Background: T helper type 1 (Th1), Th2, and Th17 cells produce interferon (IFN)-γ, interleukin (IL)-4, and IL-17A, respectively. We reported that IFN-γ and IL-4 gene polymorphisms, which are relate...

Increases of the Th1/Th2 Cell Ratio in Severe Hashimoto's Disease and in the Proportion of Th17 Cells in Intractable Graves' Disease

Although emerging evidence suggests that low levels of vitamin D may contribute to the development of autoimmune disease, the relationship between vitamin D reduction and autoimmune thyroid disease (AITD), which includes Graves’ disease (GD) and Hashimoto thyroiditis (HT), is still controversial. The aim was to evaluate the association between vitamin D levels and AITD through systematic literature review. We identified all studies that assessed the association between vitamin D and AITD from PubMed, Embase, CENTRAL, and China National Knowledge Infrastructure (CNKI) databases. We included studies that compared vitamin D levels between AITD cases and controls as well as those that measured the odds of vitamin D deficiency by AITD status. We combined the standardized mean differences (SMD) or the odds ratios (OR) in a random effects model. Twenty case-control studies provided data for a quantitative meta-analysis. Compared to controls, AITD patients had lower levels of 25(OH)D (SMD: −0.99, 95% CI: −1.31, −0.66) and were more likely to be deficient in 25(OH)D (OR 2.99, 95% CI: 1.88, 4.74). Furthermore, subgroup analyses result showed that GD and HT patients also had lower 25(OH)D levels and were more likely to have a 25(OH)D deficiency, suggesting that low levels of serum 25(OH)D was related to AITD.

https://www.mdpi.com/2072-6643/7/4/2485/pdf

Meta-analysis of the association between vitamin D and autoimmune thyroid disease.

Hashimoto's thyroiditis (HT) is the most prevalent autoimmune thyroid disorder. Intrathyroidal lymphocytic infiltration is followed by a gradual destruction of the thyroid gland which may lead to subclinical or overt hypothyroidism. Biochemical markers of the disease are thyroid peroxidase and/or thyroglobulin autoantibodies in the serum which are present with a higher prevalence in females than in males and increase with age. Although exact mechanisms of aetiology and pathogenesis of the disorder are not completely understood, a strong genetic susceptibility to the disease has been confirmed predominantly by family and twin studies. Several genes were shown to be associated with the disease occurrence, progression, and severity. Genes for human leukocyte antigen, cytotoxic T lymphocyte antigen-4, protein tyrosine phosphatase nonreceptor-type 22, thyroglobulin, vitamin D receptor, and cytokines are considered to be of utmost importance. Amongst endogenous factors for the disease development, the attention is focused predominantly on female sex, pregnancy with postpartum period and fetal microchimerism. Environmental factors influencing HT development are iodine intake, drugs, infections and different chemicals. Disturbed self-tolerance accompanied by the increased antigen presentation is a prerequisite for the HT occurrence, whereas proper interaction of thyroid cells, antigen presenting cells, and T cells are necessary for the initiation of thyroid autoimmunity. Secreted cytokines lead predominantly to T-helper type 1 (Th1) response as well as to Th 17 response which has only recently been implicated. Final outcome of HT is thyroid destruction which is mostly a consequence of the apoptotic processes combined with T-cell mediated cytotoxicity.

Hashimoto's Thyroiditis: From Genes to the Disease.

The severity of Hashimoto's disease (HD) and intractability (or inducibility to remission) of Graves' disease (GD) varies among patients. Forkhead box P3 (FoxP3) is a crucial regulatory factor for the development and function of regulatory T (T(reg) ) cells, and deficiency of the FoxP3 gene (FOXP3) suppresses the regulatory function of T(reg) cells. To clarify the association of the functional polymorphisms of the FOXP3 with the prognosis of GD and HD, we genotyped -3499A/G, -3279C/A and -2383C/T polymorphisms in FOXP3 gene obtained from 38 patients with severe HD, 40 patients with mild HD, 65 patients with intractable GD, in whom remission was difficult to induce, 44 patients with GD in remission and 71 healthy volunteers. The -3279CA genotype was more frequent in patients with GD in remission than in patients with intractable GD, and the -3279AA genotype, which correlates to defective transcription of FOXP3, was absent in patients with GD in remission. The -2383CC genotype was more frequent in patients with severe HD than in those with mild HD. In conclusion, the -3279A/C polymorphism is related to the development and intractability of GD and the -2383CC genotype to the severity of HD.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.2010.04229.x

Association of functional polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases.

