The association between autoimmune atrophic gastritis and thyroid disorders has been observed since the early 1960s and the expression "thyrogastric syndrome" was coined to indicate the presence of thyroid autoantibodies or autoimmune thyroid disease in patients with pernicious anemia, a late clinical stage of autoimmune atrophic gastritis. More recently, it was confirmed that autoimmune thyroid disorders, in particular Hashimoto's thyroiditis, may be frequently associated with other organ-specific, immune-mediated disorders, such as autoimmune atrophic gastritis or celiac disease. The association of Hashimoto's thyroiditis with autoimmune atrophic gastritis or celiac disease in adult patients is currently considered part of the polyglandular autoimmune syndromes which include several autoimmune disorders associated with an autoaggressive impairment of endocrine glands. From a clinical point of view, the thyro-entero-gastric autoimmunity may lead to potentially serious consequences like anemia, micronutrients deficiencies, and drugs malabsorption, as well as to an increased risk for malignancies. These alterations may frequently present in an underhand manner, with consequent diagnostic and treatment delays. Many aspects of the association between thyroid, gastric and intestinal autoimmune diseases still await clarification. The present review focuses on the embryological, genetic and pathophysiological aspects of thyro-entero-gastric autoimmunity. In particular, the current diagnostic criteria of autoimmune thyroid disease, autoimmune atrophic gastritis, and celiac disease are reviewed, along with the evidences for their association in poly-autoimmunity syndromes. The benefits of proactive screening of autoimmune thyroid disorders in patients with autoimmune gastritis or enteropathy and viceversa are also discussed.

Eight years prior to her present admission, a 61-year-old Japanese woman was diagnosed with autoimmune hepatitis, slowly progressive insulin-dependent diabetes mellitus, and chronic thyroiditis; she had been treated with oral prednisolone (PSL). After she suddenly discontinued PSL, she newly developed systemic lupus erythematosus. A combination therapy of oral PSL and intravenous cyclophosphamide resulted in remission. She was finally diagnosed with autoimmune polyglandular syndrome (APS) type 3 (3A ,3B, 3D), complicated with four different autoimmune diseases. Since patients with type 3 APS may present many manifestations over a long period of time, they should be carefully monitored.

A 31-year-old woman experienced tetany and was diagnosed with Hashimoto thyroiditis and hypoparathyroidism. At 33 years of age, her renal function gradually decreased. At 39 years of age, she moved to our hospital and was diagnosed with tubulointerstitial nephritis by renal biopsy. Simultaneously, she was diagnosed with Sjögren's syndrome by autoantibodies and salivary gland biopsy. At 40 years of age, based on hypoglycaemia and eosinophilia, she was suspected of adrenal insufficiency, and was diagnosed with primary adrenal insufficiency by both corticotropin stimulation and corticotropin-releasing hormone stimulation test. She was diagnosed as autoimmune polyglandular syndrome (APS) (Hashimoto thyroiditis and possible primary adrenal insufficiency) as well as primary hypoparathyroidism and Sjögren's syndrome, which are very rarely complicated in APS-2. Therefore, in this patient, it was helpful to pay attention for new onset of other autoimmune diseases.

Adrenal insufficiency is a rare, potentially life-threatening condition whose diagnosis requires a high index of suspicion. Adrenal insufficiency may be primary, secondary, or tertiary with varied etiologies. Primary insufficiency may be part of a cluster of autoimmune diseases, referred to as autoimmune polyglandular syndrome(s) (APS). We describe a case of a 15-year-old male who presents to a local emergency department complaining of fatigue, fever, abdominal pain, nausea, and vomiting for a few days with a preceding viral illness. The patient was hyponatremic and hyperkalemic with skin hyperpigmentation, raising concern for adrenal insufficiency. Laboratory workup confirmed autoimmune primary adrenal insufficiency, with subsequent laboratory studies revealing autoimmune thyroiditis and celiac disease. Concomitant Addison's and Hashimoto's diseases led to a diagnosis of APS type 2. The patient was started on steroid replacement with rapid clinical improvement.

The coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes is defined as autoimmune polyglandular syndrome (APS) type 2 or Schmidt's syndrome. Vitiligo, hypergonadotropic hypogonadism, chronic autoimmune hepatitis, alopecia, pernicious anaemia and seronegative arthritis may also be present. We present a case of 45-year-old Indian man with progressive jaundice and asthenia for 3 months. He was also found to have pallor, icterus, dry coarse skin and delayed relaxation of ankle jerk. Investigations showed pancytopaenia with megaloblastic changes due to pernicious anaemia, autoimmune hypothyroidism and autoimmune adrenalitis with evolving adrenal insufficiency. Upper gastrointestinal endoscopy guided biopsy showed evidence of gastric mucosal atrophy. Patient responded well to hydroxocobalamin and thyroxine replacement. Detailed workup to check for evolving APS II is prudent in a hypothyroid patient presenting with pallor and jaundice. It may alert physicians to possible adrenal crisis in the future, especially after starting levothyroxine replacement in these patients.

A 24-year-old man with no significant medical history presented to the medical clinic with vomiting and giddiness for 2 days, loss of appetite for 1 month and progressive fatigability for the preceding 4 months. On examination, he was found to be hypotensive and was admitted to the hospital for work-up. Considering his abnormal labs and physical findings, he was worked up and was diagnosed with primary adrenal insufficiency. On further work-up for the aetiology of his Addison's disease, he was found to have concurrent autoimmune thyroiditis and vitiligo. A final diagnosis of autoimmune polyglandular syndrome type 2 was made. The patient was started on hormone replacement therapy and reported improvement of symptoms on 3-month follow-up visit.

A 30-year-old woman with polyglandular autoimmune type 2 syndrome was found collapsed at home with a cardiac arrest, which required direct current cardioversion. On admission, she was hypothermic, hypotensive and bradycardic. Initial biochemical investigations were consistent with a pre-renal acute kidney injury, metabolic acidosis and a possible sepsis. She had significantly elevated thyroid-stimulating hormone levels on admission with the clinical profile consistent with dual Addisonian and myxoedema crisis. She received intravenous liothyronine and hydrocortisone along with supportive therapy. Echo showed severe left ventricular impairment with apical ballooning although coronary angiogram disclosed nothing abnormal. She made a gradual recovery and was discharged home after 2 weeks. She was diagnosed to have primary autoimmune hypothyroidism, Addison's diseaseand type 1 diabetes and coeliac disease in October 2006, July 2007, May 2010 and September 2016, respectively. Her inability to stick to gluten-free diet at her workplace was considered a significant contributory factor for out-of-hospital cardiac arrest.

We experienced a 6-year-old case of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) with subsequent development autoimmune thyroiditis (Hashimoto's thyroiditis), type 1 diabetes with antithyroglobulin, thyroid peroxidase, insulinoma-associated antigen and anti-insulin antibodies at 4 months, alopecia at 7 months, vitiligo, uveitis due to Vogt-Koyanagi-Harada disease at 8 months after clinical resolution of the DiHS/DRESS. He was diagnosed as type III polyglandular autoimmune syndrome (PASIII) after DiHS/DRESS. Prompted by this case, we sought to determine which triggering factors were responsible for later development of PASIII in previously published cases with autoimmune sequelae. In the literature review, five patients with DIHS/DRESS were found to develop autoimmune sequelae consistent with PASIII. All cases with PASIII were much younger than those without them. Four out of the five patients were treated with intravenous immunoglobulin or pulsed prednisolone in the acute stage, although effective in short-term outcomes.

