Low-normal FT3 and FT3/FT4 ratio are associated with elevated serum lipoprotein(a) levels in Northern Chinese euthyroid population without fatty liver disease

To the Editor: Lipoprotein(a) (Lp[a]) is a cholesteryl ester-rich lipoprotein exclusively produced in the liver, comprising two major components: a low-density lipoprotein (LDL)-like particle containing apolipoprotein B (apoB) and a glycoprotein apolipoprotein(a) (apo[a]) linked to apoB by a disulfide bridge.[1] Both genomic and epidemiological evidence support the strong pathogenic role of elevated serum Lp(a) levels in cardiovascular disease (CVD) risk, independent of well-controlled LDL cholesterol (LDL-C) levels.[1] Unlike other conventional lipid profiles, serum Lp(a) levels are relatively stable throughout life and are primarily determined by variations in the hepatic LPA gene, which encodes the apo(a) protein.[1] Substantial evidence has revealed a causal association between thyroid dysfunction and dyslipidemia. Notably, serum Lp(a) levels are significantly altered in the context of thyroid dysfunction.[2] However, in participants with euthyroidism, limited studies have evaluated the effect of thyroid function on Lp(a) metabolism, which could have significant implications for the general population. This large-scale study aimed to explore the relationship between serum Lp(a) levels and thyroid parameters in the general Chinese euthyroid population. A total of 44,774 participants undergoing routine physical examinations, with Lp(a) and thyroid function measurements between April 2016 and December 2022 at Beijing Chaoyang Hospital, were included. After applying specific exclusion criteria [Supplementary Figure 1, https://links.lww.com/CM9/C611], 27,102 participants were analyzed. Although fatty liver disease (FLD) and Lp(a) are well-established risk factors for CVD, several studies have indicated an inverse association between Lp(a) and FLD, a condition characterized by reduced hepatic LPA gene expression and decreased serum Lp(a) concentrations.[3] Therefore, the analysis was conducted separately for participants with or without FLD to better understand the relationship between thyroid parameters and Lp(a). Ethical approval for this study was obtained from the Ethics Committee of Beijing Chaoyang Hospital (approval number: 2022-517). Given the retrospective nature of the study and the use of anonymized patient data, the requirement for informed consent was waived. The methods of thyroid parameters and Lp(a) detection, and variable definition can be found in the methods section of the Supplementary Materials, https://links.lww.com/CM9/C611. Associations of thyroid parameters quartiles with elevated Lp(a) levels were detected using binary logistic regression analyses. Data were expressed as odds ratios (ORs) and 95% confidence intervals (CIs) and data analyses were performed using R software version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria). The baseline characteristics of the participants are shown in Supplementary Table 1, https://links.lww.com/CM9/C611. Participants with elevated Lp(a) levels were older and were more likely to be women, have a lower proportion of FLD (all P values <0.05). Furthermore, higher normal thyroid-stimulating hormone (TSH) levels and lower normal free triiodothyronine (FT3), free thyroxine (FT4), and FT3/FT4 levels were observed in the elevated Lp(a) group (all P values <0.05). We further divided participants according to the presence or absence of FLD. As shown in Supplementary Table 2, https://links.lww.com/CM9/C611, FT3 levels were significantly decreased in the elevated Lp(a) group in both participants with non-FLD and FLD. However, the FT3/FT4 ratio only decreased in the elevated Lp(a) group under non-FLD conditions. Log Lp(a) levels decreased linearly across FT3, FT4, and FT3/FT4 quartiles [Supplementary Table 3, https://links.lww.com/CM9/C611] (all P values for linear trend <0.001). Generalized additive model (GAM) analysis showed a significant negative association between FT3, FT3/FT4 ratio, and log Lp(a) levels under both non-FLD and FLD statuses (all P values <0.05) [Supplementary Figure 2, https://links.lww.com/CM9/C611]. Consistently, the proportions of participants with elevated Lp(a) levels linearly decreased across FT3 quartiles in participants with or without FLD, and decreased across FT3/FT4 ratio quartiles in participants without FLD (all P values for linear trend <0.05) [Supplementary Figure 3, https://links.lww.com/CM9/C611]. Logistic regression analysis showed that per standard deviation (SD) increase in FT3 and FT3/FT4 ratio were negatively associated with elevated Lp(a) levels in