hypergas-
trinemia causes the ECL cells in the oxyntic mucosa to undergo
hyperplasia (22), which may progress toward dysplasia and gas-
tric carcinoid tumors (11, 21) (Fig. 1).
PCA are detected by immunofluorescence staining of the cy-
toplasma of gastric parietal cells (23). However, Karlsson et al.
(24) showed that the ELISA to detect gastric H
/K
ATPase an
-
tibodies is 10-fold more sensitive than the indirect immunoflu-
orescence technique and has a high specificity. Current ELISAs
have a sensitivity and specificity of respectively 85–93% and
80 85%. PCA are detected 60–90% of patients with autoim-
mune gastritis and/or pernicious anemia (1, 8, 23).
The recognition of antibodies to intrinsic factor derives from
the work of Taylor et al. (25) and Schwartz (15). Two types of
autoantibodies bind to intrinsic factor (AIF). Type I AIF block
the binding of vitamin B12 to intrinsic factor, thereby preventing
the transport of vitamin B12 from the stomach to its absorption
site in the terminal ileum. Type I AIF are demonstrable in 70%
of patients with pernicious anemia (24). Type II autoantibodies
do not interfere with vitamin B12 transport. They can be found
in 30 40% of patients with pernicious anemia.
The destruction of H
/K
ATPase-containing parietal cells
results in hypo- or achlorhydria. This can be measured using
24-h gastric pH-metry or after stimulation with pentagastrin.
Hypochlorhydria is defined as a maximal acid output less than
15 mmol H
/h after injection of pentagastrin. A progressive
decrease in acid secretion in the case of autoimmune gastritis
with a decreased parietal cell mass has been found (21, 26, 27).
Total achlorhydria is diagnostic of pernicious anemia. Achlo-
rhydria interrupts the negative feedback of somatostatin on
antral gastrin-producing cells causing hypergastrinemia (28).
Fasting serum gastrin levels correlate negatively with peak
acid output, and positively with the degree of corpus atrophy
(21, 29) and with PCA levels (21). Low serum pepsinogen I
levels, resulting from destruction of chief cells or zymogenic
cells, are also characteristic of autoimmune gastritis
(20, 30, 31).
Endoscopy and Pathology
On endoscopy, the affected corpus and fundus mucosa appears
shiny and red because of the visibility of submucosal blood ves-
sels. The stomach wall thins, and the rugal folds flatten or dis-
appear. In biopsy specimens, lymphocytic infiltrates are present
in the submucosa and lamina propria (19, 21). In the next stage,
there is a marked reduction in the number of oxyntic glands,
parietal and zymogenic cells, followed by replacement of normal
glands by glandular structures lined with mucus-containing cells
resembling those of the small bowel mucosa (intestinal metapla-
sia) (Fig. 1). A proliferation of ECL cells in the oxyntic mucosa
(22), due to sustained hypergastrinemia, can be seen, which may
progress in a small proportion of patients toward gastric carci-
noid tumors (11, 32–34).
Epidemiology
In the general population, there is an age-related increase in the
prevalence of PCA, from 2.5% in the third decade to 12% in the
eighth decade (1, 2). The prevalence is even higher in subjects
affected by another autoimmune disorder. In type 1 diabetes,
PCA are found in 10 –15% of children and 15–25% of adults (4,
5, 35–37) (Fig. 2). The respective prevalences of autoimmune
gastritis and pernicious anemia in the general population are 2
and 0.15–1% (2, 3, 38, 39), compared with respectively 5–10%
and 2.6 4% in type 1 diabetes (5, 21, 38, 40, 41).
Iron deficiency anemia is present in 20 40% of patients with
autoimmune gastritis (10, 42), whereas pernicious anemia can be
diagnosed in up to 15–25% of patients (43). The progression of
autoimmune gastritis to pernicious anemia is likely to span
20–30 yr (44).
Finally, gastric carcinoid tumors are observed in 4 –9% of
patients with autoimmune gastritis/pernicious anemia, which is
13 times more frequent than in controls (11, 32–34, 45). Patients
with autoimmune gastritis/pernicious anemia also have a 3- to
TABLE 1. Characteristics of autoimmune gastritis
Atrophic fundus and corpus, antrum spared
PCA and AIF
Hypo/achlorhydria
Hypergastrinemia
Low serum pepsinogen I concentrations
Vitamin B12 deficient megaloblastic (pernicious) anemia
Iron deficiency anemia
Increased chromogranin A levels: ECL cell hyperplasia and gastric
carcinoids
Association with endocrine organ-specific autoimmune disease
Type 1 diabetes mellitus
Hashimoto’s thyroiditis, Graves’ disease
Addison’s disease
Autoimmune polyglandular syndrome types II and III
364 De Block et al. Autoimmune Gastritis in Type 1 Diabetes J Clin Endocrinol Metab, February 2008, 93(2):363–371
6-fold increased gastric cancer risk, ranging from 0.9–9% (11,
32, 34, 46 48).
Pathogenesis
The target autoantigens in autoimmune gastritis are the 100-kd
catalytic
-subunit and the 60- to 90-kd glycoprotein
-subunit
of the gastric H
/K
ATPase (49, 50). Autoantibodies to the PCA
and to their secretory product, intrinsic factor, are present in the
serum and in gastric juice. The titer of PCA correlates with the
severity of corpus atrophy and is inversely proportional to the
concentration of parietal cells (21, 29). CD4 T cells recognizing
parietal cell H
/K
ATPase mediate autoimmune gastritis. Dur
-
ing normal cell turnover, parietal cells release H
/K
ATPase,
which may result in its selective uptake and processing by anti-
gen-presenting cells (51). Alternatively, Helicobacter pylori in-
fection may play an initiating role in the pathogenesis of auto-
immune gastritis and pernicious anemia (52–55) by inducing
autoreactive T cells through gastric H
/K
ATPase-H. pylori
molecular mimicry at the T-cell level (53, 54), epitope spreading,
and bystander activation. B cells produce autoantibodies to gas-
tric H
/K
ATPase and to their secretory product, intrinsic fac
-
tor with help from activated CD4 T cells (50). Finally, parietal
cell loss from the gastric mucosa may result from CD4 T cells
initiated perforin-mediated cytotoxicity or Fas-FasL apoptosis
(55).
Regardless of whether PCA are pathogenic or not, their pres-
ence provides a convenient diagnostic probe for autoimmune
atrophic gastritis. A precise understanding of the pathogenesis of
autoimmunity may lead to rational therapeutic strategies di-
rected toward restoration of tolerance or impeding the progres-
FIG. 1. Schematic presentation of manifestations of autoimmune gastropathy.
J Clin Endocrinol Metab, February 2008, 93(2):363–371 jcem.endojournals.org 365
sion of autoimmunity. Whether H. pylori could trigger autoim-
mune gastritis or not remains controversial. However, should
this be the case, H. pylori eradication could prevent autoimmune
gastric disease. Currently, it is recommended that H. pylori in-
fection should be tested and treated in patients with gastric at-
rophy, intestinal metaplasia/dysplasia, and hypo- or
achlorhydria.
Predisposing Factors
Accurate prediction of autoimmune diseases (autoimmune gas-
tritis) using antibodies (PCA and AIF), and demographic (age,
gender) and genetic [human leukocyte antigen (HLA) class II,
cytotoxic T lymphocyte-associated protein 4, others] risk factors
might help to prevent these diseases. Primary prevention includes
avoiding those environmental factors (H. pylori) that might trig-
ger the disease. Secondary prevention consists of modulating the
destructive process (CD4 T cells mediating oxyntic gland at-
rophy) before the onset of clinical symptoms [iron deficiency,
pernicious anemia, and (pre)malignant gastric lesions]. How-
ever, at present, there is no consensus on whom to screen or at
what frequency.
