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.

New aspects in the pathogenesis and management of subacute thyroiditis.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease, whose pathogenesis and determinants of the clinical course were unclear for many decades. The last few years have brought many clinically significant new data on the epidemiology, pathogenesis and management of SAT. Several human leukocyte antigen (HLA) alleles were demonstrated not only to increase the risk of SAT, but also to correlate with SAT clinical course and determine the risk of recurrence. The world-wide epidemic of the coronavirus disease 19 (COVID-19) has provided new observations that the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can be a potent SAT-triggering factor, and that the clinical course of SAT in patients affected by COVID-19 is different from a typical one. Additionally, many new trends in the clinical course are emerging. In the last years, painless course of SAT is more and more often described, constituting a special challenge in patients hospitalized due to COVID-19. Despite an excellent availability of diagnostic methods, several difficulties in SAT differential diagnosis can be currently encountered and the proper diagnosis and treatment is frequently delayed. False positive diagnoses of SAT in patients with malignancies of poor prognosis constitute a life-threatening problem. Taking into account all the new aspects of SAT pathogenesis and of its clinical course, the new - modified - SAT diagnosis criteria have been proposed.

Contribution of Ghrelin to the Pathogenesis of Growth Hormone Deficiency.

In this review we described the interactions between ghrelin and the growth hormone (GH)-insulin-like growth factor 1 (IGF-1) axis in children and adults with growth hormone deficiency (GHD). A possible involvement of these interactions in the pathogenesis of unexplained cases of GHD was suggested. Current research provides more and more details to the knowledge on the circadian rhythm of ghrelin. We gathered reports on the decreasing effect of Helicobacter pylori-related chronic gastritis on the number of ghrelin immunopositive cells and the consequent decrease in ghrelin serum concentration. The gastrointestinal tract microflora modification of the ghrelin action, by the mechanism of molecular mimicry, was also stressed. Moreover, the mutual relationships between ghrelin and the TSH-FT4/FT3 axis in growth and metabolic processes are described. It is to be recalled that FT4 and FT3 exert a permissive impact on IGF-1 action and, in turn, GH, in reaction mediated by IGF-1, enhances the monodeiodination of FT4 to FT3. Finally, we discussed the latest attempts to use the GH secretagogue receptor (GHS-R) analogues for possible diagnostic and therapeutic purposes.

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.

Thyroid primary and metastatic malignant tumours of poor prognosis may mimic subacute thyroiditis - time to change the diagnostic criteria: case reports and a review of the literature.

BACKGROUND: The diagnosis of subacute thyroiditis (SAT) is based mainly on the presence of painful thyroid goitre and a significant increase in erythrocyte sedimentation rate (ESR). Proceeding according to these diagnostic criteria may lead to an incorrect diagnosis and treatment. Extremely dangerous is the situation when the diagnosis of SAT is erroneously made based on criteria other than ultrasound (US) image and fine needle aspiration biopsy (FNAB), which leads to delayed diagnosis of malignant tumour with poor prognosis. CASE PRESENTATION: Five patients with typical SAT symptoms are presented. In all of them, anaplastic thyroid cancer or metastatic thyroid tumours were finally diagnosed as the cause of the initial symptoms resembling SAT. Most of the patients were initially misdiagnosed and the proper diagnosis of malignancy was delayed. CONCLUSIONS: The authors have proposed the new diagnostic criteria for SAT, and strongly suggest that thyroid gland US should be included in the main criteria of SAT diagnosis, together with FNAB result excluding the presence of malignant tumour.

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.

Differences of the Structure of Immune Regulatory Cell Populations between Cellular Material from Sonographically Detected Focal Thyroid Lesions and Peripheral Blood in Humans.

Focal thyroid lesions are common ultrasound findings with the estimated prevalence up to 67% of the population. They form characteristically enveloped regions with individual encapsulated microenvironment that may involve the specific distribution of immune system compounds-especially antigen presenting cells (APC). We analyzed and compared the most potent APC-plasmacytoid and conventional dendritic cells (DCs) subpopulations and three monocyte subpopulations as well as other immune cells-in peripheral blood and local blood of thyroid gland obtained parallelly in patients with focal thyroid lesions using flow cytometry. The analysis revealed significant differences in the distribution of main subsets of assessed cells between peripheral blood and biopsy material. The results support the existence of local, organ-specific immune reaction control networks within thyroid nodules.

Cognitive Function, APOE Gene Polymorphisms, and Thyroid Status Associations in Postmenopausal Women in Poland.

