The correlation between triiodothyronine and the severity of liver fibrosis

Abstract

Background: The severity of liver fibrosis is an important predictor of death in patients with non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). However, there is still no definite conclusion on the relationship between triiodothyronine (T3) and the severity of liver fibrosis. Thus, the aim of this study was to analyze the correlation between T3 level and the severity of liver fibrosis.

Methods: We performed a cross-sectional study of 2072 T2DM patients with normal thyroid function from January 2017 to January 2020. NAFLD fibrosis score (NFS), Fibrosis index based on the 4 factors (FIB-4) and BARD score (BARD) were used to assess the severity of fibrosis in T2DM patients, and linear regression analyses were used to determine the factors independently associated with liver fibrosis. Further experiments were performed to assess the impact of low T3 on fibrosis progression in mice model and explore possible mechanisms.

Results: Free triiodothyronine (fT3) levels had significantly inverse correlations with NFS and FIB-4, and BARD in T2DM patients (P < 0.05). In multiple linear regression analyses, decreased fT3 level was an independent risk factor for the severity of liver fibrosis of T2DM patients (P < 0.01). Findings from in-vivo experiment using mice model proved that hypothyroidism mice had more severe of liver fibrosis than those mice with normal thyroid function. We also found that T3 could inhibit the profibrotic TREM2⁺CD9⁺ macrophage, which had been identified an important player in the progression of liver fibrosis.

Conclusion: The findings from this study proved an inverse correlation between T3 level and the severity of liver fibrosis, and lower fT3 level within the normal range was an independent risk factor for severe liver fibrosis.

Keywords: Fibrosis; Free triiodothyronine; Non-alcoholic fatty liver disease; Type 2 diabetes mellitus.

Fig. 1

Changes in fT3, fT4, and TSH levels in the groups classified by the severity of liver fibrosis according to NFS, FIB-4 and BARD (A. Changes in fT3, fT4, and TSH levels among the groups classified by NFS; B. Changes in fT3, fT4, and TSH levels among the groups classified by FIB-4; C. Changes in fT3, fT4, and TSH levels among the groups classified by BARD. Patients were divided into 3 groups according to NFS, FIB-4 and BARD score from low to high, and differences between groups were analyzed.)

Fig. 2

Linear correlation analyses of liver fibrosis scores with fT3, fT4 and TSH levels (A. Linear correlation analyses of NAFLD fibrosis score (NFS) with fT3, fT4 and TSH levels; B. Linear correlation analyses of FIB-4 score with fT3, fT4 and TSH levels. All T2DM patients were included, and the correlation coefficient r and corresponding P value were shown in the figure.)

Fig. 3

Experiment using mice model showed that T3 deficiency may promote liver fibrosis progression (A. Representative images of liver sections stained by HE and Masson staining from control, NASH and NASH + PTU mice (original magnification, ×200); B. Immunohistochemistry of a-SMA and Collagen 1 expression in each group.)

Fig. 4

T3 inhibited the profibrotic TREM2 ⁺CD9⁺macrophage(A. Flow cytometry showing the proportion of TREM2⁺CD9⁺ macrophages in the T3 intervention group versus the control group; B. Difference in the TREM2⁺CD9⁺ macrophages percentage (left) and cell counts (right) between groups.)