subclinical hypothyroidism ( sh ) , which refers to the status of mild elevation of thyroid - stimulating hormone ( tsh ) in patients with normal serum thyroxine levels , is the most common thyroid disorder , with a prevalence of 3.810% in adult populations [ 14 ] . although the relationships between sh and lipid profile have been reported in several studies , the results are conflicting . cross - sectional studies on 7000 consecutive patients in austria and 1423 females in australia found no significant differences in serum total cholesterol ( tc ) , low - density lipoprotein cholesterol ( ldl - c ) , high - density lipoprotein cholesterol ( hdl - c ) , and triglyceride ( tg ) . on the other hand , many studies reported disparate results . several studies found serum ldl - c levels increased in sh patients [ 914 ] , some of them found higher serum tc levels in sh patients [ 912 ] , and other studies found lower serum tc level . contradictory results were also reported in the alteration of serum hdl - c and tg levels under sh [ 13,1518 ] . abnormal lipid profile has been established as a risk factor of coronary heart disease ( chd ) . to prevent chd in sh patients , since the results of lipid profiles alteration in sh patients were disparate in previous studies , we attempted to form a conclusion about the alteration of each parameter of lipid profiles under sh . therefore , we reviewed previous studies and performed a meta - analysis to answer this question . we searched the pubmed , cochrane library , and china national knowledge infrastructure ( cnki ) database for studies in humans that reported relationships between sh and lipid profiles or at least 1 parameter of lipid profiles ( tc , ldl - c , hdl - c , and tg ) . google scholar was then used to search for studies that were not included in pubmed , cnki , or cochrane library . we also searched pqdt ( proquest theses and dissertations ) and cdmd ( chinese doctoral dissertations and master s theses full - text database ) to find relevant unpublished data . because the standardized diagnostic for sh and sensitive tsh assay were applied in the 1990s , we limited the publication date from january 1990 to january 2014 . subclinical hypothyroidism  ,  lipid profile  ,  tc  ,  ldl - c  ,  hdl - c  ,  tg  , and  cholesterol  were used as key words in the search . to avoid missing any potential articles , we also used relevant words as key words , such as  thyroid disease  ,  thyroid disorder  ,  thyroid dysfunction  ,  hypothyroidism  ,  dysthyroidism  ,  thyroid hormone  ,  tsh  ,  thyrotropin  , and  dyslipidemia  . two investigators reviewed the articles independently . to avoid repeated selection , if 2 or more articles that studied the same population were published within 2 years by the same research group , only the article with the largest sample size the included articles should provide full text , and describe their study populations , and diagnostic standard for sh , and measured at least 1 of 4 lipid profile parameters in sh and euthyroidism ( eu ) groups . the reference range of tsh was unclear , and several studies suggested different tsh upper limit cutoffs ranging from 2.5 to 5.0 iu / l [ 2125 ] . since there were no clear standards , we did not set the cutoff value of tsh to define sh , and instead performed a meta - regression based on tsh cutoff values . considering that most patients with increased tsh were subclinical but did not have overt hypothyroidism , we also included 3 studies which measured tsh without a thyroxine measurement [ 2729 ] , and performed a meta - regression to assess the effects ; this strategy was used in a previous article . we assessed the quality of articles by using the strengthening the reporting of observational studies in epidemiology ( strobe ) checklists for cohort , case - control , or cross - sectional studies , depending on the design of studies . although those checklists were initially designed to improve the quality of observation studies , they have been used as quality assessment tools in previous studies . all checklists contained 22 main items , and 2 investigators gave scores of 0 or 1 for each item for all included articles . five of the main items had sub - items , and those sub - items would also be scored 0 or 1 , and then averaged as the score of the main items . the score of the 22 main items would be summed as the strobe scores to assess the articles . the following information was extracted from each included article : author , study design , match strategy , year of publication , tsh cutoff value to define sh , characteristics of study populations ( sample source , sample size , sex ratios , mean age , and race ) , mean value and standard deviation of serum tc , ldl - c , hdl - c , and tg levels in both sh and eu groups . units of lipid profile parameters in all included articles were measured in either mmol / l or mg / dl . we converted units of cholesterol ( tc , ldl - c , and hdl - c ) and tg from mmol / l into mg / dl by multiplying by 38.67 and 88.57 , respectively . for each parameter of lipid profiles , summary