Autoimmune-poly-endocrinopathy-candidiasis-ectodermal-dystrophy syndrome (APECED) is a rare monogenic recessive disorder caused by mutations in the autoimmune regulator (AIRE) gene. Criteria for the diagnosis of APECED are the presence of two of the following disorders: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CHP), and Addison's disease. APECED develops at high incidence in Finns, Sardinians, and Iranian Jews and presents with a wide range of clinical phenotypes and genotypes. In this manuscript, we report the clinical, endocrinological, and molecular features of a 16-year-old female patient from Pakistan living in Italy and presenting the major APECED clinical manifestations CMC, CHP, and primary adrenal insufficiency. Premature ovarian failure, chronic bronchopneumopathy, vitiligo, Hashimoto's thyroiditis emerged as associated diseases. In our patient, AIRE gene screening revealed the novel c.396G>C (p.Arg132Ser; p.R132S) mutation in homozygosity thus confirming APECED diagnosis. This is the first reported mutation within the nuclear localization signal (NLS) that is associated with APECED. The NLS mutation affects the nuclear import of classical transcription factors through nuclear pore by recognition of nuclear import receptors, the importin α molecules. By displaying crystal structures of the peptide containing the KRK basic residue cluster bound to α importins, we show that p.R132S replacement in 131-KRK-133 does not reproduce these interactions. Thus, we propose that the novel mutation exerts its pathogenetic effect by impairing the nuclear import of the Aire protein. The present case report is added to a limited series of Pakistani APECED patients who we reviewed from the scientific literature, mostly diagnosed on clinical findings.

This study included 161 patients: 92 patients had type 1 diabetes (T1D) while 69 patients had a combination of T1D and autoimmune thyroiditis, the so-called autoimmune polyglandular syndrome type 3 variant (APS3v). Those patients, as well as 93 controls, were typed for HLA-DRB1 and -DQB1 genes to assess their possible contribution to the development/protection of T1D with/without autoimmune thyroiditis. Both HLA-DRB1*04 and -DRB1*03 frequencies were significantly higher among T1D and APS3v patients than in controls. The frequencies of HLA-DRB1*11 and -DRB1*15 were lower among T1D patients, while HLA-DRB1*07 and -DRB1*11 occurred significantly less frequently among APS3v patients in comparison to controls. HLA-DQB1*03:01 and -DQB1*03:02 were associated with a higher risk of developing T1D and APS3v; HLA-DQB1*02 was significantly more present among APS3v patients while HLA-DQB1*03:03 was observed with a significantly lower frequency only among T1D patients. HLA-DRB1*03~DQB1*02 and HLA-DRB1*04~DQB1*03:02 were associated with both diseases. The higher frequency of HLA-DRB1*03/DRB1*03 among APS3v patients was the only significant difference in genotype frequency when compared to T1D patients, while high risk (HLA-DRB1*03/DRB1*04) and medium risk genotypes for T1D (HLA-DRB1*04/DRB1*04) occurred with similar frequencies in both patient groups. Although some of the results point toward shared genetic susceptibility of T1D and APS3v, observed differences in both susceptible/protective HLA profiles indicate the necessity of further studies in order to elucidate the pathogenesis of these diseases.

Celiac disease is a small intestinal inflammatory disease with autoimmune features that is triggered and maintained by the ingestion of the storage proteins (gluten) of wheat, barley, and rye. Prevalence of celiac disease is increased in patients with mono- and/or polyglandular autoimmunity and their relatives. We have reviewed the current and pertinent literature that addresses the close association between celiac disease and endocrine autoimmunity. The close relationship between celiac disease and glandular autoimmunity can be largely explained by sharing of a common genetic background. Further, between 10 and 30% of patients with celiac disease are thyroid and/or type 1 diabetes antibody positive, while around 5⁻7% of patients with autoimmune thyroid disease, type 1 diabetes, and/or polyglandular autoimmunity are IgA anti-tissue transglutaminase antibody positive. While a gluten free diet does not reverse glandular autoimmunity, its early institution may delay or even prevent its first manifestation. In conclusion, this brief review highlighting the close association between celiac disease and both monoglandular and polyglandular autoimmunity, aims to underline the need for prospective studies to establish whether an early diagnosis of celiac disease and a prompt gluten-free diet may positively impact the evolution and manifestation of glandular autoimmunity.

