Thyroid-Stimulating Hormone, Degree of Obesity, and Metabolic Risk Markers in a Cohort of Swedish Children with Obesity

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1 HORMONE RESEARCH IN PÆDIATRICS Originl Pper Received: Februry 10, 2017 Accepted: April 18, 2017 Published online: June 14, 2017 Thyroid-Stimulting Hormone, Degree of Obesity, nd Metbolic Risk Mrkers in Cohort of Swedish Children with Obesity Veroniq Lundbäck Kerstin Ekbom Emili Hgmn Ingrid Dhlmn b Clude Mrcus Division of Peditrics, Deprtment of Clinicl Science, Intervention nd Technology, Krolinsk Institutet, Stockholm, Sweden; b Deprtment of Medicine, Huddinge, Krolinsk Institutet, Stockholm, Sweden Keywords Thyroid-stimulting hormone Triiodothyronine Thyroxine Childhood obesity Body mss index stndrd devition scores Abstrct Bckground/Aims: Thyroid-stimulting hormone (TSH) is ffected in obesity nd might influence metbolic risk. It is uncler wht mechnisms cuse elevted TSH in obesity. We imed to investigte TSH sttus within the norml rnge nd the ssocition of TSH with degree of obesity nd metbolic prmeters in children with obesity. Methods: A totl of 3,459 children, ged yers, were identified in the Swedish Childhood Obesity Tretment Registry, BORIS. Age, gender, TSH, free triiodothyronine (ft3), free thyroxine (ft4), body mss index stndrd devition scores (BMI SDS), s well s vribles of lipid nd glucose metbolism were exmined. Results: Children with high-norml TSH (>3.0 mu/l) (28.8%) hd higher BMI SDS compred to children with low-norml TSH (<3.0 mu/l) (p < 0.001). Multivrible regression nlysis djusted for ge nd gender showed tht TSH levels were ssocited with BMI SDS (β: 0.21, 95% CI: , p < 0.001). Associtions of thyroid hormones with mrkers of lipid nd glucose metbolism were observed, where TSH ws ssocited with fsting insulin, HOMA (homeosttic model ssessment of insulin resistnce), totl cholesterol, nd triglycerides. Conclusions: A positive ssocition between TSH levels nd BMI SDS ws seen in children with obesity. Associtions of TSH nd free thyroid hormones with glucose metbolism indicted tht TSH might be one of severl fctors cting to determine body weight nd obesity co-morbidities, lthough the underlying mechnism remins uncler. Introduction 2017 S. Krger AG, Bsel Thyroid-stimulting hormone (TSH) nd body composition re closely relted. TSH both directly [1 3], nd indirectly vi thyroid hormones [4], is involved in the regultion of bsl metbolism nd thermogenesis nd thereby lso in glucose nd lipid metbolism [4 6]. In dults with obesity, TSH hs frequently been reported to be elevted, but conflicting dt with unltered TSH nd thyroid hormones hve lso been reported [7, 8]. In dults, positive correltion hs been reported between weight gin during 5 yers nd progressive increse in E-Mil krger@krger.com S. Krger AG, Bsel Veroniq Lundbäck Division of Peditrics, Deprtment of Clinicl Science, Intervention nd Technology Endocrine Reserch Unit, Blickgången 6A Novum, Krolinsk Institutet Krolinsk University Hospitl Huddinge, SE Stockholm (Sweden) E-Mil ki.se

