| Background:The prevalence of obesity has increased seriously worldwide and has become a global public health problem in recent decades.In 2015,about 107.7 million children and 603.7 million adults were obese worldwide,and the overall prevalence of obesity was 5.0%among children and 12.0%among adults.Obesity and its determinants are risk factors for 75%leading causes of non-communicable diseases(NCDs)worldwide,including cardiovascular diseases,type2 diabetes,and certain cancers.In recent years,intensive attention has been paid to the relationship of body mass index(BMI)and thyroid dysfunction.Several studies have revealed that obesity was associated with the elevated serum thyrotropin(TSH),but the relationships between obesity and free thyroid hormones(including free triiodothyronine[FT3]and free thyroxin[FT4])remain controversial.Epidemiological data also indicated that the prevalence of hypothyroidism and subclinical hypothyroidism was higher in obese individuals,and the elevated TSH concentration was the result of weight gaining rather than its etiology.Hyperthyrotropinaemia is a potential risk factor for insulin resistant and metabolic syndrome,independent of thyroid hormone.Besides,hyperthyrotropinaemia can also contribute to elevated proinflammatory and cardiovascular risk markers,increasing the risk for development of cardiovascular diseases.The exact pathophysiology of obesity-induced hyperthyrotropinaemia remains unclear,but several hypotheses are as follows:firstly,this is a requirement of energy homeostasis.The increase of TSH and thyroid hormone in obese people is to consume more calories;secondly,leptin plays an important role in it.The hyperleptinemia in obese people acts on the hypothalamus,making it synthesize and secrete more thyrotropin releasing hormone;lastly,the pituitary glands of obese people are more sensitive to thyrotropin releasing hormone(TRH).However,the most important and controversial viewpoint is that weather thyroid autoimmunity plays an intermediate role in the relationship between BMI and TSH.Several studies revealed higher positive rates of thyroid peroxidase antibody(TPOAb)and thyroglobulin antibody(TgAb)in overweight and obese individuals,but other studies have come to the contrary conclusions.Nevertheless,all these studies were conducted with relatively small sample size,and no one attempted to explore the interactive action of obesity and thyroid autoimmunity on the prevalence of hyperthyrotropinaemia.Therefore,we designed this large population-based cross-sectional study to assess the relationship between obesity,thyroid autoimmunity and hyperthyrotropinaemia.Purpose:1.To explore the relationship between BMI and hyperthyrotropinaemia,and to evaluate the regulatory role of thyroid autoimmunity among them.2.To investigate the regulatory role of body weight in the relationship between thyroid autoimmunity and hyperthyrotropinaemia.3.To assess the interaction effect between obesity and thyroid autoimmunity on hyperthyrotropinaemia.Materials and Methods:1.Study populationThe data of this population-based cross-sectional study was composed of two parts:one was derived from the epidemiological survey(10999 people)in Ningyang County of Shandong Province in 2011,and the other was derived from the health examination population(25684 people)in Shandong Provincial Hospital from 2012 to 2016.We included 13913 individuals aged 18 to 80 who tested thyroid function and thyroid autoantibodies(TPOAb and TgAb).Our exclusion criteria are as follows:(1)important data missing,such as sex,age,height and weight;(2)underweight individuals(BMI<18.5kg/m2);(3)hyperthyroidism(including overt and subclinical hyperthyroidism);(4)conditions that affect thyroid status,such as pregnancy,lactation,malignant tumors or severe hepatic or renal dysfunction;(5)taking any medicine that affects the thyroid status,including thyroid hormone,antithyroid drugs,amiodarone,alemtuzumab,lithium,tyrosine kinase inhibitors,interferon,estrogens,androgens,glucocorticoids,nonsteroidal anti-inflammatory drugs,antiepileptic drugs,rifampicin,furosemide,heparin or ?