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Sensitivity to thyroid hormones is associated with advanced fibrosis in euthyroid patients with non-alcoholic fatty liver disease: A cross-sectional study
The relationship between thyroid hormone sensitivity and the occurrence of advanced hepatic fibrosis in non-alcoholic fatty liver disease (NAFLD) remains unclear. We aimed to explore the association between sensitivity to thyroid hormones and advanced fibrosis (F3-F4) of NAFLD in patients with biopsy-proven euthyroid NAFLD.
Methods
In this study, 129 participants with biopsy-proven euthyroid NAFLD were enrolled, all of whom underwent thyroid function tests and liver biopsy. Indicators reflecting the sensitivity to thyroid hormones were also calculated. A logistic regression model was used to evaluate the association between thyroid hormone sensitivity and risk of advanced liver fibrosis.
Results
Among the 129 participants, 40 (31.0%) had advanced fibrosis. Advanced fibrosis was independently associated with TSH, FT3, FT3/FT4, thyrotroph T4 resistance index (TT4RI), TSH index (TSHI), and thyroid feedback quantile-based index (TFQI) (P<0.05), even after adjusting for sex, age, and metabolic factors. The combination of TFQI with age, waist circumference (WC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C) performed best for advanced fibrosis diagnosis.
Conclusion
In euthyroid NAFLD patients, higher FT3/FT4, TFQI, TT4RI, and TSHI values were strongly associated with an increased incidence of advanced liver fibrosis. The combination of TFQI with age, WC, TGs, and LDL-C can be used as a predictor for advanced fibrosis in patients with NAFLD.
. NAFLD is a wide-spectrum clinical pathological syndrome involving simple steatosis and non-alcoholic steatohepatitis (NASH), where the latter may gradually progress to liver fibrosis or cirrhosis without effective intervention [
Dysregulation of hepatic lipid metabolism may contribute to intrahepatic fat deposition and the subsequent progression to NAFLD. Thyroid hormones (THs) play an important role in liver lipid metabolism by regulating de novo lipogenesis (DNL), fatty acid oxidation, and cholesterol and carbohydrate metabolism [
. Hypothyroidism-induced NAFLD has been attributed to decreased lipid utilization, including reduced β-oxidation of free fatty acids (FFAs) and the clearance of TGs, with a consequent increase in the accumulation of TGs and low-density lipoprotein within hepatocytes [
]. Moreover, hypothyroidism is correlated with hepatic insulin resistance, which fails to suppress the production of endogenous glucose and stimulates DNL [
. In particular, only a few studies have investigated the potential correlation between thyroid hormones and histological characteristics related to NAFLD progression, including steatosis and fibrosis. To our knowledge, no study has focused on the relationship between sensitivity to THs and the occurrence of advanced liver fibrosis in patients with NAFLD. Thyroid feedback quantile-based index (TFQI) is a novel metabolism-related indicator that reflects the sensitivity of the hypothalamus–pituitary–thyroid axis to THs [
]. Therefore, we analyzed thyroid function in a biopsy-proven NAFLD cohort with euthyroidism, and investigated the potential relationship between THs sensitivity and NAFLD-related fibrosis.
2. Materials and methods
2.1 Study population
We designed a cross-sectional study using a biopsy-proven NAFLD cohort from the Department of Hepatology, Tianjin Second People's Hospital, China from January 2017 to January 2021. The inclusion criteria were biopsy-proven NAFLD patients between the age of 18–75 years. The exclusion criteria were as follows:1) excessive alcohol intake (> 140 g/week for women or > 210 g/week for men, patients with alcohol dependence or alcoholism); 2) presence of other forms of liver disease, including Wilson disease, viral hepatitis, autoimmune liver disease, primary biliary cholangitis or other cholangitis, drug-induced liver injury, Budd-Chiari syndrome, and human immunodeficiency virus infection; and 3) presence of over-hypothyroidism or hyperthyroidism. Finally, 129 patients with biopsy-proven NAFLD and euthyroidism were enrolled in this study. The protocols and informed consent were approved by the Ethics Committee of Tianjin Second People's Hospital. The study complied with the principles of the Declaration of Helsinki. All participants provided informed consent before the study.