Demographic factors
Advancing age is a risk factor that has been associated with
PCA positivity. In the general population, PCA positivity in-
creases from 2.5% in the third decade to 12% in the eighth
decade (1, 2). In type 1 diabetic patients, PCA are present in
10–15% of children and 15–25% of adults (41). Some authors
(4, 35) report a female preponderance for PCA positivity, al-
though this has not been consistently observed (37, 41).
Endocrine and immunological factors
Autoimmune gastritis is frequently accompanied by other au-
toimmune diseases, including type 1 diabetes (5) and autoim-
mune thyroid disease (Hashimoto’s thyroiditis and Graves’ dis-
ease) (6, 38, 56). Autoimmune gastritis is also part of the
autoimmune polyglandular syndrome type 3 (57). Pernicious
anemia occurs in up to 4% of type 1 diabetic patients (5, 40),
2–12% of patients with autoimmune thyroid disease (6, 58), 6%
of those with Addison’s disease, 9% of those with primary hy-
poparathyroidism, and 3–8% of those with vitiligo (1) (Fig. 3).
In patients with type 1 diabetes, immunological risk factors
that have been associated with PCA positivity include persistent
islet cell antibody positivity (35, 36), glutamic acid decarboxyl-
ase-65 antibody positivity (41, 59), and thyroid peroxidase au-
toantibody positivity (41, 59). The association with glutamic
acid decarboxylase-65 antibodies might be explained by the fact
that glutamate decarboxylase-65 is not only present in the pan-
creas and brain but can also be found in the thyroid gland and
stomach. PCA are more frequent in type 1 diabetic patients than
in their first-degree relatives, even after HLA matching, suggest-
ing that the diabetic condition itself plays an important role (60).
PCA can be found in 22% of patients with Graves’ disease and
32–40% of those with autoimmune hypothyroidism (61–64).
Pernicious anemia is present in 2% of patients with Graves’ dis-
ease and 4 –12% of those with Hashimoto’s thyroiditis (6, 61,
62). Moreover, up to 50% of patients with autoimmune gastritis/
pernicious anemia show thyroid peroxidase autoantibodies (21,
62). These results support the recommendation of screening pa-
tients with autoimmune thyroid disease for autoimmune gastri-
tis. The close association between autoimmune thyroid disease
and autoimmune gastritis suggests an immunological cross-re-
action. In this respect, one group found a homologous 11-residue
peptide in thyroid peroxidase and the gastric parietal cell anti-
gen, the H
/K
ATPase (65).
Immunogenetic factors
A genetic predisposition to autoimmune gastritis/pernicious
anemia has been suggested by its familial occurrence, and the
presence of PCA and autoimmune gastritis in 20–30% of rela-
tives of patients with pernicious anemia (1, 5, 58).
HLA haplotypes can partly determine the tissue to which an
autoimmune process develops. However, the evidence of a link
between pernicious anemia and particular HLA haplo/genotypes
is weak. Associations of pernicious anemia with HLA DR4, with
DR2 (66, 67) and DR5 haplotypes (5), have been reported. In
type 1 diabetic patients, a weak association between PCA pos-
FIG. 2. Prevalence of PCA in type 1 diabetes. , Positive; f, female; m,
male.
Fig. 3. Prevalence of PCA, AIF, autoimmune gastritis, and pernicious
anemia in the general population and endocrine diseases. , Positive; Ab,
; t1DM, type 1 diabetes mellitus.
366 De Block et al. Autoimmune Gastritis in Type 1 Diabetes J Clin Endocrinol Metab, February 2008, 93(2):363–371
itivity and the HLA-DQA1*0501-B1*0301 haplotype, linked to
HLA-DR5, has been observed (59). Patients who manifest both
pernicious anemia and endocrine disease often have a DR3/DR4
genotype (66). These data suggest genetic heterogeneity.
In mouse models of autoimmune gastritis, four distinct ge-
netic regions that confer susceptibility to autoimmune gastritis
have been identified (68): two loci on distal chromosome 4,
called Gasa1 and Gasa2; and two on chromosome 6, called
Gasa3 and Gasa4 (51). Importantly, three of these four suscep-
tibility loci are nonmajor histocompatibility complex genes that
colocalize with those of type 1 diabetes (51, 54). This is the
strongest concordance identified between any two autoimmune
diseases so far.
No association of autoimmune gastritis/pernicious anemia
with another two autoimmune disease candidate genes (the
AIRE gene and cytotoxic T lymphocyte-associated protein 4) has
been reported.
Environmental factors
H. pylori might be implicated in the induction of autoimmune
gastritis (52, 53, 55). This hypothesis is supported by studies
reporting a high prevalence of H. pylori seropositivity and a low
prevalence of positive H. pylori staining in subjects with atrophic
corpus gastritis (69 –72). Furthermore, the finding of gastric au-
toantibodies in 20–50% of H. pylori-infected patients and re-
ports of a positive correlation between gastric autoantibodies
and antibodies to H. pylori in patients with autoimmune gastri-
tis/pernicious anemia (71, 73–76) suggest that chronic H. pylori
infection is linked with gastric autoimmunity. However, a cor-
relation between H. pylori and PCA has not been reported in all
studies (39, 77, 78). Moreover, others found no or a negative link
between H. pylori and atrophic corpus gastritis (79). On the
other hand, H. pylori eradication in patients who have antigas-
tric antibodies leads to the loss of those antibodies in some sub-
jects (80). These data add new information to the possible re-
versibility of gastric mucosa atrophy.
Clinical Presentation
Iron deficiency anemia
Approximately 20–30% of patients with iron deficiency ane-
mia with no evidence of gastrointestinal blood loss may have
autoimmune gastritis (9, 42, 81). Iron deficiency anemia may
develop in advance of pernicious anemia, or both conditions may
coexist (82, 83).
Examination of the peripheral blood shows a hypochromic,
microcytic anemia, decreased serum iron levels (male 50
g/dl
and female 40
g/dl), a transferrin saturation less than or equal
to 20%, and a decreased ferritin concentration (male 20
g/
liter and female 12
g/liter). However, these parameters are
influenced by gender, acute phase responses, acute liver injury, or
malnutrition (84). A Perls staining of a bone marrow smear
showing absence of iron that is stored as hemosiderin in the
reticuloendothelial cells of the bone marrow is definitive proof of
iron deficiency, but invasive. The soluble transferrin receptor has
been proposed as the best noninvasive and sensitive marker of
functional iron status because of its small day-to-day variation,
and independence of inflammation, liver parenchymal, and hor-
monal status (10, 85).
Symptoms and signs of iron deficiency include pallor, fatigue,
reduced exercise or work performance, and palpitations, re-
duced learning ability, defects in immunity, and even an in-
creased frequency of premature births (84). Early detection and
treatment of iron deficiency and the conditions that are at its
origin could significantly reduce morbidity. Treatment consists
of oral supplementation of 600 mg FeSO
4
. Alternatively, iron
can be infused iv (84).
The iron status of an individual depends on the amount of
dietary iron, its bioavailability, and the extent of iron losses (84).
Although no absorption of iron occurs in the stomach, the gastric
hydrochloric acid plays a significant role. Hydrochloric acid not
only helps to remove protein-bound iron by protein denaturation
but also helps in the reduction of ferric iron (Fe
2
) to the ferrous
state (Fe
3
), necessary to improve absorption (86). Decreased
gastric acidity, due to chronic autoaggression to parietal H
/
K
ATPase in autoimmune gastritis (27), may reduce the avail
-
ability of iron for absorption and lead to iron deficiency anemia
(9, 10).
Pernicious anemia
Pernicious anemia can be considered an end stage of auto-
immune gastritis (44). Approximately 10–15% of PCA-positive
patients and up to 25% of those with autoimmune gastritis
present with pernicious anemia (1, 5).
Two mechanisms are responsible for vitamin B12 malabsorp-
tion in patients with pernicious anemia. First, the progressive loss
of parietal cells leads to failure of intrinsic factor production and
a reduction in vitamin B12 absorption. Second, intrinsic factor
autoantibodies prevent the formation of the vitamin B12-intrin-
sic factor complex (19).
