Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, P = 8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, P = 2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, P = 6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, P = 1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, P = 6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, P = 1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.

Reference intervals for serum osteocalcin concentrations in adult men and women from the study of health in Pomerania.

BACKGROUND: Osteocalcin (OC) is a bone-specific protein produced primarily by osteoblasts during bone formation. Besides its role in bone formation, osteocalcin may play a role in the regulation of energy metabolism and male fertility. To interpret serum OC data, reference intervals adapted to a specific laboratory method are needed. METHODS: A healthy reference population was selected from the first follow-up of the Study of Health in Pomerania. Serum OC concentrations were measured with the IDS-iSYS N-Mid Osteocalcin assay on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range (2.5th-97.5th percentile). Age-specific reference intervals were calculated by quantile regression for 1107 men (25-79 years) and 545 premenopausal women (25-54 years). The reference interval for 498 postmenopausal women (50-79 years) was calculated irrespective of age. RESULTS: Median (1st-3rd quartile) serum OC concentrations were 15.4 ng/mL (12.0-19.4 ng/mL) in men, 14.4 ng/mL (11.3-18.5 ng/mL) in premenopausal women, and 18.6 ng/mL (13.6-25.6 ng/mL) in postmenopausal women. Serum OC concentrations were highest in men and premenopausal women aged 25-29 years, were stable during midlife, and rose again after 65 years of age in men and at transition to menopause in women. Serum OC concentrations were lower in women taking oral contraceptives or who were under hormone replacement therapy after menopause and in subjects with diabetes mellitus or with body mass index < 18 or > 30 kg/m2 than in subjects without these conditions. CONCLUSIONS: We established sex-specific adult reference intervals for the serum OC concentration measured by the IDS-iSYS N-Mid Osteocalcin assay.

Prevalence of hypopituitarism after intracranial operations not directly associated with the pituitary gland.

BACKGROUND: Over the last few years, awareness and detection rates of hypopituitarism following traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) has steadily increased. Moreover, recent studies have found that a clinically relevant number of patients develop pituitary insufficiency after intracranial operations and radiation treatment for non-pituitary tumors. But, in a substantial portion of more than 40%, the hypopituitarism already exists before surgery. We sought to determine the frequency, pattern, and severity of endocrine disturbances using basal and advanced dynamic pituitary testing following non-pituitary intracranial procedures. METHODS: 51 patients (29 women, 22 men) with a mean age of 55 years (range of 20 to 75 years) underwent prospective evaluation of basal parameters and pituitary function testing (combined growth hormone releasing hormone (GHRH)/arginine test, insulin tolerance test (ITT), low dose adrenocorticotropic hormone (ACTH) test), performed 5 to 168 months (median 47.2 months) after intracranial operation (4 patients had additional radiation and 2 patients received additional radiation combined with chemotherapy). RESULTS: We discovered an overall rate of hypopituitarism with distinct magnitude in 64.7% (solitary in 45.1%, multiple in 19.6%, complete in 0%). Adrenocorticotropic hormone insufficiency was found in 51.0% (partial in 41.2%, complete in 9.8%) and growth hormone deficiency (GHD) occurred in 31.4% (partial in 25.5%, severe in 5.9%). Thyrotropic hormone deficiency was not identified. The frequency of hypogonadism was 9.1% in men. Pituitary deficits were associated with operations both in close proximity to the sella turcica and more distant regions (p = 0.91). Age (p = 0.76) and gender (p = 0.24) did not significantly differ across patients with versus those without hormonal deficiencies. Groups did not significantly differ across pathology and operation type (p = 0.07). CONCLUSION: Hypopituitarism occurs more frequently than expected in patients who have undergone neurosurgical intracranial procedures for conditions other then pituitary tumors or may already exists in a neurosurgical population before surgery. Pituitary function testing and adequate substitution may be warranted for neurosurgical patients with intracranial pathologies at least if unexplained symptoms like fatigue, weakness, altered mental activity, and decreased exercise tolerance are present.

Systemic iodine absorption associated with the use of preoperative ophthalmic antiseptics containing iodine.