-adrenoceptor blockers in the past 3 months.Ultimately,12531 individuals were included in our study.2.Data collectionThe data of lifestyle were collected by standardized questionnaires.Height,weight and blood pressure were determined.BMI was calculated as the weight in kilograms divided by the square of the height in meters.We used our own method of grouping BMI in China as follows:underweight was defined as BMI<18.5 kg/m2,normal weight was defined as 18.5?BMI<24 kg/m2,Overweight was defined as 24<BMI<28 kg/m2,and obesity was defined as BMI?28 kg/m2.All the subjects were divided into three groups:normal weight group,overweight group and obese group.Blood samples were obtained from all participants between 8:00A.M and 10:00A:.M after overnight fasting.Chemiluminescent methods(Cobas E601,Roche,Basel,Switzerland)were employed to determine thyroid function(FT3,FT4 and TSH)for the overall population.Cobas E601(Roche,Basel,Switzerland)and AD VIA Centaur XP(Siemens,Germany)were used to determine thyroid autoantibodies(TPOAb and TgAb)for population of epidemiological survey and Health Examination respectively.Serum glucose,lipid profile,hepatic function and renal function were determined using the ARCHITECT ci16200 Integrated System(Abbott,Illinois,USA).The intra-assay and inter-assay coefficients of variation were always below 5%for all of the above parameters.3.Study outcomes definitionThe laboratory reference ranges were as follows:0.27-4.2mIU/L for TSH,12-22 pmol/L for FT4 and 3.1-6.8 pmol/L for FT3 were suitable for overall population;0-34 IU/L for TPOAb and 0-115 IU/L for TgAb were suitable for population of epidemiological survey;0-60 IU/L for TPOAb and TgAb were suitable for population of Health Examination respectively.Hyperthyrotropinaemia was defined as that TSH concentrations were greater than or equal to their upper limits of reference ranges,while FT4 concentrations were normal(subclinical hypothyroidism)or lower than(overt hypothyroidism)their lower limits of reference ranges.Positive of thyroid autoantibodies was defined as that the serum TPOAb or/and TgAb were higher than their upper limits of reference ranges.4.Statistical analysisStatistical analyses were performed using SPSS version 24(IBM Corp,Armonk,NY,USA).Kolmogorov-Smirnov test and Shapiro-Wilk test were used to evaluate the normal distribution of continuous variables.Continuous variables of normal and skewed distribution are presented as mean ±standard deviation(SD)and median(interquartile range),respectively.Categorical variables are presented as number(percentage).Comparisons between groups were performed by one-way analysis of variance(ANOVA)or Kruskal-Wallis test.The categorical variables between groups were compared by Chi-square test.Stratified analysis by thyroid auto-antibodies was employed to further compare thyroid function and prevalence of hyperthyrotropinaemia between different BMI groups.Cochran-Armitage Chi Squared test for trend and ANOVA trend test were conducted to assess the trend of categorical variables and continuous variables between the three BMI groups respectively,and continuous variables of skewed distribution were tested after log-transformation.Multivariate logistic regression was performed to assess the correlations and to obtain odds ratio(OR)values,adjusted odds ratio(aOR)values and 95%confidence interval(CI).Interaction effect between BMI and thyroid autoantibodies on the prevalence of hyperthyrotropinaemia was evaluated by multivariate logistic regression model which including interaction term.Considering to the close correlation among the confounders,principal component analysis was used to overcome the multicollinearity and improve the predictive ability of the multivariate logistic regression model.All statistical tests were two-tailed,and statistical significance was defined as P<0.05.Results:1.Comparison of thyroid related indexes between the three BMI groups in pooled populationOverweight and obese groups had higher serum FT3(P<0.001,P for trend<0.001)and FT4(P<0.001,P for trend<0.001)concentrations than normal group with linear trend.There were statistical differences of serum TSH concentration(P=0.042)among the three groups,but it presented only between obesity and overweight groups by post hoc test.There was no significant difference for prevalence of hyperthyrotropinaemia(14.8%,15.0%and 15.6%,P=0.637)among the three groups.Nevertheless,with the increasing of BMI category,the positive rates of thyroid autoantibodies(TgAb or TPOAb was positive)were decreasing(22.0%,17.5%and 17.1%,P<0.001,P for trend<0.001)with linear trend.2.Stratification according to thyroid autoimmune statusWe divided the 12531 subjects into three different layers according to different thyroid autoimmune status.When both TPOAb and TgAb were negative,there were no significant difference of serum TSH concentration(P=0.110)and prevalence of hyperthyrotropinaemia(P=0.802)between the three BMI groups.When one of TPOAb and TgAb was positive,only obese group had higher serum TSH concentration(P=0.004)and prevalence of hyperthyrotropinaemia(P=0.008)compared to normal group.When both TPOAb and TgAb were positive,all the overweight and obese groups had higher serum TSH