BACKGROUND: The objective of the study was to analyze a potential association between cognitive functions and thyroid status in postmenopausal women with different polymorphisms of the apolipoprotein E gene (APOE). METHODS: The examined population included 402 postmenopausal women from south-eastern Poland. The evaluation of cognitive functions was made with the use of the diagnostic Central Nervous System-Vital Signs equipment (Polish version). Multiplex polymerase chain reactions were performed to assess APOE polymorphisms. The thyroid hormone tests were assessed by an accredited laboratory. RESULTS AND CONCLUSION: Lower results of cognitive functions were associated with the presence of the ε4 APOE allele in postmenopausal women. The ε4 APOE polymorphism was associated with a higher concentration of thyroid-stimulating hormone and lower concentrations of free triiodothyronine and total triiodothyronine.

[Erectile dysfunction - treatment with substances of natural origin].

The article discusses erectile dysfunction (ED) with the special emphasis on epidemiology, as well as the currently available medical treatments. Describing treatment methods authors paid special attention to natural therapies (as Panax ginseng, Tribulus terrestris, Vaccinium macrocarpon), because taking into consideration their safety profile, they appear to be an important alternative to therapies with synthetic molecules. From substances of natural origin, extract from the fruit of Tribulus terrestris ranks itself high on in collation at the end. The results of most clinical trials and experiments clearly demonstrate its effectiveness in improving sexual function in men.

[Erectile dysfunction - treatment with substances of natural origin].

The article discusses erectile dysfunction (ED) with the special emphasis on epidemiology, as well as the currently available medical treatments. Describing treatment methods authors paid special attention to natural therapies (as Panax ginseng, Tribulus terrestris, Vaccinium macrocarpon), because taking into consideration their safety profile, they appear to be an important alternative to therapies with synthetic molecules. From substances of natural origin, extract from the fruit of Tribulus terrestris ranks itself high on in collation at the end. The results of most clinical trials and experiments clearly demonstrate its effectiveness in improving sexual function in men.

Levels of FSH, LH and testosterone, and sperm DNA fragmentation.

OBJECTIVE: Having an offspring is the most important human biological goal, which is necessary for survival of the human species. Lack of offspring is a phenomenon concerning approximately 15% of married couples in Poland. In a half of the cases, a causative agent is the male factor infertility problem. There is evidence that certain male fertility problems are related with disorders of the process of spermatogenesis. The course of normal spermatogenesis depends on proper pituitary secretion of folliculostimulin (FSH), luteinizing hormone (LH), as well as testicular secretion of testosterone. It is considered that in approximately 20% of patients with idiopathic infertility an elevated level of sperm DNA fragmentation may be the cause of failure in reproduction. The objective of the present study was determination of the relationship between FSH, LH and testosterone levels, and the occurrence of sperm DNA fragmentation. METHODS: The present study was conducted in the year 2012 in the Non-Public Health Care Unit 'Ovum Reproduction and Andrology' in Lublin, and covered 186 men treated for infertility. For inclusion into the study group we qualified males aged 25-35, who have been treated for infertility for more than 1 year, with no pathological features observed in the female partner. The structure of sperm chromatin was evaluated using the technique of flow cytometry-Sperm Chromatin Structure assay (SCSA). The result of the examination was a sperm DNA Fragmentation Index (DFI), i.e., the percentage of sperm with DNA lesions (DNA fragmentation). A morning blood sample (5 mL volume) was obtained and sent to an authorized laboratory to assess serum levels of testosterone, LH and FSH. RESULTS: An intensified sperm DNA fragmentation co-occurred with both extremely low and extremely high levels of FSH and LH. Sperm DNA fragmentation was negatively correlated with testosterone level.

Persistent remission of Graves` disease or evolution from Graves' disease to Hashimoto's thyroiditis in childhood - a report of 6 cases and clinical implications.

