Hashimoto’s Thyroiditis and Autoimmune Gastritis


La thyroïdite de Hashimoto et la gastrite auto-immune.

Résumé :

Le terme «syndrome thyrogastrique» définit l’association entre la maladie thyroïdienne auto-immune et la gastrite auto-immune chronique (CAG), et il a été décrit pour la première fois au début des années 1960. Plus récemment, cette association a été incluse dans le syndrome auto-immun polyglandulaire de type IIIb, dans lequel la thyroïdite auto-immune représente le trouble central. La thyroïdite de Hashimoto (HT) est la maladie auto-immune la plus fréquente et elle a été associée à des troubles gastriques chez 10 à 40% des patients, tandis qu’environ 40% des patients atteints de gastrite auto-immune présentent également une HT. Certaines similitudes intrigantes ont été décrites sur le mécanisme pathogène de ces deux troubles, impliquant une interaction complexe entre les gènes, facteurs embryologiques, immunologiques et environnementaux. Le CAG est caractérisé par une disparition partielle ou totale des cellules pariétales impliquant une altération de la production d’acide chlorhydrique et de facteur intrinsèque. Le résultat clinique de cette lésion gastrique est la survenue d’une anémie ferriprive hypochlorhydrique, suivie d’une anémie pernicieuse concomitante avec la progression vers une atrophie gastrique sévère. Une malabsorption de la lévothyroxine peut également survenir. Nous avons brièvement résumé dans cette mini review les réalisations les plus récentes sur cette association particulière de maladies qui, au cours des dernières années, ont été diagnostiquées de plus en plus.                                                                 source : https://www.ncbi.nlm.nih.gov/pubmed/28491051

