Overweight as a biomarker for concomitant thyroid cancer in patients with Graves' disease.

The incidence of concomitant thyroid cancer in Graves' disease varies and Graves' disease can make the diagnosis and management of thyroid nodules more challenging. Since the majority of Graves' disease patients primarily received non-surgical treatment, identifying biomarkers for concomitant thyroid cancer in patients with Graves' disease may facilitate planning the surgery. The aim of this study is to identify the biomarkers for concurrent thyroid cancer in Graves' disease patients and evaluate the impact of being overweight on cancer risk. This retrospective cohort study analyzed 122 patients with Graves' disease who underwent thyroid surgery at Seoul St. Mary's Hospital (Seoul, Korea) from May 2010 to December 2022. Body mass index (BMI), preoperative thyroid function test, and thyroid stimulating hormone receptor antibody (TR-Ab) were measured. Overweight was defined as a BMI of 25 kg/m² or higher according to the World Health Organization (WHO). Most patients (88.5%) underwent total or near-total thyroidectomy. Multivariate analysis revealed that patients who were overweight had a higher risk of malignancy (Odds ratios, 3.108; 95% confidence intervals, 1.196-8.831; p = 0.021). Lower gland weight and lower preoperative TR-Ab were also biomarkers for malignancy in Graves' disease. Overweight patients with Graves' disease had a higher risk of thyroid cancer than non-overweight patients. A comprehensive assessment of overweight patients with Graves' disease is imperative for identifying concomitant thyroid cancer.

[Treatment of Graves' disease is moving towards precision medicine]. / Behandling av Graves sjukdom.

This is the first national guideline in hyperthyroidism to harmonise and update clinical practice according to what is evidence based and direct care from patients' needs. We present 4 articles in Läkartidningen of different views of the guideline, including family care perspectives, patient care perspectives and perspectives on ophthalmology. This article concerns treatment of Graves' disease and includes endocrinological, surgical and oncological perspectives on what is established practice, but also news in the national guideline that remain to be fully implemented in Sweden in the years to come. News are precision medicine using the GREAT score, preoperative calcium/D vitamin treatment, individualized levothyroxine treatment after thyroid surgery, uniformed levothyroxine replacement strategy, access to national patient information and national guidelines on radiation protection and treatment schemes for radioactive iodine. A national guideline is the creation of many persons' views, including patient representatives, and the recommendations have undergone a thorough national review process from stakeholders. It is a guideline with future perspectives for an improved care.

Dissecting causal relationships between primary biliary cholangitis and extrahepatic autoimmune diseases based on Mendelian randomization.

As an autoimmune disease, up to 73% of patients with primary biliary cholangitis (PBC) have a combination of extrahepatic autoimmune diseases (EHAIDs); however, the causal relationship between PBC and EHAIDs is unclear. The genome-wide association analyses provided 14 GWAS data for PBC and EHAIDs, and bidirectional, two-sample MR analyses were performed to examine the relationship between PBC and EHAIDs. The analysis using MR provides a strong and meaningful estimation of the bidirectional correlation between PBC and 7 EHAIDs: rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, autoimmune hypothyroidism, inflammatory bowel disease and ulcerative colitis of its types. In addition, PBC increases the risk of autoimmune thyroid diseases such as autoimmune hyperthyroidism and Graves' disease, as well as multiple sclerosis and psoriasis. Additionally, PBC is identified as a risk factor for Crohn's disease and Celiac disease. Based on genetic evidence, there may be connections between PBC and specific EHAIDs: not all coexisting EHAIDs induce PBC, and vice versa. This underscores the significance of prioritizing PBC in clinical practice. Additionally, if any liver function abnormalities are observed during treatment or with EHAIDs, it is crucial to consider the possibility of comorbid PBC.

Thyroid stimulating receptor autoantibodies.