Examination of the peripheral blood reveals macrocytosis
and anemia, a low serum vitamin B12 concentration, and normal
folate concentration. A Schilling test, which measures vitamin
B12 absorption in the presence and absence of intrinsic factor, is
used to establish pernicious anemia as the cause of vitamin B12
deficiency (19).
The usual presentation of vitamin B12 deficiency is with
symptoms of anemia. Gastrointestinal manifestations include a
smooth and beefy red tongue (atrophic glossitis), and a predis-
position to gastric tumors (see Gastric carcinoid tumors and
Gastric cancer). Neurological complications include peripheral
neuropathy manifested by paraesthesia and numbness usually of
the legs, and cerebral manifestations such as confusion, impaired
memory, and even frank psychosis (megaloblastic madness)
(19, 87).
Early detection and treatment of vitamin B12 deficiency and
the underlying conditions could significantly reduce morbidity.
The classical treatment is by daily im injections with 100
g
vitamin B12 for 1 wk, followed by monthly injections of 100
g
vitamin B12. In severe cases, parenteral administration of 1000
g/d for 1 wk, followed by 1000
g/wk for 1 month, and then
by monthly im injection of 1000
g is proposed (19, 88).
J Clin Endocrinol Metab, February 2008, 93(2):363–371 jcem.endojournals.org 367
Gastric carcinoid tumors
Gastric carcinoid tumors, evolving from ECL cell hyper/dys-
plasia induced by hypergastrinemia, may develop in 4 –9% of
patients with autoimmune gastritis/pernicious anemia (11, 32–
34, 89). Up to 85% of gastric carcinoid tumors are associated
with autoimmune gastritis/pernicious anemia (90 –92). In type 1
diabetes, ECL cell proliferative changes occur in approximately
9% of PCA-positive patients and in up to 30% of those with
autoimmune gastritis (93). This provides a strong rationale for
screening, early diagnosis, and treatment.
The tumors are usually incidentally identified during diag-
nostic endoscopic evaluation for anemia. The most frequently
reported symptoms include abdominal pain, flushing and diar-
rhea, anemia-related symptoms, and extremely rarely a carci-
noid syndrome (92). Gastroscopy with histological examination
[immunostaining for chromogranin A (CgA) and/or neuron-spe-
cific enolase] is the most powerful diagnostic tool. However, a
gastroscopy can be considered unpleasant, and is hampered by
the fact that such lesions are usually not endoscopically detect-
able, or unevenly distributed, and may be overlooked (91, 94).
Moreover, part of an increased ECL cell density in atrophic mu-
cosa may not be true hyperplasia but rather an expression of a
selective glandular atrophy sparing the ECL cells. Thus, mor-
phology is subject to sampling error and may over- or underes-
timate ECL cell mass. Serum CgA measurements may indicate
the presence of an increased ECL cell mass more accurately than
morphological methods (95). CgA can be released into the cir-
culation from ECL cells of the stomach (65). Its levels correlate
strongly with ECL cell density in the corpus and fundus mucosa
and with gastrin levels (33, 93, 95, 96). CgA has a specificity of
85–90% and a sensitivity of 70 80% in diagnosing neuroen-
docrine tumors. A recent study showed a sensitivity of 100% and
specificity of 59% for CgA to detect ECL cell hyper/dysplasia
(93). Therefore, we recommend, besides performing a gastros-
copy with biopsy, measuring CgA in PCA-positive patients, par-
ticularly those with hypergastrinemia, who are at risk for devel-
oping autoimmune gastritis and, possibly, carcinoid tumors.
Gastric carcinoid tumors are relatively benign lesions, metas-
tasizing in less than 10% of cases, and death rarely results from
these tumors (92).
An algorithm for the appropriate management of patients
with gastric carcinoid tumors has been proposed by Gilligan et
al. (97). For autoimmune gastritis-associated carcinoid tumors
less than 1 cm and/or fewer than three to five in number, ex-
pectant therapy or endoscopic removal of accessible tumors, fol-
lowed by endoscopic surveillance are appropriate (11, 34, 91,
94, 97). For lesions more than 1 cm in size and/or more than five
in number, antrectomy has been proposed (91, 98). Either
antrectomy or endoscopic polypectomy should be followed by
endoscopic surveillance at 6-month intervals, and any recurrence
should be treated with surgical excision. Ferraro et al. (99)
showed in a limited group of eight patients with hypergastrine-
mic atrophic gastritis that once a day administration of oct-
reotide is safe and effective in reducing hypergastrinemia and
associated ECL changes. In a small number of patients, a spon-
taneous regression has been reported (100).
Gastric cancer
A three to six times higher gastric cancer risk in patients with
autoimmune gastritis/pernicious anemia has been observed in
some (11, 32, 34, 46 48) but not all (101, 102) studies. The
prevalence of gastric carcinoma in patients with pernicious ane-
mia is 1–3%, and 2% of patients with gastric carcinoma have
pernicious anemia (103).
Achlorhydria, overgrowth of bacteria promoting the forma-
tion of N-nitroso compounds, and a high dietary salt consump-
tion might promote the formation of a gastric carcinoma (104,
105).
Regular endoscopic surveillance is warranted in patients with
pernicious anemia (32–34). Patients with mild/moderate muco-
sal dysplasia should be followed endoscopically every 5 yr (32).
Polyps should be removed, and adenocarcinoma should be ex-
cised. Complete surgical eradication of a gastric tumor, with
resection of adjacent lymph nodes, is the only chance for a cure
(106).
Management Proposal
Early detection of PCA, autoimmune gastritis, and associated
pathology (Fig. 1) is important in preventing iron deficiency ane-
mia, which may influence work capacity and cardiopulmonary
status, and pernicious anemia, which can cause neurological
complications and (pre)malignant gastric lesions. For type 1 di-
abetic patients, it seems prudent to test PCA status at the onset
of diabetes and then yearly for 3 yr, then five yearly thereafter,
or at any other time if there are clinical indications because the
test may later become positive. Particularly those patients with
positive glutamate decarboxylase-65 antibodies and thyroid per-
oxidase antibodies should be screened.
Treating patients with PCA and/or autoimmune gastritis im-
plies a proper follow-up. At yearly intervals, gastrin, iron, vita-
min B12 levels, and a complete blood count should be performed.
Iron or vitamin B12 supplements should be given to patients with
iron deficiency or pernicious anemia. It is controversial whether
patients with autoimmune gastritis/pernicious anemia should be
placed under a surveillance program with regular gastroscopies,
including multiple gastric biopsies. The gastric carcinoids that
occur in these patients generally do not pose a great threat to life,
whereas the danger of developing carcinoma is controversial.
Nevertheless, awaiting a consensus statement, we suggest per-
forming gastroscopy and biopsy at least once in patients with
PCA positivity, anemia, or high gastrin levels. Patients with mild
to moderate mucosal dysplasia should be followed endoscopi-
cally every 5 yr (32). Polyps should be removed, and adenocar-
cinoma should be excised. Gastric carcinoid tumors are rare and
have a far better outcome than carcinoma (92). Endoscopic sur-
veillance at 5-yr intervals has been proposed for ECL cell hyper-
plasia (11), especially for those patients with high gastrin (300
ng/liter) and CgA (120 ng/ml) levels (93). For gastric carcinoid
tumors associated with autoimmune gastritis, smaller than 1 cm
and/or fewer than three, expectant therapy or endoscopic re-
moval of accessible tumors is proposed (97).
368 De Block et al. Autoimmune Gastritis in Type 1 Diabetes J Clin Endocrinol Metab, February 2008, 93(2):363–371
Conclusions
Autoimmune gastritis and pernicious anemia are among the
most common autoimmune diseases with respective prevalences
of 2 and 0.15–1% in the general population, increasing with age.
Moreover, in patients with autoimmune thyroid disease or type
1 diabetes, the prevalence is 3- to 5-fold increased.
In the clinical setting, PCA are a good marker of autoimmune
gastropathy, such as iron deficiency anemia, pernicious anemia,
and autoimmune gastritis. The well-known complications of
these three disorders can influence the prognosis of the patient.
