Anca Sirbu

Adiponectin, body mass index and hepatic steatosis are independently associated with IGF-I status in obese non-diabetic women.

OBJECTIVE Low IGF-I levels have been associated with obesity, insulin resistance, hepatic steatosis, and were shown to predict cardiovascular mortality. Adiponectin, on the other hand, was proved to have an important protective role against metabolic and cardiovascular diseases. This study investigates the relation between hepatic steatosis, adiponectin and IGF-I levels in a group of non-diabetic obese Romanian women. DESIGN This cross-sectional study included 201 obese non-diabetic women, with mean age of 41.1±11.9 years and mean body mass index (BMI) of 44.1±8.3 kg/m(2), consecutively admitted to the Endocrinology Department of a University Hospital to be evaluated as candidates for bariatric surgery. Main measured parameters included total adiponectin (detected by ELISA method), insulin, C reactive protein (CRP), and IGF-I (all by chemiluminescence methods). Insulin sensitivity was assessed using the Quantitative Insulin Sensitivity Check Index (QUICKI). Patients were considered IGF-deficient if IGF-I z score was ≤2 standard deviations from mean for age. Hepatic ultrasound was used to determine the presence of significant steatosis (SS+). RESULTS Significant steatosis was observed in 60.7% of our patients and this feature was associated with reduced total adiponectin levels (p<0.001) and lower IGF-I z scores (p<0.001). IGF-I z score negatively correlated with BMI (r=-0.283, p<0.001), alanine aminotransferase (ALT) (r=-0.130, p=0.032), gamma glutamyltransferase (GGT) (r=-0.158, p=0.018) and logarithmic transformed (log) CRP (r=-0.232, p=0.001) and positively correlated with QUICKI (r=0.148, p=0.023) and log adiponectin (r=0.216, p=0.003). The relationship between IGF-I z score and log adiponectin remained significant after adjusting for age, BMI, ALT, QUICKI and log CRP (r=0.183, p=0.012). IGF-I deficiency was present in 33.3% of these obese women. In multivariate logistic analysis, BMI (p<0.001), ALT (p=0.003), log adiponectin (p<0.001) and SS (p=0.043) proved to be independently associated with IGF-I deficiency. CONCLUSIONS Adiponectin is significantly correlated with IGF-I z scores and, along with BMI, ALT and significant steatosis, is independently associated with IGF-I deficiency in obese non-diabetic women.

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/m2) 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 (β = 1.11, P = .001), gender (β = 3.19, P = .001), HOMA-IR (β = 1.221, P = .005), and IGF-1 z-score (β = 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.

Serum immunoglobulin G4 levels and Graves’ disease phenotype

PurposeWe 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.MethodsThis 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.ResultsIn 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.ConclusionsOur 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.

Takotsubo cardiomyopathy and transient thyrotoxicosis during combination therapy with interferon-alpha and ribavirin for chronic hepatitis C

BackgroundThyroid dysfunction is a common complication of chronic hepatitis C (CHC) and its therapy. Takotsubo cardiomyopathy (TCM) is a multifactorial, stress related cardiomyopathy, rarely reported in association with thyrotoxicosis. Simultaneous occurrence of TCM and thyrotoxicosis due to hepatitis C and its treatment has never been reported.Case presentationA 47-year-old woman was admitted for acute chest pain, dyspnea, palpitations and diaphoresis. She had been diagnosed with CHC and had undergone 7 months of IFNα and Ribavirin therapy. At admission electrocardiogram (ECG) showed ST segment elevation, negative T waves and troponin was elevated suggesting ST segment elevation myocardial infarction (STEMI). Echocardiography demonstrated left ventricular apical akinesia and ballooning, with a left ventricular ejection fraction (LVEF) of 35%. Contrast angiography showed normal epicardial coronaries, yet a ventriculogram revealed left ventricular apical ballooning, consistent with TCM. Cardiac MRI showed left ventricle apical ballooning and no late enhancement suggesting the absence of any edema, scar or fibrosis in the left myocardium. She was diagnosed with non-autoimmune destructive thyroiditis: TSH=0.001 mU/L, free T4=2.41 ng/dl, total T3=199 ng/dl and negative thyroid antibodies. The thyroid ultrasonography showed a diffuse small goiter, no nodules and normal vascularization of the parenchyma. Following supportive treatment she experienced a complete recovery after a few weeks and she successfully completed her antiviral treatment, with no thyroid or cardiovascular dysfunction ever since. In patients treated with IFNα for CHC, the prevalence of thyroid dysfunction varies between 2.5–45.3% of cases. TCM is a stress related cardiomyopathy characterized by elevated cardiac enzymes, normal coronary angiography and an acute, transient, left ventricular apical dysfunction that mimics myocardial infarction. Most of the patients survive the initial acute event, typically recover normal ventricular function within one to four weeks and have a favorable outcome, as was the case with our patient. Thyrotoxicosis induced stress cardiomyopathy is rare and has been mostly reported in association with Graves’ disease, thyroid storm, thyrotoxicosis factitia or following radioiodine therapy for toxic multinodular goiter.ConclusionRoutine thyroid screening should be done in patients receiving IFN-alpha and Ribavirin for CHC and thyrotoxicosis should be considered as a possible and treatable underlying cause of TCM.

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 25-hydroxy 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.

