Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study.

BACKGROUND: The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. METHODS: A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. RESULTS: The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). CONCLUSIONS: The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases.

Cardiovascular risk assessment in osteoporotic patients using osteoprotegerin as a reliable predictive biochemical marker.

Osteoprotegerin (OPG), a member of the tumour necrosis factor receptor (TNFR) superfamily of proteins known to be involved in a large number of biological systems, plays a pivotal role in bone remodelling. In addition to the roles of OPG in bone metabolism, it has been reported to be associated with a high cardiovascular risk in patients with metabolic syndrome. In most cases, the exact functions of OPG remain to be established; however, the widespread expression of OPG suggests that this molecule may have multiple biological activities, mainly in the cardiometabolic environment. The aim of this study was to evaluate the value of OPG as a predictive marker for cardiovascular and metabolic risk in osteoporotic patients. The study group comprised patients with osteoporosis, in order to evaluate the association between OPG serum levels and cardiovascular pathology. Our results revealed significant correlations between classical biochemical bone and metabolic parameters, such as osteocalcin and parathyroid hormone with lipid and glucose biomarkers, sustaining the crosstalk between calcium and bone parameters and cardiovascular risk. The OPG serum level proved to have a significant and independent predictive value for metabolic syndrome (MetS) as a cardiovascular risk standard in osteoporotic patients. The OPG serum levels were increased in patients with MetS as a protective response against the atherosclerotic lesions. The serum levels of 25­hydroxy vitamin D had significant and independent predictive value for cardiovascular and metabolic risk in our subjects, sustaining the active role of vitamin D beyond the area of bone metabolism.

Serum immunoglobulin G4 levels and Graves' disease phenotype.

PURPOSE: We investigated, at diagnosis, the relationship between serum immunoglobulin G4 levels and the main characteristics of Graves' disease: hyperthyroidism severity, goiter size, presence of active Graves' ophthalmopathy, antithyroid antibodies status, and titer. METHODS: This prospective study included 80 newly diagnosed Graves' disease patients. The main parameters measured at diagnosis: thyroid-stimulating hormone, free thyroxine, free triiodothyronine, total triiodothyronine, thyroglobulin, antithyroid peroxidase antibodies, anti-thyroglobulin antibodies, thyroid-stimulating hormone receptor antibodies, immunoglobulin G4. RESULTS: In Graves' disease patients, serum immunoglobulin G4 levels were higher than in general population (p = 0.028) and higher in men compared to women (p = 0.002). Only one female patient with intense hypoechoic goiter, high anti-thyroglobulin antibody, and antithyroid peroxidase antibody titers had an elevated serum immunoglobulin G4 level at diagnosis. Patients with immunoglobulin G4 levels above the 75th percentile (>237.52 mg/dl, N = 20) were younger at Graves' ophthalmopathy onset (p < 0.001), had higher antithyroid peroxidase antibody (p = 0.01), and anti-thyroglobulin antibody levels (p = 0.006) and required shorter duration of the first methimazole treatment cycle (p = 0.041) than patients with immunoglobulin G4 below the 75th percentile. At diagnosis, patients with immunoglobulin G4 levels above the 90th percentile (>286.28 mg/dl, N = 8) had lower total triiodothyronine values (p = 0.001) than patients with IgG below the 90th percentile. No significant correlations were found between smoking status (p = 0.58), goiter size (p = 0.50), the presence of ophthalmopathy (p = 0.42) or thyroid-stimulating hormone receptor antibody titers (p = 0.45) and the mean value of immunoglobulin G4 levels at diagnosis. CONCLUSIONS: Our data suggest that Graves' disease patients with elevated immunoglobulin G4 levels at diagnosis have a phenotype characterized by higher anti-thyroglobulin antibody and antithyroid peroxidase antibody titers, less severe T3 hyperthyroidism, younger age at ophthalmopathy onset and require a shorter duration of the first methimazole treatment cycle.

Is prolactin the missing link in adipose tissue dysfunction of polycystic ovary syndrome patients?