2.2 Clinical data and demographic information
Clinical data, including sex, age, medical history (hypertension, diabetes, or impaired fasting glucose [IFG]), self-reported alcohol consumption, and medication history, were obtained from medical records. Anthropometric information included blood pressure (BP), WC, height, and body weight. Body mass index (BMI) was calculated by dividing the weight by the square of height. The anthropometric characteristics of the participants were measured according to standard methods.
2.3 Serological data
All participants underwent blood tests at the time of liver biopsy. Blood samples were collected at 6:00 a.m. after overnight fasting. The serum concentrations of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TIBL), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), albumin (ALB), prothrombin time (PT), platelets (PLT), fasting blood glucose (FBG), high-density lipoprotein cholesterol (HDL-C), LDL-C, total cholesterol (TC), and TGs were biochemically analyzed using a Hitachi-7180 (Hitachi Co., Tokyo, Japan) analyzer.
Serum levels of FT3, FT4, and TSH were obtained using electrochemical luminescent immunoassays (Cobas e 411 analyzer, Roche Diagnostics, Switzerland). Normal reference value ranges of thyroid function in adults were 0.27–4.2 mIU/L for TSH, 3.1–6.8 pmol/L for FT3, and 12.0–22.0 pmol/L for FT4. Serum levels of TSH, FT3, and FT4 within the normal reference range were defined as the euthyroid state [
]. Three indices (TFQI, thyrotroph T4 resistance index [TT4RI], and TSH index [TSHI]) were used to evaluate the central sensitivity to thyroid hormones. The calculation formulas for TSHI and TT4RI were obtained from a previous study [
]. Lower TT4RI, TSHI, and TFQI values indicate higher central sensitivity to thyroid hormones.
2.4 Histological assessments
Each liver tissue section measured at least 10 mm and contained more than 11 portal tracks. Liver sections were stained with hematoxylin-eosin and Masson trichrome after formalin fixation and paraffin embedding. Liver sections were reviewed and described by experienced pathologists, who were unable to obtain any clinical information. The diagnosis of NAFLD was based on the Brunt criteria [
]. Liver fibrosis stages were graded from F0 to F4 according to the Kleiner score (stage F0: Absence of fibrosis; stage F1: perisinusoidal or periportal fibrosis without septa; stage F2: combined periportal and perisinusoidal fibrosis with tiny septa; stage F3: septal or bridging fibrosis, without cirrhosis; and stage F4: cirrhosis) [
Categorical variables are shown as numbers (n) with proportions (%) and were compared using the chi-square test. Continuous variables with or without normal distribution are shown as mean ± standard deviation (SD) or median (25th quartile and 75th quartile), respectively. The Student's t-test or Mann–Whitney U test was used to compare the variables in different groups. The association between thyroid parameters and the clinical and pathological characteristics of the patients was evaluated using Spearman's coefficient correlation analysis (r). Logistic regression analysis was performed to evaluate the association between thyroid parameters and advanced fibrosis. Confidence intervals (CIs) and odds ratios (ORs) were calculated. Receiver operating characteristic (ROC) was also analyzed to evaluate the effectiveness of the indicators in predicting advanced fibrosis. The optimal cut-off points, sensitivity, and specificity of the indicators were determined using the DeLong method. P values < 0.05 (two-sided) were considered statistically significant. Statistical analysis was performed using IBM SPSS software (version 23 for Mac).