Treating patients with PCA and/or autoimmune gastritis implies
a proper follow-up. At yearly intervals, gastrin, iron, vitamin
B12 levels, and a complete blood count should be performed.
Moreover, both autoimmune gastritis and pernicious anemia
predispose to gastric carcinoid tumors, which manifest them-
selves only late in the disease process. The possible adverse im-
pact on the health of the patient provides a strong rationale for
screening, periodic surveillance by gastroscopy with biopsy,
early diagnosis, prevention, and/or treatment.
Understanding the current advances in autoimmune gastritis
is key to the development of novel therapeutic strategies directed
toward restoration of tolerance or toward impeding the progres-
sion of autoimmunity, and for making rational choices in the
management of autoimmune gastropathy.
Acknowledgments
We thank Professor doctor Paul Pelckmans of the Department of Gas-
troenterology and Hepatology, and Professor doctor E. Van Marck of
the Department of Pathology for their collaboration throughout this
project.
Address all correspondence and requests for reprints to: Christophe
De Block, M.D., Ph.D., Department of Diabetology-Endocrinology,
Antwerp University Hospital and University of Antwerp, Wilrijkstraat
10, B-2650 Edegem, Belgium. E-mail: christophe.deblock@ua.ac.be;
christophe.de.block@uza.be.
Part of the studies mentioned and performed by the authors has been
supported by a grant from the European Foundation for the Study of
Diabetes.
Disclosure Statement: The authors have nothing to disclose.
References
1. Whittingham S, Mackay IR 1985 Pernicious anemia and gastric atrophy. In:
Rose NR, Mackay IR, eds. The autoimmune diseases. New York: Academic
Press; 243–266
2. Jacobson DL, Gange SJ, Rose NR, Graham NM 1997 Epidemiology and
estimated population burden of selected autoimmune diseases in the United
States. Clin Immunol Immunopathol 84:223–243
3. Carmel R 1996 Prevalence of undiagnosed pernicious anemia in the elderly.
Arch Intern Med 156:1097–1100
4. Riley WJ, Toskes PP, Maclaren NK, Silverstein J 1982 Predictive value of
gastric parietal cell autoantibodies as a marker for gastric and hematologic
abnormalities associated with insulin dependent diabetes. Diabetes 31:1051–
1055
5. De Block CE, De Leeuw IH, Van Gaal LF 1999 High prevalence of manifes-
tations of gastric autoimmunity in parietal cell antibody-positive type 1 (in-
sulin-dependent) diabetic patients. The Belgian Diabetes Registry. J Clin En-
docrinol Metab 84:4062–4067.
6. Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G,
Andreoli M, Annibale B 1999 Atrophic body gastritis in patients with auto-
immune thyroid disease. An underdiagnosed association. Arch Intern Med
159:1726–1730
7. Irvine WJ, Scarth L, Clarke BF, Cullen R, Duncan LJP 1970 Thyroid and
gastric autoimmunity in patients with diabetes mellitus. Lancet 2:163–168
8. Strickland RG, Mackay I 1973 A reappraisal of the nature and significance
of chronic atrophic gastritis. Am J Dig Dis 18:426 440
9. Marignani M, Delle Fave G, Mecarocci S, Bordi C, Angeletti S, D’Ambra G,
Aprile MMR, Corleto VD, Monarca B, Annibale B 1999 High prevalence of
atrophic body gastritis in patients with unexplained microcytic and macro-
cytic anemia. Am J Gastroenterol 94:766 –772
10. De Block CE, Van Campenhout CM, De Leeuw IH, Keenoy BM, Martin M,
Van Hoof V, Van Gaal LF 2000 Soluble transferrin receptor level: a new
marker of iron deficiency anemia, a common manifestation of gastric auto-
immunity in type 1 diabetes. Diabetes Care 23:1384 –1388
11. Kokkola A, Sjo¨ blom SM, Haapiainen R, Sipponen P, Puolakkainen P, Jarvi-
nen H 1998 The risk of gastric carcinoma and carcinoid tumours in patients
with pernicious anaemia: a prospective follow-up study. Scand J Gastroen-
terol 33:88 –92
12. Addison T 1849 Anaemia: disease of the suprarenal capsules. London Med
Gaz 8:517–518
13. Flint A 1860 A clinical lecture on anaemia, delivered at the Long Island
College Hospital. American Medical Times 1:181–186
14. Castle WB 1953 Development of knowledge concerning the gastric intrinsic
factor and its relation to pernicious anemia. N Engl J Med 249:603– 614
15. Schwartz M 1960 Intrinsic factor antibody in serum from patients with per-
nicious anaemia. Lancet 2:1263–1267
16. Irvine WJ, Davies SH, Delamore IW, Williams AW 1962 Immunological
relationship between pernicious anemia and thyroid disease. Br J Med 2:454
456
17. Irvine W 1965 Immunologic aspects of pernicious anemia. N Engl J Med
273:432–438
18. Kaye MD 1987 Immunological aspects of gastritis and pernicious anaemia.
Baillieres Clin Gastroenterol 1:487–506
19. Toh BH, Van Driel IR, Gleeson PA 1997 Mechanisms of disease: pernicious
anemia. N Engl J Med 337:1441–1448
20. Varis K, Kekki M, Ha¨rko¨ nen M, Sipponen P, Samloff IM 1991 Serum pep-
sinogen I and serum gastrin in the screening of atrophic pangastritis with high
risk of gastric cancer. Scand J Gastroenterol Suppl 186:117–123
21. De Block C, De Leeuw I, Bogers J, Pelckmans P, Ieven M, Van Marck E, Van
Acker K, Van Gaal L 2003 Autoimmune gastropathy in type 1 diabetic pa-
tients with parietal cell antibodies: histological and clinical findings. Diabetes
Care 26:82– 88
22. Solcia E, Fiocca T, Villani L, Gianatti A, Cornaggia M, Chiaravalli A, Curzio
M, Capella C 1991 Morphology and pathogenesis of endocrine hyperplasias,
precarcinoid lesions, and carcinoids arising in chronic atrophic gastritis.
Scand J Gastroenterol Suppl 180:146–159
23. Fisher JM, Taylor KB 1965 A comparison of autoimmune phenomena in
pernicious anemia and chronic atrophic gastritis. N Engl J Med 272:499–503
24. Karlsson FA, Burman P, Lo¨o¨ f L, Olsson M, Scheynius A, Mardh S 1987
Enzyme linked immunosorbent assay of H
/K
ATPase, the parietal cell an
-
tigen. Clin Exp Immunol 70:604610
25. Taylor KB, Roitt IM, Doniach D, Couchman KG, Shapland C 1962 Auto-
immune phenomena in pernicious anemia: gastric antibodies. Br Med J
2:1347–1352
26. Perasso A, Testino G, de’Angelis P, Augeri C, de Grandi R 1990 Gastric chief
cell mass in chronic gastritis. Count and relationships to parietal cell mass and
functional indices. Hepatogastroenterology 38(Suppl 1):63–66
27. Burman P, Mardh S, Norberg L, Karlsson FA 1989 Parietal cell antibodies in
pernicious anemia inhibit H,K-adenosine triphosphatase, the proton
pump of the stomach. Gastroenterology 96:1434 –1438
28. Trudeau WL, McGuigan JE 1971 Relations between serum gastrin levels and
rates of gastric hydrochloric acid secretion. N Engl J Med 284:408 412
29. Sipponen P, Valle J, Varis K, Kekki M, Ihama¨ki T, Siurala M 1990 Fasting
levels of serum gastrin in different functional and morphologic states of the
antrofundal mucosa. An analysis of 860 subjects. Scand J Gastroenterol 25:
513–519
30. Samloff IM, Varis K, Ihamaki T, Siurala M, Rotter JI 1982 Relationships
among serum pepsinogen I, serum pepsinogen II, and gastric mucosal histol-
ogy. A study in relatives of patients with pernicious anemia. Gastroenterology
83:204–209
31. Alonso N, Granada ML, Salinas I, Lucas AM, Reverter JL, Junca J, Oriol A,
Sanmarti A 2005 Serum pepsinogen I an early marker of pernicious anemia
in patients with type 1 diabetes. J Clin Endocrinol Metab 90:5254 –5258
32. Armbrecht U, Stockbru¨ gger RW, Rode J, Menon GG, Cotton PB 1990 De-
J Clin Endocrinol Metab, February 2008, 93(2):363–371 jcem.endojournals.org 369
velopment of gastric dysplasia in pernicious anaemia: a clinical and endo-
scopic follow-up study of 80 patients. Gut 31:1105–1109
33. Borch K, Renvall H, Liedberg G 1985 Gastric endocrine cell hyperplasia and
carcinoid tumors in pernicious anemia. Gastroenterology 88:638 648
34. Sjo¨ blom SM, Sipponen P, Jarvinen H 1993 Gastroscopic follow-up of per-
nicious anaemia patients. Gut 34:28–32
35. Maclaren NK, Riley WJ 1985 Thyroid, gastric, and adrenal autoimmunities
associated with insulin-dependent diabetes mellitus. Diabetes Care 8(Suppl
1):34–38
36. Betterle C, Zanette F, Pedini B, Presoto F, Rapp LB, Monciotto CM, Rigon
F 1984 Clinical and subclinical organ-specific autoimmune manifestations in
type 1 (insulin-dependent) diabetic patients and their first-degree relatives.