The aims of the study were to evaluate whether adiposity was among the determinants of circulating prolactin levels and to determine whether serum prolactin independently predicted metabolic abnormalities in patients with polycystic ovary syndrome (PCOS). A total of 322 PCOS patients with normal serum prolactin levels were recruited between January 2007 and January 2014. Anthropometric, metabolic, and hormonal parameters were measured in all of the patients. HOMA-IR was calculated as an index of insulin resistance. Serum prolactin was negatively correlated with age (p < 0.0001), all the adiposity indices [body mass index p < 0.0001; waist circumference p < 0.0001; waist-hip ratio (WHR) p < 0.0001], visceral adiposity index (VAI, p = 0.043), fasting insulinemia (p = 0.002), and HOMA-IR (p = 0.002), and was positively correlated with serum adiponectin (p = 0.034), but not with circulating androgens or serum leptin levels. Serum adiponectin, but not HOMA-IR or fasting insulinemia, was independently associated with serum prolactin after adjustment for age, leptin, and anthropometrical adiposity parameters. Of the adiposity parameters, only WHR and VAI were independent predictors of serum prolactin after adjustment for adiponectin. Circulating prolactin was also negatively correlated with fasting glycemia (only in patients with normal glucose metabolism, p = 0.037) and was inversely correlated with the presence of metabolic syndrome (p < 0.001), but this association was not maintained after adjustment for possible confounders. In PCOS patients, serum prolactin level was related to adipose tissue quantity and function, and adiponectin was a possible mediator of this relationship. Low serum prolactin levels were associated with an unfavorable metabolic profile, but this association seemed to be due to the complex interplay among prolactin, adiposity, and insulin resistance rather than to a direct metabolic effect of prolactin.

IGF-1 and Insulin Resistance Are Major Determinants of Common Carotid Artery Thickness in Morbidly Obese Young Patients.

We assessed the relationship between insulin resistance, serum insulin-like growth factor 1 (IGF-1) levels, and common carotid intima-media thickness (CC-IMT) in morbidly obese young patients. A total of 249 patients (aged 37.9 ± 9.8 years, body mass index [BMI] 45.6 ± 8.3 kg/m(2)) were evaluated (metabolic tests, serum IGF-1 measurements, homeostasis model assessment-insulin resistance [HOMA-IR], and ultrasonographically assessed CC-IMT) in a research program for bariatric surgery candidates. After adjusting for age, gender, BMI, systolic blood pressure, uric acid, antihypertensive and lipid-lowering treatment, metabolic syndrome, and metabolic class, both HOMA-IR and IGF-1 z-score were significantly associated with CC-IMT. These results were confirmed in logistic regression analysis, in which age (ß = 1.11, P = .001), gender (ß = 3.19, P = .001), HOMA-IR (ß = 1.221, P = .005), and IGF-1 z-score (ß = 1.734, P = .009) were the only independent determinants of abnormal CC-IMT, presumably modulating the effect of the other risk factors included in the regression. Area under the receiver-operating characteristic curve for the model was 0.841 (confidence interval: 0.776-0.907; P < .001). In conclusion, in morbidly obese young adults, insulin resistance and IGF-1 z-score are significantly associated with CC-IMT, independent of other major cardiovascular risk factors.

IGF1 deficiency in newly diagnosed Graves' disease patients.

OBJECTIVE: Thyroid hormones influence the GH/IGF1 axis, but previous studies have reported discrepant results regarding serum IGF1 levels in hyperthyroidism. We have therefore investigated, at diagnosis, the relationship between serum IGF1 levels and the main characteristics of Graves' disease (GD): severity of hyperthyroidism, goiter size, presence of active Graves' ophthalmopathy (GO), antythyroid antibodies status and titer. DESIGN AND METHODS: This cross-sectional study included 98 newly diagnosed hyperthyroid patients with GD who presented consecutively at our clinic. The main measured parameters were: TSH, FT4, FT3, TT3, thyroglobulin,anti-thyroid peroxidase antibodies (TPOAb), anti-thyroglobulin antibodies (ATA), thyrotropin receptor antibodies (TRAb), IGF1. Patients were considered IGF deficient if IGF1 z score was ≤-2SD from mean for age. RESULTS: In GD patients, men had higher IGF1 levels (p=0.023) and IGF1 z scores (p=0.013) than women. 18.4% of GD patients were, at diagnosis, IGF1 deficient. Compared to patients without IGF1 deficiency, these patients presented higher thyroglobulin (median=72.55, IQR=116.02 vs median=11.40, IQR=80.74 ng/ml, p=0.002) and FT3 (median=11.30, IQR=7.64 vs median=7.33, IQR=5.72 pg/ml, p=0.027), and lower ATA (median=20, IQR=0 vs median=34.05, IQR=161 iu/ml, p<0.001) levels. Thyroglobulin was independently associated with IGF1 deficiency (AUROC=0.732, 95% CI: 0.620-0.844, p=0.002; cut-off for thyroglobulin=50.40 ng/ml, Se=77.8%, Sp=70%). IGF1 status was not influenced by gender (p=0.084), current smoking (p=0.558), goiter size (p=0.533), active ophthalmopathy (p=0.334), TRAb (p=0.239) or TPOAb status (p=0.367). CONCLUSIONS: Nearly one fifth of newly diagnosed GD patients had IGF1 deficiency. IGF1 deficiency was associated with lower ATA titers, higher thyroglobulin levels and more severe FT3 hyperthyroidism at diagnosis.