Thyroid-stimulating hormone receptor autoantibodies (TRAbs) play a crucial role as pathogenic antibodies in both the diagnosis and management of Graves' disease (GD). GD, an autoimmune disease resulting from a combination of genetic and environmental factors, is the most common cause of hyperthyroidism. With advancements in technology for TRAb detection and the availability of automated commercial kits, TRAb has become an essential clinical laboratory marker for the diagnosis of GD, as well as extra-thyroidal manifestations like Graves' ophthalmopathy (GO). This article provides a comprehensive review of TRAb, encompassing its clinical assays along with its significance in the clinical setting.

A Mendelian randomization study of the effect of selenium on autoimmune thyroid disease.

OBJECTIVE: The impact of selenium on autoimmune thyroid disease (AITD) is a subject of ongoing debate. This study aimed to analyze the causal correlations of selenium with autoimmune thyroiditis (AIT), autoimmune hyperthyroidism (AIH), and Graves' disease (GD) by Mendelian randomization (MR). MATERIALS AND METHODS: Single nucleotide polymorphisms related to selenium, AIT, AIH, and GD were sourced from the IEU Open GWAS project and FinnGen. Exposure-outcome causality was assessed using inverse variance weighted, MR-Egger, and weighted median. Horizontal pleiotropy was examined using the MR-Egger intercept, heterogeneity was evaluated with Cochran's Q test, and the robustness of the results was confirmed via leave-one-out sensitivity analysis. RESULTS: The MR analysis revealed that selenium did not exhibit a causal relationship with AIT (OR 0.993, 95% CI 0.786 to 1.108, p=0.432), AIH (OR 1.066, 95% CI 0.976 to 1.164, p=0.154), or GD (OR 1.052, 95% CI 0.984 to 1.126, p=0.138). Moreover, the MR-Egger intercept and Cochran's Q test demonstrated the absence of horizontal pleiotropy or heterogeneity in these results (p>0.05). Sensitivity analysis affirmed the robustness of these results. CONCLUSIONS: This MR analysis concluded that selenium was not linked to AIT, AIH, or GD risk. Therefore, indiscriminate selenium supplementation is not advisable for AITD patients without concurrent selenium deficiency.

Thyroid ultrasound pattern in primary hypothyroidism is similar to Graves' disease: a report of three cases.

Ultrasound can identify important characteristics in primary hypothyroidism and diffuse hyperthyroidism (Graves' disease). Therefore, sonologists are actively investigating ultrasound criteria to differentiate between these two conditions. Nevertheless, practice shows the absence of such ultrasonic landmarks. For the first time in the literature, three cases of primary hypothyroidism have demonstrated an ultrasound pattern identical to that of Graves' disease. This pattern includes the presence of goiter, marked total hypoechogenicity of the parenchyma, significantly or moderately increased blood flow intensity ('thyroid inferno'), and elevated peak systolic velocity of the superior thyroid arteries. These signs are less common in hypothyroidism compared to hyperthyroidism. Diagnostic data suggest that the pathogeneses of primary hypothyroidism and Graves' disease share the same mechanisms, leading to similar thyroid ultrasound patterns. One of these shared mechanisms is presumably thyroid overstimulation by the autonomic nervous system, which is adequate to the body's hormonal requirements in hypothyroidism but excessive in hyperthyroidism.

Predictive value of bone turnover markers and thyroid indicators for bone metabolism in GD patients after treatment.

Purpose: To investigate the relationship between bone turnover markers (BTMs) and thyroid indicators in Graves' disease (GD) and to further assess predictive value of changes in early stage retrospectively. Methods: We studied 435 patients with GD and 113 healthy physical examiners retrospectively and followed up these two groups of patients after 6 months. We investigated the correlations between BTMs and other 15 observed factors, and analyzed the predictive value of FT3 and FT4 before and after treatment (FT3-P/FT3-A, FT4-P/FT4-A) on whether BTMs recovered. Results: The levels of thyroid hormones and BTMs in GD group were significantly higher than those in control group (P < 0.05) and decreased after 6 months of treatment. FT3, W, Ca and ALP were independent factors in predicting the elevation of OST. Duration of disease, FT3, TSH and ALP were independent factors in predicting the elevation of P1NP. Age, duration of disease, TRAb and ALP were independent factors in predicting the elevation of CTX-1. The AUC of FT3-P/FT3-A and FT4-P/FT4-A for predicting OST recovery were 0.748 and 0.705 (P < 0.05), respectively, and the cut-off values were 0.51 and 0.595. There was no predictive value for P1NP and CTX-1 recovery (P > 0.05). Conclusion: BTMs were abnormally elevated in GD and were significantly correlated with serum levels of FT3, FT4, TRAb, Ca, and ALP. FT3 decreased more than 51% and FT4 dropped more than 59.5% after 6 months of treatment were independent predictors for the recovery of BTMs in GD.

