The present study focuses on the association between serum lipids and thyroid autoimmunity. We have shown the significant associations of increasing HDL-C and LDL-C levels with thyroid antibodies (TPOAb and TgAb) in the general population with normal TSH levels in a gender-dependent manner. Some literature has concentrated on the effects of thyroid autoantibodies on lipids . However, few studies have explored the relationship between lipids and the positivity of thyroid autoantibodies. Especially, recent data have shown that serum lipids are novel risk factors for developing autoimmune diseases, such as systemic lupus erythematosus (SLE), celiac disease, idiopathic thrombocytopenic purpura (ITP) and Sjögren’s disease [8,16]. Therefore, we aimed to evaluate whether similar associations can be observed in thyroid autoimmunity.
TSH is a pituitary gland hormone that plays a vital role in maintaining normal thyroid function. Abnormal levels of serum TSH can lead to dyslipidemia [17,18], and it’s association with serum lipid levels may be independent of thyroid hormone action. Hence, our study was conducted in a normal TSH population. Interestingly, our findings suggested that TSH levels of the TgAb+ groups were higher than the negative control group even though TSH is within the reference range. Similar results have been reported in the previous studies [5,6,20] and may be explained by the fact that positivity for thyroid autoantibodies is associated with significantly higher risks of overt and subclinical hypothyroidism.
In the present study, we observed that lower concentrations of HDL-C were associated with a higher risk of TgAb positivity, which contrary to the result from an earlier study . In this report, higher HDL-C levels were found in TPOAb-TgAb+ when compared with TPOAb-TgAb-. The likely explanation for this is that the statistical analysis methods used are different. Zhang et al.  analyzed the relationships between lipids and thyroid autoantibody by analysis of variance, which was statistically less robust than the binary logistic regression from our study. Furthermore, we found no association between HDL-C levels and TPOAb positivity. Several studies support our finding [6,7,21-24] but conflicting evidence have also been reported. For example, TPOAb was found negatively correlated with HDL-C levels in Iranian and Turkish studies by Tamer et al. and Mazaheri et al., respectively [3,4]. The reason for the discrepancy may be due to differences in the study design. These case-control studies had predominantly patients with HT who have higher titers of TPOAb and much higher risk of overt and subclinical hypothyroidism in comparison to the general population. In contrast, a domestic study found that TPOAb was positively correlated to HDL-C levels , which is supported by the Copenhagen City Heart Study by Madsen et al. . The Copenhagen Study reported U-shaped associations between HDL-C and autoimmune diseases, that is, high concentrations of HDL-C (> 77 mg/dL) is also associated with higher risk of autoimmune diseases. It seems to differ from the traditional perception of HDL-C as the “good cholesterol”. Possible explanations include: (i) the presence of residual confounding factors such as cancer, infection and other influence factors affected the results ; (ii) the presence of genetic variants  changed composition and function of HDL particles; and (iii) individuals who have high HDL-C (> 60 mg/dL) and very high HDL-C (> 100 mg/dL) concentrations are often grouped with participants with moderate concentrations. As a result of the above factors, researchers may not be able to observe this U-shaped relationship between HDL-C and autoimmune diseases [27,28].
Our data also suggested that increasing LDL-C levels were positively associated with TgAb and TPOAb positivity, which is supported by previous studies [5,7,24]. However, we did not find any association between TC levels and TgAb or TPOAb positivity, even though roughly seventy percent of serum TC is composed of LDL-C and the level of TC is usually parallel to that of LDL-C [5,29]. This lack of association observed in our study is inconsistent with previous reports. Kang et al. and Srivastava et al. reported that serum TC and LDL-C were positively correlated to TPOAb [5,7]. In another study, serum TC and LDL-C were found positively correlated to TgAb . Since TC is the aggregate of cholesterol contained in various lipoproteins in the blood, including LDL-C, HDL-C, extremely low-density lipoprotein (VLDL), lipoprotein (a), and others, it is not ruled out that the association between TC and thyroid autoantibody may be affected by other cholesterol composition. Therefore, caution should be exercised when interpreting the results from the relationship of TC and LDL-C with the thyroid autoantibodies.
Moreover, we did not observe any association between TG and thyroid autoantibodies, which is consistent with several reports [4,6,21]. However, TG has also been observed to be positively correlated with TgAb and/or TPOAb in some studies [3,7,22]. These differences in findings could be due to geographical location, ethnicity, genetics, thyroid autoantibody cutoff values, sample size and statistical analyses methods.
Unexpectedly, we detected that the relationships between the serum lipids and thyroid autoantibody positivity were significant only in women. The disparate results from gender could be related to the immune system exhibiting sexual dimorphism in humans . The unique effect of estrogen on the immune system may determine the susceptibility of women to autoimmune diseases and the greater immune response in women than in men .
Three main questions arise based on our study: First, what are the underlying mechanisms of the associations between serum lipids and thyroid autoantibodies? Evidence indicates that toll-like receptors (TLRs) play an essential role in the pathogenesis of AITD, HDL and LDL can inhibit and activate TLRs thus affect the progress of Graves’ disease (GD) or HT, respectively [32-35]. In addition, reactive oxygen species (ROS) are necessary for thyroid hormone synthesis in physiological conditions, but excessive ROS may result in thyrocytes apoptosis and necrosis. HDL and LDL are capable of modulating and stimulating oxidative stress further involvement in the development of AITD, respectively [36-38]. Further research is required in this field. Second, would management of blood lipids be beneficial to the patients at high risk of thyroid autoimmunity, given that lower serum HDL-C level or higher serum LDL-C level is associated with higher risk of this disease? Third, whether management of blood lipids could specifically prevent the onset of AITD in susceptible populations or decrease thyroid autoantibody titer? These questions of great clinical significance remain to be explored in the future.
To the best of our knowledge, this is the first report evaluating the issue of the association of serum lipids with thyroid autoantibody in the general population from a serum lipid perspective, and we unexpectedly identified that these relationships differed with gender. Moreover, in comparison to other reports, our study had a larger sample size and stronger statistical methods, which made the results more reliable. However, several limitations of this study should also be considered. First, due to the cross-sectional design of this study, the direction of any causal relationship could not be established. Second, this study was conducted in a single center, which suggests that the results may be inadequate to generalize to the broader population or even to different races. Finally, due to the lack of information on medication, smoking, alcohol consumption, and other concomitant autoimmune diseases, the results may also be affected by some unknown confounding factors.
In conclusion, we have shown the associations of increasing HDL-C and LDL-C levels with thyroid autoantibody positivity in the general population with normal TSH levels in a gender-dependent manner. This study highlights that lipid profiles may be new predictors of thyroid autoimmunity even when TSH is within the normal reference range. However, further validation is required in future prospective studies.