Genome-wide association studies have revealed several susceptibility genes among patients with autoimmune thyroid disease (AITD), including CTLA4, PTPN22, FCRL3, and ZFAT. However, any possible association between these genes and AITD prognosis remains unknown. The objective of this study was to identify associations between polymorphisms of these genes and AITD prognosis. We genotyped functional polymorphisms, including CTLA4 CT60, CTLA4 +49A/G, CTLA4 -1147C/T, CTLA4 -318C/T, PTPN22 -1123C/G, PTPN22 SNP37, CD40 -1C/T, FCRL3 -169C/T, ZFAT Ex9b-SNP10, and ZFAT Ex9b-SNP2, in 197 AITD patients carefully selected from 456 registered AITD patients, and 86 control subjects. The restriction fragment length polymorphism method was used for genotyping. The CD40 -1CC genotype and C allele were significantly more frequent in patients with Graves’ disease (GD) in remission than in those with intractable GD (P = 0.041 and P = 0.031, respectively). The FCRL3 -169TT genotype was significantly less frequent in patients with intractable GD than in those with GD in remission (P = 0.0324). For a ZFAT Ex9b-SNP10 polymorphism, the TT genotype and T allele were significantly more frequent in patients with severe Hashimoto’s disease (HD) than in those with mild HD (P = 0.0029 and P = 0.0049, respectively). For a CTLA4 CT60 polymorphism, the antithyrotropin receptor antibody levels at the onset of GD were significantly higher in those with the GG genotype than in those with other genotypes (P = 0.0117). CD40 and FCRL3 gene polymorphisms were associated with GD intractability, and ZFAT polymorphism was associated with HD severity but not its development.

Associations Between Autoimmune Thyroid Disease Prognosis and Functional Polymorphisms of Susceptibility Genes, CTLA4, PTPN22, CD40, FCRL3, and ZFAT, Previously Revealed in Genome-wide Association Studies

CD8+ CD25+-activated cytotoxic T cells and anti-thyroglobulin antibodies (TgAb) are independently involved in the severity of Hashimoto's disease (HD). Interferon gamma (IFN-gamma) activates cytotoxic T cells. To evaluate the hypothesis that the functional +874A/T polymorphism in the gene encoding IFN-gamma is associated with the severity of HD, we examined the frequencies of this polymorphism in 34 HD patients who developed hypothyroidism (severe HD); 22 untreated, euthyroid HD patients (mild HD); 49 patients with intractable Graves' disease (GD); 16 GD patients in remission; and 57 healthy volunteers. Frequency of the +874T allele, which is associated with high IFN-gamma production, was higher in patients with severe HD than in those with mild HD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.0-12.4; p = 0.047), but there was no difference in the frequency between GD patients. The difference in the frequency of +874T was observed in the subset of patients with HD negative for TgAb (OR, 8.4; 95% CI, 1.2-57.3; p = 0.029) but not in the subset of patients with HD positive for TgAb. Our data indicate that the +874A/T polymorphism in the IFN-gamma gene is associated with severity of HD.

Association between the severity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene.

Introduction Estimates of future disease burden supports public health decision-making. Multistate modeling of chronic diseases is still limited despite a long history of mathematical modeling of diseases. We introduce a discrete time approach to the illness-death model and a recursion formula, which can be utilized to project chronic disease burden. We further illustrate an example of the technique applied to anxiety disorders in Germany. Materials and Equipment The illness-death model is a multistate model that relates prevalence, incidence, mortality, and remission. A basic recursion formula that considers prevalence, incidence, mortality among the susceptible, and mortality among the diseased can be applied to irreversible chronic diseases such as diabetes. Among several mental disorders, remission plays a key role and thus an extended recursion formula taking remission into account is derived. Methods Using the Global Burden of Disease Study 2019 data and population projections from the Federal Statistical Office of Germany, a total number of individuals with anxiety disorders by sex in Germany from 2019 to 2030 was projected. Regression models were fitted to historical data for prevalence and incidence. Differential mortality risks were modeled based on empirical evidence. Remission was estimated from prevalence, incidence, and mortality, applying the extended recursion formula. Sex- and age-specific prevalence of 2019 was given as the initial value to estimate the total number of individuals with anxiety disorders for each year up to 2030. Projections were also made through simple extrapolation of prevalence for comparison. Results From 2019 to 2030, we estimated a decrease of 52,114 (−1.3%) individuals with anxiety disorders among women, and an increase of 166,870 (+8.5%) cases among men, through the illness-death model approach. With prevalence extrapolation, an increase of 381,770 (+9.7%) among women and an increase of 272,446 (+13.9%) among men were estimated. Discussion Application of the illness-death model with discrete time steps is possible for both irreversible chronic diseases and diseases with possible remissions, such as anxiety disorders. The technique provides a framework for disease burden prediction. The example provided here can form a basis for running simulations under varying transition probabilities.