3. Results
3.1 General characteristics of the cohort
Table 1 presents the baseline characteristics of the study cohort. In total, 129 patients with a median age of 47.0 years were enrolled in this study. In this study population, 65 (50.4%) patients were women, and the occurrence of advanced liver fibrosis was 31.0%. The prevalence of diabetes and IFG was 46.5%. The mean level of BMI and the median level of WC were 27.7 kg/m2 and 95.0 cm, respectively. The number and proportion of patients based on fibrosis stage were as follows: F0, 28 (21.7%); F1, 31 (24.0%); F2, 30 (23.3%); F3, 21 (16.3%); and F4, 19 (14.7%). The patients were divided into two groups according to sex. Female patients were more likely to have higher serum TC and HDL-C levels than male patients. Additional information regarding the participants is provided in Table 1.
Table 1General characteristics of euthyroid NAFLD patients.
Index
Total (N = 129)
Male (n = 64)
Female (n = 65)
p
Age
47.0 (32.0, 57.0)
47.0 (30.5, 55.8)
49.0 (33.0, 59.5)
0.287
Hypertension, n (%)
44 (34.1)
22 (34.4)
22 (33.8)
0.949
Diabetes/IFG, n (%)
60 (46.5)
26 (40.6)
34 (52.3)
0.183
BMI(Kg/m2)
27.7 ± 3.7
27.5 ± 3.6
27.8 ± 3.6
0.572
WC (cm)
95.0 (89.0, 101.5)
95.5 (90.0, 102.5)
95.0 (87.0, 101.5)
0.424
ALT (U/L)
32.0 (20.7, 49.0)
30.0 (21.3, 48.2)
33.0 (20.0, 50.0)
0.779
AST (U/L)
26.0 (19.5, 35.0)
26.5 (19.3, 34.0)
26.0 (19.5, 39.5)
0.458
ALP (U/L)
74.0 (58.0, 95.5)
78.0 (64.0, 97.1)
71.0 (55.6, 95.5)
0.208
GGT (U/L)
66.0 (43.0, 107.0)
64.5 (44.0, 104.0)
71.0 (42.0, 110.7)
0.903
TBIL (umol/L)
14.0 (10.3, 19.0)
14.1 (10.7, 17.9)
13.8 (9.9, 19.3)
0.989
ALB (g/L)
45.1 (41.0, 47.8)
46.1 (41.1, 48.2)
44.4 (40.5, 47.0)
0.219
PLT (109/L)
221.2 ± 83.6
220.1 ± 81.9
222.3 ± 85.9
0.88
PT (s)
12.2 (10.9, 12.9)
12.2 (10.8, 13.0)
12.0 (11.0, 12.8)
0.576
TC (mmol/L)
5.43 (4.60, 5.97)
5.15 (4.30, 5.77)
5.48 (4.88, 6.05)
0.03
TGs (mmol/L)
1.69 (1.31, 2.06)
1.77 (1.33, 2.06)
1.63 (1.30, 2.12)
0.262
HDL-C (mmol/L)
1.32±0.36
1.24±0.33
1.39±0.37
0.016
LDL-C (mmol/L)
2.99±0.79
3.00±0.75
2.99±0.84
0.974
FBG (mmol/L)
5.86 (5.27, 6.63)
5.75 (5.08, 6.51)
6.01 (5.37, 6.70)
0.166
FT3 (pmol/L)
4.86±0.72
4.91±0.66
4.80±0.77
0.392
FT4 (pmol/L)
15.72±2.21
15.73±2.21
15.72±2.22
0.986
TSH (uIU/ml)
2.29 (1.60, 3.40)
2.22 (1.55, 3.54)
2.32 (1.65, 3.33)
0.929
FT3/FT4
0.31±0.05
0.32±0.05
0.31±0.05
0.357
TT4RI
36.2 (26.3, 48.3)
35.7 (25.3, 49.6)
38.6 (26.7, 48.1)
0.966
TSHI
3.01 (2.71, 3.20)
3.06 (2.66, 3.20)
2.99 (2.72, 3.20)
0.845
TFQI
0.01±0.31
0.01±0.32
0.01±0.31
0.951
NAFLD activity score (NAS), n (%)
0–4
44 (34.1)
25 (39.1)
19 (29.2)
0.239
5–8
85 (65.9)
39 (60.9)
46 (70.8)
0.239
Fibrosis stage, n (%)
0
28 (21.7)
12 (18.8)
16 (24.6)
0.419
1
31 (24.0)
16 (25.0)
15 (23.1)
0.798
2
30 (23.3)
14 (21.9)
16 (24.6)
0.713
3
21 (16.3)
14 (21.9)
7 (10.8)
0.088
4
19 (14.7)
8 (12.5)
11 (16.9)
0.478
Advanced fibrosis, n (%)
40 (31.0)
22 (34.4)
18 (27.7)
0.412
Data are expressed as mean (± standard deviation), median (quartile 25, quartile 75).
