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.

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 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.

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.

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.

Management of obesity in the times of climate change and COVID-19: an interdisciplinary expert consensus report.

Obesity is a chronic disease associated with increased metabolic and cardiovascular risk, excessive morbidity and mortality worldwide. The authors of the present consensus, clinicians representing medical specialties related to the treatment of obesity and its complications, reviewed a number of European and American guidelines, published mostly in 2019-2021, and summarized the principles of obesity management to provide a practical guidance considering the impact that increased adiposity poses to health. From a clinical perspective, the primary goal of obesity treatment is to prevent or slow down the progression of diseases associated with obesity, reduce metabolic and cardiovascular risk, and improve the quality of life by achieving adequate and stable weight reduction. However, obesity should be not only considered a disease requiring treatment in an individual patient, but also a civilization disease requiring preventive measures at the populational level. Despite the evident benefits, obesity management within the health care system-whether through pharmacotherapy or bariatric surgery-is only a symptomatic treatment, with all its limitations, and will not ultimately solve the problem of obesity. The important message is that available treatment options fail to correct the true drivers of the obesity pandemic. To this end, new solutions and efforts to prevent obesity in the populations are needed.

Clinical Manifestation of Subacute Thyroiditis Triggered by SARS-CoV-2 Infection Can Be HLA-Dependent.

In the last two years, we have been struggling with the pandemic of SARS-CoV-2, the virus causing COVID-19. Several cases of subacute thyroiditis (SAT) have already been described as directly related to SARS-CoV-2 infection. The clinical course of SAT induced by SARS-CoV-2 can be entirely different from the classic SAT course, and one of the most important differences is a very rapid SAT onset observed in some patients, especially a phenomenon of the simultaneous presence of both diseases. The aim of this report is to compare HLA profile and clinical course of SAT in four patients, in whom SAT was considered as triggered by COVID-19, with special attention paid to the differences between a patient with rare simultaneous presence of SAT and COVID-19, and patients with longer time lag between the diseases. The unusual phenomenon of simultaneous occurrence of COVID-19 and SAT induced by SARS-CoV-2 infection can be HLA-dependent and related to the presence of homozygosity at HLA-B*35. Additionally, the clinical course of SAT triggered by COVID-19 can be HLA-related in regard to the risk of recurrence, and to a variety of other aspects, including severity of thyrotoxicosis.

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.

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.

Transient Hyperthyrotropinemia in Outpatient Children with Acute Infections of the Respiratory System.

BACKGROUND: Diagnostics of thyroid disorders (TD) are frequently based on the measurements of thyroid stimulating hormone (TSH) concentration only. If TSH is outside the reference range, the diagnostic procedure used in patients with TD isintroduced. Observations indicate that in a considerable number of these patients, TD is not confirmed. The aim of the study was to assess the incidence of transient hyperthyrotropinemia in healthy children during acute infections of the respiratory system. PATIENTS AND METHODS: The study included consecutive children (49 boys and 45 girls), aged 2.2-17.3 years, who visited one General Practitioner (GP) due to respiratory tract infections. The tests: complete blood count (CBC), C-reactive protein (CRP), TSH and FT4 were run on the next day after the visit at the physician's (initial visit) and ≥2 weeks after recovery. RESULTS: Among these children, elevated TSH values were found in about 10% of patients, and they went back to normal values after recovery. A prospective analysis showed a reduction of TSH values in approx. 65% of all groups and TSH at the follow-up visit was significantly lower. CONCLUSIONS: Transient hyperthyrotropinemia was observed in about 10% of children with acute respiratory tract infection. This preliminary finding remains unexplained.

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.

Strong Correlation between HLA and Clinical Course of Subacute Thyroiditis-A Report of the Three Siblings.

Subacute thyroiditis (SAT) is a thyroid inflammatory disease with susceptibility associated with the presence of human leukocyte antigen (HLA)-B*35, -B*18:01, -DRB1*01 and -C*04:01. Previous viral infection is considered as a triggering factor in genetically predisposed individuals. The influence of HLA on the SAT course was previously suggested. We aim to present the three siblings-female twins and their brother-with very close onset but different clinical courses of SAT, which appeared to be HLA-dependent. The HLA profile in the reported three siblings is strongly correlated with both SAT and Graves' disease (GD), however the coexistence of particular sets of high risk and protective alleles seems to be crucial for the GD development and the SAT course. The co-occurrence of HLA-DRB1*15:01 and/or -B*07:02, possibly together with the lack of HLA-A*01:01 and -B*41:01 seems to be key factors protecting against the development of GD with high TRAb levels, as well as against the recurrent SAT course and steroid dependence.

Novel Germline c.105_107dupGCT MEN1 Mutation in a Family with Newly Diagnosed Multiple Endocrine Neoplasia Type 1.

In multiple endocrine neoplasia type 1 (MEN1), the causative MEN1 gene mutations lead to the reduced expression of menin, which is a tumor suppressor protein. In this study, we present a case of a 16-year-old woman with severe primary hyperparathyroidism and a non-functioning pituitary microadenoma. Genetic testing demonstrated a novel germline heterozygote variant c.105_107dupGCT of MEN1, leading to Leu duplication in position 37 of the menin polypeptide chain. As such a mutation was not reported before as a causative one, confirmation of its pathogenicity required showing the same mutation in a symptomatic first-degree relative. An identical mutation was found in the patient's father, who was further diagnosed with hyperparathyroidism and a pituitary microadenoma. We observed the presence of the same MEN1-related tumors but an entirely different symptom severity. To the best of our knowledge, this is the first report of MEN1 syndrome caused by the c.105_107dupGCT MEN1 mutation. This case report demonstrates the importance of genetic evaluation towards MEN1. Genetic testing for MEN1 mutations should be performed in all patients with MEN1-related tumors, and in the young patients even with only one such tumor, despite the supposedly negative family history.

The value of the ablation index in patients undergoing ablation for atrial fibrillation.

BACKGROUND: Data on the results of ablation for atrial fibrillation (AF) in Poland are scarce. AIMS: The aim of the study was to compare the efficacy of ablation index (AI)-guided pulmonary vein isolation (PVI) with that of conventional contact force-based PVI. METHODS: Consecutive patients undergoing PVI for the first time were included in the study. A nonrandomized retrospective comparison was made between patients ablated with contact force before AI was introduced (non -AI group) and patients ablated with the use of AI (AI group). The AI threshold for the anterior wall / roof of left veins was 500 and 380 elsewhere. The maximal interlesion distance was 6 mm. The follow -up included outpatient visits and 7-day Holter monitoring 6 and 12 months after ablation. RESULTS: A total of 275 patients were included in the analysis: 133 in the AI group and 142 in the non--AI group. The duration of AF ablation was slightly longer in the AI group, but the fluoroscopy time and the radiofrequency ablation time were shorter in the same group. During the 12-month follow -up period, 25.8% and 40.6% of patients from the AI and non -AI groups, respectively, experienced recurrences (P = 0.02). The log -rank test with an extended follow -up period of up to 18 months confirmed the difference between the AI and non -AI groups, both in the whole group and in the paroxysmal AF and nonparoxysmal AF subgroups (P = 0.001, P = 0.04, and P = 0.006, respectively). CONCLUSION: The AI -based protocol provides a significant advantage over traditional contact force-based radiofrequency ablation in nonselected patients undergoing PVI.

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.