/pdf/illness-death-model-as-a-framework-for-chronic-disease-bsjxvzqb.pdf

Illness-Death Model as a Framework for Chronic Disease Burden Projection: Application to Mental Health Epidemiology


 Introduction: Most breast cancers are diagnosed after an image-guided biopsy. When performed under stereotactic guidance, biopsy markers (clips) are almost always placed. In comparison, clip placement after ultrasound (US) guided biopsy is variable. Neoadjuvant chemotherapy (NAT) may be administered before surgery to shrink large tumors so breast conservation therapy (BCT) instead of mastectomy can be done. After NAT, tumors may no longer be clinically palpable or visible on imaging. The clip localizes tumors so that the site can be identified and less extensive and more precise surgery can be performed. If no clip is placed at the time of biopsy, NAT is delayed and mastectomy may be required in a patient who would have otherwise qualified for BCT. Most often, a second US procedure for clip placement will be required and sometimes a second biopsy prior to NAT. International and national guidelines state that clips should be placed when the radiologist suspects the patient is a candidate for NAT. The aim of this project was to decrease the number of patients presenting to the NAT clinic at BC Cancer Vancouver Center without a clip in situ to less than 5% by the end of 2020. Methods: Ethical risk assessed using the ARECCI screening tool were minimal. Initial data included all patients who presented for NAT at BC Cancer VCC from January 2018 to January 2019 and final data was from January 2021 to March 2021 (delayed due to Covid-19 pandemic). All lower mainland health authority sites (LMMI) were surveyed in regards to whether they perform US guided breast biopsies. An online survey about specific radiologist practices was sent out to radiologists at all LMMI sites, as well as in community imaging clinics (CICs) and other health authorities in the province. Patient interviews have been conducted through BC Cancer Patient Engagement. A fee code specific to CICs in the lower mainland, which perform over 60% of the US guided breast biopsies, to encourage and support appropriate clip use was proposed to the British Columbia ministry of health and was implemented in July 2019. Education was targeted at other community sites where surgeons were engaged to explain the impact on clinical outcomes when clips are not used. An online webinar about clip placement was developed in conjunction with a local surgeon and was hosted by the Canadian Society of Breast Imaging. Results: 19 LMMI sites perform US breast biopsies. 25% of radiologists surveyed stated anticipation of NAT as a reason for clip placement and 21% were aware of the national guidelines for clip placement. Initial data included 121 patients who presented for NAT clinic in our time frame and 77 were included in our analysis (received NAT and clip status was known). Final data included 33 patients who presented to the NAT clinic and 30 were include in our analysis. Before intervention, 49% of patients considered for NAT had a clip placed at the initial biopsy. Of 50 patients who did not have a clip at initial biopsy, 21 (42%) required a clip prior to NAT. There was a 5.5 day difference in time to NAT after biopsy for patients who had clips placed initially at the time of biopsy (34.7 days) and patients who did not (40.2 days). There was no difference in mastectomy rates. After intervention, 80% of patients considered for NAT had a clip placed at the initial biopsy. Though it is difficult to quantify the clinical impact a 5.5 day delay to start of therapy may have, patient interviews indicate significant anxiety associated with the time between diagnosis and treatment. Conclusion: Targeted education on clip use with engagement of surgeons to explain the clinical implications, and development of a fee code to encourage and support appropriate use of clip placement, reduced the number of patients presenting for NAT without a clip in place. Future projects include exploring the financial costs or savings of increasing clip use.
 Citation Format: Charlotte J. Yong-Hing, Chisato Ito, Lauren Corke, Christine Simmons, Bethina Abrahams. Clip placement after ultrasound guided biopsy in the setting of neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-03-02.

Abstract P1-03-02: Clip placement after ultrasound guided biopsy in the setting of neoadjuvant chemotherapy

It is intended to provide a novel method of presuming the risk of worsening in an autoimmune disease accompanied by dysfunction due to tissue destruction. The above problem can be solved by providing a method which comprises detecting a single nucleotide polymorphism in a cytokine or cytokine receptor gene participating in the regulation of an immune function and presuming the risk of worsening in an autoimmune disease accompanied by dysfunction due to tissue destruction based on the allele or genotype of the single nucleotide polymorphism, and a kit for presuming the risk of worsening in an autoimmune disease accompanied by dysfunction due to tissue destruction.

Chisato Ito

Papers

Association between the severity of Hashimoto's disease and the functional +874A/T polymorphism in the interferon-gamma gene.

Illness-Death Model as a Framework for Chronic Disease Burden Projection: Application to Mental Health Epidemiology

Abstract P1-03-02: Clip placement after ultrasound guided biopsy in the setting of neoadjuvant chemotherapy

Method of presuming the risk of worsening in autoimmune disease accompanied by dysfunction due to tissue destruction