concentration(P=0.002,P for trend=0.019)and prevalence of hyperthyrotropinaemia(P=0.001,P for trend<0.001)with linear trend compared to normal group.When BMI was introduced as a categorical variable,multivariate logistic regression showed that BMI was an independent risk factor for hyperthyrotropinaemia only when TPOAb and TgAb were all positive.The risk of hyperthyrotropinaemia increased 1.857-fold(adjusted OR,1.857;95%CI,1.188-2.905)in the overweight group and 2.201-fold(adjusted OR,2.201;95%CI,1.253-3.868)in the obesity group compared with the normal weight group.When BMI was introduced as a continuous variable,multivariate logistic regression showed that BMI was an independent risk factor for hyperthyrotropinaemia only when TPOAb or TgAb was positive.The risk of hyperthyrotropinaemia increased 1.065-fold(adjusted OR,1.065;95%CI,1.019-1.113)if BMI increased one unit.3.Comparison of the effects of thyroid autoimmunity on hyperthyrotropinaemia between different BMI groupsThe effect of thyroid autoimmunity on hyperthyroidism(adjusted OR)increased with the increase of BMI categories.Compared with individuals with two negative thyroid autoantibodies,the risk of hyperthyrotropinaemia increased 1.987-fold in normal weight group,1.626-fold in overweight group and 2.112-fold in obese group after adjustment for potential confounders,when one of the autoantibodies was positive.Compared with individuals with two negative thyroid autoantibodies,the risk of hyperthyrotropinaemia increased 3.310-fold in normal weight group,4.969-fold in overweight group and 5.122-fold in obese group after adjustment for potential confounders,when all the autoantibodies were positive.4.Multivariate logistic regression for interaction effectWe performed a multivariate logistic regression model with hyperthyrotropinaemia as dependent variable,and BMI,thyroid autoantibodies and their multiplicative interaction term as independent variables.When BMI was introduced as a categorical variable,adjusted OR(95%CI)of interaction terms between BMI and antibodies were as follows:1.033(0.752-1.419)for overweight and one positive antibody,1.935(1.252-2.990)for overweight and two positive antibodies,1.435(0.978-2.105)for obesity and one positive antibody,2.191(1.252-3.832)for obesity and two positive antibodies.When BMI was introduced as a continuous variable,the adjusted OR(95%CI)of the interaction terms between BMI and antibodies were 1.026(1.019-1.032)for BMI and one positive antibody,and 1.059(1.051-1.068)for BMI and two positive antibodies.Conclusion:1.Overweight and obesity were associated with hyperthyrotropinaemia only in presence of thyroid autoimmunity.2.Obesity might aggravate the pathogenic effect of autoimmunity on hyperthyrotropinaemia.3.There was an interaction effect between obesity and autoimmunity on the prevalence of hyperthyrotropinaemia.Background:With the development of social economy,the prevalence of obesity is increasing year by year.According to the official website of the World Health Organization,the prevalence of obesity in the world has almost tripled since 1975.By 2016,more than 1.9 billion adults aged 18 and over were overweight,of which more than 650 million were obese,and more than 340 million children and adolescents aged 5-18 were overweight or obese;39%of adults aged 18 and over are overweight and 13%were obese;by 2018,40 million children under the age of 5 are overweight or obese.The expression of inflammatory factors is closely related to the expression of histone deacetylase(HDACs)in visceral adipose tissue(VAT)and subcutaneous adipose tissues(SAT),which leads to a series of metabolic disorders and inflammation related concomitant diseases.Macrophages are the main immune cells in adipose tissue(AT).They are mainly responsible for the regulation of decompensated cell metabolism in obesity.When the regulation is out of balance,a series of metabolic related diseases will occur.Previous studies on the health problems caused by obesity mainly focused on cardiovascular and cerebrovascular diseases,type 2 diabetes,lipid metabolism disorders,primary hypertension,non-alcoholic fatty liver disease(NAFLD),obstructive sleep apnea(OSA),musculoskeletal system diseases and malignant tumors.However,in recent years,more and more researchers pay attention to the relationship between obesity and thyroid dysfunction.Previous studies have reported that in obese and morbidly obese people,the level of thyrotropin was higher than that in normal weight people.A new meta-analysis summarizes 22 studies in this field.The results show that obesity is significantly related to hypothyroidism(including overt and subclinical hypothyroidism),Hashimoto's