estimates of weighted mean difference ( wmd ) and 95% confidence interval ( ci ) were obtained with a random effects model . the variation across studies attributable to heterogeneity beyond chance was estimated with the i heterogeneity test , where a value greater than 50% may be considered substantial heterogeneity . to determine the possible sources of heterogeneity , we performed meta - regression which included study design , match strategy , tsh cutoff value , whether thyroxine was measured or not , sample size , sex , mean age , and race as variates for each lipid profile parameter , and then performed stratified analysis based on the results of the meta - regression . finally , we used the egger test and the begg test to assess potential publication bias . if any possible bias was found , the trim and fill method would be used to identify those results . for all tests , a two - tailed p value smaller than 0.05 was considered statistically significant . all statistical analyses were performed in stata software , version 11.0 ( stata , college station , texas , usa ) . this study was supported by the national natural science foundation of china ( no . 81102127 ) and science project of shenzhen ( no . 201202103 ) . the funding source had no role in the study design , data collection , data analysis , or writing of the report . we searched the pubmed , cochrane library , and china national knowledge infrastructure ( cnki ) database for studies in humans that reported relationships between sh and lipid profiles or at least 1 parameter of lipid profiles ( tc , ldl - c , hdl - c , and tg ) . google scholar was then used to search for studies that were not included in pubmed , cnki , or cochrane library . we also searched pqdt ( proquest theses and dissertations ) and cdmd ( chinese doctoral dissertations and master s theses full - text database ) to find relevant unpublished data . because the standardized diagnostic for sh and sensitive tsh assay were applied in the 1990s , we limited the publication date from january 1990 to january 2014 . subclinical hypothyroidism  ,  lipid profile  ,  tc  ,  ldl - c  ,  hdl - c  ,  tg  , and  cholesterol  were used as key words in the search . to avoid missing any potential articles , we also used relevant words as key words , such as  thyroid disease  ,  thyroid disorder  ,  thyroid dysfunction  ,  hypothyroidism  ,  dysthyroidism  ,  thyroid hormone  ,  tsh  ,  thyrotropin  , and  dyslipidemia  . two investigators reviewed the articles independently . to avoid repeated selection , if 2 or more articles that studied the same population were published within 2 years by the same research group , only the article with the largest sample size the included articles should provide full text , and describe their study populations , and diagnostic standard for sh , and measured at least 1 of 4 lipid profile parameters in sh and euthyroidism ( eu ) groups . the reference range of tsh was unclear , and several studies suggested different tsh upper limit cutoffs ranging from 2.5 to 5.0 iu / l [ 2125 ] . since there were no clear standards , we did not set the cutoff value of tsh to define sh , and instead performed a meta - regression based on tsh cutoff values . considering that most patients with increased tsh were subclinical but did not have overt hypothyroidism , we also included 3 studies which measured tsh without a thyroxine measurement [ 2729 ] , and performed a meta - regression to assess the effects ; this strategy was used in a previous article . we assessed the quality of articles by using the strengthening the reporting of observational studies in epidemiology ( strobe ) checklists for cohort , case - control , or cross - sectional studies , depending on the design of studies . although those checklists were initially designed to improve the quality of observation studies , they have been used as quality assessment tools in previous studies . all checklists contained 22 main items , and 2 investigators gave scores of 0 or 1 for each item for all included articles . five of the main items had sub - items , and those sub - items would also be scored 0 or 1 , and then averaged as the score of the main items . the score of the 22 main items would be summed as the strobe scores to assess the articles . the following information was extracted from each included article : author , study design , match strategy , year of publication , tsh cutoff value to define sh , characteristics of study populations ( sample source , sample size , sex ratios , mean age , and race ) , mean value and standard deviation of serum tc , ldl - c , hdl - c , and tg levels in both sh and eu groups . units of lipid profile parameters in all included articles were measured in either mmol / l or mg / dl . we converted units of cholesterol ( tc , ldl - c , and hdl - c ) and tg from mmol / l into mg / dl by multiplying by 38.67 and 88.57 , respectively . for each parameter of lipid profiles , summary estimates of weighted mean difference ( wmd ) and 95% confidence interval ( ci ) were obtained with a random effects model . the variation across studies attributable to heterogeneity beyond chance was estimated with the i heterogeneity test , where a value greater than 50% may be considered substantial heterogeneity . to determine the possible sources of heterogeneity , we performed meta - regression which included study design , match strategy , tsh cutoff value , whether thyroxine was measured or not , sample size , sex , mean age , and race as variates for each lipid profile parameter , and then performed stratified analysis based on the results of the meta - regression . finally , we used the egger test and the begg test to assess potential publication bias . if any possible bias was found , the trim and fill method would be used to identify those results . for all tests , a two - tailed p value smaller than 0.05 was considered statistically significant . all statistical analyses were performed in stata software , version 11.0 ( stata , college station , texas , usa ) . this study was supported by the national natural science foundation of china ( no . 81102127 ) and science project of shenzhen ( no . the funding source had no role in the study design , data collection , data analysis , or writing of the report . we identified 2084 studies and excluded 1963 studies that were unrelated to the association between sh and lipid profile . then , 73 studies were excluded due to lack of diagnostic code to define sh , and 31 studies were excluded due to special selection criteria for participants , or lack of data about sample sizes or lipid profiles . of the 17 prospective studies which met our criteria , 2 studies   published by the same research group may have used repeated data , so we only included the one with the larger sample size . during the selection process , we failed to make contact with the authors to obtain the necessary data for 1 article which was carried out in colorado , usa . finally , 16 studies were included in our analysis ( figure 1 ) . those studies were carried out in 12 countries and included a total of 41 931 adults , among whom 4526 were identified as sh patients and 37405 as having a status of eu . thirteen studies were cross - sectional studies ; another 3 were cohort studies which reported lipid profile as baseline of participants before l - t4 or thyroxine treatment . four studies applied sex - age individual match strategy and 4 studies applied the frequency match strategy . one study included 1 patient with radioiodine therapy history , 1 study included 2 patients who underwent levothyroxine treatment , and other studies declared no thyroid medication history in sh patients . fifteen studies measured all 4 parameters of lipid profile , and 1 study only measured tg and hdl - c levels . the strobe scores of the included articles varied from 13 to 20 , with a median of 15.5 . the tsh cutoff value varied from 3.5 to 6.7 iu / l with a median of 4.5 iu / l ( table 1 ) . we identified 2084 studies and excluded 1963 studies that were unrelated to the association between sh and lipid profile . then , 73 studies were excluded due to lack of diagnostic code to define sh , and 31 studies were excluded due to special selection criteria for participants , or lack of data about sample sizes or lipid profiles . of the 17 prospective studies which met our criteria , 2 studies   published by the same research group may have used repeated data , so we only included the one with the larger sample size . during the selection process , we failed to make contact with the authors to obtain the necessary data for 1 article which was carried out in colorado , usa . finally , 16 studies were included in our analysis ( figure 1 ) . those studies were carried out in 12 countries and included a total of 41 931 adults , among whom 4526 were identified as sh patients and 37405 as having a status of eu . thirteen studies were cross - sectional studies ; another 3 were cohort studies which reported lipid profile as baseline of participants before l - t4 or thyroxine treatment . four studies applied sex - age individual match strategy and 4 studies applied the frequency match strategy . one study included 1 patient with radioiodine therapy history , 1 study included 2 patients who underwent levothyroxine treatment , and other studies declared no thyroid medication history in sh patients . fifteen studies measured all 4 parameters of lipid profile , and 1 study only measured tg and hdl - c levels . the strobe scores of the included articles varied from 13 to 20 , with a median of 15.5 . the tsh cutoff value varied from 3.5 to 6.7 iu / l with a median of 4.5 iu / l ( table 1 ) . most studies suggested that there were higher serum tc levels in sh patients compared with eu participants and only 2 studies reported lower levels without statistical significance . in a random effects model , the overall serum tc level in sh patients was significantly higher than in eu participants ( figure 2a , wmd=12.17 , 95% ci : 7.7916.54 , p<0.001 ) . univariate meta - regression found heterogeneity was not associated with source of participants , mean age , sex ratio , tsh