2 TSH level. Even slightly elevted TSH levels might be involved in the occurrence of obesity [9], but the cuse of the higher TSH concentrtions in obesity nd the underlying mechnisms re uncler [10, 11]. It is well known tht totl nd resting energy expenditure re positively ssocited with free triiodothyronine (ft3) levels [12], nd it hs been suggested tht n increse in TSH, nd secondrily in ft3, in obesity is n ttempt to increse resting energy expenditure nd inhibit the conversion of ccumulted energy into ft [13]. In other words, n increse in TSH hs been suggested s n dption to weight gin [14]. Studies investigting ssocitions of free thyroxine (ft4) with metbolic risk hve been limited in size, but it hs been demonstrted in popultion-bsed cohort tht low ft4 levels mong euthyroid subjects re ssocited with hyperlipidemi nd insulin resistnce [15]. Studies in children with obesity hve reported n incresed prevlence of elevted TSH [16, 17], but lck of ssocition hs lso been described [18, 19]. Incresed levels of TSH hve been reported to be ssocited with slightly elevted or norml ft4 nd/or ft3 in the bsence of overt thyroid dysfunction [10, 16]. Elevted TSH within the norml rnge hs previously been shown to be ssocited with metbolic risk fctors in obese children [19, 20] s well s in youths in the generl popultion [21]. In some studies, weight loss hs been reported to normlize TSH levels s well s metbolic prmeters of glucose metbolism nd lipid profile [22, 23], wheres 1 study did not find n ssocition of TSH with lipid prmeters even though TSH ws reduced fter weight loss [24]. However, despite lrge number of studies, it is still uncler whether high TSH levels re compenstory to mintin norml thyroid hormone levels, nd it is lso uncler whether TSH is ssocited with metbolic disturbnces in children with obesity since previously published reserch re inconsistent [25]. In order to clrify these issues we imed to investigte TSH sttus nd its ssocition with the degree of obesity in children. We hypothesize tht TSH levels re incresed within the norml rnge to mintin norml thyroid hormone levels. Second, we imed to investigte whether TSH nd thyroid hormones within the norml rnge re ssocited with metbolic risk mrkers fsting insulin (f-insulin), fsting glucose (f-glucose), HOMA (homeosttic model ssessment of insulin resistnce), triglycerides, totl cholesterol, low-density lipoprotein (LDL) cholesterol, nd high-density lipoprotein (HDL) cholesterol in obese children, nd we hypothesize tht high-norml TSH is ccompnied with more dernged metbolic profile. Subjects in dtbse, n = 18,448 n = 18,037 n = 4,027 n = 3,937 n = 3,564 Included, n = 3,459 Mterils nd Methods Not fitting ge criteri, n = 411 TSH missing, n = 14,010 TSH not eligible or not within norml rnge for ge, n = 90 Not clssified s hving obesity, n = 373 Syndromes nd chronic disese, n = 105 Fig. 1. Age criteri: yers. Thyroid-stimulting hormone reference rnges: ge yers, mu/l; ge yers, mu/l; nd ge yers, mu/l (reference intervls for children nd dults, Elecsys Thyroid Tests Elecsys 2010 system; Roche Dignostics 2009). Obesity ws defined ccording to the Interntionl Obesity Tsk Force (IOTF) BMI cutoffs [26]. The design ws retrospective cohort study consisting of children nd dolescents registered in the Swedish Childhood Obesity Tretment Registry, BORIS ( The children were enrolled in obesity tretment from peditric clinics ll over Sweden between August 1995 nd June Inclusion criteri were children clssified s obese ccording to Cole nd Lobstein [26] with records of TSH levels. Exclusion criteri were dignosed thyroid disese (subclinicl nd overt hypo- nd hyperthyroidism, Grves disese, Hshimoto s thyroiditis, nd thyroid hormone tretment in generl) nd the presence of hypothlmic or pituitry disturbnces, centrl nervous system dmge, or syndromes (Prder- Willi syndrome, Down syndrome, nd Lurence-Moon-Brdet- Biedl syndrome) nd other chronic diseses (Fig. 1). After exclusion totl of 3,459 children, ged yers, were identified within ech ge-specific norml TSH rnge. Ethicl permission for dt collection in BORIS ws obtined by the regionl committee of ethics in Stockholm (2014/381-31/5). Procedure All children hd undergone nthropometric mesurements by trined personnel. Body mss index (BMI) ws clculted s weight in kilogrms divided by height in squre meters (kg/m 2 ), nd interntionl ge- nd gender-djusted BMI stndrd devition scores (BMI SDS) were used [26]. Fsting blood smples were obtined fter n overnight fst, nd routine biochemicl nlysis ws performed t ccredited hospitl lbortories. 