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, χ2 = 20.81) and DRB1*11 (42.85% vs. 30.56%, p = 0.045, χ2= 3.98)were higher, whereas those of HLA-DRB1*01(3.89% vs. 16.40%, p = 0.007, χ2 = 7.281) and DRB1*15 (10.38% vs. 21.34%, p = 0.038, χ2 = 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.

Association of serum adiponectin and insulin-like growth factor I levels with parameters of cardiac remodeling in severely obese patients

Background: Obesity is associated with various changes in cardiac geometry and this process involves both hemodynamic and non-hemodynamic factors, among which adipocitokines and growth factors may play an important role. The aim of this study was to identify the extent and pattern of cardiac remodeling in a group of severely obese patients and analyze the relationship between adiponectin, IGF-I and cardiac parameters reflecting obesity-associated structural changes. Subjects and methods: Our study included 344 patients (104 men) with severe obesity [mean body mass index (BMI)= 45.7±8.5 kg/m2], extensively evaluated clinically and biologically (complete metabolic tests, serum adiponectin, and IGF-I measurements). Left ventricular (LV) mass index (LVMI), left atrium (LA) size, and LV geometry were determined by means of cardiac ultrasound. Results: The most prevalent pattern of LV geometry was eccentric hypertrophy (28.7% of patients). In a gender-, age-, BMI-, diabetes- and hypertension-adjusted general linear model, patients with concentric or eccentric hypertrophy had significantly lower values of adiponectin than those with normal geometry (6.75±0.41, 6.96±0.53, vs 9.04±0.42 mg/l, p<0.05). In multivariate analysis, independent determinants for LVMI were BMI (β=0.364, p<0.001), systolic blood pressure (BP) (β=0.187, p=0.004), age (β=0.246, p<0.001), adiponectin (β=−0.151, p=0.012), and IGF-I z-score (β=0.134, p=0.025) while factors independently related to LA size were systolic BP (β=0.218, p<0.001), BMI (β=0.194, p<0.001), age (β=0.273, p<0.001), gender (β=−0.195, p<0.001), and adiponectin (β=−0.180, p=0.005). Conclusions: In patients with severe obesity, IGF-I z score and adiponectin correlate with parameters of cardiac remodeling independently of anthropometric, hemodynamic or metabolic factors.

Adiponectin expression in visceral adiposity is an important determinant of insulin resistance in morbid obesity

INTRODUCTION Visceral adiposity is associated with decreased serum adiponectin levels, peripheral resistance to insulin and an increased risk of cardio-metabolic complications. However, the link between adiponectin expression in visceral adipose tissue (VAT), its serum levels and metabolic protection is controversial. The aim of this study was to investigate the relationship between the adiponectin gene expression in VAT and clinical and metabolic parameters in patients with severe obesity. MATERIAL AND METHODS This is a cross-sectional study that included 51 severely obese patients (age 43.24±11.29 years, BMI 45.13±8.67 kg/m2), extensively evaluated clinically and biologically (metabolic tests, serum adiponectin measurements, HOMA-IR) before bariatric surgery. Omental adipose tissue was sampled during the intervention and the relative quantification of adiponectin gene expression was performed by real-time PCR, using beta-actin as reference gene. RESULTS Adiponectin mRNA in VAT was significantly higher in obese insulin-sensitive patients than in the rest of obese patients (p < 0.05) and negatively correlated with HOMA-IR (r =-0.354, p=0.016) and uric acid (r =-0.304, p=0.045). After adjustment for gender, TG/HDL ratio and uric acid, adiponectin expresion (β= -0.439, p=0.001), waist circumference (β=0.467, p=0.001) and serum adiponectin (β =-0.339, p=0.011) remained significantly associated with HOMA-IR, together explaining more than 50% of its variation. CONCLUSIONS In severely obese patients, adiponectin gene expression in VAT is negatively correlated with serum levels of uric acid and is an independent determinant, together with anthropometric parameters of visceral obesity and serum adiponectin levels, of insulin resistance.

All-cause and cardiovascular mortality associated with sulphonylurea and metformin therapy in type 2 diabetes

ABSTRACT Purpose: To test the hypothesis that cumulative exposure to sulphonylurea (SU) or metformin (MET) have different effects on mortality when taken as a replacement or add-on of one for the other. Methods: All consecutive diabetes patients aged over 20 years were screened at their first diabetes outpatient visit between 2001 and 2008 (n = 79869). Only patients on MET (n = 11374) or SU (n = 18502) monotherapy were retained. All patients were followed up for death until December 31, 2011, but censored at first exposure to anything else besides MET/SU. Adjusted time-dependent Cox regression and competing risk regression analysis, with daily updates of treatment modalities were performed. Results: Mean age was 62.1 ± 11.2 years and follow-up was 4.6 ± 3.2 years (138496 person-years). Adjusted all-cause and cardiovascular mortality rates were significantly higher in MET as compared with SU group. All-cause mortality hazard ratios (HR) for cumulative time exposure were as follows: HR 0.956 (95%CI 0.951–0.962, p < 0.001) for SU added to MET, HR 1.092 (95%CI 1.087–1.096, p < 0.001) for SU replacing MET, HR 0.979 (95%CI 0.975–0.983, p < 0.001) for MET added to SU, and HR 1.127 (95%CI 1.118–1.136, p < 0.001) for MET replacing SU. Conclusion(s): The effect on all-cause mortality was beneficial for MET+SU combined therapy, but deleterious for either SU replacing MET, or MET replacing SU. There were no major outcome differences when analyzing individual SU, or specific mortality.