Graves' Disease: Acquired Cause of a Moderate Increase in Hemoglobin A2 Level.

BACKGROUND: Hyperthyroidism can lead to diverse hematological disorders, such as microcytosis and a mild increase in hemoglobin A2 fraction. METHODS: This study reported a 31-year-old woman of Moroccan origin recently diagnosed with Graves' disease. Her blood tests revealed microcytosis, hypochromia, and a normal ferritin level. A phenotypic analysis of hemo-globin was performed using two techniques: capillary electrophoresis and reversed-phase high performance liquid chromatography. RESULTS: Both techniques indicated a slight increase in hemoglobin A2 level. These results initially suggested het-erozygous beta-thalassemia, eventually correlating with the concurrent presence of Graves' disease, as evidenced by the normalization of hemoglobin A2 level following treatment. CONCLUSIONS: This case highlights the importance of having clinical, biological, and therapeutic data for a relevant interpretation of a phenotypic hemoglobin study.

Refractory hypothyroidism.

INTRODUCTION: Persistently elevated thyroid stimulating hormone (TSH) despite levothyroxine (LT4) treatment that exceeds the standard weight-adjusted dose is a common clinical presentation. This may lead to additional testing for LT4 malabsorption or poor LT4 adherence, the latter of which is challenging to confirm because it is predicated on accurate patient accountability. CASE REPORT: A 35-year-old lady, post-radioactive iodine therapy for Graves' disease remained euthyroid for a year on oral LT4. Two years later, she was clinically and biochemically hypothyroid despite claiming LT4 compliance. As all laboratory investigations were within the reference range, pseudomalabsorption was suspected and a LT4 absorption test was done. During the test, her free thyroxine increased significantly at 4 hours, reaching a peak of more than 50% from baseline while TSH decreased appropriately from 0 minute to 360 minutes. This was followed by normalisation of TSH with LT4 treatment under direct observation. DISCUSSION: The LT4 absorption test is a prompt and economical means to rule out true malabsorption, decrease unwarranted subspecialty referrals and validate the weight-adjusted LT4 dose reduction.

Successful guselkumab treatment of a refractory psoriasis patient with Graves' disease: a case report.

Psoriasis is a chronic inflammatory skin disease. It is associated with many autoimmune diseases such as rheumatoid arthritis, Crohn's disease and thyroid diseases. Graves' disease (GD) is a common organ-specific autoimmune disease characterized by diffuse goitre and thyrotoxicosis. Management of psoriasis patients with GD is challenging. This current report presents the case of a 34-year-old female patient with refractory psoriasis with GD who was hospitalized for drug eruption and then experienced new-onset erythema and scaling following treatment with adalimumab and secukinumab. Despite the sequential move to phototherapy, tofacitinib and ustekinumab, the erythema and scaling continued unabated and exacerbated. Finally, switching to guselkumab resulted in the psoriasis lesions significantly improving. These findings suggest that guselkumab might be an effective treatment option for refractory psoriasis combined with GD.

Methylation levels of the IL10 gene in peripheral blood are related to the intractability of Graves' disease.

