Miriam Cellini, Maria Giulia Santaguida, Camilla Virili, Silvia Capriello, Nunzia Brusca,
Lucilla Gargano and Marco Centanni*
Endocrinology Unit, Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University, Latina, Italy
The term “thyrogastric syndrome” defines the association between autoimmune
thyroid disease and chronic autoimmune gastritis (CAG), and it was first described
in the early 1960s. More recently, this association has been included in polyglandular
autoimmune syndrome type IIIb, in which autoimmune thyroiditis represents
the pivotal disorder. Hashimoto’s thyroiditis (HT) is the most frequent autoimmune
disease, and it has been reported to be associated with gastric disorders in 10–40%
of patients while about 40% of patients with autoimmune gastritis also present HT.
Some intriguing similarities have been described about the pathogenic mechanism of
these two disorders, involving a complex interaction among genetic, embryological,
immunologic, and environmental factors. CAG is characterized by a partial or total
disappearance of parietal cells implying the impairment of both hydrochloric acid and
intrinsic factor production. The clinical outcome of this gastric damage is the occurrence
of a hypochlorhydric-dependent iron-deficient anemia, followed by pernicious
anemia concomitant with the progression to a severe gastric atrophy. Malabsorption
of levothyroxine may occur as well. We have briefly summarized in this minireview the
most recent achievements on this peculiar association of diseases that, in the last
years, have been increasingly diagnosed.
Keywords: thyroiditis, polyglandular autoimmune syndrome, thyroxine malabsorption, gastric atrophy, pernicious
anemia, Helicobacter pylori infection, cellular immunity
INTRODUCTION
The thyrogastric syndrome was initially described in the early 1960s and initially characterized
by the presence of thyroid autoantibodies in patients with pernicious anemia, the latter being
used as synonymous for atrophic gastritis (1). More recently, the autoimmune gastritis has been
better characterized classifying chronic atrophic gastritis, with or without the PA, based on the
histological evaluation and the presence of serum parietal cell (PCA) and/or intrinsic factor
(IFA) autoantibodies (2, 3). Based on these criteria, the association between autoimmune thyroid
disorders and chronic autoimmune gastritis (CAG) has also been reassessed (4, 5) and nowadays
is included in the adult form of polyglandular autoimmune syndrome (PAS), characterized by
two or more endocrine and non-endocrine autoimmune disorders (6). In particular, Betterle
and colleagues have proposed the inclusion of thyrogastric syndrome in the PAS Type 3b, in
which Hashimoto’s thyroiditis (HT) occurs also associated with non-endocrine autoimmune
gastrointestinal disorders and where it plays a pivotal role (7, 8). This is in keeping with the
Table 1 | Shared characteristics between thyroid and stomach.
Embryological origin • Primitive gut for both thyroid and stomach
Cell features • Presence of cells polarity
• Cells characterized by apical microvilli
Biochemical features • Presence of Na+/I− symporter (sodium-iodide
symporter)
• Presence of peroxidase isoenzymes (TPO and GPO)
Function • Ability to concentrate iodine
• Presence of antioxidative activities
• Secretion of mucinous glycoproteins: thyroglobulin
and mucine
Pathogenesis • Cellular immune involvement
• Similarity of autoaggressive processes
• Mechanisms of cellular damage
• Expression of autoantigens and related cross-reacting
autoantibodies
Pathology • Clinically related autoimmune disorders
• Peculiar associative clinical features
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evidence that chronic autoimmune thyroiditis represents the
more prevalent autoimmune disorder worldwide making the
frequency of thyrogastric syndrome quite high (4). This notion
is supported by the high percentage (12–40%) of positivity of
PCA in adult patients with HT (9) which, in turn, is present
in approximately 40% of patients with atrophic gastritis (10).
Besides the fact that the thyroid and the stomach share some
embryological and biochemical features (11), some intriguing
similarities have been observed even in the putative pathogenic
mechanisms, which characterize the thyrogastric syndrome
(12). Furthermore, some specific clinical features characterize
or lead to the suspicion of the coexistence of both thyroid and
gastric autoimmune (13, 14) disorders. These similar peculiar
features will be briefly described in this minireview.
THYROID AND STOMACH:
EMBRYOLOGIC DERIVATION AND ROLE
of Na+/I
− SYMPORTER
The thyroid gland and stomach, despite the different localization
and function, share some similar morphologic and functional
characteristics, likely due to their common embryologic origin
(11). In fact, the thyroid gland develops from the primitive gut
and therefore thyroid follicular share with parietal cells the same
endodermal origin. Also, both these cells are polarized and are
characterized by the presence of apical microvilli housing enzymatic
activities.
Furthermore, gastric mucosal and thyroid follicular cells
both show the ability to concentrate and transport iodine across
the cell membrane (15). This process is mediated by the Na+/I−
symporter (15) and involves similar enzymes with an efficient
peroxidase activity (12) (Table  1). Furthermore, besides its
essential role for the synthesis of thyroid hormones, iodine
regulates the proliferation of gastric mucosal cells (16). In fact,
in the presence of gastric peroxidase, iodine acts as an electron
donor and participates in the removal of free oxygen radicals,
thus playing an antioxidant action (17). These effects may explain
the regulatory role of iodine in the proliferation of mucosal cells
and its protective role against gastric carcinogenesis (11, 16).
