Significance of HLA in Graves' disease and Graves' orbitopathy in Asian and Caucasian populations - a systematic review.

Introduction: Graves' disease (GD) and Graves' orbitopathy (GO) development were suspected to be HLA-related in both Asian and Caucasian populations. However, most studies were performed with application of serological methods or low resolution genetic typing, which led to inconsistent results even among the same population. The present review is intended to summarize the state-of-art knowledge on the HLA significance in GD and GO in Asians and Caucasians, as well as to find the most significant alleles for each of the populations. Methods: PubMed was searched for relevant articles using the following search terms: HLA plus thyroid-associated ophthalmopathy or Graves' disease or Graves' orbitopathy or thyroid eye disease or thyroid-associated orbitopathy. Results: In Asian population GD was found to be associated mostly with B*46:01, DPB1*05:01, DRB1*08:02/03, DRB1*16:02, DRB1*14:03, DRB1*04:05, DQB1*05:02 and DQB1*03:03, while DRB1*07:01, DRB1*01:01, DRB1*13:02, DRB1*12:02 are potentially protective. HLA-B*38:02, DRB1*16:02, DQA1*01:02, DQB1*05:02 can be considered associated with increased risk of GO in Asians, while HLA-B*54:01 may play protective role. In Caucasians, C*07:01, DQA1*05:01, DRB1*03, DQB1*02:01 are associated with GD risk while DRB1*07:01, DQA1*02:01 may be protective. Significance of HLA in the course of GD and novel aspects of HLA amino acid variants and potential HLA-based treatment modalities were also discussed.

Associations between Lipid Profiles and Graves' Orbitopathy can Be HLA-Dependent.

The risk of Graves' orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves' disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent.

Significance of HLA in the development of Graves' orbitopathy.

Graves' disease (GD), similarly to most autoimmune disease, is triggered by environmental factors in genetically predisposed individuals. Particular HLA alleles increase or decrease GD risk. No such correlation was demonstrated for Graves' orbitopathy (GO) in Caucasian population. HLA-A, -B, -C, -DQB1 and -DRB1 genotyping was performed using a high-resolution method in a total number of 2378 persons including 70 patients with GO, 91 patients with non-GO GD and 2217 healthy controls to compare allele frequencies between GO, non-GO and controls. Significant associations between GO and HLA profile were demonstrated, with HLA-A*01:01, -A*32:01, -B*37:01, -B*39:01, -B*42:01, -C*08:02, C*03:02, DRB1*03:01, DRB1*14:01 and DQB1*02:01 being genetic markers of increased risk of GO, and HLA-C*04:01, -C*03:04, -C*07:02 and -DRB1*15:02 being protective alleles. Moreover, correlations between HLA alleles and increased or decreased risk of non-GO GD, but with no impact on risk of GO development, were revealed. Identification of these groups of GO-related and GO-protective alleles, as well as the alleles strongly related to non-GO GD, constitutes an important step in a development of personalized medicine, with individual risk assessment and patient-tailored treatment.

Novel Insight into Non-Genetic Risk Factors of Graves' Orbitopathy.

An assessment of the risk of Graves' orbitopathy (GO) is an important challenge in Graves' disease (GD) management. The purpose of this study was to compare non-genetic parameters in GD patients with and without GO in order to find novel risk factors and to verify the factors already reported. A total number of 161 people, 70 with GO and 91 non-GO patients were included in this study. GO was confirmed to be associated with smoking, older age, higher TSH receptor antibodies (TRAb) and lower thyroglobulin antibody (TgAb) levels and hypercholesterolemia. We demonstrated the latter correlation even for only a mild increase in LDL cholesterol. Importantly, our study provides novel potential GO risk factors, including higher serum creatinine levels, higher MCV and lower PLT. If further confirmed, these new, simple and easily accessible potential GO markers may constitute valuable auxiliary markers in GO risk assessments. We additionally proved that in moderate to severe GO, gender-related differences attenuate. No impact of vitamin D deficiency in GO development in patients with 25-hydroxyvitamin D [25(OH)D] > 20 ng/mL was found. The present report provides a set of GO risk factors, which can be used as a precise tool for an individual GO risk assessment.

Actual Associations between HLA Haplotype and Graves' Disease Development.

