The aggregation between AITD with rheumatologic, or dermatologic, autoimmune diseases

The Pathogenesis of Graves’ Disease

to be aware that polymyositis and autoimmune thyroiditis can coexist and a thorough evaluation of both conditions may be necessary in patients presenting with myalgia or muscle weakness.

To characterize and compare autoimmune comorbidity patterns and temporal dynamics in patients with Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) within an autoimmune polyglandular syndrome (APS) framework. We retrospectively analysed patients with an autoimmune thyroid disease (AITD) and at least one additional autoimmune disease fulfilling APS criteria, followed at a tertiary APS referral centre between 2000 and 2025. The prevalence of associated autoimmune diseases was compared between HT and GD. Time to development of subsequent autoimmune diseases was assessed using Kaplan–Meier analysis and Cox proportional hazards models, with adjustment for sex and age. A total of 1,057 patients (76% women; mean age 53.7 ± 16.4 years) were included, of whom 964 had HT and 93 GD. Type 1 diabetes was the most frequent autoimmune comorbidity, but was significantly less prevalent in GD than in HT (OR 0.48, 95% CI 0.31–0.75; FDR-adjusted p = 0.008). GD was selectively enriched for systemic sclerosis (OR 51.54, 95% CI 10.96–242.41; FDR-adjusted p < 0.001) and vitiligo (OR 3.46, 95% CI 1.82–6.55; FDR-adjusted p < 0.001). In patients in whom AITD was the first autoimmune manifestation (n = 333), GD was associated with a longer latency to additional autoimmune diseases and a lower hazard of subsequent autoimmunity compared with HT (HR 0.52, 95% CI 0.37–0.73; p < 0.001). Within APS-related AITD, HT and GD anchor distinct autoimmune phenotypes with different clustering patterns and temporal trajectories. These differences have relevant clinical implications for risk stratification and personalized surveillance of patients with autoimmune thyroid disease.

Autoimmune thyroid disease (AITD) shows the highest incidence among organ-specific autoimmune diseases and is the most common thyroid disease in humans, including Graves' disease (GD) and Hashimoto's thyroiditis (HT). The susceptibility to autoimmune diseases is affected by increased autoantibody levels, susceptibility gene polymorphisms, environmental factors, and psychological factors, but the pathogenesis remains unclear. Various cytokines and related genes encoding them play important roles in the development and progression of AITD. CD152, an expression product of the CTLA-4 gene, downregulates T cell activation. The A/A genotype polymorphism in the CT60 locus may reduce the production of thyroid autoantibodies. The C1858T polymorphism of the PTNP22 gene reduces the expression of its encoded LYP, which increases the risk of GD and HT. GD is an organ-specific autoimmune disease involving increased secretion of thyroid hormone, whereas HT may be associated with the destruction of thyroid gland tissue and hypothyroidism. These two diseases exhibit similar pathogenesis but opposite trends in the clinical manifestations. In this review, we focus on the structure and function of these cytokines and related genes in AITD, as well as the association of polymorphisms with susceptibility to GD and HT, and attempt to describe their differences in pathogenesis and clinical manifestations.

A coexistence of mitral valve prolapse (MVP) with autoimmune thyroid disease (AITD) has been described, but there are not sufficient data to explain this association. The aim of the present study was to investigate the prevalence of MVP in patients with AITD and to evaluate whether any correlation between MVP and certain immunological parameters exists. M-mode, two-dimensional Doppler echocardiography was performed in 29 patients with Graves' disease (GD), 35 with Hashimoto's thyroiditis (HT), 20 with nonautoimmune goiter, and 30 normal controls. Serum samples were examined for antinuclear antibodies (ANA), antibodies against extractable nuclear antigen (ENA), antiphospholipid antibodies (aCL), rheumatoid factor (RF), thyroid autoantibodies (TAAb), immunoglobulins and C3, C4. Eight of 29 GD patients and 8 of 35 HT patients had MVP, while none of the control group and 2 of 20 of the simple goiter group had MVP (p < 0.05). ANA were detected at low titers in 5 of 8 in MVP(+) GD versus 3 of 21 in MVP(-) GD (p < 0.05). In the HT group the MVP(+) patients had a significantly higher incidence of ANA and ENA, 5 of 8 and 2 of 8 versus 5 of 27 and 0 of 27 of MVP(-) patients, respectively, p < 0.05. A statistically significant higher incidence of aCL was found in HT MVP(+) patients. (3/8) versus HT MVP(-) 1/27, p < 0.05. RF levels (immunoglobulin A [IgA]) were significantly higher in MVP(+) patients. The association of MVP with nonorgan-specific autoantibodies indicates that MVP may also be an autoimmune disease. It is possible that patients with AITD who also have MVP may be at an increased risk to develop systemic autoimmunity.