The prognosis of autoimmune thyroid diseases (AITDs), including Hashimoto's disease (HD) and Graves' disease (GD), is difficult to predict. DNA methylation regulates gene expression of immune mediating factors. Interleukin (IL)-10 is a Th2 cytokine that downregulates inflammatory cytokines produced by Th1 cells. To clarify the role of methylation of the IL10 gene in the prognosis of AITD, we evaluated the methylation levels of two CpG sites in the IL10 promoter using pyrosequencing. The methylation levels of the -185 CpG site of the IL10 gene were related to age and GD intractability in GD patients. Furthermore, the C carrier of the IL10-592 A/C polymorphism was related to low methylation levels of the -185 CpG site. The methylation levels of the IL10-185 CpG site of the IL10 gene were related to the intractability of GD and were lower in individuals with the C allele of the IL10-592 A/C polymorphism.

Increased interleukin-9 and Th9 cells in patients with refractory Graves' disease and interleukin-9 polymorphisms are associated with autoimmune thyroid diseases.

Introduction: Autoimmune thyroid diseases (AITDs) are prevalent disorders, primarily encompassing Graves' disease (GD) and Hashimoto's thyroiditis (HT). Despite their common occurrence, the etiology of AITDs remains elusive. Th9 cells, a new subset of CD4+T cells with immunomodulatory properties, have been linked to the development of various autoimmune diseases. However, research on the role of Th9 cells in AITDs is limited. Methods: We investigated the expression of Th9 cells,their functional cytokine IL-9, and transcription factor IRF4 in peripheral blood mononuclear cells (PBMCs) and plasma of AITD patients and healthy controls. Additionally, we explored the genetic association between four loci polymorphisms (rs31564, rs2069879, rs1859430, and rs2069868) of the IL-9 gene and AITDs. Results: We reported, for the first time, that refractory GD patients exhibited elevated mRNA levels of IL-9 and IRF4 in PBMCs, increased IL-9 protein levels in plasma, and a higher proportion of Th9 cells in peripheral blood when compared to normal controls. Furthermore, human recombinant IL-9 protein was found to enhance IFN-g secretion in PBMCs from both GD patients and normal controls. At the genetic association level, after adjusting for age and sex, the rs2069879 polymorphism exhibited a significant association with AITDs under an additive model (P<0.001, OR= 0.05, 95% CI=0.03-0.08). Discussion: Our results reveal that Th9 cells may exert a pivotal role in the pathogenesis and progression of refractory GD and HT, and IL-9 holds promise as a novel therapeutic target for the management of AITDs.

Factors affecting timing of hypothyroidism following radioactive iodine therapy (RAIT) for patients with Graves' disease: A 12-month observational study.

BACKGROUND: This retrospective study analyzed factors influencing hypothyroidism development after radioactive iodine therapy for Graves' disease. PATIENTS AND METHODS: Three hundred and three patients with Graves' disease treated with radioactive iodine (RAI) from 2013 to 2022 at two Egyptian hospitals were included. Data collected included demographics, lab values, thyroid imaging, RAI doses, and outcomes. Patients were followed for ≥1 year to assess hypothyroidism onset. RESULTS: At the end of 1 year, around 79.5% of the individuals developed hypothyroidism while 12.5% continued to experience hyperthyroidism. The onset of hypothyroidism occurred earlier in those with thyroid volume (≤75.5 cm 3 ), lower thyroid weight (≤84.7 g), thyroid uptake (≤18.8%), and higher RAI dose/volume (≥0.1022 mCi/ml) ( P  < 0.001). Additionally, there was a correlation between anti-thyroid peroxidase (anti-TPO) antibodies and faster development of hypothyroidism compared to those who were negative for antibodies (2.9 vs 8.9 months, P  = 0.001). When considering factors in analysis it was found that anti-TPO antibodies were the only independent predictor, for developing hypothyroidism (hazard risk 30.47, P  < 0.001). Additionally, thyroid volume and uptake independently predicted successful treatment outcomes ( P  < 0.05). CONCLUSION: Positive anti-TPO antibodies strongly predict hypothyroidism risk after RAI therapy for Graves' disease. Smaller thyroid size, lower uptake, and higher RAI dose/volume correlate with earlier hypothyroidism onset but are less significant predictors than anti-TPO status. Findings can guide RAI therapy personalization to optimize outcomes.