2 Lundbäck/Ekbom/Hgmn/Dhlmn/ Mrcus

3 Tble 1. Anthropometric nd biochemicl prmeters in groups with moderte nd severe obesity, nd in low-norml nd high-norml TSH groups All Per group, n Moderte obesity Severe obesity Per group, n Low-norml TSH High-norml TSH Age, yers 11.5±3.44 1,682/1, ± ±3.76 2,463/ ± ±3.45** Mle/femle, % 51/49 1,682/1,777 48/52 49/51 2,463/996 48/52 49/51 BMI SDS 2.94±0.46 1,682/1, ± ±0.36** 2,463/ ± ±0.48** Tnner stge 2.80± / ± ±1.78 1,120/ ± ±1.71** TSH, mu/l 2.47±0.92 1,682/1, ± ±0.93** 2,463/ ± ±0.53** ft3, pmol/l 6.11± / ± ± / ± ±0.91 ft4, pmol/l 14.0±2.73 1,330/1, ± ±2.72 2,063/ ± ±2.74 TSH/fT4 rtio 0.17 ( ) 1,330/1, ( ) 0.18 ( )** 2,063/ ( ) 0.26 ( )** Fsting insulin, mu/l 12.0 ( ) 275/ ( ) 13.0 ( )** 1,523/ ( ) 13.0 ( ) fsting glucose, mmol/l 5.22 ( ) 293/ ( ) 5.20 ( )* 2,195/ ( ) 5.20 ( ) HOMA 2.72 ( ) 257/ ( ) 2.95 ( )** 1,448/ ( ) 2.88 ( )* Totl cholesterol, mmol/l 4.26±0.78 1,491/1, ± ±0.78 2,224/ ± ±0.78* Triglycerides, mmol/l 1.0 ( ) 314/ ( ) 1.08 ( )** 2,284/ ( ) 1.00 ( )** LDL cholesterol, mmol/l 2.66±0.72 1,463/1, ± ±0.72* 2,100/ ± ±0.71 HDL cholesterol, mmol/l 1.21±0.30 1,479/1, ± ±0.29** 2,114/ ± ±0.30 Dt re presented s men ± SD or medin (min mx) for prmetric nd nonprmetric vribles, respectively. TSH, thyroid-stimulting hormone; BMI SDS, body mss index stndrd devition scores; ft3, free triiodothyronine; ft4, free thyroxine; HOMA, homeosttic model ssessment of insulin resistnce. Mnn-Whitney U Test. * p < 0.05, ** p < Outcome Mesurements TSH, thyroid hormones ft3 nd ft4, f-insulin, f-glucose, nd fsting lipid profiles (including totl cholesterol, triglycerides, nd LDL nd HDL cholesterol) were extrcted from BORIS. As the smples were collected from ll over Sweden, the methods for nlyses my hve differed. However, ll routine nlyses were performed by certified lbortories. Age-specific reference intervls used for TSH, ft3, nd ft4 re s follows: ge 1 6 yers: TSH mu/l, ft pmol/l, nd ft pmol/l; ge 7 11 yers: TSH mu/l, ft pmol/l, nd ft pmol/l; ge yers: TSH mu/l, ft pmol/l, nd ft pmol/l (reference intervls for children nd dults, Elecsys Thyroid Tests Elecsys 2010 system; Roche Dignostics 2009). The homeosttic model ssessment of insulin resistnce (HOMA) ws clculted to obtin mesure of insulin sensitivity: (f-glucose mmol/l f-insulin miu/l)/22.5). We used cutoff of 3.0 mu/l to ctegorize individuls s hving low- or high-norml TSH within the norml rnge for ge. The TSH/fT4 rtio ws clculted to investigte the reltionship between TSH nd ft4. To define the degree of obesity the Interntionl Obesity Tsk Force (IOTF) BMI cutoffs were used, where ge- nd sex-djusted BMI cutoffs corresponding to BMI 30 nd 35 re defined s obesity nd severe obesity, respectively [26]. In the multivrible liner regression nlysis the subjects were strtified by ge ccording to ge-specific norml intervls for TSH nd thyroid hormones (3 6.9, , nd yers of ge). We lso investigted the cohort divided by gender nd stge of puberty ssessed by Tnner stge s prepuberty, erly puberty, nd puberty (Tnner stges 1 nd 2 s prepuberty, 3 s erly puberty, nd 4 nd 5 s puberty were documented [27]). Children without documented pubertl stge were strtified s follows: <7 yers s Tnner stge 1 nd dolescents >15.9 yers s Tnner stge 5. Sttisticl Anlysis Dt were processed nd nlyzed using the sttisticl softwre IBM SPSS version 23. All dt were controlled for norml distribution by inspection of histogrms. Normlly distributed dt were presented s men ± SD, nd nonprmetric dt were presented s medin (min mx). Between-group comprisons were performed using independent t tests or Mnn-Whitney U nd Kruskl-Wllis tests ccording to norml or nonprmetric distribution of the tested vrible. Multivrible liner regression models were clculted to investigte the impct of BMI SDS (independent vrible) on TSH nd thyroid hormones (dependent vribles) fter controlling for ge nd gender. To study how TSH nd thyroid hormones were ssocited with metbolic prmeters, multivrible regression nlyses djusted for ge, gender, nd BMI SDS were performed with TSH, ft3, nd ft4, respectively (independent vribles) on prmeters of lipid nd glucose metbolism (dependent vribles). To further evlute the independent contribution of TSH nd ft3, we simultneously included TSH nd ft3 s covrites in the regression model. All tests for significnce were 2-sided, nd p vlues <0.05 were considered sttisticlly significnt. TSH Levels nd Metbolic Prmeters in Childhood Obesity 3

4 Tble 2. Multivrible regression nlysis of the impct of BMI SDS (independent vrible) on TSH, ft3, nd ft4 respectively (dependent vribles) controlling for ge nd gender, nd multivrible regression nlysis of the impct of TSH, ft3, or ft4 (independent vribles) on vribles of lipid nd glucose metbolism (dependent vribles), controlling for ge, gender, nd BMI SDS TSH (n = 3,459) ft3 (n = 1,087) ft4 (n = 2,914) BMI SDS 0.21 (0.14 to 0.28)** 0.09 ( 0.22 to 0.04) 0.01 ( 0.22 to 0.21) Fsting insulin, mu/l 0.77 (0.27 to 1.26)* 0.91(0.19 to 1.62)* 0.14 ( 0.31 to 0.04) Fsting glucose, mmol/l 0.02 ( 0.02 to 0.04) 0.08 (0.04 to 0.12)** 0.01 ( 0.02 to 0.001) HOMA 0.19 (0.06 to 0.31)* 0.28 (0.10 to 0.46)* 0.02 ( ) Totl cholesterol, mmol/l 0.05 (0.02 to 0.08)* 0.07 ( 0.12 to 0.02)* 0.02 ( 0.03 to 0.01)** Triglycerides, mmol/l 0.06 (0.04 to 0.09)** 0.03 ( to 0.01 to 0.07) 0.02 ( 0.03 to 0.01)** LDL cholesterol, mmol/l 0.01 ( 0.02 to 0.04) 0.04 ( 0.10 to 0.01) 0.02 ( 0.03 to 0.01)* HDL cholesterol, mmol/l 0.01 ( to 0.02) 0.01 ( 0.03 to 0.01) 0.01 (0.004 to 0.01)** Dt re presented s β coefficient (95% CI). TSH, thyroid-stimulting hormone; BMI SDS, body mss index stndrd devition scores; ft3, free triiodothyronine; ft4, free thyroxine; HOMA, homeosttic model ssessment of insulin resistnce. * p < 0.05, ** p < Results In totl, 3,459 individuls (49% femle) with men ge of 11.5 ± 3.44 yers were included; 51.3% (n = 1,777) were severely obese. The prevlence of high-norml TSH levels ( 3.0 mu/l) ws 28.8% (n = 996) in our cohort of obese children. Clinicl chrcteristics of the study popultion re presented in Tble 1. TSH ws significntly ssocited with BMI SDS (p < 0.001) djusted for ge nd gender. No significnt ssocitions were observed between ft3 (p = 0.17) or ft4 (p = 0.94) nd BMI SDS (Tble 2). Consequently, when children with high-norml nd low-norml TSH levels were compred, higher BMI SDS ws found in the group with high-norml TSH levels (2.92 ± 0.45 vs ± 0.78, p < 0.001). There were no significnt differences in ft4 (p = 0.63) or ft3 levels (p = 0.34) between the groups (Tble 1). We did not find ny significnt differences in