Landscape of congenital adrenal hyperplasia cases in adult endocrinology clinics of Türkiye-a nation-wide multicentre study.

BACKGROUND AND AIMS: Congenital adrenal hyperplasia (CAH) is a group of disorders that affect the production of steroids in the adrenal gland and are inherited in an autosomal recessive pattern. The clinical and biochemical manifestations of the disorder are diverse, ranging from varying degrees of anomalies of the external genitalia to life-threatening adrenal insufficiency. This multicenter study aimed to determine the demographics, biochemical, clinical, and genetic characteristics besides the current status of adult patients with CAH nationwide. METHODS: The medical records of 223 patients with all forms of CAH were evaluated in the study, which included 19 adult endocrinology clinics. A form inquiring about demographical, etiological, and genetic (where available) data of all forms of CAH patients was filled out and returned by the centers. RESULTS: Among 223 cases 181 (81.16%) patients had 21-hydroxylase deficiency (21OHD), 27 (12.10%) had 11-beta-hydroxylase deficiency (110HD), 13 (5.82%) had 17-hydroxylase deficiency (17OHD) and 2 (0.89%) had 3-beta-hydroxysteroid-dehydrogenase deficiency. 21OHD was the most prevalent CAH form in our national series. There were 102 (56.4%) classical and 79 (43.6%) non-classical 210HD cases in our cohort. The age of the patients was 24.9 ± 6.1 (minimum-maximum: 17-44) for classical CAH patients and 30.2 ± 11.2 (minimum-maximum: 17-67). More patients in the nonclassical CAH group were married and had children. Reconstructive genital surgery was performed in 54 (78.3%) of classical CAH females and 42 (77.8%) of them had no children. Thirty-two (50.8%) NCAH cases had homogenous and 31 (49.2%) had heterogeneous CYP21A2 gene mutations. V281L pathological variation was the most prevalent mutation, it was detected in 35 (55.6%) of 21OHD NCAH patients. CONCLUSION: Our findings are compatible with the current literature except for the higher frequency of 110HD and 17OHD, which may be attributed to unidentified genetic causes. A new classification for CAH cases rather than classical and non-classical may be helpful as the disease exhibits a large clinical and biochemical continuum. Affected cases should be informed of the possible complications they may face. The study concludes that a better understanding of the clinical characteristics of patients with CAH can improve the management of the disorder in daily practice.

Disease-free survival and the prognostic factors affecting disease-free survival in patients with medullary thyroid carcinoma: a multicenter cohort study.

PURPOSE: Despite several factors that may have been associated with poor disease-free survival (DFS) in patients with medullary thyroid carcinoma (MTC), only a few studies have evaluated the prognostic factors affecting DFS in MTC patients. Therefore, this study evaluated the prognostic factors affecting DFS, in a large number of patients with MTC. METHODS: Patients treated for MTC were retrospectively analyzed. Patients were stratified as having persistent/recurrent disease and no evidence of disease (NOD) at the last follow-up. The factors affecting DFS after the initial therapy and during the follow-up period were investigated. RESULTS: This study comprised 257 patients [females 160 (62.3%), hereditary disease 48 (18.7%), with a mean follow-up time of 66.8 ± 48.5 months]. Persistent/recurrent disease and NOD were observed in 131 (51%) and 126 (49%) patients, respectively. In multivariate analysis, age > 55 (HR: 1.65, p = 0.033), distant metastasis (HR: 2.41, p = 0.035), CTN doubling time (HR: 2.7, p = 0.031), and stage III vs. stage II disease (HR 3.02, p = 0.048) were independent predictors of persistent/recurrent disease. Although 9 (8%) patients with an excellent response after the initial therapy experienced a structural recurrence, the absence of an excellent response was the strongest predictor of persistent/recurrent disease (HR: 5.74, p < 0.001). CONCLUSIONS: The absence of an excellent response after initial therapy is the strongest predictor of a worse DFS. However, a significant proportion of patients who achieve an excellent response could experience a structural recurrence. Therefore, careful follow-up of patients, including those achieving an excellent response is essential.