Zone contenant les pièces jointes



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
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
• 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
Pathology • Clinically related autoimmune disorders
• Peculiar associative clinical features
Cellini et al. Thyrogastric Syndrome
Frontiers in Endocrinology | www.frontiersin.org April 2017 | Volume 8 | Article 92
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.
of Na+/I
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
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 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).
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
Cellini et al. Thyrogastric Syndrome
Frontiers in Endocrinology | www.frontiersin.org April 2017 | Volume 8 | Article 92
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 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
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).
Cellini et al. Thyrogastric Syndrome
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.
All authors listed have made substantial, direct, and intellectual
contribution to the work and approved it for publication.
1. Doniach D, Roitt IM, Taylor KB. Autoimmune phenomena in pernicious
anaemia. Serological overlap with thyroiditis, thyrotoxicosis, and systemic
lupus erythematosus. Br Med J (1963) 1:1374–9. doi:10.1136/bmj.1.5342.1374
2. Sipponen P, Maaroos HI. Chronic gastritis. Scand J Gastroenterol (2015)
50:657–67. doi:10.3109/00365521.2015.1019918
3. Neumann WL, Coss E, Rugge M, Genta RM. Autoimmune atrophic
gastritis – pathogenesis, pathology and management. Nat Rev Gastroenterol
Hepatol (2013) 10:529–41. doi:10.1038/nrgastro.2013.101
4. Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G,
et al. Atrophic body gastritis in patients with autoimmune thyroid disease:
an underdiagnosed association. Arch Intern Med (1999) 159:1726–30.
5. Lahner E, Intraligi M, Buscema M, Centanni M, Vannella L, Grossi E, et al.
Artificial neural networks in the recognition of the presence of thyroid disease
in patients with atrophic body gastritis. World J Gastroenterol (2008) 14:563–8.
6. Kahaly GJ. Polyglandular autoimmune syndromes. Eur J Endocrinol (2009)
161:11–20. doi:10.1530/EJE-09-0044
7. Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency
and autoimmune polyendocrine syndromes: autoantibodies, autoantigens,
and their applicability in diagnosis and disease prediction. Endocr Rev
(2002) 23:327–64. doi:10.1210/edrv.23.3.0466
8. Fallahi P, Ferrari SM, Ruffilli I, Elia G, Biricotti M, Vita R, et al. The association
of other autoimmune diseases in patients with autoimmune thyroiditis: review
of the literature and report of a large series of patients. Autoimmun Rev (2016)
15:1125–8. doi:10.1016/j.autrev.2016.09.009
9. Checchi S, Montanaro A, Ciuoli C, Brusco L, Pasqui L, Fioravanti C, et al.
Prevalence of parietal cell antibodies in a large cohort of patients with autoimmune
thyroiditis. Thyroid (2010) 20:1385–9. doi:10.1089/thy.2010.0041
10. Lahner E, Centanni M, Agnello G, Gargano L, Vannella L, Iannoni C, et al.
Occurrence and risk factors for autoimmune thyroid disease in patients
with atrophic body gastritis. Am J Med (2008) 121:136–41. doi:10.1016/j.
11. Gołkowski F, Szybiński Z, Rachtan J, Sokołowski A, Buziak-Bereza M,
Trofimiuk M, et al. Iodine prophylaxis – the protective factor against stomach
cancer in iodine deficient areas. Eur J Nutr (2007) 46:251–6. doi:10.1007/
12. Kandemir EG, Yonem A, Narin Y. Gastric carcinoma and thyroid status. J Int
Med Res (2005) 33:222–7. doi:10.1177/147323000503300210
13. Sibilla R, Santaguida MG, Virili C, Gargano L, Nardo S, Della Guardia M,
et al. Chronic unexplained anemia in isolated autoimmune thyroid disease or
associated with autoimmune related disorders. Clin Endocrinol (Oxf) (2008)
68:640–5. doi:10.1111/j.1365-2265.2007.03091.x
14. Centanni M. Thyroxine treatment: absorption, malabsorption, and
novel therapeutic approaches. Endocrine (2013) 43:8–9. doi:10.1007/
15. Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I- symporter (NIS):
mechanism and medical impact. Endocr Rev (2014) 35:106–49. doi:10.1210/
16. Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A. Role of iodine
in evolution and carcinogenesis of thyroid, breast and stomach. Adv Clin Path
(2000) 4:11–7.
17. Das D, De PK, Banerjee RK. Thiocyanate, a plausible physiological electron
donor of gastric peroxidase. Biochem J (1995) 305:59–64. doi:10.1042/
18. Tabaeizadeh M, Haghpanah V, Keshtkar A, Semnani S, Roshandel G, Adabi
K, et al. Goiter frequency is more strongly associated with gastric adenocarcinoma
than urine iodine level. J Gastric Cancer (2013) 13:106–10. doi:10.5230/
19. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical
and diagnostic criteria. Autoimmun Rev (2014) 13:391–7. doi:10.1016/j.
20. Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi
P. Autoimmune thyroid disorders. Autoimmun Rev (2015) 14:174–80.
21. Venerito M, Radünz M, Reschke K, Reinhold D, Frauenschläger K, Jechorek
D, et  al. Autoimmune gastritis in autoimmune thyroid disease. Aliment
Pharmacol Ther (2015) 41:686–93. doi:10.1111/apt.13097
22. Toh BH. Diagnosis and classification of autoimmune gastritis. Autoimmun
Rev (2014) 13:459–62. doi:10.1016/j.autrev.2014.01.048
23. Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med (2003)
348:2646–55. doi:10.1056/NEJMra021194
24. Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune
thyroid disease: old and new players. Eur J Endocrinol (2014) 170:R241–52.
25. Kristensen B. Regulatory B and T cell responses in patients with autoimmune