BACKGROUND: The main clinical manifestations of autoimmune thyroid diseases are Graves' disease (GD) and Hashimoto's thyroiditis (HT). Graves' disease is the cause of most cases of hyperthyroidism in childhood. Indications for radical therapy (surgery or 131I treatment) in children are still a matter of discussion, as sustained (sometimes very long) remission of GD is possible, while the radical therapy almost always leads to hypothyroidism. Spontaneous evolution from GD with hyperthyroidism to HT with hypothyroidism may also be observed. OBJECTIVE: The aim of the study was to analyze the clinical course of 6 cases of hyperthyroid girls with GD in whom a normalization of previously increased autoantibodies against thyrotropin (TSH) receptor (anti-TSHR) was observed together with a significant increase in autoantibodies against thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg), with concomitant hypo- or euthyroidism but no recurrence of hyperthyroidism. SUBJECTS: Patients' age at diagnosis ranged from 5.0 to 16.5 years. Two (2) patients had Turner syndrome, another one (1), diabetic, was on insulin therapy. RESULTS: In all the girls, antithyroid drugs were administered and euthyroid state was achieved during the first 2.0-3.5 months of the treatment. Mild side effects were observed in only one case. The therapy was continued up to 1.5-4.0 years. Relapses during the therapy were observed in 2 cases. Up to now, no relapses have been observed for 0.5-7.5 years since the therapy withdrawal in 5 patients (1 patient was lost to follow-up), 2 patients are currently treated with levothyroxine due to hypothyroidism. CONCLUSIONS: It seems that the prolonged pharmacotherapy with antithyroid drugs, followed by observation after remission of hyperthyroidism, may be an appropriate therapeutic option at least in some children with GD as they can be cured without radical therapy and the potential risks of such treatment.

Response to Osilodrostat Therapy in Adrenal Cushing's Syndrome.

Cushing's disease (CD) is the most common cause of endogenous hypercortisolism. Osilodrostat was demonstrated to be efficient in treating CD, and the mean average dose required for CD control was <11 mg/day. Potential differences in osilodrostat treatment between cortisol-producing adenoma (CPA) and CD have not been reported. The aim of this study was to present two patients with CPA in whom significant differences in the response to therapy compared to CD were found. We demonstrated a case of inverse response of cortisol levels with adrenal tumor progression during the initial dose escalation (Case 1). Simultaneously, severe exaggeration of hypercortisolism symptoms and life-threatening hypokalemia occurred. A further rapid dose increase resulted in the first noticeable cortisol response at a dose of 20 mg/day, and a full response at a dose of 45 mg/day. We also present a case that was initially resistant to therapy (Case 2). The doses required to achieve the first response and the full response were the same as those for Case 1. Our study demonstrated that osilodrostat therapy in patients with CPA may require a different approach than that in CD, with higher doses, faster dose escalation, and a possible initial inverse response or lack of response.

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.

The Importance of a Distance between the Lines Encircling Pulmonary Veins in Atrial Fibrillation Ablation on First-Pass Isolation Ratio and Clinical Outcomes.

INTRODUCTION: How wide the encircling line is made may influence the outcomes of pulmonary vein isolation (PVI). In the present study we hypothesised that the distance between the lines encircling the pulmonary veins may correspond with the extent of wide antral circumferential ablation (WACA). The aim of the study was to assess the impact of the distance and the area between the lines on the posterior wall of the left atrium on first-pass isolation rate and 12-month freedom from atrial arrhythmia in patients undergoing PVI ablation. METHODS AND RESULTS: One hundred sixteen patients underwent circumferential ablation index (AI)-guided PVI. The distance between the encircling ablation lines was measured off-line between the uppermost points (right and left) and the lowest points and as the area between the encircling lines on the posterior wall. The first-pass isolation rate and 12-month freedom from atrial arrhythmia were 59% and 73%, respectively. Distance between the encircling lines measured linearly or as the area of the posterior wall, assessed as direct values or indexed to left atrial dimensions, did not differ between patients with and without first-pass isolation or between patients with and without recurrences of atrial arrhythmia. CONCLUSIONS: The distance between the ablation lines did not influence the rate of first-pass isolation and arrhythmia recurrence in the long-term follow-up after PVI procedures incorporating the ablation index protocol.

Value of Left Atrial Strain in Predicting Recurrence after Atrial Fibrillation Ablation.

This study tested the relationship between left atrial (LA) function parameters and the results of pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF). Consecutive patients undergoing PVI for the first time between 2019 and 2021 were included. Patients underwent radiofrequency ablation using contact force catheters and an electroanatomical system. Follow-up consisted of ambulatory visits/televisits and 7-day Holter monitoring (at 6 and 12 months after ablation). On the day of ablation, all patients underwent transesophageal and transthoracic echocardiography with LA strain analysis. The primary endpoint was atrial tachyarrhythmia recurrence during the follow-up period. Of 221 patients, 22 did not meet the echocardiographic quality criteria, leaving 199 patients. The median follow-up period was 12 months, and 12 patients were lost to follow-up. Recurrences were observed in 67 patients (35.8%) after a mean of 1.06 procedures per patient. The patients were divided into a sinus rhythm (SR, n = 109) group and an AF (n = 90) group based on their cardiac rhythm at the time of echocardiography. In the SR group, univariable analysis showed that LA reservoir strain, LA appendage emptying velocity (LAAV), and LA volume index predicted AF recurrence, with only LAAV being significant in the multivariable analysis. In AF patients, univariable analysis revealed no LA strain parameters predicting AF recurrence.

