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 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.

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).

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).

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.