thyroid disease and healthy controls. Dan Med J (2016) 63:B5177.
26. Toh BH, Chan J, Kyaw T, Alderuccio F. Cutting edge issues in autoimmune
gastritis. Clin Rev Allergy Immunol (2012) 42:269–78. doi:10.1007/
27. Ajjan RA, Weetman AP. The pathogenesis of Hashimoto’s thyroiditis: further
developments in our understanding. Horm Metab Res (2015) 47:702–10.
28. Varbanova M, Frauenschläger K, Malfertheiner P. Chronic gastritis – an
update. Best Pract Res Clin Gastroenterol (2014) 28:1031–42. doi:10.1016/
29. Smyk DS, Koutsoumpas AL, Mytilinaiou MG, Rigopoulou EI, Sakkas LI,
Bogdanos DP. Helicobacter pylori and autoimmune disease: cause or bystander.
World J Gastroenterol (2014) 20:613–29. doi:10.3748/wjg.v20.i3.613
30. Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C,
et al. Molecular mimicry between Helicobacter pylori antigens and H+, K+ –
adenosine triphosphatase in human gastric autoimmunity. J Exp Med (2003)
198:1147–56. doi:10.1084/jem.20030530
31. D’Elios MM, Bergman MP, Azzurri A, Amedei A, Benagiano M, De Pont JJ,
et al. H+/K+-ATPase (proton pump) is the target autoantigen of Th1-type
cytotoxic T cells in autoimmune gastritis. Gastroenterology (2001) 120:377–86.
32. Yu S, Sharp GC, Braley-Mullen H. Thyrocytes responding to IFN-gamma are
essential for development of lymphocytic spontaneous autoimmune thyroiditis
and inhibition of thyrocyte hyperplasia. J Immunol (2006) 176:1259–65.
33. Figueroa-Vega N, Alfonso-Pérez M, Benedicto I, Sánchez-Madrid F,
González-Amaro R, Marazuela M. Increased circulating pro-inflammatory
cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis. J Clin Endocrinol
Metab (2010) 95:953–62. doi:10.1210/jc.2009-1719
34. Weetman AP. Cellular immune responses in autoimmune thyroid disease. Clin
Endocrinol (Oxf) (2004) 61:405–13. doi:10.1111/j.1365-2265.2004.02085.x
35. Li D, Cai W, Gu R, Zhang Y, Zhang H, Tang K, et al. Th17 cell plays a role in
the pathogenesis of Hashimoto’s thyroiditis in patients. Clin Immunol (2013)
149:411–20. doi:10.1016/j.clim.2013.10.001
36. Santaguida MG, Nardo S, Del Duca SC, Lococo E, Virili C, Gargano L, et al.
Increased interleukin-4-positive lymphocytes in patients with Hashimoto’s
Cellini et al. Thyrogastric Syndrome
Frontiers in Endocrinology | www.frontiersin.org April 2017 | Volume 8 | Article 92
thyroiditis and concurrent non-endocrine autoimmune disorders. Clin Exp
Immunol (2011) 165:148–54. doi:10.1111/j.1365-2249.2011.04419.x
37. De Maria R, Testi R. Fas-FasL interactions: a common pathogenetic mechanism
in organ-specific autoimmunity. Immunol Today (1998) 19:121–5.
38. Hershko C, Ronson A, Souroujon M, Maschler I, Heyd J, Patz J. Variable
hematologic presentation of autoimmune gastritis: age-related progression
from iron deficiency to cobalamin depletion. Blood (2006) 107:1673–9.
39. Toh BH, Alderuccio F. Pernicious anemia. Autoimmunity (2004) 37:357–61.
40. Hays MT. Localization of human thyroxine absorption. Thyroid (1991)
1:241–8. doi:10.1089/thy.1991.1.241
41. Centanni M, Gargano L, Canettieri G, Viceconti N, Franchi A, Delle Fave G,
et al. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N
Engl J Med (2006) 354:1787–95. doi:10.1056/NEJMoa043903
42. Lahner E, Virili C, Santaguida MG, Annibale B, Centanni M. Helicobacter
pylori infection and drugs malabsorption. World J Gastroenterol (2014)
20:10331–7. doi:10.3748/wjg.v20.i30.10331
43. Bach-Huynh TG, Nayak B, Loh J, Soldin S, Jonklaas J. Timing of levothyroxine
administration affects serum thyrotropin concentration. J Clin Endocrinol
Metab (2009) 94:3905–12. doi:10.1210/jc.2009-0860
44. Pabla D, Akhlaghi F, Zia H. A comparative pH-dissolution profile study of
selected commercial levothyroxine products using inductively coupled plasma
mass spectrometry. Eur J Pharm Biopharm (2009) 72:105–10. doi:10.1016/
45. Virili C, Trimboli P, Romanelli F, Centanni M. Liquid and softgel levothyroxine
use in clinical practice: state of the art. Endocrine (2016) 54:3–14. doi:10.1007/
46. Vita R, Fallahi P, Antonelli A, Benvenga S. The administration of l-thyroxine as
soft gel capsule or liquid solution. Expert Opin Drug Deliv (2014) 11:1103–11.
47. Santaguida MG, Virili C, Del Duca SC, Cellini M, Gatto I, Brusca N, et al.
Thyroxine softgel capsule in patients with gastric-related T4 malabsorption.
Endocrine (2015) 49:51–7. doi:10.1517/17425247.2014.918101
48. Fallahi P, Ferrari SM, Ruffilli I, Antonelli A. Reversible normalisation of serum
TSH levels in patients with autoimmune atrophic gastritis who received l-T4
in tablet form after switching to an oral liquid formulation: a case series. BMC
Gastroenterol (2016) 24(16):22. doi:10.1186/s12876-016-0439-y
49. Vita R, Benvenga S. Tablet levothyroxine (l-T4) malabsorption induced by
proton pump inhibitor; a problem that was solved by switching to l-T4 in soft
gel capsule. Endocr Pract (2014) 20:e38–41. doi:10.4158/EP13316.CR
50. Vita R, Saraceno G, Trimarchi F, Benvenga S. Switching levothyroxine from
the tablet to the oral solution formulation corrects the impaired absorption of
levothyroxine induced by proton-pump inhibitors. J Clin Endocrinol Metab
(2014) 99:4481–6. doi:10.1210/jc.2014-2684
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.
Copyright © 2017 Cellini, Santaguida, Virili, Capriello, Brusca, Gargano and
Centanni. This is an open-access article distributed under the terms of the Creative
Commons Attribution License (CC BY). The use, distribution or reproduction in
other forums is permitted, provided the original author(s) or licensor are credited
and that the original publication in this journal is cited, in accordance with accepted
academic practice. No use, d