Diabetologia 26:431– 436
37. Landin-Olsson M, Karlsson FA, Lernmark A
´
, Sundkvist G 1992 Islet cell and
thyrogastric antibodies in 633 consecutive 15- to 34-yr-old patients in the
diabetes incidence study in Sweden. Diabetes 41:1022–1027
38. Betterle C, Mazzi PA, Pedini B, Accordi F, Cecchetto A, Presotto F 1988
Complement-fixing gastric parietal cell autoantibodies. A good marker for
the identification of type A chronic atrophic gastritis. Autoimmunity 1:267–
274
39. Oksanen A, Sipponen P, Karttunen R, Miettinen A, Veijola L, Sarna S, Raute-
lin H 2000 Atrophic gastritis and Helicobacter pylori infection in outpatients
referred for gastroscopy. Gut 46:460463
40. Ungar B, Stocks AE, Whittingham S, Martin FIR, Mackay IR 1968 Intrinsic-
factor antibody, parietal-cell antibody, and latent pernicious anaemia in di-
abetes mellitus. Lancet 2:415– 417
41. De Block CE, De Leeuw IH, Vertommen JJ, Rooman RP, Du Caju MV, Van
Campenhout CM, Weyler JJ, Winnock F, Van Autreve J, Gorus FK, Belgian
Diabetes Registry 2001
-cell, thyroid, gastric, adrenal and coeliac autoim-
munity and HLA-DQ types in type 1 diabetes. Clin Exp Immunol 126:236
241
42. Annibale B, Capurso G, Delle Fave G 2003 The stomach and iron deficiency
anaemia: a forgotten link. Dig Liver Dis 35:288 –295
43. Toh BH, Alderuccio F 2004 Pernicious anaemia. Autoimmunity 37:357–361
44. Irvine WJ, Cullen DR, Mawhinney H 1974 Natural history of autoimmune
achlorhydric atrophic gastritis. Lancet 2:482–485
45. Kaplan LM, Graeme-Cook FM 1997 Case records of the Massachusetts Gen-
eral Hospital (Case 9 –1997). A 39 year-old woman with pernicious anemia
and a gastric mass. N Engl J Med 336:861– 867
46. Hsing A, Hansson L, McLaughlin J, Nyren O, Blot W, Ekbom A, Fraumeni
Jr JF 1993 Pernicious anemia and subsequent cancer: a population-based
cohort study. Cancer 71:745–750
47. Brinton L, Gridley G, Hrubec Z, Hoover R, Fraumeni Jr JF 1989 Cancer risk
following pernicious anaemia. Br J Cancer 59:810 813
48. Carpenter C, Patalas E 2000 Case records of the Massachusetts General
Hospital (Case 40 –2000): a 38-year-old woman with gastric adenocarci-
noma. N Engl J Med 343:1951–1958
49. Karlsson FA, Burman P, Lo¨o¨ f L, Mardh S 1988 Major parietal cell antigen in
autoimmune gastritis with pernicious anemia is the acid-producing H,K-
adenosine triphosphatase of the stomach. J Clin Invest 81:475– 479
50. Toh BH, Sentry JW, Alderuccio F 2000 The causative H
/K
ATPase antigen
in the pathogenesis of autoimmune gastritis. Immunol Today 21:348 –354
51. van Driel IR, Baxter AG, Laurie KL, Zwar TD, La Gruta NL, Judd LM, Scarff
KL, Silveira PA, Gleeson PA 2002 Immunopathogenesis, loss of T cell toler-
ance and genetics of autoimmune gastritis. Autoimmun Rev 1:290 –297
52. Appelmelk B, Faller G, Claeys D, Kirchner T, Vandenbroucke-Grauls C 1998
Bugs on trial: the case of Helicobacter pylori and autoimmunity. Immunol
Today 19:296 –299
53. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini
C, van der Zee R, Telford JL, Vandenbroucke-Grauls CM, D’Elios MM, Del
Prete G 2003 Molecular mimicry between Helicobacter pylori antigens and
H,K-adenosine triphosphatase in human gastric autoimmunity. J Exp
Med 198:1147–1156
54. van Driel IR, Read S, Zwar T, Gleeson PA 2005 Shaping the T cell repertoire
to a bona fide autoantigen: lessons from autoimmune gastritis. Curr Opin
Immunol 17:570 –576
55. D’Elios MM, Appelmelk BJ, Amedei A, Bergman MP, Del Prete GF 2004
Gastric autoimmunity: the role of Helicobacter pylori and molecular mim-
icry. Trends Mol Med 10:316–323
56. Lam-Tse WK, Batstra MR, Koeleman BP, Roep BO, Bruining MG, Aanstoot
HJ, Drexhage HA 2003 The association between autoimmune thyroiditis,
autoimmune gastritis and type 1 diabetes. Pediatr Endocrinol Rev 1:22–37
57. Betterle C, Dal Pra C, Mantero F, Zanchetta R 2002 Autoimmune adrenal
insufficiency and autoimmune polyendocrine syndromes: autoantibodies, au-
toantigens, and their applicability in diagnosis and disease prediction. Endocr
Rev 23:327–364
58. Doniach D, Roitt IM, Taylor KB 1963 Autoimmune phenomena in perni-
cious anaemia: serological overlap with thyroiditis, thyrotoxicosis and sys-
temic lupus erythematosus. Br Med J 1:1374 –1379
59. De Block CE, De Leeuw IH, Rooman RP, Winnock F, Du Caju MV, Van Gaal
LF 2000 Gastric parietal cell antibodies are associated with glutamic acid
decarboxylase-65 antibodies and the HLA DQA1*0501-DQB1*0301 hap-
lotype in Type 1 diabetes mellitus. Belgian Diabetes Registry. Diabet Med
17:618622
60. De Block CE, De Leeuw IH, Decochez K, Winnock F, Van Autreve J, Van
Campenhout CM, Martin M, Gorus FK, Belgian Diabetes Registry 2001 The
presence of thyrogastric antibodies in first-degree relatives of type 1 diabetic
patients is associated with age and proband antibody status. J Clin Endocrinol
Metab 86:4358 4363
61. Burman P, Ma JY, Karlsson FA 1998 Autoimmune gastritis and pernicious
anaemia. In: Weetman AP, ed. Endocrine autoimmunity and associated con-
ditions. Dordrecht, The Netherlands: Kluwer Academic Publishers; 243–267
62. Weetman AP 2005 Non-thyroid autoantibodies in autoimmune thyroid dis-
ease. Best Pract Res Clin Endocrinol Metab 19:17–32
63. Carmel R, Spencer CA 1982 Clinical and subclinical thyroid disorders asso-
ciated with pernicious anemia. Arch Intern Med 142:1465–1469
64. Segni M, Borrelli O, Pucarelli I, Delle Fave GF, Pasquino AM, Annibale B
2004 Early manifestations of gastric autoimmunity in patients with juvenile
autoimmune thyroid disease. J Clin Endocrinol Metab 89:4944 4948
65. Elisei R, Mariotti S, Swillens S, Vassart G, Ludgate M 1990 Studies with
recombinant autoepitopes of thyroid peroxidase: evidence suggesting an
epitope shared between the thyroid and the gastric parietal cell. Autoimmu-
nity 8:65–70
66. Ungar B, Mathews J, Tait BD, Cowling DC 1981 HLA-DR patterns in per-
nicious anaemia. Br Med J (Clin Res Ed) 282:768 –770
67. Van den Berg-Loonen EM, Hilterman TL, Bins M, Engelfriet CP 1982 In-
creased incidence of HLA-DR2 in patients with pernicious anemia. Tissue
Antigens 19:158 –160