The clinical value of human leukocyte antigen HLA-DRB1 subtypes associated to Graves' disease in Romanian population.

The aim of this study was to identify the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population and to seek whether specific HLA-DRB1 haplotypes are associated with differences in the clinical presentation of GD at diagnosis. Molecular typing of HLA-DRB1 alleles was performed in 77 Romanian Caucasian GD patients and 445 racially matched controls. In GD patients, age, presence of eye disease, goiter grade, autoantibody status and titer, TSH, FT4, FT3, TT3 levels were recorded at diagnosis. The allelic frequencies of HLA-DRB1*03 (41.55% vs. 17.75%, p < 0.0001, χ(2) = 20.81) and DRB1*11 (42.85% vs. 30.56%, p = 0.045, χ(2) = 3.98)were higher, whereas those of HLA-DRB1*01(3.89% vs. 16.40%, p = 0.007, χ(2) = 7.281) and DRB1*15 (10.38% vs. 21.34%, p = 0.038, χ(2) = 4.309)were lower in GD patients than in controls. FT4/TT3 ratio (p = 0.015) and anti-thyroglobulin antibodies (p = 0.024) were higher in *03/11 patients compared to *X/X, *11/Z, *03/Y patients (where X is any other allele than *03 and *11, Y is any other allele than *11, Z is any other allele than *03). In conclusion, HLA-DRB1*03 and DRB1*11 may be the primary susceptibility HLA-DRB1 alleles associated with GD in Romanian population, whereas HLA-DRB1*01 and DRB1*15 seem to be protective. At diagnosis, HLA-DRB1*03/11 GD patients had higher FT4/TT3 ratio and anti-thyroglobulin antibody levels.

Thyroid autoimmunity in 72 children with type 1 diabetes mellitus: relationship with pancreatic autoimmunity and child growth.

The aim of this study was to assess the association between pancreatic and thyroid autoimmunity (TA) and determine impact of thyroid antibodies on statural growth. Seventy-two children with type 1 diabetes mellitus (TIDM) and no clinical evidence of thyroid disorders were evaluated: glycated haemoglobin (A1c), thyroid peroxidase antibodies (TPOAb), glutamic acid decarboxylase antibody (GADA), tyrosine phosphatase antibodies (IA2A), and thyroid-stimulating hormone (TSH). The score of standard deviation for height (SDS) was calculated. There were 72 patients, 38 (52.7%) boys and 34 (47.2%) girls, with a mean age of 10.89 +/- 4.26 years and a mean duration of T1DM of 3.41 +/- 2.56 years. TPOAb were present in 23.6% of patients; 12.5% of subjects were positive for GADA and 41.6% for IA2A. Patients with TA had more prevalent GADA and IA2A (23.5% vs. 9%, p < 0.001, and 58.8% vs. 36.3%, p < 0.001, respectively). A1c was higher in patients with TA (9.7% +/- 2.05% vs. 8.6% +/- 2.11%, p = 0.05). TA was associated with lower SDS (0.26 vs. 0.98, p = 0.043). TSH was higher in patients with TA (3.39 vs. 2.15 microU/mL, p < 0.05). Logistic regression analysis revealed that a negative SDS for height was independently associated with duration of diabetes (p = 0.049) and TSH (p = 0.027) but not with birth weight, A1c, and TPOAb. In conclusion, TA was found in 23.6% TIDM children. Patients with TA had significantly higher prevalence of GADA and IA2A and significantly higher A1c vs. patients without TA. Our data suggest significant association between TA and height in children with T1DM. SDS was independently associated with diabetes duration and TSH.