thyroiditis and the titer of antithyroid peroxidase antibody(TPOAb),suggesting that controlling obesity is the key to preventing thyroid dysfunction.It has also been reported that overweight and obesity are closely related to the incidence of thyroid papillary carcinoma.Even overweight or obesity in adolescence can increase the risk of thyroid papillary carcinoma in adulthood,while obesity in childhood and adolescence can also lead to the decrease of the number and function of islet B cells in adulthood.However,on the contrary,thyroid hormone plays an important role in all material metabolic pathways,including protein metabolism,carbohydrate metabolism,lipid metabolism,energy consumption and heat production.Many studies have reported that changes in thyroid hormones play a key role in weight regulation.Higher baseline free triiodothyronine(FT3)or free thyroxine(FT4)and lower baseline thyrotropin(TSH)indicate more weight loss;in general,overt hypothyroidism,or even subclinical hypothyroidism,can lead to obesity or obesity related concomitant diseases,such as metabolic syndrome,hypertension,and lipids Abnormal and type 2 diabetes.Hypothyroidism was also recognized as a risk factor for cardiovascular disease.The underlying mechanisms that link these two conditions are thought to be the direct effects of endothelial dysfunction,blood pressure changes,dyslipidemia,weight gain,and thyroid hormones on the heart muscle.In conclusion,the causal relationship between obesity and hyperthyroidism has been controversial.In the first part of our study,we found that body mass index was positively correlated with serum thyrotropin concentration,and obesity could increase the prevalence of hyperthyrotropinaemia in the presence of thyroid autoimmunity;Obesity could aggravate the pathogenic effect of thyroid autoimmunity on hyperthyrotropinaemia.But limited by the cross-sectional design,it cannot explain the causal relationship between obesity and hyperthyrotropinaemia.So,in order to further explore the pathogenetic effect of obesity on hyperthyrotropinaemia,we designed this retrospective cohort study to preliminarily explore the causal relationship between them.Furthermore,in order to explore the role of obesity in the pathogenesis of hyperthyrotropinaemia,we designed this retrospective cohort study to try to explain the causal relationship between them.Research purpose:To explore the causal relationship between obesity and hyperthyrotropinaemia by retrospective cohort studyMaterials and methods:1.Research population and designThis study population comes from the people who had a physical examination in Shandong Provincial Hospital in 2013 and had a physical examination again in 2016.The inclusion criteria were as follows:thyroid function(FT3,FT4 and TSH)was tested in both physical examinations,and thyroid function was normal in 2013.The exclusion criteria are as follows:(1)those who lack important data such as sex,age,height and weight;(2)those who are emaciated(BMI<18.5kg/m2);(3)hyperthyroidism(including overt and subclinical hyperthyroidism);(4)those who are pregnant,breast-feeding,malignant tumor or severe hepatic or renal dysfunction that affect thyroid function;(5)taking any medicine that affects the thyroid status,including thyroid hormone,antithyroid drugs,amiodarone,alemtuzumab,lithium,tyrosine kinase inhibitors,interferon,estrogens,androgens,glucocorticoids,nonsteroidal anti-inflammatory drugs,antiepileptic drugs,rifampicin,furosemide,heparin or ?-adrenoceptor blockers in the past 3 months.Finally,2263 eligible subjects were included in our study.This study was designed by retrospective cohort study.The data of all subjects in 2013 were used as baseline data,and the data of subjects in 2016 were used as end-point follow-up data after 3 years.According to the follow-up data in 2016,patients were divided into three groups:BMI decreased group,BMI unchanged group and BMI increased group.The changes of thyroid function indexes were compared before and after the follow-up,and the difference of the incidence rate of hyperthyroidism between the three groups was compared after follow-up.2.Data collectionThe data of lifestyle were collected by standardized questionnaires.Height and weight were determined to the nearest 0.1 cm and 0.1 kg,respectively.BMI was calculated as the weight in kilograms divided by the square of the height in meters.We used our own method of grouping BMI in China as follows:underweight was defined as BMI<18.5 kg/m2,normal weight was defined as 18.5? BMI<24 kg/m2,Overweight was defined as 24?BMI<28 kg/m2,and obesity was defined as BMI?28 kg/m2.Blood samples were obtained from all participants