Patients were further divided into advanced (stages F3-F4) and non-advanced (stages F0-F2) fibrosis groups. Table 2 shows the general characteristics of the patients with different liver fibrosis stages. The incidence of advanced fibrosis in this cohort was 31.0%. There was no statistically significant difference in sex between the two groups (P = 0.412). Compared with patients without advanced fibrosis, patients with advanced fibrosis were older, and the serum concentrations of TGs, AST, ALP, PT, TSH, FT3, and values of FT3/FT4, TT4RI, TSHI, and TFQI were statistically higher (P<0.05), whereas the PLT count and ALB were significantly lower (P<0.05).
Table 2General characteristics of euthyroid NAFLD patients according to fibrosis stage.
Index
F (0–2) n = 89
F (3–4) n = 40
p
Female sex, n (%)
47 (52.8)
18 (45.0)
0.412
Age
43.0 (28.0,56.0)
51.5 (42.0,61.0)
0.031
Diabetes/IFG, n (%)
39 (43.8)
21 (52.5)
0.361
BMI(Kg/m2)
27.4 ± 3.8
28.1 ± 3.5
0.539
WC (cm)
95.0 (87.0, 99.5)
96.0 (91.3, 103.0)
0.106
TC (mmol/L)
5.43 (4.51, 5.87)
5.45 (4.88, 6.07)
0.378
TGs(mmol/L)
1.55 (1.21, 1.99)
1.81 (1.58, 2.26)
0.006
HDL-C (mmol/L)
1.33±0.38
1.30±0.28
0.676
LDL-C (mmol/L)
2.94 (2.43, 3.45)
3.31 (2.57, 3.55)
0.268
FBG (mmol/L)
5.82 (5.22, 6.65)
6.28 (5.30, 6.61)
0.521
ALT (U/L)
35.6 ± 23.7
42.3 ± 21.8
0.131
AST (U/L)
27.4 ± 15.0
38.1 ± 18.7
0.001
ALP (U/L)
79.4 ± 30.4
94.7 ± 54.1
0.042
GGT (U/L)
65.0 (42.5, 103.1)
68.0 (45.3, 115.3)
0.656
TBIL (umol/L)
15.1 ± 6.8
15.8 ± 7.5
0.613
ALB (g/L)
46.0 (42.6, 48.1)
41.7 (39.5, 47.0)
0.003
PLT (109/L)
238.0 (186.0, 282.5)
173.5 (136.5, 242.3)
<0.001
PT (s)
11.5 (10.6, 12.6)
12.9 (12.1, 13.7)
<0.001
FT3 (pmol/L)
4.74±0.78
5.11±0.49
0.002
FT4 (pmol/L)
15.75±2.23
15.67±2.18
0.838
TSH (uIU/ml)
2.11 (1.45, 3.02)
2.87 (2.08, 3.79)
0.001
FT3/FT4
0.30±0.05
0.33±0.05
0.004
TT4RI
34.8 ± 13.5
44.4 ± 13.4
<0.001
TSHI
2.93 (2.57, 3.14)
3.12 (2.88, 3.34)
0.001
TFQI
0.01 (−0.24, 0.16)
0.16 (−0.14, 0.33)
0.023
Data are expressed as mean (±standard deviation), median (quartile 25, quartile 75).