men TSH between genders (p = 0.46). However, girls hd lower ft3 (5.95 ± 1.03 vs ± 1.06 mu/l, p < 0.001) s well s BMI SDS (2.89 ± 0.45 vs ± 0.45, p < 0.001) thn boys (dt not shown). When the severely obese nd modertely obese groups were compred, higher levels of TSH were found in the severely obese (2.57 ± 0.93 vs ± 0.89 mu/l, p < 0.001), but there were no differences regrding ft3 (p = 0.10) nd ft4 (p = 0.46) levels between the groups. Consequently, the TSH/fT4 rtio ws significntly higher in the severely obese group (Mnn-Whitney U test, p < 0.001) (Tble 1). To study how TSH nd thyroid hormones were ssocited with metbolic prmeters, multivrible regression nlysis djusted for ge, gender, nd BMI SDS ws performed. TSH ws significnt positively ssocited with f-insulin (p = 0.002), HOMA (p = 0.004), totl cholesterol (p = 0.001), nd triglycerides (p < 0.001). ft3 ws positively ssocited with f-insulin (p = 0.013), f-glucose (p < 0.001), nd HOMA (p = 0.003) nd inversely ssocited with totl cholesterol (p = 0.004), nd ft4 ws inversely ssocited with totl cholesterol (p < 0.001), triglycerides (p < 0.001), LDL (p = 0.002), nd HDL (p < 0.001) (Tble 2). After djustment for ft3 nd TSH simultneously in the regression model, TSH remined ssocited with BMI SDS (p = 0.003), f-insulin (p < 0.001), nd HOMA (p = 0 001), nd the previously observed ssocitions between ft3 nd metbolic risk mrkers remined significnt (f-insulin, p = 0.010; f-glucose, p < 0.001; HOMA, p = 0.003; nd totl cholesterol, p = 0.004) (dt not shown). Multivrible regression strtified by ge groups nd djusted for gender showed positive ssocitions between BMI SDS nd TSH in ll ge groups (ge yers, p = 0.015; ge yers, p < 0.001; nd ge yers, p = 0.001). BMI SDS ws ssocited with ft3 in the oldest ge group (p = 0.020), nd BMI SDS ws not ssocited with ft4 in ny of the ge groups (Tble 3). Similr results were observed when the model ws strtified by pubertl sttus (dt not shown). In the ge group yers, TSH ws significntly ssocited with totl cholesterol (β = 0.05; 95% CI: Lundbäck/Ekbom/Hgmn/Dhlmn/ Mrcus

5 Tble 3. Multivrible regression nlysis of the impct of BMI SDS (independent vrible) on TSH, ft3, nd ft4 (dependent vribles), controlling for gender n BMI SDS (3 6.9 yers) BMI SDS ( yers) BMI SDS ( yers) TSH 381/1,474/1, (0.04 to 0.36)*; R ( )**; R (0.08 to 0.29)*; R ft3 60/337/ ( 0.65 to 0.40) 0.03 ( 0.30 to 0.24) 0.22 ( 0.40 to 0.04)*; R ft4 308/1,212/1, ( 0.71 to 0.14) 0.13 ( 0.52 to 0.25) 0.04 ( 0.31 to 0.40) Dt re presented s β coefficient (95% CI). TSH, thyroid-stimulting hormone; BMI SDS, body mss index stndrd devition scores; ft3, free triiodothyronine; ft4, free thyroxine. * p < 0.05, ** p < 0.001, with djusted Person correltion coefficient (R 2 ). 0.10; p = 0.018) nd triglycerides (β = 0.08; 95% CI: ; p < 0.001). In the oldest ge group ( yers), we found significnt ssocitions with f-insulin (β = 1.30; 95% CI: ; p = 0.003), HOMA (β = 0.31; 95% CI: ; p = 0.006), totl cholesterol (β = 0.06; 95% CI: ; p = 0.027), triglycerides (β = 0.06; 95% CI: ; p = 0.001), nd HDL cholesterol (β = 0.02; 95% CI: ; p = 0.023). TSH ws not ssocited with ny metbolic mrkers in the youngest ge group (3 6.9 yers) (dt not shown). Discussion In this study of children from severl obesity tretment clinics cross Sweden, the levels of TSH nd the degree of obesity were positively ssocited. This is, to the best of our knowledge, the lrgest study so fr investigting TSH levels in children with obesity, nd the results re in line with previous studies [17, 22, 28] but not with other