The association between HLA and the risk of Graves' disease (GD) has been analyzed for many years. However, the results were often inconsistent and mostly regarded Asian populations. The purpose of our study was to perform HLA genotyping using a next-generation sequencing (NGS) method in Caucasians, to find out which alleles are eventually correlated with GD morbidity as well as which of them can be considered protective. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 2376 persons, including 159 GD patients and 2217 healthy controls. We have demonstrated a significant association between the risk of GD and the following alleles: HLA-B*08:01, -B*39:06, -B*37:01, -C*07:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*03:01, -DRB1*11:01, -DRB1*13:03, -DRB1*01:03, -DRB1*14:01, -DQB1*03:01, DQB1*02:01. The alleles HLA-B*39:06, -B*37:01, -C*14:02, -C*03:02, -C*17:01, -DRB1*14:01 are novel GD-associated, previously not-reported independent ones with no linkage disequilibrium with other high-risk alleles. On the other hand, the frequencies of HLA-B*07:02, -C*07:02, -C*03:04, DRB1*07:01, -DQB1*02:02, -DQB1*03:03 were significantly lower in GD compared to controls. This study demonstrated the actual relationships between HLA and GD based on the NGS method and provided a novel set of alleles as a reliable tool for an individual personalized risk assessment.

Interobserver Agreement and Plane-Dependent Intraobserver Variability of Shear Wave Sonoelastography in the Differential Diagnosis of Ectopic Thymus Tissue.

Shear wave elastography (SWE) has been demonstrated to be a useful tool in the differential diagnosis of ectopic thymus tissues (ETs), providing quantitative values of the shear wave stiffness (SWS) of both ETs and adjacent thyroid tissue. However, no data are available on the potential influence of the imaging plane (transverse vs. longitudinal) on the obtained SWS and shear wave ratio (SWR) values in SWE of these tissues. Moreover, no reports on the interobserver repeatability of SWE were published in regard to ETs. The aim of this study has been to evaluate the potential influence of the examination plane-transverse vs. longitudinal-on the SWS and SWR results, as well as to determine whether SWE of ETs is subjected to interobserver variability. SWE was demonstrated to have high inter- and intraobserver agreement in the evaluation of ETs and adjacent thyroid tissue. Significant differences between SWS values, but not SWR values, obtained in the transverse and longitudinal planes were observed. This phenomenon is probably a result of anisotropy-related artifacts and does not reduce the reliability of the method. SWE operators should be aware of the presence of plane-dependent artifacts to properly interpret the obtained results.

Application of Shear Wave Sonoelastography in the Differential Diagnosis of Extra- and Intra-Thyroidal Ectopic Thymic Tissue.

The ultrasound (US) pattern of intrathyroidal ectopic thymus (IET) can resemble papillary thyroid carcinoma (PTC) while the extrathyroidal ectopic thymus (EET) can mimic pathological lymph nodes. Recently, the usefulness of strain elastography (SE) was demonstrated in the differential diagnosis, however this method has several limitations. The aim of the current study was to assess the usefulness of shear wave elastography (SWE) in this field. The US, SE, and SWE were performed in 31 children with 53 ectopic thymuses (ETs) and quantitative values of SWE parameters were calculated, so as to generate potential normative values of ET elasticity and of the shear wave ratio (SWR). The mean SWRIET was 0.89 ± 0.21 and the mean shear wave stiffness (SWS) was 7.47 ± 1.93 kPa. The mean SWREET was 0.84 ± 0.15 and the mean SWSEET was 11.28 ± 2.58 kPa. The results have proven that the stiffness of ETs is lower or equal to the thyroid's. SWE was demonstrated to be a useful diagnostic method for ET evaluation. Therefore, the application of SWE in ET diagnosis allows more accurate evaluation of ET-like lesions and, in many cases, allows one to avoid invasive procedures, simultaneously providing a precise monitoring method based on combined US and SWE evaluation.