BACKGROUND: Polyvinylpyrrolidone-Iodine (PVP-I) is routinely used as preoperative antiseptic during ophthalmic surgery. Iodine absorption from iodine-containing antiseptics can lead to the development of thyroid disorders. Therefore, a quantitative measurement of iodine absorption from these antiseptics was performed in patients undergoing elective cataract surgery. METHODS: This study enrolled 241 patients to evaluate systemic iodine absorption after exposure to conjunctival and/or periorbital 1.25% and 10% PVP-I compared to an iodine-free antiseptic. RESULTS: All patients who received the 10% PVP-I regardless of the application site showed a 1.2-1.5-fold increase in urinary iodine excretion after 24 h (p = 0.01). In 17 out of 110 (15.5%) patients in whom 10% PVP-I was used, the critical threshold of urinary iodine excretion as defined by WHO (>300 µg/L) was exceeded. In contrast, no significant ioduria was observed with the use of 1.25% PVP-I except in patients after 48 h (p = 0.01) and with a concurrent conjunctival and periorbital application. The proportion of the excreted iodine in urine ranged from 0.24% to 1.77%. No correlation was found between the total applied concentration of iodine and the amount excreted in urine. CONCLUSION: Based on our findings, we believe that the use of 10% PVP-I as preoperative ophthalmic antiseptic should undergo further clinical evaluation in regard to its impact on thyroid function. Conjunctival or periorbital application of 1.25% PVP-I does not result in significant ioduria.

The association of serum prolactin concentration with inflammatory biomarkers - cross-sectional findings from the population-based Study of Health in Pomerania.

OBJECTIVE: Prolactin (PRL) is involved in immune regulation and may contribute to an atherogenic phenotype. Previous results on the association of PRL with inflammatory biomarkers have been conflicting and limited by small patient studies. Therefore, we used data from a large population-based sample to assess the cross-sectional associations between serum PRL concentration and high-sensitivity C-reactive protein (hsCRP), fibrinogen, interleukin-6 (IL-6), and white blood cell (WBC) count. DESIGN AND POPULATION: From the population-based Study of Health in Pomerania (SHIP), a total of 3744 subjects were available for the present analyses. METHODS AND MEASUREMENTS: PRL and inflammatory biomarkers were measured. Linear and logistic regression models adjusted for age, sex, body-mass-index, total cholesterol and glucose were analysed. RESULTS: Multivariable linear regression models revealed a positive association of PRL with WBC. Multivariable logistic regression analyses showed a significant association of PRL with increased IL-6 in non-smokers [highest vs lowest quintile: odds ratio 1·69 (95% confidence interval 1·10-2·58), P = 0·02] and smokers [OR 2·06 (95%-CI 1·10-3·89), P = 0·02]. Similar results were found for WBC in non-smokers [highest vs lowest quintile: OR 2·09 (95%-CI 1·21-3·61), P = 0·01)] but not in smokers. Linear and logistic regression analyses revealed no significant associations of PRL with hsCRP or fibrinogen. CONCLUSIONS: Serum PRL concentrations are associated with inflammatory biomarkers including IL-6 and WBC, but not hsCRP or fibrinogen. The suggested role of PRL in inflammation needs further investigation in future prospective studies.

Age- and sex-specific reference limits for creatinine, cystatin C and the estimated glomerular filtration rate.

BACKGROUND: Early detection of patients with chronic kidney disease is of great importance. This study developed reference limits for serum creatinine and serum cystatin C concentrations and for the estimated glomerular filtration rate (eGFR) in healthy subjects from the general population aged 25-65 years. METHODS: This study defined a reference population including 985 subjects from the first follow-up of the Study of Health in Pomerania. Serum creatinine was measured with a modified kinetic Jaffé method. Serum cystatin C was measured with a nephelometric assay. The eGFR was calculated from serum creatinine according to the Cockcroft-Gault (eGFR(CG)) and the Modification of Diet in Renal Disease (eGFR(MDRD)) equation, respectively, as well as from serum cystatin C according to the formula by Larsson (eGFR(Larsson)). Non-parametric quantile regression was used to estimate the reference limits. For serum creatinine and serum cystatin C the 95th percentile and for eGFR(CG), eGFR(MDRD) and eGFR(Larsson) the 5th percentile were selected as reference limits. All data was weighted to reflect the age- and sex-structure of the German population in 2008. RESULTS: The reference limits for serum creatinine (men: 1.11-1.23 mg/dL; women: 0.93-1.00 mg/dL) and serum cystatin C levels (men: 0.92-1.04 mg/L; women: 0.84-1.02 mg/L) increased with advancing age. The reference limits for eGFR decreased with increasing age (eGFR(CG) men: 106.0-64.7 mL/min, women 84.4-57.9 mL/min; eGFR(MDRD) men: 82.5-62.2 mL/min/1.73 m², women 75.0-58.2 mL/min/1.73 m²; eGFR(Larsson) men: 85.5-72.9 mL/min, women 94.5-75.7 mL/min). CONCLUSIONS: This study presents age- and sex-specific reference limits for five measures of renal function based on quantile regression models.