68. Baxter AG, Jordan MA, Silveira PA, Wilson WE, van Driel IR 2005 Genetic
control of susceptibility to autoimmune gastritis. Int Rev Immunol 24:55– 62
69. Karnes Jr WE, Samloff IM, Siurala M, Kekki M, Sipponen P, Kim SW, Walsh
JH 1991 Positive serum antibody and negative tissue staining for Helicobacter
pylori in subject with atrophic body gastritis. Gastroenterology 101:167–174
70. Fong TL, Dooley CP, Dehesa M, Cohen H, Carmel R, Fitzgibbons PL, Perez-
Perez GI, Blaser MJ 1991 Helicobacter pylori infection in pernicious anemia:
a prospective controlled study. Gastroenterology 100:328 –332
71. Ma JY, Borch K, Sjo¨ strand SE, Janzon L, Mardh S 1994 Positive correlation
between H,K-adenosine triphosphatase autoantibodies and Helicobacter py-
lori antibodies in patients with pernicious anemia. Scand J Gastroenterol
29:961–965
72. Annibale B, Aprile MR, D’ambra G, Caruana P, Bordi C, Delle Fave G 2000
Cure of Helicobacter pylori infection in atrophic body gastritis patients does
not improve mucosal atrophy but reduces hypergastrinemia and its related
effects on body ECL-cell hyperplasia. Aliment Pharmacol Ther 14:625– 634
73. Uibo R, Vorobjova T, Metsku¨ la K, Kisand K, Wadstro¨ m T, Kivik T 1995
Association of Helicobacter pylori and gastric autoimmunity: a population-
based study. FEMS Immunol Med Microbiol 11:65– 68
74. Negrini R, Savio A, Poiesi C, Appelmelk B, Buffoli F, Paterlini A, Cesari P,
Graffeo M, Vaira D, Franzin G 1996 Antigenic mimicry between Helicobac-
ter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis.
Gastroenterology 111:655– 665
75. Faller G, Steiniger H, Kra¨ nzlein J, Maul H, Kerkau T, Hensen J, Hahn EG,
Kirchner T 1997 Antigastric autoantibodies in Helicobacter pylori infection:
implications of histological and clinical parameters of gastritis. Gut 41:619
623
76. Claeys D, Faller G, Appelmelk BJ, Negrini R, Kirchner T 1998 The gastric
H/K ATPase is a major autoantigen in chronic Helicobacter pylori gas-
tritis with body mucosa atrophy. Gastroenterology 115:340 –347
77. Kohlstadt IC, Antunez De Mayolo EA 1993 Parietal cell antibodies among
Peruvians with gastric pathology changes. Scand J Gastroenterol 28:973–977
78. De Block CEM, De Leeuw IH, Bogers JJPM, Pelckmans PA, Ieven M, Van
Marck EAE, Van Hoof V, Ma´ day E, Van Acker KL, Van Gaal LF 2002
Helicobacter pylori, parietal cell antibodies and autoimmune gastropathy in
type 1 diabetes mellitus. Aliment Pharmacol Ther 16:281–289
79. Villako K, Kekki M, Maaroos HI, Sipponen P, Tammur R, Tamm A, Ke-
evallik R 1995 A 12-year follow-up study of chronic gastritis and Helico-
bacter pylori in a population-based random sample. Scand J Gastroenterol
30:964–967
80. Faller G, Winter M, Steininger H, Lehn N, Meining A, Bayerdorffer E, Kirch-
370 De Block et al. Autoimmune Gastritis in Type 1 Diabetes J Clin Endocrinol Metab, February 2008, 93(2):363–371
ner T 1999 Decrease of antigastric autoantibodies in Helicobacter pylori
gastritis after cure of infection. Pathol Res Pract 195:243–246
81. Rockey DC, Cello JP 1993 Evaluation of the gastrointestinal tract in patients
with iron-deficiency anemia. N Engl J Med 329:1691–1695
82. McIntyre AS, Long RG 1993 Prospective survey of investigations in outpa-
tients referred with iron deficiency anaemia. Gut 34:1102–1107
83. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J 2006 Vari-
able hematologic presentation of autoimmune gastritis: age-related progres-
sion from iron deficiency to cobalamin depletion. Blood 107:1673–1679
84. Andrews NC 1999 Disorders of iron metabolism. N Engl J Med 341:1986
1995
85. Skikne BS, Flowers CH, Cook JD 1990 Serum transferrin receptor: a quan-
titative measure of tissue iron deficiency. Blood 75:1870 –1876
86. Schade SS, Cohen RJ, Conrad ME 1968 The effect of hydrochloric acid on
iron absorption. N Engl J Med 279:672– 674
87. Lindenbaum J, Healton EB, Savage DG, Brust JCM, Garrett TJ, Podell ER,
Marcell PD, Stabler SP, Allen RH 1988 Neuropsychiatric disorders caused by
cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med
318:1720–1728
88. Lane LA, Rojas-Fernandez C 2002 Treatment of vitamin B12-deficiency ane-
mia: oral versus parenteral therapy. Ann Pharmacother 36:1268 –1272
89. De Block CE, De Leeuw IH, Pelckmans PA, Michielsen PP, Bogers JJ, Van
Marck EA, Van Gaal LF 2000 Autoimmune hepatitis, autoimmune gastritis,
and gastric carcinoid in a type 1 diabetic patient: a case report. J Diabetes
Complications 14:116 –120
90. Harvey RF, Bradshaw MJ, Davidson CM, Wilkinson SP, Davies PS 1985
Multifocal gastric carcinoid tumours, achlorhydria, and hypergastrinaemia.
Lancet 1:951–954
91. Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E 1993 Three subtypes
of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a
clinicopathologic study. Gastroenterology 104:994 –1006
92. Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD 2005 Current
status of gastrointestinal carcinoids. Gastroenterology 128:1717–1751
93. De Block CE, Colpin G, Thielemans K, Coopmans W, Bogers JJ, Pelckmans
PA, Van Marck EA, Van Hoof V, Martin M, De Leeuw IH, Bouillon R, Van
Gaal LF 2004 Neuroendocrine tumor markers and enterochromaffin-like cell
hyper/dysplasia in type 1 diabetes. Diabetes Care 27:1387–1393
94. Gough DB, Thompson GB, Crotty TB, Donohue JH, Kvols LK, Carney A,
Grant CS, Nagorney DM 1994 Diverse clinical and pathologic features of
gastric carcinoid and the relevance of hypergastrinemia. World J Surg 18:
473–479
95. Borch K, Stridsberg M, Burman P, Rehfeld JF 1997 Basal chromogranin A
and gastrin concentrations in circulation correlate to endocrine cell prolifer-
ation in type A gastritis. Scand J Gastroenterol 32:198 –202
96. Peracchi M, Gebbia C, Basilisco G, Quatrini M, Tarantino C, Vescarelli S,
Massironi S, Conte D 2005 Plasma chromogranin A in patients with auto-
immune chronic atrophic gastritis, enterochromaffin-like cell lesions and gas-
tric carcinoids. Eur J Endocrinol 152:443– 448
97. Gilligan CJ, Lawton G, Tang L, West A, Modlin I 1995 Gastric carcinoid
tumors: the biology and therapy of an enigmatic and controversial lesion.