Subacute Thyroiditis is Associated with HLA-B*18:01, -DRB1*01 and -C*04:01-The Significance of the New Molecular Background.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease whose pathogenesis is still not completely defined. Previous viral infection is considered to be a triggering factor in genetically predisposed individuals. In about 70% of patients, susceptibility to SAT is associated with the HLA-B*35 allele. The correlation between SAT and other human leukocyte antigens (HLA) has not yet been unequivocally demonstrated and the genetic background is still unknown in about 30% of patients. The purpose of our study was to perform HLA genotyping using a next-generation sequencing method, to find out whether alleles other than HLA-B*35 are correlated with SAT morbidity. HLA-A, -B, -C, -DQB1, -DRB1 were genotyped using a next-generation sequencing method in 1083 subjects, including 60 SAT patients and 1023 healthy controls. Among 60 patients diagnosed with SAT, 81.7% of subjects were identified as having allele HLA-B*35, 23.3% had HLA-B*18:01, 28.3% had HLA-DRB1*01 and 75.5% had HLA-C*04:01. These alleles occurred in the control group at frequencies of 10.2%, 7.2%, 12.9% and 12.5%, respectively. The differences were statistically significant, with p < 0.05. In addition to its previously described relationship with HLA-B*35, genetic susceptibility to SAT was associated with the presence of HLA-B*18:01, DRB1*01 and C*04:01. The alleles HLA-B*18:01 and DRB1*01 were independent SAT risk factors. The assessment of these four alleles allows the confirmation of genetic predisposition in almost all patients with SAT.

Time-Lag Between Symptom Onset and Diagnosis of Subacute Thyroiditis - How to Avoid the Delay of Diagnosis and Unnecessary Overuse of Antibiotics.

Clinical symptoms of subacute thyroiditis (SAT) may be misleading and the proper diagnosis is significantly delayed, and many unnecessary therapeutic methods are used, including application of antibiotics. The purpose of the study is to analyze the reasons and frequency of delayed SAT diagnosis and unnecessary antibiotic treatment and to propose a simple algorithm to facilitate the diagnosis and prevent antibiotic abuse. Sixty-four SAT patients were divided into groups depending on the period of time from the first symptoms of SAT to diagnosis and on the unnecessary use of antibiotics. Data from medical history and laboratory test results were analyzed for individual groups to determine the reasons for delayed diagnosis and incorrect treatment. In 73% of patients, the diagnosis was delayed from over two weeks up to six months. Among 62 patients who provided data on antibiotic use, 29 (46.77%) were treated with one or more antibiotics due to SAT symptoms. Fever, preceding infection, increased C-reactive protein (CRP), and WBC were characteristic for the antibiotic treated group. Fever, preceding infection, increased CRP and WBC are typical for both SAT and infection and are the main symptoms leading to misdiagnosis and unnecessary antibiotic treatment in SAT. Thus, in all patients with neck pain or other SAT-like symptoms, thorough clinical examination of the neck is mandatory. When firm and/or tender thyroid nodule/goitre is present and erythrocyte sedimentation rate /CRP is increased, patient should be promptly referred to an endocrinologist, and antibiotics are not recommended.

Clinical characteristics of subacute thyroiditis is different than it used to be - current state based on 15 years own material.

INTRODUCTION: The clinical characteristics of subacute thyroiditis (SAT) has been changing in recent years. There are more and more patients with painless SAT, and more cases of SAT with elevated levels of anti-thyroid antibodies were reported. The aim of the study was to evaluate the clinical characteristics of SAT patients with special regard to the differences between the previously described and currently observed features of the disease. MATERIAL AND METHODS: Clinical and laboratory data were retrospectively reviewed for 64 patients with confirmed SAT. RESULTS: Mean age of the patients was 42.67 years. The male to female ratio was 1:7. Neck or ear pain was reported by 93.75% of patients, while fever occurred in 65.63% of patients. The aTPO and aTg levels were increased in 15.5% and 33.3% of patients, respectively. TRAb level was increased in 6% of patients. Transient microhaematuria was present in 63% of analyzed cases. No statistically significant differences in clinical characteristics or laboratory results were found between the groups with- and without neck/ear pain, with- and without elevated TRAb, and with- and without elevated aTPO and/or aTg. CONCLUSION: In our study, several new features of current SAT course, different from what we used to know about the disease, were reported. Higher frequency of painless SAT than it was ever described, was observed. Moreover, in as much as one third of the patients aTPO and/or aTg were present, and in 6% of SAT cases the coexistence of TRAb was demonstrated. Transient microhaematuria was typical for the acute SAT phase.

The Risk of Recurrence of Subacute Thyroiditis Is HLA-Dependent.

