To the best of our knowledge, it is the first study that investigated the association of thyroid hormone sensitivity with PTC. We found that higher TFQI, TSHI and TT4RI levels, which represented reduced sensitivity to thyroid hormone, were associated with an increased risk of PTC. In addition, impaired thyroid hormone sensitivity was associated with a higher risk of cervical LNM in PTC patients.
All previous studies analyzed the association between thyroid function and PTC using a single index, and the results were inconsistent. The majority of these studies reported an increased risk of thyroid cancer with higher TSH concentrations within the normal ranges(10, 11, 13). An meta-analysis of 28 studies suggested that an increased thyroid cancer risk was related to high TSH concentrations at normal and subnormal levels (7). However, two other studies observed an inverse association between the risk of PTC and TSH levels within the normal range(6, 8). In addition, several studies found lower FT3 and FT4 levels were associated with higher risk of thyroid cancer(5, 10, 11), while others reported no association (8, 12). Furthermore, there were several studies which evaluated the relationship between the clinicopathological features of PTC and TSH level. Research by Demircioglu, Z. G et al. showed that increased TSH level was associated with an increased risk of extrathyroidal spread and central lymph node metastasis(28). McLeod, D. S.et al. found that increased TSH level was associated with higher TNM stage, extrathyroidal extension, and neck node metastases(29).However, the study by Oksana Sulaieva et al. showed the lack of significant relationship between TSH levels and LNM, TNM stage and BRAFV600E mutation of PTC(30). Furthermore, some genetic study observed an inverse association between TSH levels and thyroid cancer. A GWAS meta-analysis of 22.4 million genetic markers in 119,715 individuals showed that genetically predicted increased TSH levels are associated with a reduced risk of thyroid cancer(31). A two-sample Mendelian randomization study using TSH index variants as instrumental variables also showed that lower TSH causes an increased risk of thyroid cancer(32). Inconsistency in previous studies reveals that TSH or thyroid hormone levels alone may be insufficient to explain the relationship between thyroid homeostasis and PTC progression.
Resistance to thyroid hormone (RTH) is an inherited syndrome defined by impaired responsiveness to thyroid hormones and mostly caused by mutations of the thyroid hormone receptor beta (TRβ) gene (33). Recently, some researchers hypothesized that acquired resistance to thyroid hormone might exist in general populations as a more common disease and not just as an inherited rare disorder(18, 34). Therefore, new indices derived from thyroid hormones and TSH were calculated for estimating the sensitivity of pituitary to thyroid hormones, which was named as TT4RI and TSHI(16, 17). In 2019, Laclaustra et al. reported that TFQI was better in assessing sensitivity to thyroid hormones than TSHI and TT4RI(18). They also proposed that all these resistance to thyroid hormone indices measure central sensitivity, representing the degree of pituitary gland inhibition by FT4 (18). Generally, central resistance may be related to a general decrease in thyroid hormone sensitivity, not only centrally but also in the periphery, which means peripheral resistance could also be present among participants with higher values of TFQI, TT4RI and TSHI(18).
There exists complicated and feedback relationship between TSH and thyroid hormone, which was regulated via the negative feedback loop of the HPT axis. In addition, the tissue enrichment analyses of genes in a GWAS meta-analysis revealed that TSH-lowering alleles were generally associated with higher free thyroxine levels(35). Due to the complex interactions between TSH and thyroid hormone, using a single index may cause the inconsistent results of the relationship between thyroid hormone or TSH levels and thyroid cancer risk in previous studies. Indices of sensitivity to thyroid hormone are composite indices that reflect the regulation of thyroid hormone homeostasis, and they are more sufficient to explain the relationship between thyroid function and diseases than a single index.
Impaired sensitivity to thyroid hormone has been suggested to be associated with multiple unfavorable clinical outcomes, including obesity(18, 20), diabetes(18, 19, 21, 26), hypertension(21), non-alcoholic fatty liver disease(23, 24), coronary artery disease(20), reduced renal function(25), osteoarthritis (22)and metabolic syndrome (18). Moreover, reduced sensitivity to thyroid hormone was associated with higher remnant cholesterol levels(36), higher serum uric acid levels(20) and elevated homocysteine levels(37). However, there is no study about the relationship between sensitivity to thyroid hormones and PTC.
In this study, we investigated the correlation between sensitivity to thyroid hormones and PTC for the first time. Patients with PTC had a significantly higher levels of TFQI, TSHI and TT4RI compared to the patients with benign nodules. Those with higher TFQI, TSHI and TT4RI levels were more likely to have larger tumor size and lymph node metastasis than the patients with lower TFQI, TSHI and TT4RI levels. Moreover, the results of multiple logistic regression showed that reduced thyroid hormone sensitivity was related to an increased risk of PTC after adjusting for multiple risk factors. Furthermore, PTC patients with decreased sensitivity to thyroid hormones had higher risk of cervical LNM. Our results suggested that impaired sensitivity to thyroid hormone is associated with the development and progression of PTC. Our study provided evidence that using the merged indices of thyroid homeostasis including TFQI, TSHI and TT4RI may be superior to the single indices of thyroid function, which should be validated in the future research.
The mechanisms about how impaired thyroid hormone sensitivity affect the development and progression of PTC were unclear. We hypothesized that there may be the following mechanisms. First, patients with reduced sensitivity to thyroid hormone had relatively higher TSH and thyroid hormone levels. The elevated TSH and thyroid hormones may promote tumor progression through pathways regulating both tumor growth, tumor evasion and tumor-related angiogenesis(38–40). Secondly, as thyroid hormone resistance is associated with Metabolic Syndrome and its components(18–21, 26), and insulin resistance may play a role in the development of thyroid cancer(41–43), insulin resistance may partially explain the relationship between impaired sensitivity to thyroid hormones and the development and progression of PTC.
There were some limitations in our study. First, our study was a retrospective study included a relatively small number of patients, which was insufficient to assess the causal relationship between thyroid hormone sensitivity and PTC. Large prospective studies from different areas and different populations are required to confirm our results. Secondly, we demonstrated that impaired sensitivity to thyroid hormone is associated with the risk of PTC and aggressiveness of PTC, but the exact mechanism remains unclear. Further investigations are necessary to understand its underlying mechanism.
In conclusion, the present study showed that impaired sensitivity to thyroid hormones was associated with an increased risk of PTC, and it is also associated with a higher risk of cervical LNM in PTC patients. Thyroid hormone sensitivity indices may be new valuable indicators for predicting the development and progression of PTC, which need to be verified in large prospective cohort studies in the future.