Prevalence of Selected Polymorphisms of Il7R, CD226, CAPSL, and CLEC16A Genes in Children and Adolescents with Autoimmune Thyroid Diseases.

Hashimoto's thyroiditis (HT) and Graves' disease (GD) are common autoimmune endocrine disorders in children. Studies indicate that apart from environmental factors, genetic background significantly contributes to the development of these diseases. This study aimed to assess the prevalence of selected single-nucleotide polymorphisms (SNPs) of Il7R, CD226, CAPSL, and CLEC16A genes in children with autoimmune thyroid diseases. We analyzed SNPs at the locus rs3194051, rs6897932 of IL7R, rs763361 of CD226, rs1010601 of CAPSL, and rs725613 of CLEC16A gene in 56 HT patients, 124 GD patients, and 156 healthy children. We observed significant differences in alleles IL7R (rs6897932) between HT males and the control group (C > T, p = 0.028) and between all GD patients and healthy children (C > T, p = 0.035) as well as GD females and controls (C > T, p = 0.018). Moreover, the C/T genotype was less frequent in GD patients at rs6897932 locus and in HT males at rs1010601 locus. The presence of the T allele in the IL7R (rs6897932) locus appears to have a protective effect against HT in males and GD in all children. Similarly, the presence of the T allele in the CAPSL locus (rs1010601) seems to reduce the risk of HT development in all patients.

The Role of FOXP3 Polymorphisms in Graves' Disease with or without Ophthalmopathy in a Turkish Population.

Objectives: Forkhead box P3 (FOXP3) gene polymorphisms have been evaluated in many autoimmune diseases, including Graves' disease (GD), in different populations. However, those polymorphisms have not been analyzed in GD or Graves' ophthalmopathy (GO) in the Turkish population. In this study, we aimed to evaluate the frequency of FOXP3 polymorphisms in GD with or without ophthalmopathy in a Turkish population. Materials and Methods: The study included 100 patients with GO, 74 patients with GD without ophthalmopathy, and 100 age- and sex-matched healthy controls. In all study participants, rs3761547 (-3499 A/G), rs3761548 (-3279 C/A), and rs3761549 (-2383 C/T) single nucleotide polymorphisms (SNPs) were detected using the polymerase chain reaction-restriction fragment length polymorphism method. The chi-square test was used to evaluate genotype and allele frequencies. Odds ratios and 95% confidence intervals were calculated for genotype and allele risks. Results: In the patient group (including GD with or without ophthalmopathy), the rs3761548 AC and AA genotype and rs3761549 CT genotype were significantly more frequent than in the control group (all p<0.05). No genotypic and allelic differences were observed for rs3761547 between the patient and control groups (all p>0.05). There was no statistically significant difference between the GO and GD without ophthalmopathy groups concerning the allele and genotype frequencies of all three FOXP3 SNPs (all p>0.05). Conclusion: The AC and AA genotypes of rs3761548 (-3279) and CT genotype of rs3761549 (-2383 C/T) were shown to be possible risk factors for GD development in the Turkish population. However, none of the three SNPs was shown to be associated with the development of GO in patients with GD.

Examination of quality of life and psychiatric symptoms in childhood Graves' disease.

OBJECTIVES: The aim of our study is to examine the emotional, behavioral problems, and psychiatric symptoms of children diagnosed with Graves' disease (GD), to assess their quality of life, and to compare with control group. METHODS: The research was planned as a cross-sectional study and included 16 patients with GD (13 female and three male) and 29 healthy children for control group (19 female and 10 male). Sociodemographic form, Pediatric Quality of Life Inventory, Revised Child Anxiety and Depression Scale-Child Version (RCADS-CV), Strengths and Difficulties Questionnaire (SDQ), Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale (T-DSM-IV-S), and Affective Reactivity Index scale were applied to the children and their families. RESULTS: Eighty one percent of GD group (GG) (n=13, mean age 15.1 ± 2.2) and 66 % of control group (CG) (n=19, 14.6 ± 2.2) were girls. No significant difference was found between GG and CG in terms of quality of life, anxiety, and depression scores. GG had higher scores in affective reactivity index, SDQ-P total score, and T-DSM-IV-S total scores (p values 0.039; 0.009; 0.023, respectively). While no significant difference was detected in the T-DSM-IV-S-inattention and hyperactivity scores, significantly higher scores were detected in oppositional defiance and conduct disorder scores (p values 0.172; 0.294; 0.019; 0.027, respectively). CONCLUSIONS: In children with GD, irritability, oppositional defiant, and conduct disorder symptoms have been detected. Children with these mental health symptoms experience behavioral and emotional difficulties in their daily lives. It is important to follow up children with GD for possible comorbid psychiatric disorders.