Am J Gastroenterol 3:338 –352
98. Hirschowitz BI, Griffith J, Pellegrin D, Cummings OW 1992 Rapid regres-
sion of enterochromaffinlike cell gastric carcinoids in pernicious anemia after
antrectomy. Gastroenterology 102(4 Pt 1):1409–1418
99. Ferraro G, Annibale B, Marignani M, Azzoni C, D’Adda T, D’Ambra G,
Bordi C, Delle Fave G 1996 Effectiveness of octreotide in controlling fasting
hypergastrinemia and related enterochromaffin-like cell growth. J Clin En-
docrinol Metab 81:677–683
100. Harvey RF 1988 Spontaneous resolution of multifocal gastric enterochro-
maffin-like cell carcinoid tumours. Lancet 1:821
101. Eriksson S, Clase L, Moquist-Olsson I 1981 Pernicious anemia as a risk factor
in gastric cancer: the extent of the problem. Acta Med Scand 210:481–484
102. Schafer LW, Larson DE, Melton III LJ, Higgins JA, Zinsmeister AR 1985 Risk
of development of gastric carcinoma in patients with pernicious anemia: a
population-based study in Rochester, Minnesota. Mayo Clin Proc 60:444
448
103. Kuipers EJ 1998 Review article: relationship between Helicobacter pylori,
atrophic gastritis and gastric cancer. Aliment Pharmacol Ther 12(Suppl 1):
25–36
104. Ruddell WS, Bone ES, Hill MJ, Walters CL 1978 Pathogenesis of gastric
cancer in pernicious anaemia. Lancet 1:521–523
105. Correa P 2004 Is gastric cancer preventable? Gut 53:1217–1219
106. Fuchs CS, Mayer RJ 1995 Gastric carcinoma. N Engl J Med 333:32– 41
J Clin Endocrinol Metab, February 2008, 93(2):363–371 jcem.endojournals.org 371
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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease in which destruction of the insulin-producing β-cells in the pancreatic islets requires regular lifelong insulin replacement therapy, the only lifesaving treatment available at this time. In young persons with a genetic predisposition, it usually manifests after being exposed to environmental triggers. A subtype of autoimmune diabetes mellitus (ADM) that typically occurs in adulthood is often referred to as latent autoimmune diabetes of adults (LADA). LADA is characterized by a milder process of β-cells destruction and less intensive insulin treatment, which may become necessary even many years after diagnosis. Genetic predisposition of T1D carries an increased risk for other autoimmune diseases, such as autoimmune thyroiditis, the most frequently associated condition, and pernicious anaemia (PA), present in approximately 4% of all individuals with T1D. Here, we describe the case of a 90-year-old woman with vitiligo and a mute medical history who was admitted to our University Hospital in Perugia with hyperglycaemia and severe anaemia due to vitamin B12 (VB12) depletion. A short time after setting the beginning treatment with a basal-bolus insulin regimen, her insulin requirement rapidly declined and treatment with sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP4), was started. A complete autoimmunity screening panel showed that GAD65 and intrinsic factor autoantibodies were positive.
... These factors could contribute to the occurrence of B12 deficiency in these patients. In addition, the dietary habits which vary from one population to another could also contribute to the deficiency [10]. Biochemical and clinical vitamin B12 deficiency has been demonstrated to be highly prevalent among patients with type 1 and type 2 diabetes mellitus (T2DM) [11]. ...
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B12 deficiency causes permanent debilitating peripheral neuropathy, balance and gait disorders, tremors, frequent falls, and visual disturbances. It also shares many of the outcomes as diabetes, by attacking the autonomic nervous system (i.e. gastroparesis, impotence, urinary incontinence). However, there is insufficient data regarding association between vitamin B12 deficiency and T1D in the Egyptian population. This study aimed to find out an association between vitamin B12 deficiency and T1D in Egyptian population attending a primary care unit, to assess the need for regular screening and supplementation of vitamin B12. Subjects and Methods: The study was performed as a case control study, and was conducted in El Arab school health insurance unit in port-Said city. The study included 40 diabetic patients as study group and 40 healthy control group. Both groups were subjected to complete history, physical examination, and peripheral blood samples were withdrawn for Serum vitamin B12 level, diabetic profile (Fasting, random blood sugar and HbA1c) and anti-parietal cell antibody, (APCA) APCA was estimated by ELISA, for exclusion of PA (for group A only). The data were collected, revised and summarized, the results were tabulated and analysed. Conclusions: there is no association between vitamin B12 deficiency, and type 1 diabetes in children and adolescents apart from pernicious anemia and there is no relation between serum vitamin B 12 level and duration of diabetes, diabetic control, age or gender of type 1 diabetes children and adolescents. So, there is no need for routine screening or supplementation of vitamin B12 for children and adolescents with Type 1 diabetes.
... These factors could contribute to the occurrence of B12 deficiency in these patients. In addition, the dietary habits which vary from one population to another could also contribute to the deficiency [10]. Biochemical and clinical vitamin B12 deficiency has been demonstrated to be highly prevalent among patients with type 1 and type 2 diabetes mellitus (T2DM) [11]. ...
Article
Full-text available
B12 deficiency causes permanent debilitating peripheral neuropathy, balance and gait disorders, tremors, frequent falls, and visual disturbances. It also shares many of the outcomes as diabetes, by attacking the autonomic nervous system (i.e. gastroparesis, impotence, urinary incontinence). However, there is insufficient data regarding association between vitamin B12 deficiency and T1D in the Egyptian population. This study aimed to find out an association between vitamin B12 deficiency and T1D in Egyptian population attending a primary care unit, to assess the need for regular screening and supplementation of vitamin B12. Subjects and Methods: The study was performed as a case control study, and was conducted in El Arab school health insurance unit in port-Said city. The study included 40 diabetic patients as study group and 40 healthy control group. Both groups were subjected to complete history, physical examination, and peripheral blood samples were withdrawn for Serum vitamin B12 level, diabetic profile (Fasting, random blood sugar and HbA1c) and anti-parietal cell antibody, (APCA) APCA was estimated by ELISA, for exclusion of PA (for group A only). The data were collected, revised and summarized, the results were tabulated and analysed. Conclusions: there is no association between vitamin B12 deficiency, and type 1 diabetes in children and adolescents apart from pernicious anemia and there is no relation between serum vitamin B 12 level and duration of diabetes, diabetic control, age or gender of type 1 diabetes children and adolescents. So, there is no need for routine screening or supplementation of vitamin B12 for children and adolescents with Type 1 diabetes.
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Resumen Objetivo Conocer la prevalencia de las enfermedades autoinmunes (EA) asociadas a la diabetes mellitus tipo 1 (DM1). Pacientes y métodos Estudio transversal analítico, anidado en una cohorte prospectiva multicéntrica de 1.121 adultos con DM1 con seguimiento activo en consultas de endocrinología. Se analizaron variables sociodemográficas, clínicas y la presencia de EA en el año 2010 y en el año 2020. Resultados En este segundo análisis, la edad media fue de 49,4 ± 12,8 años, siendo el 49,5% varones, con una mediana de tiempo de evolución de la DM1 de 27,1 años (20,7-35,1) y una media de hemoglobina glicosilada de 7,66 ± 1,06%. Existe un incremento absoluto del 13% (IC 95% 11-15) (p < 0,001) de pacientes con al menos una EA y un incremento absoluto de 11,6% (IC 95% 9,7-13,5) (p < 0,0001) de cualquier tipo de enfermedad tiroidea autoinmune (ETA) tras 10 años de seguimiento. Así mismo, aumentó la prevalencia de manera estadísticamente significativa de la gastritis autoinmune, enfermedad celiaca y otras EA. En el análisis de regresión logística multivariante, los factores que se asociaron de manera independiente a la presencia de ETA fueron el género femenino (OR 2,9 [IC 95% 2,3-3,7]; p < 0,0001) y la DM1 tipo b (OR 0,5 [IC 95% 0,3-0,9]; p = 0,041). Conclusiones Tras 10 años de seguimiento activo se produce un incremento sustancial de otro tipo de EA en pacientes con DM1. Parece necesario realizar un cribado sistemático de dichas EA para optimizar el seguimiento de los pacientes con DM1, fundamentalmente de la ETA.