cutoff values , and whether thyroxine was measured . match strategy was found associated with heterogeneity ( figure 2b , p=0.001 ) , which reduced the overall heterogeneity i to 52.84% . in the multivariate analysis , the combination of match strategy ( p=0.001 ) and source of participants ( p=0.403 ) reduced the overall i to 46.5% . grouped by match strategy and source of participants , the stratified analysis showed that individual match studies tended to report considerable alterations of tc levels in sh patients with a large confidence interval ( wmd=32.58 , 95% ci : 24.8140.34 ) ; in contrast , studies with no match tended to provide conservative results with a much smaller confidence interval ( wmd=6.72 , 95% ci : 3.3010.14 ) . nine of these studies reported significantly higher ldl - c levels in sh patients when compared with eu participants . only 1 article reported a slightly decreased ldl - c level in sh patients , which was not statistically significant . in a random effects model , the overall serum ldl - c level in sh patients was significantly higher than in eu participants ( figure 3a , wmd=7.01 , 95% ci : 3.9510.05 , p<0.001 ) . univariate meta - regression found that match strategy was associated with heterogeneity ( figure 3b , p=0.002 ) but other variates were not . the overall heterogeneity i was reduced to 38.6% after pull - in effects of match strategy . multivariate analysis did not find any combination of variates that was associated with heterogeneity . grouped by match strategy , the stratified analysis found individual match studies reported larger wmd and wider 95% ci ( wmd=22.27 , 95% ci : 15.0729.48 ) , compared with no match studies ( wmd=6.37 , 95% ci : 1.744.97 ) . the included studies included a total 40 516 participants whose serum hdl - c levels were measured . three of these studies reported significant lower hdl - c levels in sh patients and 1 reported significant higher level compared with eu participants . in a random effects model , the overall serum hdl - c level in sh patients was lower than in eu participants , but was not statistically significant ( figure 4 , wmd=0.50 , 95% ci : 1.900.89 , p=0.481 ) . meta - regression found no variates that were associated with heterogeneity . sixteen studies measured serum tg levels . however , 2 studies used the median ( and min , max ) to describe tg levels . to avoid potential statistical errors , we eliminated those studies in analysis of tg . a random effects model including other 14 studies with 40 420 participants found that the overall serum tg level in sh patients was significant higher than in eu participants ( figure 5 , wmd=13.19 , 95% ci : 4.9221.46 , p<0.001 ) . univariate meta - regression failed to find any variates associated with heterogeneity . in the multivariate analysis , the model included match strategy ( p=0.296 ) , source of participant ( p=0.033 ) , mean age ( p=0.774 ) , tsh cutoff value ( p=0.039 ) , and whether measured thyroxine ( p=0.029 ) explained 75.7% heterogeneity , which reduced the i to 31.48% . egger test and begg test found no evidence of publication bias for studies on hdl - c ( p=0.562 for egger test , p=0.753 for begg test ) and tg ( p=0.343 for egger test , p=0.101 for begg test ) . for tc , although the egger test indicated a potential publication bias ( p=0.014 ) , the begg test ( p=0.235 ) and the trim and fill method did not confirm this possibility . for ldl - c , both the egger test and begg test found publication bias ( p=0.010 for egger test , p=0.048 for begg test ) . however , the trim and fill method found that the conclusions did not significantly change after adjusting for publication bias . nine of these studies reported significantly higher ldl - c levels in sh patients when compared with eu participants . only 1 article reported a slightly decreased ldl - c level in sh patients , which was not statistically significant . in a random effects model , the overall serum ldl - c level in sh patients was significantly higher than in eu participants ( figure 3a , wmd=7.01 , 95% ci : 3.9510.05 , p<0.001 ) . univariate meta - regression found that match strategy was associated with heterogeneity ( figure 3b , p=0.002 ) but other variates were not . the overall heterogeneity i was reduced to 38.6% after pull - in effects of match strategy . . grouped by match strategy , the stratified analysis found individual match studies reported larger wmd and wider 95% ci ( wmd=22.27 , 95% ci : 15.0729.48 ) , compared with no match studies ( wmd=6.37 , 95% ci : 1.744.97 ) . the included studies included a total 40 516 participants whose serum hdl - c levels were measured . three of these studies reported significant lower hdl - c levels in sh patients and 1 reported significant higher level compared with eu participants . in a random effects model , the overall serum hdl - c level in sh patients was lower than in eu participants , but was not statistically significant ( figure 4 , wmd=0.50 , 95% ci : 1.900.89 , p=0.481 ) . sixteen studies measured serum tg levels . however , 2 studies used the median ( and min , max ) to describe tg levels . to avoid potential statistical errors , we eliminated those studies in analysis of tg . a random effects model including other 14 studies with 40 420 participants found that the overall serum tg level in sh patients was significant higher than in eu participants ( figure 5 , wmd=13.19 , 95% ci : 4.9221.46 , p<0.001 ) . univariate meta - regression failed to find any variates associated with heterogeneity . in the multivariate analysis , the model included match strategy ( p=0.296 ) , source of participant ( p=0.033 ) , mean age ( p=0.774 ) , tsh cutoff value ( p=0.039 ) , and whether measured thyroxine ( p=0.029 ) explained 75.7% heterogeneity , which reduced the i to 31.48% . egger test and begg test found no evidence of publication bias for studies on hdl - c ( p=0.562 for egger test , p=0.753 for begg test ) and tg ( p=0.343 for egger test , p=0.101 for begg test ) . for tc , although the egger test indicated a potential publication bias ( p=0.014 ) , the begg test ( p=0.235 ) and the trim and fill method did not confirm this possibility . for ldl - c , both the egger test and begg test found publication bias ( p=0.010 for egger test , p=0.048 for begg test ) . however , the trim and fill method found that the conclusions did not significantly change after adjusting for publication bias . altered lipid profiles , which include elevated levels of tc , tg , ldl - c , and/or a lower level of hdl - c , are thought to confer the risk of cardiovascular disease development . several cross - sectional studies with large sample sizes were carried out in different countries . the colorado , usa study showed that sh patients had higher tc and ldl - c level compared with eu populations . an explanation for these conflicting results among these cross - sectional studies is poor control in potential confounding factors , such as sex , age , race , insulin resistance , smoking , and drinking behavior , which may be associated with lipid levels [ 4749 ] . an analysis of national health and nutrition examination survey ( nhanes iii ) samples found higher serum tc and tg levels in sh patients than in eu participants . however , this difference disappeared after adjusting for variables such as sex , age , and race . to control for potential confounding factors , many studies applied the sex - age match method . those studies reported higher tc and ldl - c levels in sh patients compared with eu participants . in the article selection process of our study , we found many cohort studies reported lipid profile as baseline of sh and eu groups before l - thyroxine therapy [ 5254 ] . we had to exclude those studies since their selection of participants , such as use the body mass index as part of the inclusion criteria or excluded patients with dyslipidemia , may have led to bias . we also had to exclude a cross - sectional study with a large sample size ( the colorado , usa study ) due to lack of the standard deviation data . it is plausible that many small studies with insignificant results might have never been published , which could change the results of this study . since we only searched articles published in english and chinese , publication language may be another cause of bias . we found significant heterogeneity between studies , which could also result in publication bias . for tc and ldl - c , many previous studies suggested sh patients had higher levels of these parameters compared with eu populations . alteration to ldl - c receptor levels caused by slight decreases of thyroxine in sh may explain those results . some studies suggested that tsh , independent of thyroxine , may elevate serum tc and ldl - c levels . our study found increased levels of serum tc and ldl - c in sh patients compared with eu participants . for each included study , the trends of alterations in serum tc and ldl - c levels were consistent , and this is reasonable since low - density lipoprotein ( ldl ) contains 65% total cholesterol . only 2 studies reported an insignificant decrease in tc and ldl - c levels in sh patients . one study explained this result as due to older patients and difference in tsh cutoff values . however , we did not find that these 2 studies differed in study design , mean age , sex ratio , or tsh cutoff , compared with other studies . sex - age individual match studies found more significant results than no - match studies did , which indicated that individual s sex and age may be associated with serum tc and ldl - c levels ; insignificant results from some studies may have been due to differences in the sex and age between eu and sh groups . hence , we recommend that further studies should consider the effects of sex and age more carefully . higher serum tg levels were found in sh patients compared with eu participants in our study . although this result was consistent with those of many previous studies , it should be treated with caution since there was large and unexplainable heterogeneity between studies . convictive results on the association between sh and serum tg were not reported , as well as believable