between 8:00A.M and 10:00A.M after overnight fasting.Chemiluminescent methods(Cobas E601,Roche,Basel,Switzerland)were employed to determine thyroid function(FT3,FT4 and TSH).ADVIA Centaur XP(Siemens,Germany)were used to determine thyroid autoantibodies(TPOAb and TgAb).Serum glucose,lipid profile,hepatic function and renal function were determined using the ARCHITECT ci16200 Integrated System(Abbott,Illinois,USA).The intra-assay and inter-assay coefficients of variation were always below 5%for all of the above parameters.3.Definition of research resultsThe laboratory reference ranges were as follows:0.27-4.2mIU/L for TSH,12-22 pmol/L for FT4 and 3.1-6.8 pmol/L for FT3;0-60 IU/L for TPOAb and TgAb.Hyperthyrotropinaemia was defined as that TSH concentrations were greater than or equal to their upper limits of reference ranges,while FT4 concentrations were normal(subclinical hypothyroidism)or lower than(overt hypothyroidism)their lower limits of reference ranges.Positive of thyroid autoantibodies was defined as that the serum TPOAb or/and TgAb were higher than their upper limits of reference ranges.4.Statistical analysisStatistical analyses were performed using SPSS version 24(IBM Corp,Armonk,NY,USA).Kolmogorov-Smirnov test and Shapiro-Wilk test were used to evaluate the normal distribution of continuous variables.Continuous variables of normal and skewed distribution are presented as mean±standard deviation(SD)and median(interquartile range),respectively.Categorical variables are presented as number(percentage).Comparisons between groups were performed by one-way analysis of variance(ANOVA)or Kruskal-Wallis test at baseline.Comparisons before and after follow-up were performed by paired sample t-test for continuous variables of normal distribution,and by Wilcoxon test for continuous variables of skewed distribution.The categorical variables between groups were compared by Chi-square test.All the statistical tests were double tail tests,with statistical significance of P<0.05.Result:After three years of follow-up,229 of 2263 subjects showed no change in BMI compared with the baseline,1158 of them showed a decrease in BMI compared with the baseline(P<0.001),and 876 of them showed an increase in BMI compared with the baseline(P<0.001).1.Comparison of general variables and thyroid function between the three groups at baselineAt baseline,BMI of BMI decreased group was slightly higher than that of BMI unchanged group and BMI increased group(P<0.001).In terms of lipid metabolism,the serum triglyceride(P<0.001),total cholesterol(P=0.015)and low-density lipoprotein cholesterol(P=0.031)were relatively high in the BMI decreased group,while the serum high-density lipoprotein cholesterol(P=0.002)was relatively low.In terms of glucose metabolism,the fasting blood glucose level of the BMI decreased group was relatively high(P=0.012),but there was no significant difference among the three groups in the level of glycosylated hemoglobin(P=0.667).In terms of thyroid function,there was no significant difference in FT3(P=0.301),FT4(P=0.276)and TSH(P=0.760)among the three groups.2.Comparison of thyroid function between the three groups after follow-upAfter 3 years of follow-up,the BMI of the BMI increased group was higher than that of theBMI decreased group and the BMI unchanged group(P<0.001);the FT4 of the BMI increased group was lower than that of the BMI decreased group and the BMI unchanged group(P=0.008);There was no significant difference in FT3(P=0.955),TSH(P=0.107)and the incidence rate of hyperthyrotropinaemia(3.9%,4.8%and 3.4%,P=0.544)between the three groups(BMI increased group,BMI unchanged group and BMI decreased group).3.Changes of thyroid function in three groups before and after follow-up Compared with the baseline level,the levels of serum FT3(P<0.001)and FT4(P=0.013)decreased,and the level of serum TSH(<0.001)increased for BMI increased group after 3 years of follow-up.Compared with the baseline level,the levels of serum FT3(P<0.001)and FT4(P<0.001)decreased,and the level of serum TSH(P=0.762)did not change for BMI decreased group after 3 years of follow-up.Compared with the baseline level,the level of serum FT3(P=0.006)decreased,while the level of serum FT4(P=0.471)and TSH(P=0.703)did not change for BMI unchanged group after 3 years of follow-up.Conclusion:1.The increase of BMI could lead to the increase of serum TSH concentration and the decrease of serum FT4 concentration for euthyroid individuals.2.The variation of BMI did not lead to the change of the incidence rate of hyperthyrotropinaemia,and it may be related to the short follow-up time. |
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