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Environmental factors have been implicated in the development of autoimmune thyroid disease (AITD). Anti-Saccaromyces Cerevisiae Antibodies (ASCA) were shown to be elevated in several autoimmune diseases. The aim of the study was to determine ASCA levels and their relationship with thyroid autoantibodies in patients with AITD. One-hundred and twelve patients with AITD (age 41.1±12.8 years; F/M:96/16) and 103 healthy controls (38.5±10.3 years; F/M:82/21) were included. Twenty-four patients had Graves disease (GD), and 88 had Hashimoto's thyroiditis (HT). ASCA IgA and IgG, TSH, free T4, anti-thyroglobulin, and anti-thyroid peroxidase antibody concentrations were determined. ASCA IgA positivity in patients with GD (16.6%) was similar to patients with HT (13.6%) and was higher than controls (5.8%). No significant difference was present between the frequencies of IgG positivity among GD (12.5%), HT (7.9%), and control groups (5.8%). The mean levels of ASCA IgA and IgG were comparable within the groups. No correlation of ASCA and anti-thyroglobulin and anti-thyroid peroxidase levels was observed. Increased IgA ASCA positivity is observed in patients with GD, suggesting a role of environmental stimuli in its pathogenesis. The role of ASCA in the etiology of AITD needs to be further examined.

To the Editor: The presence of Down’s syndrome (DS) associated with moyamoya disease has been increasingly noted in the last years. Several reports suggest that the incidence of moyamoya disease is higher in children with DS than in other children. Since 1977, when this association was described for the first time, more than twenty cases have been reported.1 2 3 However, the reason of this association is unknown. Furthermore, DS is associated with autoimmune disorders.4 We describe a child with trisomy 21 affected by moyamoya and Graves’ disease, associated with anti-thyroid microsome antibodies and antiphospholipid antibodies (aPL). This patient was included in the prospective study of stroke in young adults in Cantabria, Spain.5 6 A 21-year-old man was admitted to the hospital on May 27, 1986. Thirteen days before, his mother noticed a sudden muscle weakness in his left arm; 3 days later she also noted that he had difficulty in walking because of a weakness in his left leg. The patient was the eighth pregnancy of a mother who was 39 years of age at the time of delivery. When he …

BackgroundThe autoimmune thyroid diseases (AITD), including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT), are caused by interactions between susceptibility genes and environmental triggers. Single nucleotide polymorphisms (SNPs) of Solute carrier family 22, member 4 (SLC22A4) have been shown to be associated with several autoimmune diseases, including Crohn’s disease (CD) and rheumatoid arthritis (RA). The aim of this study is to investigate whether SNP rs3792876 in the SLC22A4 gene is associated with GD, HT and AITD in a Chinese Han population.MethodsIn this study, we collected specimens from 553 Chinese Han individuals of 92 AITD pedigrees in 10 cities in Liaoning province, China (80 GD pedigrees, 478 members; 12 HT pedigrees, 75 members). SNP rs3792876 was genotyped using the TaqMan allelic discrimination assay. Hardy-Weinberg Equilibrium tests were performed among founders of the pedigrees using Haploview software. Family-based association tests performed using FBAT software.ResultsNo deviation from Hardy-Weinberg equilibrium was observed (p > 0.05). There were not significant association between the SLC22A4 gene polymorphism (rs3792876) and GD, HT and AITD was found.ConclusionsThese results suggest a lack of association between the SLC22A4 gene polymorphism rs3792876 and susceptibility to GD, HT and AITD in a Chinese Han population.

Background:Rheumatoid arthritis is systemic autoimmune disease with progressive development leading to disabilities. The presence of thyroid autoantibodies and thyroid autoimmune disease has been known for more than six decades. The...

Autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) are main autoimmune liver diseases. The term overlap syndrome describes the coexistence of two autoimmune liver diseases in the same patient, and AIH/PBC overlap is the most common form 1–3. Patients with AIH/PBC overlap also have other organ and nonorgan specific autoimmune diseases. In the may issue of the European Journal of Gastroenterology & Hepatology, Efe et al. 4 described this association in a large group of AIH/PBC patients. In this study, they found a 43.6% (31/71) prevalence of extrahepatic autoimmune diseases in patients with AIH/PBC overlap. Autoimmune thyroid diseases, Sjögren syndrome, celiac disease, psoriasis, and rheumatoid arthritis were the most commonly associated autoimmune diseases. To contribute additional information in this area of active investigation, we would like to present a case of AIH/PBC overlap that developed in a patient with Hashimoto thyroiditis and vitiligo. A 52-year-old man with a known history of both Hashimoto thyroiditis and vitiligo first presented to our clinic with fatigue, pruritus, and yellowish discoloration of the sclera and skin. Laboratory examinations yielded the following results: alanine aminotransferase 278 IU/l (0–54 IU/l), aspartate aminotransferase 228 IU/l (0–34 IU/l), alkaline phosphatase 512 IU/l (64–160 IU/l), γ-glutamyl transpeptidase 1315 IU/l (20–64 IU/l), total bilirubin 6.5 mg/dl (0.6–1.2 mg/dl), IgG 36.6 g/l (7–16 g/l), and IgM 3.5 g/l (0.4–2.3 g/l). Antinuclear antibody was positive at the titer of 1/320, smooth-muscle antibody was 1/320, antimitochondrial antibody (AMA-M2) was 1/160, and anti-double-stranded DNA (ds-DNA) was 3.4 (0.1–1.1). Findings on a subsequent liver biopsy were consistent with both AIH and PBC, with moderate interface hepatitis along with proliferation of the bile ducts. With a diagnosis of AIH/PBC overlap syndrome, the patient was started on a daily regimen of 30 mg prednisolone, 50 mg azathiopyrine, and 1250 mg ursodeoxycholic acid (UDCA). After remission was achieved, prednisolone was tapered slowly to a maintenance dose of 5 mg/day whereas azathioprine and UDCA were continued at the same doses. The overlap of AIH and PBC is a very rarely encountered clinical entity in clinical practice. Although still there is no consensus on diagnosis and therapy regimes, the Paris criteria suggested by Chazouillères et al.2 are widely used for the diagnosis of these patients. Our patient fulfilled the criteria of overlap syndrome and also showed concomitant AMA and ds-DNA seropositivity, which was found to be a highly specific serological marker of AIH/PBC overlap 5,6. Therapy of these patients includes UDCA combination with immunosuppressive or UDCA alone 1,7. For our patient, we preferred the combination therapy regime and this led to complete biochemical remission 3 months after the initiation of therapy. The coexistence of AIH and PBC with other autoimmune disorders has been well described in large population-based studies 8,9. However, until recently, this association has been described in only small case-based studies for patients with overlap syndromes 10–12. However, in the study by Efe et al.4, a high prevalence of concurrent autoimmune diseases have been reported in a large population of AIH/PBC overlap patients. This study highlighted the importance of considering the association of AIH/PBC overlap syndrome in patients with other known autoimmune disorders presenting with liver dysfunction or extended screening for existing autoimmune diseases during the routine assessment of patients with overlap syndrome. Acknowledgements Conflicts of interest There are no conflicts of interest.

Introduction: Hashimoto's Thyroiditis (HT) and Graves' Disease (GD) reflect two extremes in the spectrum of autoimmune thyroid diseases. In HT, there are anti-thyroid peroxidase antibodies thought, but not proven, to be destructive to thyroid follicles as well as thyroid stimulating hormone (TSH) stimulation-blocking antibodies which block the action of TSH and cause damage and atrophy of the thyroid gland leading to hypothyroidism. On the other hand, GD is characterized by primary hyperthyroidism due to stimulating autoantibodies against TSH receptors. While some of the patients with GD can develop spontaneous hypothyroidism due to HT, development of GD with hyperthyroidism following HT is unusual (1). We report a case of development of GD in a case of long standing HT. Case Report: A 55-year-old woman with a 20-year history of HT on stable doses of levothyroxine was found to be hyperthyroid on routine follow up. She presented with clinical signs of hyperthyroidism including weight loss of 40 pounds over 1 year and periorbital edema. The dose of levothyroxine was tapered and ultimately stopped over six months. Despite discontinuation of thyroid hormone, she continued to remain hyperthyroid. Labs were significant for elevated free T4 2.28 (0.82-1.77 ng/dL), elevated free T3 9.2, (2.0-4.4 pg/mL) and suppressed TSH, 0.006 (0.0-0.55 IU/L). Further testing revealed elevated thyroid antibodies including TSI of 10.4 (0.0-0.55 IU/L), Thyroglobulin Ab of 50.6 (0.0-0.9 IU/mL), TSH receptor Ab of 6.1 (>1.5 U/L positive) and TPO Ab of > 600 (0.0-34 IU/mL). Thyroid ultrasound disclosed an enlarged, heterogenous and hyperemic thyroid parenchyma. The 24-hour radioactive iodine uptake was elevated at 52% (8-35%) indicative of hyperthyroidism, most likely from GD. She was treated with methimazole and atenolol, followed by total thyroidectomy. Surgical pathologyrevealed diffuse chronic lymphocytic thyroiditis with lymphoid aggregates, fibrosis, adenomatous nodules with oncocytic changes and reactive nuclear atypia. Conclusion: Although development of GD following HT is rare, it can occur suggesting that HT does not always result in irreversible destruction of the thyroid gland. Patients with thyroid autoimmune disease have both thyroid hormone receptor stimulating and thyroid hormone receptor blocking antibodies and clinical manifestations depend upon the level of these antibodies and the state of the thyroid gland. Because patients with HT can transform to GD at any point due to a change of blocking to stimulating antibodies, clinicians should be aware of the potential for this transformation.