3.2 Correlation between thyroid parameters with clinical and pathological characteristics of NAFLD patients
Table 3 shows the correlations between thyroid parameters and the clinical and pathological characteristics of the participants. Serum FT3 levels were positively correlated with WC, BMI, TGs, LDL-C, AST, and PT, but negatively correlated with HDL-C and PLT (P<0.05). Serum TSH levels were positively correlated with age, AST, and PT but negatively correlated with ALB and PLT (P<0.05). FT3/FT4 ratio was positively correlated with WC and PT and negatively correlated with PLT (P<0.05). TT4RI was positively correlated with age, AST, and PT and negatively correlated with PLT and ALB (P<0.05). TSHI was positively correlated with age and TGs, AST, and PT levels and negatively correlated with ALB (P<0.05). The TFQI was positively correlated with age, TGs, AST, and PT (P<0.05). All variables except FT4 were positively correlated with fibrosis stage (P<0.05).
Table 3Association of thyroid parameters with clinical characteristics of patients.
3.3 Relationship between thyroid parameters with advanced fibrosis
Table 4 shows the association between thyroid parameters and advanced fibrosis. In the unadjusted model (Model 1), increased levels of TSH (OR=1.868, 95% CI 1.263–2.765), FT3 (OR=2.135, 95% CI 1.205–3.785), FT3/FT4 (OR=1.755, 95% CI 1.178–2.615), TT4RI (OR=2.078, 95% CI 1.367–3.16), TSHI (OR=2.152, 95% CI 1.339–3.459), and TFQI (OR=1.725, 95% CI 1.133–2.627) were associated with a higher risk of advanced fibrosis. After adjusting for age and sex (Model 2), increased TSH (OR=1.777, 95% CI 1.189–2.656), FT3 (OR=2.102, 95% CI 1.178–3.75), FT3/FT4 (OR=1.697, 95% CI 1.133–2.541), TT4RI (OR=1.933, 95% CI 1.302–3.05), TSHI (OR=2.047, 95% CI 1.261–3.322), and TFQI (OR=1.65, 95% CI 1.072–2.539) were positively associated with advanced fibrosis. After further adjustments for age, sex, diabetes or IFG, BMI, WC, TC, TGs, and FBG (Model 3), elevated TSH (OR=1.831, 95% CI 1.2–2.795), FT3 (OR=2.128, 95% CI 1.122–4.037), FT3/FT4 (OR=1.726, 95% CI 1.116–2.67), TT4RI (OR=2.026, 95% CI 1.296–3.167), TSHI (OR=2.046, 95% CI 1.242–3.369), and TFQI (OR=1.628, 95% CI 1.047–2.53) remained significantly positively associated with advanced fibrosis (Table 4).
Table 4Association of thyroid parameters with advanced fibrosis.
Thyroid parameters
Model 1
Model 2
Model 3
OR (95% CI)
p
OR (95% CI)
p
OR (95% CI)
p
FT3
2.135 (1.205, 3.785)
0.009
2.102 (1.178, 3.75)
0.012
2.128 (1.122, 4.037)
0.021
FT4
0.982 (0.829, 1.164)
0.836
0.982 (0.826, 1.166)
0.833
0.969 (0.809, 1.161)
0.734
TSH
1.868 (1.263, 2.765)
0.002
1.777 (1.189, 2.656)
0.005
1.831 (1.2, 2.795)
0.008
FT3/FT4 (+1SD)
1.755 (1.178, 2.615)
0.006
1.697 (1.133, 2.541)
0.01
1.726 (1.116, 2.67)
0.014
TT4RI (+1SD)
2.078 (1.367, 3.16)
0.001
1.993 (1.302, 3.05)
0.001
2.026 (1.296, 3.167)
0.002
TSHI (+1SD)
2.152 (1.339, 3.459)
0.002
2.047 (1.261, 3.322)
0.004
2.046 (1.242, 3.369)
0.005
TFQI (+1SD)
1.725 (1.133, 2.627)
0.011
1.65 (1.072, 2.539)
0.023
1.628 (1.047, 2.53)
0.03
Model 1: unadjusted.