The frequency of recurrence of subacute thyroiditis (SAT) is rather high, reaching 20⁻30%. The reason for SAT relapse is still unknown. Recently, we have demonstrated the association between SAT and the presence of HLA-B*18:01, DRB1*01, and C*04:01, apart from the previously known HLA-B*35. The aim of the present study was to evaluate the correlation between SAT-associated HLA haplotypes and the risk of SAT recurrence. HLA-A, -B, -C, -DQB1 and -DRB1 were genotyped using a next-generation sequencing method in 49 SAT patients. The patients were divided into the following HLA groups: 1. HLA-B*35 and/or HLA-C*04, but without any other of the analyzed antigens; 2. HLA-DRB1*01, regardless of the co-presence of HLA-B*35 or -C*04:01, but without HLA-B*18:01; 3. HLA-B18 only, without any other antigen; 4. HLA-B*18:01 plus -B*35, regardless of the presence of any other analyzed antigens. The recurrence rate was compared between the groups. The recurrence rate was significantly increased in patients with HLA-B*18:01 plus HLA-B*35. In conclusion, the risk of SAT recurrence was HLA-dependent and the determining factor was the co-presence of HLA-B*18:01 and -B*35. In such high-risk patients, the steroid treatment regimen should be intensified with a slower dose reduction.

Sonographic Pattern of Subacute Thyroiditis Is HLA-Dependent.

Background: Since 1977 the susceptibility to SAT has been known to be HLA-B*35-related in ~70% of patients. Recently it has been demonstrated that SAT is associated with the presence of HLA-B*18:01 and DRB1*01, as well as with HLA-C*04:01. The association between the type of genetic SAT background and sonographic pattern of the disease has never been analyzed. The aim of the study was to evaluate the potential correlation between the presence of individual HLA haplotypes and the sonographic SAT pattern, and to provide the US characteristics of the analyzed SAT cases. Methods: HLA-A, -B, -C, -DQB1, and -DRB1 were genotyped using a next-generation sequencing method in 46 SAT patients. All patients were divided into the following groups according to the HLA haplotype: 1. HLA-B*35 and/or HLA-C*04, but without any other of the analyzed antigens; 2. HLA-DRB1*01, regardless of the co-presence of HLA-B*35 or C*04:01, but without HLA-B*18:01; 3. HLA-B*18:01 only, without any other of the analyzed antigens; 4. HLA-B*18:01 plus B*35, regardless of the presence of any other analyzed antigens. The US patterns of SAT thyroid lesions were compared among the groups. Results: The US image of SAT lesions in Groups 1 and 2 were similar. The typical SAT features for these groups were as follows: hypoechoic, strongly heterogeneous, bilateral, multiple areas, with decreased vascularization, usually oval with blurred margins, infrequently affecting the whole lobe, or having nodule-like pattern. Several features of Group 3 were different from the other groups. In 60% of cases lesions were rather homogeneous, and in 100%-hypoechoic, in 80% of patients there was only one unilateral single SAT area filling the whole affected lobe. On the contrary to the other groups, in Group 4 no lesion was oval in shape. Conclusions: Our results provide for the first time the evidence that the US pattern of SAT lesions depends on HLA, and the determining factor is the presence of HLA-B*18:01. The deviations from the typical SAT US image are mostly pronounced in patients with the presence of only HLA-B*18:01, without any other analyzed haplotype. Further research is necessary to explain this phenomenon.

Multi-Channel Convolutional Neural Networks Architecture Feeding for Effective EEG Mental Tasks Classification.

Mental tasks classification is increasingly recognized as a major challenge in the field of EEG signal processing and analysis. State-of-the-art approaches face the issue of spatially unstable structure of highly noised EEG signals. To address this problem, this paper presents a multi-channel convolutional neural network architecture with adaptively optimized parameters. Our solution outperforms alternative methods in terms of classification accuracy of mental tasks (imagination of hand movements and speech sounds generation) while providing high generalization capability (∼5%). Classification efficiency was obtained by using a frequency-domain multi-channel neural network feeding scheme by EEG signal frequency sub-bands analysis and architecture supporting feature mapping with two subsequent convolutional layers terminated with a fully connected layer. For dataset V from BCI Competition III, the method achieved an average classification accuracy level of nearly 70%, outperforming alternative methods. The solution presented applies a frequency domain for input data processed by a multi-channel architecture that isolates frequency sub-bands in time windows, which enables multi-class signal classification that is highly generalizable and more accurate (∼1.2%) than the existing solutions. Such an approach, combined with an appropriate learning strategy and parameters optimization, adapted to signal characteristics, outperforms reference single- or multi-channel networks, such as AlexNet, VGG-16 and Cecotti's multi-channel NN. With the classification accuracy improvement of 1.2%, our solution is a clear advance as compared to the top three state-of-the-art methods, which achieved the result of no more than 0.3%.