Use of a dosimetry-based RAI protocol for treatment of benign hyperthyroidism optimises response while minimising exposure to ionising radiation.

BACKGROUND: The optimal treatment strategy for radioiodine (RAI) treatment protocols for benign hyperthyroidism remains elusive. Although individualised activities are recommended in European Law, many centres continue to provide fixed activities. Our institution implemented a dosimetry protocol in 2016 following years of fixed dosing which facilitates the calculation of individualised activities based on thyroid volume and radioiodine uptake. METHODS: This was a retrospective study comparing success rates using a dosimetry protocol targeting an absorbed dose of 150 Gy for Graves' disease (GD) and 125 Gy for Toxic Multinodular Goiter (TMNG) with fixed dosing (200MBq for GD and 400MBq for TMNG) among 204 patients with hyperthyroidism. Success was defined as a non-hyperthyroid state at 1 year for both disease states. Results were analysed for disease specific or patient specific modulators of response. RESULTS: This study included 204 patients; 74% (n = 151) received fixed activities and 26% (n = 53) of activities administered were calculated using dosimetry. A dosimetry-based protocol was successful in 80.5% of patients with GD and 100% of patients with TMNG. Differences in success rates and median activity administered between the fixed (204Mbq) and dosimetry (246MBq) cohort were not statistically significant (p = .64) however 44% of patients with GD and 70% of patients with TMNG received lower activities following treatment with dosimetry as opposed to fixed activities. Use of dosimetry resulted in successful treatment and reduced RAI exposure for 36% of patients with GD, 70% of patients with TMNG, and 44% of patients overall. CONCLUSION: This retrospective clinical study demonstrated that treatment with a dosimetry-based protocol for TMNG and GD achieved comparable success rates to fixed protocols while reducing RAI exposure for over a third of patients with GD and most patients with TMNG. This study also highlighted that RAI can successfully treat hyperthyroidism for some patients with activities lower than commonplace in clinical practise. No patient or disease specific modulators of treatment response were established in this study; however, the data supports a future prospective trial which further scrutinises the individual patient factors governing treatment response to RAI.

Prospective study to evaluate radioactive iodine of 20 mCi vs 10-15 mCi in Graves' disease.

OBJECTIVES: To assess whether increasing radioactive iodine dose can increase treatment efficacy in Graves' disease. METHODS: A prospective study was conducted, including 106 patients receiving 20 mCi (740 MBq) radioactive iodine (RAI), compared with a retrospective data, including 113 patients receiving 10-15 mCi (370-555 MBq) RAI. Remission and failure rates were evaluated at 6 months post-RAI. Statistical analysis was performed using logistic regression and Kaplan-Meier curves. RESULTS: Patients receiving 20 mCi RAI demonstrated a significantly higher remission rate compared to the 10-15 mCi group (82.1% vs 66.4%, p = 0.009). Median time to remission was shorter in the 20 mCI group (3 vs 4 months, p = 0.002). Hypothyroidism at 6 months was more prevalent in the 20 mCi group (67% vs 53%, p = 0.03). Larger thyroid size (> 60 g) was associated with treatment failure (p = 0.02). CONCLUSIONS: Higher dosage (20 mCi) RAI showed superior efficacy in achieving remission compared to lower dosages (10-15 mCi) in Graves' disease treatment.