The role of sex hormone-binding globulin and testosterone in the risk of incident metabolic syndrome.

AIM: The aim of this study was to further evaluate the suggested independent association of sex hormone-binding globulin (SHBG) with incident metabolic syndrome (MetS) in men. RESEARCH DESIGN AND METHODS: We used data from 1906 men aged 20-79 years from the population-based Study of Health in Pomerania (SHIP). Multivariable logistic regression models were implemented to analyse cross-sectional and longitudinal associations of total testosterone (TT), SHBG, and free testosterone (free T) concentrations with MetS. Furthermore, we associated changes between baseline and follow-up concentrations of TT, SHBG, and free T with incident MetS. RESULTS: Cross-sectional logistic regression models revealed a significant inverse association of TT (odds ratio [OR] per standard deviation [SD] decrease: 1.28; 95% confidence interval (CI): 1.10-1.50), and free T (OR per SD decrease: 1.29; 95% CI: 1.11-1.51), but not SHBG (OR per SD decrease: 1.13; 95% CI: 0.98-1.30) with prevalent MetS. At the 5-year follow-up 1435 men were repeatedly examined and of the 956 men without baseline MetS, 328 men (34.3%) had incident MetS. Longitudinal analyses showed, after adjustment for the respective sex hormone, that lower baseline SHBG (OR per SD decrease: 1.30; 95% CI: 1.03-1.65), but not TT (OR per SD decrease: 1.14; 95% CI: 0.93-1.39) was associated with incident MetS. Change analyses revealed an inverse association between TT change and incident MetS (OR per SD decrease between baseline and follow-up: 1.19; 95% CI: 1.01-1.39), independent of SHBG; whereas SHBG change was not associated with incident MetS until adjustment for TT. CONCLUSIONS: Although baseline SHBG predicts incident MetS independent of testosterone, change analyses suggest the testosterone decline as the main driver of the association between sex hormones and MetS.

The association between insulin-like growth factor I and bone turnover markers in the general adult population.

OBJECTIVES: Growth hormone (GH) and its main mediator, insulin-like growth factor I (IGF-I), play a fundamental role in human metabolism. Previous epidemiological studies investigating the association of IGF-I and bone turnover markers (BTMs) yielded conflicting results and were limited by study design or sample size. Therefore, we aimed to investigate the associations between serum levels of IGF-I or the IGF-I/IGF binging protein 3 (IGFBP-3) ratio and levels of BTMs including procollagen type 1 N-terminal propeptide (PINP), C-terminal telopeptides of type 1 collagen (CTX), and bone-specific alkaline phosphatase (BAP). METHODS: Data from 1463 men and 1481 women who participated in the first follow-up of the Study of Health in Pomerania were used. IGF-I and IGFBP-3 levels were measured using chemiluminescent immunometric assays on an Immulite 2500 analyzer. BTM levels were measured on the IDS-iSYS Multi-Discipline Automated Analyser. Analyses of variance (ANOVA) and quantile regression models were calculated. RESULTS: In men <55 years and premenopausal women ANOVA and quantile regression analyses revealed positive associations between IGF-I or even stronger the IGF-I/IGFBP-3 ratio and PINP [per unit increase in IGF-I/IGFBP-3 ratio in men: beta (95%-CI) 2.33 ng/ml (0.91; 3.75), p < 0.01; women: 3.63 ng/ml (2.31; 4.95), p < 0.01] or CTX [men: 20.8 ng/l (3.5; 38.0), p = 0.02; women: 12.0 ng/l (-1.2; 25.2), p = 0.07]. Furthermore in postmenopausal women, IGF-I and the IGF-I/IGFBP-3 ratio were inversely related with CTX levels, whereas an inverse U-shaped relation between IGF-I/IGFBP-3 ratio and PINP was found. Regarding BAP, we observed borderline significant associations with IGF-I or the IGF-I/IGFBP-3 ratio in older subjects only. CONCLUSION: IGF-I levels and particularly free IGF-I, estimated by the IGF-I/IGFBP-3 ratio, are positively related with PINP as a bone formation marker and CTX as a bone resorption marker in healthy adult men younger than 55 years and premenopausal women. In older subjects the found positive as well as negative relations with BTMs have to be further investigated.

The association between IGF-I and insulin resistance: a general population study in Danish adults.

