Elevated thyroid-stimulating hormone levels, independent of Hashimoto's thyroiditis, increase thyroid cancer risk: Insights from genetic and clinical evidence.

Purpose: Hashimoto's thyroiditis (HT) is a prevalent autoimmune disorder and thyroid cancer (TC) is the most prevalent endocrine malignancy. Recent debates have focused on whether HT increases the risk of developing TC. This study combined Mendelian randomization (MR) and observational methods to investigate the potential causal relationship between HT and TC risk.

Methods: First, we performed two-sample MR and multivariable MR (MVMR) analysis using the genome-wide association studies (GWAS) data from multiple databases, including European and East Asian populations, to estimate the effect of HT and thyroid-stimulating hormone (TSH) levels on TC risk. Second, we conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES) database and evaluated the association between HT, TSH, and TC prevalence through logistic regression model and restricted cubic spline model.

Results: Our MR findings revealed no significant association between HT and TC risk in both populations. However, elevated TSH levels significantly increased TC and papillary thyroid carcinoma (PTC) risk, while lower TSH levels were associated with reduced TC risk. Further MVMR analysis and an observational study confirmed this. Additionally, our observational study also indicated no significant relationship between HT and TC prevalence and abnormal TSH levels correlated with higher TC risk.

Conclusion: HT was not a TC risk factor, but high TSH levels increased TC risk. Controlling TSH within normal ranges through thyroid hormone replacement was recommended to reduce TC risk in HT patients with elevated TSH levels, even those without symptoms.