non-FLD subgroups [Supplementary Table 4, https://links.lww.com/CM9/C611]. The FT3 levels and FT3/FT4 ratios were further enrolled as quartiles, with first quartile (Q1) as a reference [Figure 1]. The ORs for elevated Lp(a) levels were 0.85 (95% CI: 0.75–0.96) in Q4 versus Q1 FT3 levels. Meanwhile, the ORs of the Q3 and Q4 FT3/FT4 ratio were 0.89 (95% CI: 0.81–0.99) and 0.85 (95% CI: 0.77–0.95) for elevated Lp(a) levels, respectively. There were no significant associations between FT3 and FT3/FT4 ratio and elevated Lp(a) levels in participants with FLD.Figure 1: Relationship between FT3 or FT3/FT4 ratio and Lp(a) levels in the Northern Chinese euthyroid population analysed by logistic analysis. * P <0.05, † P <0.01. (A) The association between elevated Lp(a) levels and FT3 quartiles in participants without FLD. (B) The association between elevated Lp(a) levels and FT3/FT4 quartiles in participants without FLD. (C) The association between elevated Lp(a) levels and FT3 quartiles in participants with FLD. (D) The association between elevated Lp(a) levels and FT3/FT4 quartiles in participants with FLD. FLD: Fatty liver disease; FT3: Free triiodothyronine; FT4: Free thyroxine; Lp(a): Lipoprotein(a).Existing evidence has revealed that Lp(a) levels can be elevated under hypothyroidism conditions, which can be reversed by thyroid hormone replacement therapy, indicating a causally regulating role of thyroid hormone homeostasis in Lp(a) levels.[4,5] Our study found that low FT3 levels and FT3/FT4 ratio were associated with elevated serum Lp(a) levels in euthyroid populations without FLD. These relationships were independent of age, sex, body mass index, estimated Glomerular Filtration Rate, hypertension, diabetes, and dyslipidemia. Taken together, the current evidence supports the detection of serum Lp(a) levels in the general population with euthyroidism and relatively low FT3 levels, who may face potentially higher cardiovascular risks. Normal function of the thyroid hormone is maintained through the conversion of FT4 to FT3 by deiodinases in peripheral target organs. Lower FT3 and FT3/FT4 ratios indicated relatively declined function and peripheral insensitivity of the thyroid system, even though the thyroid parameters were within the normal range. In our study, FT3 rather than TSH was independently and negatively associated with elevated Lp(a) levels. This finding is corroborated by a previous study on patients with subclinical hypothyroidism (SH), which reported no significant correlation between TSH and Lp(a) levels and no differences in Lp(a) levels between subgroups with high or low TSH values.[4] Consistently, one study revealed that the effect of elevated TSH on Lp(a) levels was mediated by reduced T3 levels.[6] These collective evidence points towards a direct regulatory role of FT3 on Lp(a) metabolism. Plasma Lp(a) concentration is mostly determined by the rate of synthesis. Expression of the LPA gene in the liver, which encodes the apo(a) component of Lp(a), is the main determinant of serum Lp(a) levels. FT3 has been shown to regulate genes related to lipid metabolism in the liver. Previous studies have confirmed that LPA genes are regulated by endogenous regulators. For instance, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 4-alpha and sex hormones could bind to the 5′-region of the LPA gene for transactivation, whereas bile acid could repress LPA through farnesoid-X receptor (FXR).[1] Therefore, FT3 could potentially directly regulate the Lp(a) levels through modulating the LPA gene expression. This observation was consistent with a previous study, which suggested a direct suppressive effect of thyroid hormones on apo(a) synthesis.[2] Taken together, further exploration is warranted to verify whether FT3 could regulate Lp(a) levels through direct transcriptional regulation. In summary, our study highlights that non-FAD individuals with low-normal FT3 levels exhibit elevated atherogenic Lp(a) levels. This observation underscores the importance of vigilant monitoring and timely intervention for those in the general population presenting with low-normal FT3 levels. To address this, we propose that clinicians consider assessing Lp(a) levels in individuals with low-normal FT3 levels and initiate management strategies accordingly. Early identification and proactive management are crucial for mitigating potential cardiometabolic risks in this population. Funding This work was supported by grants from the National Natzural Science Foundation of China (No. 82200938), National Key R&D Program of China (No. 2022YFA0806400) and Beijing Natural Science Foundation (No. 7252054). Conflicts of interest None.