OBJECTIVE: IGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate the association between IGF-I level and insulin resistance in a Danish general population. RESEARCH DESIGN AND METHODS: Included were 3,354 adults, aged 19-72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin resistance. Serum IGF-I levels were determined by an immunoassay and grouped into quintiles (Q1-Q5). Linear or multinomial logistic regression analyses were performed. RESULTS: In the study population, 520 subjects (15.5%) had increased HOMA-IR values above 2.5. After adjustment for age, sex, physical activity, and waist-to-height ratio, a U-shaped association between IGF-I and HOMA-IR was found. Low IGF-I (Q1: odds ratio [OR] 1.65 [95% CI 1.16-2.34], P < 0.01) as well as high IGF-I (Q5: 1.96 [1.38-2.79], P < 0.01) levels were related to a higher odds of increased HOMA-IR values compared with subjects with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model. CONCLUSIONS: Low- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism of this complex phenomenon has to be elucidated in more detail for future risk stratification.

Prediction of improvement in quality of life (QoL-AGHDA) in adults with growth hormone deficiency by normative reference limits: data of the German KIMS cohort.

OBJECTIVE: The objective of the present study was to calculate sex- and age-specific normative values for health-related quality of life (HRQoL) in Germany using quantile regression. Furthermore, we investigate the estimates of these normative data to and to predict the improvement of QoL-AGHDA scores in the German KIMS cohort during growth hormone treatment. DESIGN: Normative data of HRQoL was assessed by quality of life assessment of growth hormone deficiency (GHD) in adults (QoL-AGHDA) in a representative sample of the German population (n=4172). Corresponding data for 888 patients with GHD were retrieved from the German KIMS cohort (Pfizer International Metabolic Database). RESULTS: The overall mean QoL-AGHDA score of the general population was 4.8±5.2. ANOVA indicated that variability in QoL-AGHDA scores did not differ significantly across gender (p=0.20), whereas age was a significant predictor (p<0.001). Given the QoL-AGHDA score distribution of the general population, we calculated reference values based on quantile regression. In KIMS patients we observed significantly higher QoL-AGHDA scores, 7.9±6.5 (p<0.001), before GH treatment. The optimal predictive QoL-AGHDA score was 6 (70th percentile) with a sensitivity of 0.57 and a specificity of 0.70 in ROC analysis. Furthermore, a baseline QoL-AGHDA score above the 70th percentile allowed predicting an improvement of QoL by GH treatment. CONCLUSIONS: This study established normative reference values for the QoL-AGHDA in a representative sample of the German population. Based on these normative data a QoL-AGHDA cut-off value for prediction of improvement was investigated for the German population, which may facilitate clinical assessment of HRQoL response to GH replacement for patients with GHD.

The benefit of long-term growth hormone (GH) replacement therapy in hypopituitary adults with GH deficiency: results of the German KIMS database.

OBJECTIVE: To evaluate the treatment effects of long-term growth hormone (GH) replacement therapy in adults with GH deficiency (GHD) who were followed in KIMS Germany (Pfizer International Metabolic Database), a national surveillance study. DESIGN: The analysis was performed using baseline and long-term data (range: 4-10 years) of 440 consecutively documented patients (216 women and 224 men) with GHD, aged 20 to 49 years, enrolled in KIMS Germany. Serum insulin-like growth factor I (IGF-I), fasting blood glucose, fasting serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) as well as body mass index (BMI), waist circumference (WC) and hip circumference (HC) at baseline and at last visit were studied. Furthermore, QoL-AGHDA score was determined to assess quality-of-life (QoL). RESULTS: The mean dose of GH over all years was 0.41 mg per day in women and 0.37 mg per day in men. IGF-I and IGF-I SDS levels (standard deviation score) increased significantly (p<0.001) during GH treatment. The QoL-AGHDA score decreased significantly (p<0.001), indicating long-lasting improvement in QoL. In total cholesterol, LDL-C and fasting blood glucose, no significant changes were found. Only six patients developed type 2 diabetes during follow-up. Females and males similarly increased significantly in BMI, WC and HC. During GH treatment, recurrences of pituitary or central nervous system tumours or further de novo neoplasia were reported in 6 or 11 patients, respectively. The number of the most frequently reported GH treatment-associated adverse events was low. CONCLUSION: These observational data show long-term beneficial effects of GH replacement therapy on QoL and show no significant effects on total cholesterol, LDL-C or BMI, WC and HC. Additionally, our data indicate that GH replacement therapy in adults is well tolerated.