smller studies covering nrrower ge rnge where no ssocition between TSH nd BMI SDS ws observed [18, 19]. Within the obese individuls, we found ssocitions of TSH with severl mrkers of glucose metbolism s well s with lipid profile, which is in line with some previous studies [19, 21, 28] but not with others [10, 17]. One explntion for the contrdictive results might different smple sizes, different ge rnges included, different TSH intervls used, or the inclusion of both overweight nd obese subjects. Furthermore, we found ssocitions of ft3 nd ft4 with mrkers of both glucose metbolism nd lipid profile, which is consistent with some [15, 22] nd contrdictive to other studies [28]. However, the ssocitions of TSH, ft3, nd ft4 with lipids were minor, nd these ssocitions should be followed up by further studies to clrify their clinicl relevnce. We found tht ft3, independently of TSH, ws ssocited with higher f-glucose nd lower totl cholesterol nd tht both TSH nd ft3 were, independently of ech other, ssocited with higher f-insulin nd consequently HOMA. This finding supports the notion tht ft3 is n importnt meditor in energy metbolism under TSH regultion [29], lthough the cuslity of n elevted TSH in obesity together with slight elevtion of ft3 with no effect on ft4 levels is uncler, nd the underlying mechnism is unknown. It is uncler whether the compenstory increse in TSH level is due to incresed metbolism or the disturbed production of thyroid hormones in the obese stte, or whether obesity directly upregultes TSH secretion. An increse in physiologiclly inctive reverse T3 (rt3) hs previously been seen in rts fed high-ft diet whilst ft3 nd ft4 remined unltered [30]. It hs been suggested tht TSH becme elevted due to overstimultion of the hypothlmic-pituitry-thyroid xis nd tht ft3 nd ft4 remined unltered or slightly chnged due to ltered peripherl deiodinse ctivity [30]. On the other hnd, previous studies hve shown tht ft3 is higher in obese children thn in norml-weight controls. It hs therefore been suggested tht obesity ctivtes the thyroid xis to counterct the obesity by incresing resting energy expenditure or tht ft3 is higher due to n incresed turnover of thyroid hormones by ltered deiodinse ctivity converting ft4 to ft3 [17, 31]. TSH in obesity seems to enhnce ft3 production beyond the stimultion of the thyroid [29], nd extr thyroidl T3 hs been shown to fluctute substntilly with nutrient intke [32]. In norml-weight dults, deiodintion of ft4 produces pproximtely equl mounts of ft3 nd rt3, wheres in obese individuls rt3 but not ft3 hs been shown to be reduced [25]. An increse in both TSH nd ft4 hs lso been shown in rts fed high-ft diet [33], suggesting tht obesity directly induces TSH production. In the present study TSH Levels nd Metbolic Prmeters in Childhood Obesity 5

6 TSH ws incresed in the severely obese group without ny chnges in ft3 or ft4 between the obese nd severely obese groups, which could support the theory of incresed rt3 production. It is not yet cler whether chnges in thyroid function even within the norml rnge might ffect body weight. Previous studies hve confirmed tht there might be direct effect of TSH in the dipose tissue vi dipocyte TSH receptors (TSHr) [34, 35] independently of its effect on thyroid function. Previously, TSH cting on TSHr hs been shown to be involved in regulting lipolysis in neontes [36], inducing dipogenesis in mouse embryonic stem cells [37], directly stimulting leptin secretion in humn dipose tissue [38], nd inducing differentition of predipocytes [39], supporting the hypothesis tht there is reltionship between dipose tissue nd TSH. In theory, the regultion of thyroid function could be impired due to reduction of TSHr in the dipose tissue of obese individuls. In ddition to the proposed dipose tissue mechnisms, plsm TSH nd/or ft3 hve been suggested to be incresed to cope with peripherl hormone resistnce, thereby ffecting the feedbck regultion of thyroid hormones [40]. We found elevted TSH in the presence of norml free thyroid hormones, which might indicte tht the negtive feedbck regultion of TSH in our obese popultion is unffected nd tht elevted TSH levels re required to mintin norml thyroid hormone levels. Strtifying the cohort for ge ccording to ge-specific TSH reference rnges showed no ssocitions of TSH with ny of the metbolic prmeters in the youngest group. It is possible tht the physiologicl mechnism of TSH nd its ssocitions with lipids nd glucose metbolism develop slowly nd might therefore not yet be fully developed in children [28], or tht the youngest children re less ffected metboliclly since TSH ws ssocited with the degree of obesity in ll ges with the sme explntory degree (R 2 ). Only in the oldest ge group ws ft3 ssocited with BMI SDS, wheres no ssocition ws observed between BMI SDS nd ft4. Strengths nd Limittions This is lrge ntionwide study bsed on dt from the Swedish Childhood Obesity Tretment Registry (BO- RIS), supervised by the Ntionl Bord of Helth nd Welfre. The lrge smple llowed us to investigte TSH levels within ge-specific rnges, which is importnt since norml TSH rnges differ between ge intervls. It is therefore preferble to look t ech specific norml rnge, not only djusting for ge in the sttisticl nlysis. However, our study hs limittions. This is retrospective cross-sectionl exmintion nd prospective design would hve been preferble. Thus, no cusl reltionship cn be determined. Vrying TSH ssys for nlysis were used due to the children being enrolled from clinics ll over Sweden for severl yers. All smples were, however, nlyzed by certified lbortories. Different cutoffs for elevted TSH re used in previous publictions, which mkes it is difficult to directly compre results to previous studies. In ddition, the cutoff for high-norml TSH is under debte. An elevted TSH level is in some studies described s mu/l [24, 41], whilst others suggest tht the limit should be lowered [42]. Recently, TSH >3.0 mu/l is described s elevted within the norml rnge [31] nd supports the cutoff chosen in the present study. Conclusions The results confirm n ssocition between TSH nd BMI SDS within cohort of children with obesity, where n elevted TSH level ws ssocited with n incresed degree of obesity in children. As the TSH levels were elevted the ft3 nd ft4 levels remined unltered. It is therefore concluded tht n elevted TSH is needed to mintin norml thyroid hormone levels in the obese stte. Furthermore, disturbed glucose nd lipid metbolism is ssocited with incresed TSH levels. However, further longitudinl studies re necessry to clrify whether TSH nd thyroid hormones contribute to obesity co-morbidities or whether the metbolic consequences of obesity ffect thyroid hormone production nd turnover in children with obesity. Acknowledgments This study ws funded by the HRH Crown Princess Lovis Foundtion, The Swedish Order of Freemsons, the Filip Lundberg Foundtion, nd the Smriten Foundtion. Disclosure Sttement The uthors hve no conflicts of interest to disclose. 6 Lundbäck/Ekbom/Hgmn/Dhlmn/ Mrcus

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