Inclusion of ALKBH5 as a candidate gene for the susceptibility of autoimmune thyroid disease

We have postulated that a defect in specific antigenic induction of suppressor T lymphocytes may account for the immunoregulatory disorder in autoimmune thyroid disease. In this context, we have measured the proliferative responses of peripheral blood mononuclear cells (PBMC) to the synthetic peptides corresponding to the extracellular domain of the TSH receptor (TSHR) and recombinant glutamate decarboxylase (GAD65) by means of 3H thymidine incorporation. We have also studied the antigenic activation of CD4+ and CD8+ T lymphocytes by measuring human leukocyte antigen-DR (HLA-DR) expression on the cell surface by flow cytometric analysis. PBMC obtained from 47 patients with Graves' disease (GD) [including 19 hyperthyroid GD (hyper GD)], 18 with Hashimoto's thyroiditis (HT), 7 with nontoxic nodular goiter (NG), 18 with insulin-dependent diabetes (IDDM), and 20 normal controls (N), were cultured for 7 days in the presence or absence of the pool peptides representing 3 different segments of TSHR or GAD65 at final concentration of 30 micrograms/mL or 10 micrograms/mL. The proportion of subjects whose PBMC gave a positive proliferative response with a stimulation index (SI) of over 2.3 (i.e. above the mean +2 SD for N) to TSHR peptides was significantly higher in the hyper GD group than among euthyroid GD (eu GD), HT, IDDM, and N group. The corresponding differences in mean SI provided analogous results, showing significant responses above normal in only hyper GD. The CD4+ T lymphocytes from hyper GD group were significantly more activated by TSHR peptides compared to eu GD, HT, IDDM, and N, and this induction correlated to their thyroid hormone levels. Quite differently, the activation of CD8+ T lymphocytes from both hyper GD and eu GD group in response to TSHR peptides was impaired compared to HT, IDDM, and the N group; in contrast to the findings with CD4+ T lymphocytes, this was independent of thyroid hormone levels. On the other hand, while the CD8+ T lymphocytes from GD and N groups were activated equally by GAD65, the activation of CD8+ T lymphocytes from the IDDM group by GAD65 was impaired compared to the GD and N groups. In conclusion, the activation of CD8+ T lymphocytes from GD and IDDM by relevant antigens (i.e. TSHR peptides for GD and GAD65 for IDDM) was impaired, but not by irrelevant antigens (i.e. GAD65 for GD and TSHR peptides for IDDM). There was also a modest stimulation of CD8+ T cells from all groups by tetanus toxoid and cardiac myosin light chain peptide, both irrelevant antigens.(ABSTRACT TRUNCATED AT 400 WORDS)

The association of low vitamin D status with autoimmune thyroid disease (AITD), which includes Hashimoto's thyroiditis (HT) and Graves' disease (GD), is controversial. The aim of this study was to investigate the correlation between vitamin D insufficiency and AITD, HT, and GD. Our cross-sectional study included patients who visited a tertiary hospital for thyroid evaluation or follow-up. A total of 776 patients in whom serum 25-hydroxyvitamin D [25(OH)D], thyroid function, and anti-thyroid antibodies had been measured were analyzed retrospectively. Vitamin D insufficiency was defined as serum 25(OH)D level <75 nmol/L. The prevalence of vitamin D insufficiency was significantly higher in the 369 patients with AITD than in the 407 without AITD (46.1% vs. 37.1%, p=0.011), and higher in the 221 patients with HT than in those with GD or non-AITD (48.9% vs. 41.9%, 37.1%, p=0.017). Among HT cases, patients with overt hypothyroidism had a significantly higher prevalence of vitamin D insufficiency (60.4% vs. 44.1%, 21.7%, 37.1%, respectively, p <0.001) and lower 25(OH)D levels (80.1 ± 47.7 vs. 99.34 ± 61.2, 110.3 ± 69.9, 99.6 ± 53.7 nmol/L, respectively, p=0.009) compared with those with euthyroidism and subclinical hypothyroidism or those without AITD. Serum 25(OH)D levels were significantly negatively correlated with serum thyroid stimulating hormone (TSH) levels after adjustment for age, sex, body mass index, and sampling season (r= -0.127, p=0.013). Vitamin D insufficiency was associated with AITD and HT, especially overt hypothyroidism. Low serum vitamin D levels were independently associated with high serum TSH levels.