Oxidative Status and Thiol/Disulfide Homeostasis Are Changed During 75 g Oral Glucose Tolerance Test over a Five-Hour Period.

BACKGROUND: Oral glucose loading may affect oxidative status during oral glucose tolerance test (OGTT). We aimed to investigate how oxidant and antioxidant markers and thiol/disulfide parameters change during OGTT. METHODS: OGTT was performed to 42 volunteers who were considered risk of type 2 diabetes and were divided into three groups (normoglycemic, prediabetes, diabetes) according glucose levels during OGTT. Glucose, insulin, c-peptide, total antioxidant status (TAS), total oxidant status (TOS), total thiol and native thiol were investigated with auto-anaylzer for five-hours period. RESULTS: Decrease of TAS and increase of TOS levels began with the increase in glucose and insulin levels. The increase of TAS started at third hour and reached the highest levels at fifth hour. OSI levels were higher at fourth hour than fasting and first hours in normoglycemic and diabetes groups. In the prediabetic group, TAS were higher than the other groups, TOS peak was at the second hour (p < 0.05). Native thiol and total thiol levels showed variable course during OGTT, both parameters increased at the end of the process (p < 0.05). Disulfide levels showed an increase trend but it was not statistically different in normoglycemic and diabetes groups. In prediabetes group, second hour disulfide level was lower than fasting state and disulfide was significantly increased at third, fourth and fifth hours and fifth hour disulfide level was also higher than fasting. CONCLUSION: Oxidative stress parameters and thiol/disulfide balance were found to deteriorate within five-hours after glucose loading in all groups. These results indicates that oxidative stress occurs during OGTT.

NLRP3-Inflammasome Gene Variations in the Risk of Type 2 Diabetes.

Inflammation is the natural immunological response of an organism against any harmful, foreign or destructive effect to heal and repair damaged tissue. The nod-like receptor pyrin domain-containing-3 (NLRP3) inflammasome is one of the main components of the inflammatory mechanism and is associated with many inflammatory diseases, but it is also closely related to metabolic abnormalities, such as type 2 diabetes mellitus (T2DM), insulin resistance and obesity. NLRP3 activates inflammation and causes interleukin-1ß release, exogenous and endogenous danger signals, as well as insulin resistance. In this direction, we focus on the gene structure of NLRP3 in diabetes and accordingly, we aim to determine the relationship between eight gene variations in the NLRP3 gene and T2DM. We investigated the rs10802501, rs10733113, rs10754558, rs10925026, rs10925027, rs35829419, rs4612666 and rs4925659 single-nucleotide polymorphisms of NLRP3 gene using the Sequenom MassARRAY system in 100 T2DM patients and 100 control individuals. There were no significant differences between T2DM risk and the genotype frequencies of rs10802501, rs10733113, rs35829419 and rs10925026 variants (p > 0.05). However, significant genotype frequencies were determined for rs10925027 (p = 0.0013) and rs4925659 (p < 0.001). For the risk allele G of the rs10754558 variant, significant differences were found in the heterozygous and dominant model (p = 0.036, p = 0.033). The genotype distribution of the rs4612666 variant was significant only in the heterozygous model (p = 0.047). In this hospital-based case-control study, rs10925027, rs4925659 and rs10754558 variants were found to be closely related to T2DM risk. The rs10925027 CC genotype, rs4925659 GG genotype, rs10754558 GG and GC+GG genotypes of the NLRP3 were determined as important risk factors for the T2DM.

Potential associations between variants of genes encoding regulators of inflammation, and mediators of inflammation in type 2 diabetes and insulin resistance.

