Metabolite Changes during the Transition from Hyperthyroidism to Euthyroidism in Patients with Graves' Disease

Abstract

Backgruound: An excess of thyroid hormones in Graves' disease (GD) has profound effects on systemic energy metabolism that are currently partially understood. In this study, we aimed to provide a comprehensive understanding of the metabolite changes that occur when patients with GD transition from hyperthyroidism to euthyroidism with methimazole treatment.

Methods: Eighteen patients (mean age, 38.6±14.7 years; 66.7% female) with newly diagnosed or relapsed GD attending the endocrinology outpatient clinics in a single institution were recruited between January 2019 and July 2020. All subjects were treated with methimazole to achieve euthyroidism. We explored metabolomics by performing liquid chromatography-mass spectrometry analysis of plasma samples of these patients and then performed multivariate statistical analysis of the metabolomics data.

Results: Two hundred metabolites were measured before and after 12 weeks of methimazole treatment in patients with GD. The levels of 61 metabolites, including palmitic acid (C16:0) and oleic acid (C18:1), were elevated in methimazole-naïve patients with GD, and these levels were decreased by methimazole treatment. The levels of another 15 metabolites, including glycine and creatinine, were increased after recovery of euthyroidism upon methimazole treatment in patients with GD. Pathway analysis of metabolomics data showed that hyperthyroidism was closely related to aminoacyl-transfer ribonucleic acid biosynthesis and branched-chain amino acid biosynthesis pathways.

Conclusion: In this study, significant variations of plasma metabolomic patterns that occur during the transition from hyperthyroidism to euthyroidism were detected in patients with GD via untargeted metabolomics analysis.

Keywords: Graves disease; Metabolism; Metabolomics; Thyrotoxicosis.

Fig. 1.

Serum levels of thyroid hormones and thyroid-stimulating hormone (TSH)-binding inhibitor immunoglobulin (TBII) in patients with Graves’ disease at weeks 0 and 12 after commencement of methimazole treatment. (A) Changes of thyroid hormone levels before and after treatment of Graves’ disease with methimazole. (B) Levels of thyroid hormones, TBII, and TSH in male and female patients with Graves’ disease. Parametric (paired Student’s t test) and nonparametric (Wilcoxon signed-rank test) tests were used for statistical analysis. T4, thyroxine; T3, triiodothyronine; CI, confidence interval.

Fig. 2.

Plasma levels of metabolites that show remarkable age-related increases or decreases in methimazole treatment-naïve patients with Graves’ disease. Aging-related metabolite changes in Graves’ disease patients were evaluated by Spearman’s correlation analysis. RT, retention time; LCA, lithocholic acid; HDCA, hyodeoxycholic acid; LPC, lysophosphatidylcholine.

Fig. 3.

Principal component analysis (PCA) of metabolite data from patients with Graves’ disease at weeks 0 and 12 after commencement of methimazole treatment. (A) PCA of metabolite data from patients with Graves’ disease at weeks 0 and 12. The numbers in parentheses show the contribution rates. The red dots indicate week 0 (n=18) and the green dots indicate week 12 (n=18). (B) The loadings of individual metabolites on the principal components shown in (A).

Fig. 4.

Plasma levels of metabolites before and after 12 weeks of methimazole treatment in patients with Graves’ disease. Visualization of significantly differentiated plasma metabolomic data (200 metabolites) between methimazole treatment with Graves’ disease in a heatmap. RT, retention time; TG, triglyceride; PC, phosphatidylcholine; LPC, lysophosphatidylcholine; DCA, dichloroacetic acid.

Fig. 5.

Pathway analysis of plasma metabolite profiles before methimazole treatment in patients with Graves’ disease. (A) Metabolite set enrichment analysis based on the altered metabolites. (B) Serum metabolites based on pathway analysis before treatment in patients with Graves’ disease. CoA, coenzyme A.