This hypothesis has been confirmed by the reported link among
iodine deficiency, goiter, and increased risk of developing gastric
cancer (18).
CHRONIC AUTOIMMUNE/HASHIMOTO’S
THYROIDITIS AND CAG
Chronic lymphocytic thyroiditis is the most frequent autoimmune
disorder and represents the prototype of organ-specific
autoimmunity (19). Its prevalence, despite some difference of
sex, age, race, and iodine intake, reaches about 5% in the general
population (20). Much less frequent is the chronic autoimmune
atrophic gastritis (type A gastritis or body/fundus gastritis), which
represents only some 5% of the whole spectrum of chronic gastritis
and must be differentiated from the one associated with chronic
Helicobacter pylori (Hp) infection (type B gastritis or antral gastritis)
(21, 22). HT is characterized by diffuse inflammatory changes
with lymphocytic infiltration of the thyroid gland, leading to the
destruction of the thyroid epithelial cells with subsequent fibrosis
(23). Similarly, autoimmune gastritis is a chronic inflammatory
disease involving gastric body and fundus, with the progressive
reduction and/or disappearance of the native gastric glands that
are sometimes replaced by intestinal or pyloric epithelium (metaplasia)
(3). The natural history of HT is the progressive reduction
of thyroid function till overt hypothyroidism (24) with a rate of
progression of 2–4% per year (23), while that of gastric atrophy
features the progressive reduction, till disappearance, of parietal
cells, leading to reduced or absent acid production (3, 22). These
alterations interfere with absorption of essential nutrients leading,
at first, to iron-deficient anemia, followed by PA if the self-injurious
process involves the IFA (13). Increased risk of developing neuroendocrine
tumors and gastric adenocarcinoma is also associated
with the severity of damage of gastric mucosa (22).
Pathogenesis
Both these autoimmune disorders are characterized by a complex
interaction between genetic susceptibility and environmental factors
that results in the loss of immune tolerance to self-antigens
and in the development of autoimmune diseases. The loss of
immune tolerance may involve alteration both in the central tolerance
with reactive T cells escaped from intrathymic deletion and
in the peripheral tolerance as in the case of defective T regulatory
lymphocytes (25, 26). Genetic susceptibility has been confirmed
for both diseases since their incidence is higher among identical
twins and first-degree relatives as well as their presence may be
observed in association with further autoimmune disorders (6, 7,
20, 26). Both of these disorders show a definite association with
different HLA aplotypes; in HT, it has also been proven that the
involvement of many other immunoregulatory genes (27), while
this issue has not been elucidated in the pathogenesis of human
autoimmune gastritis (26).
Several environmental factors seem to be involved in the
pathogenesis of HT (excessive iodine intake, selenium deficiency,
and specific drugs use), while very weak evidence supports a role
for infectious agents as trigger for this disease (hepatitis C virus,
HHV-6, and Yersinia) (27). The role of environmental factors
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in triggering autoimmune gastritis has been more studied and
a stronger link between H. pylori infection and CAG has been
detected, despite not sufficient to establish a causative relationship
between these two diseases (21). H. pylori infection affects
approximately 50% of the world population and is in turn the most
common cause of chronic gastritis. At first, the H. pylori infection
involves the gastric antrum, but in some patients it may extend
into the gastric body (pangastritis) and, in genetically predisposed
individuals, it may be a trigger for autoimmune atrophic gastritis,
being this hypothesis still debated (3, 28, 29). The pathogenic
link may be found in a cross-reactivity mechanism (molecular
mimicry) (30): in fact, the Hp infection may induce the proliferation
of CD4+ T lymphocytes that recognize epitopes of H. pylori
structurally similar to those of H+/K+ATPase, an enzyme found
on the apical membrane of parietal cells (31). Indeed, dendritic
cells may present these shared epitopes to naïve T cells and, in
the absence of peripheral tolerance, a Th1-driven autoreactive
clone is activated (28). Again, the cellular immune mechanisms
of autoimmune thyroiditis show some similarities with those of
CAG. In HT, inflammation leads to secretion of IFN-γ, a cytokine
turning thyrocytes into antigen-presenting cells (32). The variation
of costimulatory factors that drive the binding between an
autoantigen and the T-cell receptor allows the proliferation and
polarization of autoreactive effector lymphocytes (27). Due to a
Th17  cell polarization, the inflammatory process and the subsequent
fibrosis seem to prevail in the early phase of thyroiditis
(33); in a later phase, when the lymphocytic infiltration and the
parenchymal destruction are prevalent, a polarized Th1 profile
has been reported (34, 35). The Th1 lymphocytes are able to
aid cytotoxic T-lymphocytes and to produce specific cytokines
(TNF-α and IFN-γ) able to induce the cellular apoptosis (35) in
thyroid cells. The association of a gastric autoimmune disorder
has been shown to add a Th2 cytokine profile to the described
ones (36). The precise mechanism leading to thyrocytes and/or
parietal cell death is still unknown. However, the involvement
of Fas upregulation in thyrocytes, due to IL-1beta produced by
activated macrophages, has been proven (37). Normal thyrocytes,
in fact, express FasL but not Fas, while their concomitant
expression induces an autocrine interaction that may represent
the main mechanism inducing apoptosis (37). In experimental
autoimmune gastritis, also parietal cells express Fas that, in this
case, could trigger apoptosis by binding Fas-ligand on infiltrating
T cells (28). Following cells damage, the production of specific
autoantibodies ensues in epiphenomenal fashion (34). Cellular
and humoral immune cooperation characterizes both autoimmune
thyroiditis and gastritis leading to the production of
specific autoantibodies (antithyroperoxidase, antithyroglobulin,
and antiparietal cell antibodies). These autoantibodies are of
paramount importance in the diagnosis but of little, if any, in the
pathogenesis of these autoimmune disorders.