We describe a very rare case of concurrent variant type 3 autoimmune polyglandular syndrome (APS) and pulmonary arterial hypertension (PAH). A previously healthy 65-year-old Japanese woman was referred to our university hospital with a 2-month history of general fatigue and hyperglycemia. Laboratory tests revealed severe hyperglycemia (plasma glucose 543 mg/dL and HbA1c 10.7%) with ketonuria (3+). Glutamic acid decarboxylase (GAD) and IA-2 antibodies were positive, and the serum C peptide level was markedly decreased to 0.2 ng/mL. Accordingly, type 1 diabetes was diagnosed. Hashimoto's thyroiditis was also diagnosed because she had a diffuse goiter and a mild hypothyroidism (TSH 8.20 μU/mL, and FT4 0.80 ng/mL) with positive autoantibodies for thyroid peroxidase and thyroglobulin. There was neither adrenal insufficiency nor hypocalcemia. In addition, chest X ray showed a suspicious PAH by a dilation of both pulmonary arteries, especially right descending artery, and right heart catheterization confirmed the presence of PAH. HLA Class II genotyping revealed DRB1-DQB1*0901-*0303, a common susceptibility haplotype in Japanese patients with type 3 APS or acute-onset type 1 diabetes. The combination of variant type 3 APS and PAH is extremely rare and to the best of knowledge, this is the first case reported in a Japanese patient.

Asthma therapy with monoclonal antibodies is a promising and effective approach for those with a severe and refractory type of disease. Although such a targeted therapy is considered to be safe, unusual complications may occur. We present a case of a 45 year-old female patient with severe allergic asthma and chronic spontaneous urticaria, who developed autoimmune polyendocrine syndrome type 2 (APS-2) after 26 months of omalizumab administration. The patient was diagnosed with primary adrenal insufficiency (Addison's disease) and Hashimoto's thyroiditis accompanied by autoimmune atrophic gastritis. According to our knowledge this is the first description of APS-2 that developed in conjunction with omalizumab treatment, although we have no evidence that the observed phenomenon indicated a cause-effect relationship to omalizumab.

Primary antibody deficiency syndromes are a rare group of disorders present at any age, with complex polygenic disorders. We report the forth case of polyglandular autoimmune syndrome (PAS) type IIIc worldwide with complex clinical features and no family history of endocrine disorders or primary immunodeficiencies. Our patient, a 44-year-old Caucasian female was diagnosed with PAS type IIIc due to the presence of autoimmune thyroiditis, autoimmune alopecia diffusa and primary ovarian insufficiency, associated with lymphoproliferative disease and primary antibody failure. Treatment included lifelong intravenous immunoglobulin, supplements and antibiotics. The clinical complexity and rare occurrence made it challenging to determine diagnosis and provide better treatment for the patient. The current case provides an insight of the challenges to determine primary antibody failure signs in the presence of PAS which will further help to determine diagnosis and therapeutic treatment for PAS patients.

A 26-year-old Japanese woman presented with adrenal insufficiency, and treatment was started with cortisone and fludrocortisone in 1975. A few years later, she presented with hypoparathyroidism and was diagnosed with autoimmune polyendocrine syndrome type I (APS I), and treatment with calcium and alfacalcidol was started. She was found to have subacute thyroiditis and relative adrenal failure in 2006. Her condition remained stable under treatment with cortisone, fludrocortisone, levothyroxine, calcium lactate, precipitated calcium carbonate and alfacalcidol. While antibodies against pancreatic glutamic acid decarboxylase (GAD) were strongly positive (7,690 U/ml), fasting glucose level was 4.9 mmol/L and HbA1c was 6.3% on admission. As GAD antibody showed a high-titer of >10,000 U/ml and fasting plasma glucose level showed a rising trend, we performed 75-g oral glucose tolerance test (OGTT) 6 years after discharge. Whereas OGTT in 2012 showed impaired glucose tolerance, glucose tolerance had reverted to normal in 2014. A patient with a high-titer GAD antibody does not always have progressive glucose intolerance. GAD antibody positivity is common in not only type 1 diabetes, but also APS I and stiff-person syndrome (SPS). There are differences in recognized epitopes among the three disorders. Epitopes for GAD65 antibody associated with type 1 diabetes are located in the middle region and the COOH-terminal of the GAD65 protein, whereas epitopes associated with SPS reside in the NH2-terminal in addition to the middle region and COOH-terminal. The present case suggests that these differences in epitopes may be related to various pathogenic mechanisms including glucose intolerance.