The evaluation of esophageal stenting complications in palliative treatment of dysphagia related to esophageal cancer.

BACKGROUND: Esophageal cancer is the seventh-most frequent cause of cancer-related deaths and it is usually diagnosed at an inoperable stage. In palliative treatment, endoscopic and non-endoscopic methods are applied to reduce dysphagia in patients with neoplastic esophageal obstruction. Because of severe complications, non-endoscopic treatment (surgery, radiotherapy, brachytherapy and chemotherapy) is applied rarely. Within the endoscopic methods, only the use of endoprostheses yields long-term effects. The aim of this study was to evaluate the safety and efficacy of implantation of self-expandable esophageal stents in palliative treatment of dysphagia related to esophageal cancer. MATERIAL/METHODS: A total number of 46 patients (41 males and 5 females) were qualified to palliative implantation of coated self-expandable stent. The mean age of the patients was 67 years (from 51 to 78 years). In all patients, Evolution-type coated self-expandable stents were used. In all cases, 24 hours after the implantation, radiological examination was performed to assess the stent location. RESULTS: Severe, possibly life-threatening, complications constituted 28% of all the complications and occurred in 9% of the patients. Less severe complications occurred in 17% of the observed patients and were not life-threatening. CONCLUSIONS: In patients with neoplastic esophageal stenosis, stenting with coated, self-expandable nitinol prostheses is a safe, effective and fast method of palliative dysphagia treatment.

Prevalence of hypothalamic-pituitary tumours - retrospective analysis of 20-year own material.

OBJECTIVES: The prevalence of pituitary tumours has recently been identified to be higher than previously thought. The aim of our study was to assess the occurrence of hypothalamic-pituitary tumours in 20-year material of the Department of Endocrinology and Metabolic Diseases, Polish Mother`s Memorial Hospital - Research Institute, Lodz, Poland. METHODS: We analyzed medical data of 845 patients, hospitalized from 1990 to 2009 due to presumptive diagnosis of hypothalamic-pituitary tumour. Among 340 cases with confirmed diagnosis, 278 tumours were classified as micro- or macroadenomas. Tumour type and size, as well as patient gender and age, were evaluated. In 252 tumours the exact volume was calculated, and 4 volume subgroups were assessed for each aforementioned parameter separately. RESULTS: Prolactinomas and - at the next place - non-functioning adenomas were the most frequent, followed by pituitary tumors of non-epithelial origin, and - finally, the rarest - other secreting adenomas. Prolactinomas were found mostly in females (p=0.028), while non-functioning adenomas in males (p=0.045). Prolactinomas and non-functioning adenomas were found to be predominantly microadenomas (p<0.0001 and p=0.0003, respectively), while mixed-type adenomas were mostly macroadenomas (p=0.028). In females microadenomas were the most frequent (p<0.0001). Moreover, in persons under 50 years of age microadenomas predominated, whereas in older adults macroadenomas mostly occurred. CONCLUSION: To conclude, our retrospective, single-centre study provides relevant estimates of prevalence of hypothalamic-pituitary tumours in the era of modern diagnostic tools and indicates that our data are comparable with results regarding other populations worldwide.

Significance of HLA Haplotypes in Two Patients with Subacute Thyroiditis Triggered by mRNA-Based COVID-19 Vaccine.

Subacute thyroiditis (SAT) can be triggered by several viral factors in genetically predisposed individuals. In the case of COVID-19, SAT can be induced by SARS-CoV-2 infection as well as COVID-19 vaccination. The aim of this study was to present two cases of SAT triggered by mRNA-based COVID-19 vaccines, with special attention paid to the possible significance of HLA-related SAT susceptibility. In our patients, a strong similarity of HLA profiles with regard not only to SAT high-risk alleles but also to other SAT-unrelated ones was observed. The rare phenomenon of SAT occurrence after COVID-19 vaccination can be HLA-dependent and related to a co-presence of HLA-B*35:03 and -C*04:01. Taking into account the similarity of HLA profiles in both our patients, the co-presence of other alleles, such as HLA-A*03:01, -DQA1:01, DQB1*05:01 as well as some of HLA-DRB1, can also play a role. This hypothesis is strongly consistent with autoimmune/inflammatory syndrome induced by adjuvants (ASIA) being the postulated mechanism of this post-vaccine reaction, as ASIA-related immune reactions are directly associated with HLA-based genetic susceptibility. Further research is necessary to confirm these findings.