mechanisms . previous studies found that l - t4 therapy could reduce serum tc or ldl - c levels , but in those studies serum tg levels remained consistent after l - t4 therapy . this result indicated that thyroxine may have limited effects on tg . since the association between sh and tg is still unclear , further studies based on large populations will be required . in the analysis we found several studies used median ( and min max ) values to describe their data on tg levels ; this was reasonable since many studies found that serum tg levels did not match the normal distribution [ 6163 ] . on the other hand , some studies that described their tg data by using the mean and standard deviation did not mention any tests for normality . merging those data may therefore have caused error . to improved data quality , we recommend that further studies , especial those based on small sample sizes , perform normality tests for data on serum tg levels . although many included studies reported significant alteration of hdl - c levels in sh patients , the overall wmd was insignificant . these results may contribute to the contrasting effects of thyroxine on enzymes related to hdl - c metabolism . plasma cholesteryl ester transfer protein concentration decreased with slight reductions in serum thyroxine level in sh patients , which may result in higher hdl - c level . on the other hand , the activities of hepatic lipase , lecithin cholesterol acyl transferase , and atp - binding cassette transporter also decreased in sh patients , which may lead to lower hdl - c levels . these 2 contrasting effects neutralized one another , and the hdl - c level may remain stable . polymorphisms of genes and osteocalcin concentration may effect the metabolism of hdl - c , and those factors were not taken into account in most regular epidemiology studies . another possible reason for the insignificant results was weak control for potential confounding factors in the included studies . most observational studies did not control potential confounding factors . in our analysis , only a few studies paired participants by sex and age , and even fewer studies adjusted for differences in insulin resistance and smoking and drinking behaviors . second , we could not extract information of the degree and duration of subclinical hypothyroidism in patients , which may have significantly affected their lipid profiles . to the best of our knowledge , third , we can not explain the substantial heterogeneity between studies in hdl - c and tg analysis . the heterogeneity may be associated with potential confounding factors that were not mentioned in the studies . our analysis suggested that serum tc , ldl - c , and tg levels increased under subclinical hypothyroidism ; however , weak evidence suggested subclinical hypothyroidism was associated with serum hdl - c levels . higher serum tc , ldl - c , and tg levels increased the risk of chd ; therefore , the cardiovascular status of sh patients should be monitored carefully . in the analysis of tc and ldl - c , previous studies had limitations regarding the control of potential confounding factors ; further studies should take into account those factors .
backgroundprevious studies yielded controversial results about the alteration of lipid profiles in patients with subclinical hypothyroidism . 
 we performed a meta - analysis to investigate the association between subclinical hypothyroidism and lipid profiles.material/methodswe searched pubmed , cochrane library , and china national knowledge infrastructure articles published january 1990 through january 2014 . 
 dissertation databases ( pqdt and cdmd ) were searched for additional unpublished articles . 
 we included articles reporting the relationship between subclinical hypothyroidism and at least 1 parameter of lipid profiles , and calculated the overall weighted mean difference ( wmd ) with a random effects model . 
 meta - regression was used to explore the source of heterogeneity among studies , and the egger test , begg test , and the trim and fill method were used to assess potential publication bias.resultssixteen observational studies were included in our analysis . 
 meta - analysis suggested that the serum total cholesterol ( tc ) , low - density lipoprotein cholesterol ( ldl - c ) , and total triglyceride levels were significantly increased in patients with subclinical hypothyroidism compared with euthyroidism individuals ; the wmd were 12.17 mg / dl , 7.01 mg / dl , and 13.19 mg / dl , respectively ( p<0.001 for all ) . 
 no significant difference was observed for serum high - density lipoprotein cholesterol ( hdl - c ) . 
 match strategy was the main source of heterogeneity among studies in tc and ldl - c analysis . 
 potential publication bias was found in tc and ldl - c analysis by the egger test or begg test and was not confirmed by the trim and fill method.conclusionssubclinical hypothyroidism may correlate with altered lipid profile . 
 previous studies had limitations in the control of potential confounding factors and further studies should consider those factors .