WHAT IS KNOWN AND OBJECTIVE: Type 2 diabetes (T2DM) is a multigenic disease that develops with impaired ß-cell function and insulin sensitivity and has a high prevalence worldwide. A cause often postulated for type 2 diabetes is chronic inflammation. It has been suggested that inflammatory regulators can inhibit insulin signal transduction and that inflammation is involved in insulin resistance (IR) and the pathogenesis of type 2 diabetes. In this direction, we aimed to investigate the gene variants of MyD88 (rs1319438, rs199396), IRAK4 (rs1461567, rs4251513, rs4251559) and TRAF6 (rs331455, rs331457) and serum levels of COX-2, NF-κB, iNOS in T2DM and IR. METHODS: The MyD88, IRAK4 and TRAF6 variations were genotyped in 100 newly diagnosed T2DM patients and 100 non-diabetic individuals using The MassARRAY® Iplex GOLD SNP genotyping method. The COX-2, iNOS and NF-κB levels were measured in serum samples with the sandwich-ELISA method. Results were analysed using SPSS Statistics software and the online FINNETI program. RESULTS AND DISCUSSION: In our study, a total of the 7 variants in the MyD88, IRAK4 and TRAF6 genes were genotyped, and as a result, no relationship was found between most of these variants and the risk of type 2 diabetes and insulin resistance (p > 0.05). Only, the rs1461567 variant of the IRAK4 gene was significant in the heterozygous model (CC vs. CT), and the CT genotype was most frequent in diabetic individuals compared with the non-diabetics (p = 0.033). Additionally, COX-2 and iNOS levels were found to be associated with diabetes and insulin resistance (p < 0.05). WHAT IS NEW AND CONCLUSION: Our results show that high COX-2 and iNOS levels are associated with T2DM, besides MyD88, IRAK4 and TRAF6 gene variations may not be closely related to type 2 diabetes and insulin resistance. Nevertheless, studies in this pathway with a different population and a large number of patients are important.

Assessment of fragmented QRS formation and its relationship with left ventricular hypertrophy in nonhypertensive acromegaly patients

Background/aim: It is known that the presence of fragmented QRS (fQRS) on electrocardiography (ECG) is associated with cardiovascular events. The aim of this study was the evaluation of fQRS formation and its relationship with the left ventricular hypertrophy (LVH) parameters in acromegaly patients. Materials and methods: In total, 47 previously diagnosed with non-hypertensive acromegaly patients and 48 control subjects were included in the study. ECG and transthoracic echocardiography (TTE) were performed for each participant. Acromegaly patients were divided into two groups according to the fQRS formation on the ECG. Left ventricular wall thicknesses, and left atrial diameter (LAD), left ventricular mass (LVM), left ventricular mass index (LVMi), and relative wall thickness (RWT) were obtained. Results: In control group 5 (10.4%) and in acromegaly group 17 (36.2%) patients had fQRS on ECG (p = 0.003). LAD [36.0 (34.0­38.0) vs. 38.0 (35.0­41.0) mm, p < 0.001], LVM [155.27 ± 27.00 vs. 173.0 (153.0­235.0) g, p < 0.001], LVMi [83.12 ± 13.19 vs. 92.0 (83.0­118.0) g/m², p < 0.001] and RWT [0.39 ± 0.03 vs. 0.43 (0.41­0.45), p = 0.001] were significantly higher in patients with acromegaly. Disease duration was significantly higher (11.59 ± 1.3 vs. 8.2 ± 1.8 years, p < 0.001) in the fQRS (+) group. LAD [41.0 (39.0­42.5) vs. 37.0 (34.7­38.0) mm, p < 0.001], LVM [219.0 (160.5­254.5) vs. 164.0 (153.0­188.0) g, p = 0.017], LVMi [117.0 (92.5­128.5) vs. 86.0 (82.0­100.2) g/m², p = 0.013] and RWT [0.44 (0.42­0.49) vs. 0.43 (0.40­0.44), p = 0.037] were significantly higher in fQSR (+) acromegaly patients. In multivariate logistic regression analysis, disease duration (odds ratio: 10.05, 95% CI: 1.099­92.012, p = 0.041) and LAD (odds ratio: 2.19, 95% CI: 1.030­4.660, p = 0.042) were found to be the independent predictors of fQRS formation. Conclusion: The results of our study revealed that fQRS (+) acromegaly patients had increased LVH parameters compared to fQRS (-) patients.