CLINICAL ASPECTS OF THYROGASTRIC
SYNDROME
Clinical pathological aspects of this association are attributable
to malabsorption of iron and thyroxine, both linked to a reduced
gastric acid secretion.
Iron Deficiency and PA
Chronic atrophic gastritis is clinically silent in most cases
and only a small percentage of patients may complain about
dyspeptic symptoms. A well-described clinical feature of
thyrogastric syndrome is represented by the presence of an
iron-deficient and/or a PA. In fact, it has been demonstrated
that an iron-deficient anemia, refractory to oral iron therapy,
in patients with HT, may be due to chronic atrophic gastritis
(13). The clinical signs of this disease appear after several years
of its onset, when the progressive reduction to disappearance
of the parietal cells leads to atrophy of the gastric mucosa,
impairing the absorption of iron, vitamin B12 (cobalamin),
folate, and other nutrients (22). At the physiologic acid pH
(1.5–2) of the stomach, ascorbic acid, the most active form of
vitamin C, allows iron reduction from the nutritional ferric (Fe
+++) to the ferrous form (Fe ++), thus forming a complex that
drives the absorption in the upper portion of the small intestine
(22). In the initial phase of the atrophic gastritis, the damage of
parietal cells can lead to iron deficiency microcytic anemia as
the only clinical sign (38). When the gastric atrophy becomes
severe and/or the IFA is no longer produced, even the absorption
of cobalamin becomes compromised. Besides hydrochloric
acid that promotes the separation of vitamin B12 from food,
the parietal cells also produce the IFA that binds cobalamin
and pipes it to the distal ileum, where it is absorbed following
a binding to specific receptors (39). Vitamin B12 deficiency is
responsible for hematologic changes (macrocytic anemia) and
specific neurological disorders (paresthesia and neuritis) which
are peculiar of PA (22).
Thyroxine Malabsorption in Chronic
Gastritis
The worldwide used pharmaceutical form of thyroxine (sodium
levothyroxine, T4) is obtained by native hormone through its
salification with sodium hydroxide. The absorption of T4 occurs
in all sections of small intestine being anyway incomplete and
ranging from 62 to 82% of the ingested dose (40). However,
increasing evidence of a relevant role of the intact gastric acid
secretion on the subsequent intestinal absorption of sodium
levothyroxine has been reported in the last years (41). In fact,
an increased therapeutic T4 dose has been described in patients
with gastric disorders (Hp infection, chronic gastritis, gastric
atrophy) or chronically treated with proton pump inhibitors or
in non-fasting patients (41–43). All these conditions are characterized
by a modified gastric pH that may affect T4 absorption
by changing the ionization status, as already described for
iron, or the dissolution process of the pharmaceutical T4 form.
Furthermore, in  vitro studies have shown the pH dependency
of the dissolution profile of different T4 preparations (44). This
evidence boosted the research for novel thyroxine formulations
as liquid or softgel capsules. These ones showed, as compared to
the classic tablet formulation, a similar or better bioavailability as
well as a lower number of excipients (45, 46). In clinical studies,
softgel or liquid formulations performed better in patients with
gastric disorders (47, 48) and in proton pump inhibitors users
(49, 50).
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Frontiers in Endocrinology | www.frontiersin.org April 2017 | Volume 8 | Article 92
In conclusion, the association of thyroid and gastric autoimmune
disorders represents a frequent syndrome, included in the
autoimmune polyendocrine syndrome. The similar or even common
biochemical and pathogenic features fully support the term
thyrogastric disease described some 60 years ago. From a clinical
standpoint, the presence of iron-deficient anemia and thyroxine
malabsorption may represent an alert signal for the presence of
a gastric disorder in patients with thyroid autoimmunity and
should trigger a specific diagnostic workup.
AUTHOR CONTRIBUTIONS
All authors listed have made substantial, direct, and intellectual
contribution to the work and approved it for publication.
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
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