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A 60‐year‐old woman presented with a protruding tumor at the anterior wall of the middle gastric body, and she was positive for anti‐parietal cells antibodies with elevated serum gastrin level. Final diagnosis was a mixed neuroendocrine–non‐neuroendocrine neoplasm consisting of adenocarcinoma (tub1) and neuroendocrine tumor G2 with autoimmune gastritis. Gastric mixed neuroendocrine–non‐neuroendocrine neoplasms (MiNENs) composed of neuroendocrine tumor (NET) and adenocarcinoma is extremely rare in the autoimmune gastritis background. Molecular analysis of each component of the NET and adenocarcinoma will define the pathogenesis of this rare gastric MiNEN.
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This study was undertaken to evaluate the role of serum transferrin receptor measurements in the assessment of iron status. Repeated phlebotomies were performed in 14 normal volunteer subjects to obtain varying degrees of iron deficiency. Serial measurements of serum iron, total iron-binding capacity, mean cell volume (MCV), free erythrocyte protoporphyrin (FEP), red cell mean index, serum ferritin, and serum transferrin receptor were performed throughout the phlebotomy program. There was no change in receptor levels during the phase of storage iron depletion. When the serum ferritin level reached subnormal values there was an increase in serum receptor levels, which continued throughout the phlebotomy program. Functional iron deficiency was defined as a reduction in body iron beyond the point of depleted iron stores. The serum receptor level was a more sensitive and reliable guide to the degree of functional iron deficiency than either the FEP or MCV. Our studies indicate that the serum receptor measurement is of particular value in identifying mild iron deficiency of recent onset. The iron status of a population can be fully assessed by using serum ferritin as a measure of iron stores, serum receptor as a measure of mild tissue iron deficiency, and hemoglobin concentration as a measure of advanced iron deficiency.
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The effects of long term (6-month), high (500-micrograms), once a day administration of octreotide on enterochromaffin-like (ECL) cell proliferation were evaluated in eight patients with hypergastrinemic atrophic gastritis at risk for the development of gastric carcinoids. Fasting gastrin levels were determined during treatment and up to 6 months after the end of treatment. Chromogranin A, hCG alpha, and somatostatin-immunostained cells were morphometrically evaluated in biopsy specimens of corpus mucosa taken before and after treatment. The results showed that gastrin levels significantly decreased from 950 to 238 ng/L (-74.9%; P < 0.01) at the end of treatment, a decrease that persisted 6 months after the end of treatment (450 ng/L; P < 0.05). The volume density of CgA cells (mostly ECL cells) decreased from 3.7% to 2.1% of the epithelial component (-43%; P < 0.014), that of hCG alpha-storing ECL cells decreased by 85% (P < 0.0007), and that of somatostatin-stained cells decreased by 74% (P < 0.04). No ...
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A quarter of type 1 diabetic patients have thyrogastric autoantibodies (thyroid peroxidase and gastric parietal cell antibodies). Clinical, immune, and genetic risk factors help predict antibody status. First degree relatives of these patients may also frequently exhibit these antibodies. We assessed the prevalence of thyrogastric antibodies and dysfunction in first degree relatives in relation to age, gender, human leukocyte antigen-DQ type, β-cell antibody (islet cell, glutamic acid decarboxylase-65, and tyrosine phosphatase antibodies), and proband thyrogastric antibody status. Sera from 272 type 1 diabetic patients (116 men and 156 women; mean age, 27 ± 18 yr; duration, 10 ± 9 y), 397 first degree relatives (192 men and 205 women; parents/siblings/offspring, 48/222/127; age, 22 ± 10 yr), and 100 healthy controls were tested for islet cell antibodies and gastric parietal cell antibodies by indirect immunofluorescence and for tyrosine phosphatase, glutamic acid decarboxylase-65, and thyroid peroxidase a...
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In rats, hypergastrinemia due to achlorhydria produced by antisecretory drugs or resection of the gastric fundus leads to enterochromaffinlike (ECL) cell hyperplasia and gastric carcinoids. In humans, achlorhydria due to pernicious anemia may also lead to ECL cell hyperplasia and multicentric gastric carcinoids in as many as 5% of cases. To examine the apparent gastrin dependence of gastric ECL carcinoids, three patients were studied (2 men aged 59 and 73 years; 1 woman aged 45 years) who had pernicious anemia, serum gastrin concentrations of >1000 ng/L (>1000 pg/mL), and multicentric gastric carcinoids. Antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6–16 weeks. In each of the three patients, a focus of microcarcinoid was found at 12–18 months. Further follow-up in each of the three patients 21–30 months after antrectomy again showed no carcinoids or ECL cell hyperplasia. It is concluded that multicentric ECL gastric carcinoids in patients with pernicious anemia and achlorhydria appear to be gastrin dependent and disappear after normalization of serum gastrin by antrectomy. Antrectomy rather than total gastrectomy may be the most appropriate treatment for this condition.
Chapter
In 1849 in the London Medical Gazette Dr Thomas Addison drew attention to a remarkable form of anaemia of idiopathic origin which in his view had not received the interest it deserved, although its existence had occasionally been pointed out by others. He described the clinical picture in three men with insidious anaemia who at postmortem examination all displayed “a diseased condition of the suprarenal capsules” [1]. Pathogenic relevance of the anaemia was suspected, but this was questioned by Dr Austin Flint, who himself had had experience of patients with insidious anaemia and who considered the possibility of a degenerative disease of the gastric tubular glands. At a clinical lecture at the Long Island College hospital in 1860, he referred to an article by Dr Handheld Jones, who some years earlier had published his findings on light microscopic examinations of a hundred stomachs. In 12 cases considerable degeneration of the gastric tubuli was noted. Dr Flint stated: “It is not difficult to see how fatal anaemia must follow an amount of degenerative disease reducing the amount of gastric juice so far that the assimilation of food is rendered wholly inadequate to the wants of the body. I shall be ready to claim the merit of this idea when the difficult and laborious researches of someone have shown it to be correct” [2]. Seventeen years later Fenwick observed atrophic glands and failure of the scrapings of the gastric mucosa to digest egg white in autopsy studies [3], and during the following decades, after analysis of the amount of ‘free acid’ in gastric juice from patients with insidious anaemia, several investigators reported achylia to be a constant finding [4].
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• Of 162 patients with pernicious anemia whom we studied, 24.1% had clinical thyroid disease; 11.7% were hypothyroid and 8.6% were hyperthyroid. When abnormal serum thyroid-stimulating hormone (TSH) levels were also considered, thyroid disorders existed in 48.3% of 143 patients. Increased or decreased TSH levels as the sole dysfunction occurred in 14.7% and 6.3% of cases, respectively, and were often associated with thyroid antibodies. The high TSH group fits the picture of subclinical hypothyroidism. The nature of the low TSH group remains to be defined. We conclude that TSH screening in patients with pernicious anemia uncovers frequent abnormalities, which are superimposed on a higher coincidence of overt thyroid disease than previously described. Interestingly, also, eight of nine hyperthyroid patients and all seven patients with low TSH levels had blood type O, contrasting significantly with hypothyroid subjects, who more often had blood type A, and with patients without thyroid disorders. (Arch Intern Med 1982;142:1465-1469)