Common variants of genes encoding TLR4 and TLR4 pathway members TIRAP and IRAK1 are effective on MCP1, IL6, IL1ß, and TNFα levels in type 2 diabetes and insulin resistance.

OBJECTIVE AND DESIGN: Type 2 diabetes is a pandemic disease characterized by hyperglycemia, ineffective insulin use, and insulin resistance and affecting 1 in 11 people worldwide. Inflammation-related insulin resistance is thought to play an important role in the etiology of the disease. TLR4 is the central receptor of the natural immune system and has an important role as a trigger of the inflammatory response. The IRAK1 and TIRAP are members of the TLR4 pathway and involved in the TLR4-mediated inflammatory response. Genetic variants in the TLR4 gene or in the IRAK1 and TIRAP genes may have an important role in the development of insulin resistance and type 2 diabetes by disrupting the inflammatory response. In this direction, we aimed to investigate the relationship among TLR4 and IRAK1, TIRAP gene variants, and type 2 diabetes and insulin resistance, and investigate how these variants affect inflammatory factors (TNF-α, IL-6, MCP-1, and IL-1ß). SUBJECTS AND METHODS: In our study, a total of seven variations on the genes of TLR4 (rs4986790, rs4986791), IRAK1 (rs1059703, rs3027898, rs7061789), and TIRAP (rs8177374, rs8177400) were genotyped by the MassARRAY® Iplex GOLD SNP genotyping in 100 type 2 diabetic patients and 100 non-diabetic individual. The TLR4 rs4986790 and rs4986791 variation was confirmed by PCR-RFLP method also. The serum IL1-ß, IL6, MCP-1, and TNF-α levels were measured using enzyme-linked immunosorbent assay kits. RESULTS AND CONCLUSION: As a result of our study, no correlation was found among TLR4, IRAK1, and TIRAP gene variants and the risk of type 2 diabetes and insulin resistance. However, TNF-α, IL-6, MCP-1, and IL-1ß levels were also associated with diabetes and insulin resistance (p > 0.05). Although the gene variants were not significant in type 2 diabetes and insulin resistance groups, IRAK1, TLR4, and TIRAP gene variants were found to be associated with TNF-α, IL-6, MCP-1, and IL-1ß levels.

Genetic variant in the 3'-untranslated region of the COX2 gene is associated with type 2 diabetes: A hospital-based case-control study.

Type 2 diabetes (T2DM) is caused by the decreased ß-cell mass and insulin deficiency, and disease is characterized by hypoglycemia. The insulin resistance also plays an important role in T2DM pathogenesis. Insulin resistance is the reduced biological response to insulin at the normal concentration in the circulation and develops with the influence of environmental factors with genetic abnormalities. In recent years, it has been reported that inflammatory pathway causes activation of the insulin resistance. Chronic inflammation inhibits the insulin sensitivity through activation of signaling pathways which are directly associated with the key components of insulin signaling pathway. Cyclooxygenase (COX) enzymes are key enzymes that catalysis prostaglandin synthesis from arachidonic acid. COX2 is an inducible COX isoform and that plays an important role in inflammatory process by leading the synthesis of pro- and anti- inflammatory prostaglandins. In our study, we aimed to investigate the relationship between variants of COX-2 gene which is one of the key components of the inflammatory pathway, and T2DM risks. In this study, we evaluated rs5275 and rs689466 variants located on the COX-2 gene by PCR-RFLP in 100 T2DM patients and 100 control subjects. The interaction among COX2 variants and T2DM was analyzed using appropriate methods. The both variants were in Hardy-Weinberg equilibrium in patients and controls (p > 0.05). A significant association was observed for genotype distribution of COX2 rs5275 site between control and T2DM cases (p = 0.042). In a dominant model, the cases who had at least one copy of allele C, were at increased risk of T2DM (p = 0.016). We found no significant association for the COX2 rs689466 domain by evaluating homozygous, heterozygous, dominant, and recessive models (p > 0.05). According to our data, the rs5275 variant of the COX2 in the 3'-UTR may contribute to the etiology or modulate the risk of T2DM, whereas the rs689466 variant of the COX2 gene is not associated with T2DM risk.