Model 2: adjusted for age and sex.
Model 3: Model 2 + further adjusted for diabetes/IFG, WC, BMI, TC, TGs and FBG.
The TFQI, FT3/FT4, TT4RI, and TSHI were selected for predicting advanced fibrosis in patients with NAFLD. As shown in Fig. 1, the area under the ROC curve (AUC), optimal cut-off points, sensitivity, and specificity for advanced fibrosis prediction were as follows: TFQI, 0.625, 0.14, 0.525, and 0.73; FT3/FT4, 0.658, 0.30, 0.775, and 0.584; TT4RI, 0.698, 43.0, 0.55, and 0.764; and TSHI, 0.678, 3.07, 0.65, and 0.64, respectively. Multifactor models, including age, WC, TGs, and indicators reflecting sensitivity to THs, were further applied to better predict advanced fibrosis (Fig. 2). The combination of TFQI with age, WC, TGs, and LDL-C performed best for advanced fibrosis diagnosis, with 0.725 sensitivity, 0.64 specificity, and an AUC of 0.7.
Fig. 1ROC curves for prediction of advanced liver fibrosis in NAFLD patients. (A) ROC curve for prediction of advanced liver fibrosis from TFQI; (B) ROC curve for prediction of advanced liver fibrosis from FT3/FT4. (C) ROC curve for prediction of advanced fibrosis from TT4RI. (D) ROC curve for prediction of advanced fibrosis from TSHI. ROC, receiver operating characteristic; FT3, free triiodothyronine; FT4, free thyroxine; TFQI, Thyroid Feedback Quantile-based Index; FT3/FT4, FT3 to FT4 ratio; TT4RI, TSH T4 resistance Index; TSHI, TSH Index.
To the best of our knowledge, the association between sensitivity to THs and NAFLD-related advanced liver fibrosis has not been studied, especially in euthyroid individuals. The present study demonstrated that increased central resistance to thyroid hormones was positively associated with an increased incidence of advanced hepatic fibrosis. The innovation of this study was the inclusion of sensitivity to THs, in addition to thyroid function, as a predictor of advanced fibrosis.
THs are critical regulators of hepatic lipid metabolism, including the synthesis and metabolism of fatty acids and cholesterol [
]. Moreover, THs can help regulate serum concentrations of cholesterol by increasing the biosynthesis, export, reverse transport, and conversion of cholesterol into bile acids [
]. Furthermore, THs can regulate hepatic mitochondrial activity and fatty acid oxidation (FAO) via the electron transport chain and tricarboxylic acid (TCA) cycle [
NAFLD is a metabolic syndrome that manifests in the liver. The development of NAFLD is closely associated with metabolic abnormalities, including diabetes mellitus, hyperlipidemia, and cardiovascular disease [
]. As noted, THs exhibit multiple effects on hepatic lipid metabolism; therefore, thyroid dysfunction is positively correlated with obesity and metabolic disorders [
Association between thyroid dysfunction and lipid profiles differs according to age and sex: results from the Korean national health and nutrition examination survey.
. Recently, several clinical studies conducted in euthyroid individuals have investigated the link between thyroid function and the occurrence of NAFLD; however, the results failed to reach a consensus. Previous studies have shown that lower serum concentrations of FT4 are strongly correlated with the occurrence of NAFLD [
Association between thyroid hormone levels and advanced liver fibrosis in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease.
, while another study reported that the occurrence of NAFLD was strongly correlated with increased concentration of FT3 and decreased concentration of FT4, but not TSH [
]. In addition, a large meta-analysis conducted by Mantovani et al. indicated that hypothyroidism is closely related to the prevalence and severity of NAFLD [
]. All of the above studies failed to explore the link between thyroid parameters and NAFLD-related advanced fibrosis, especially in a biopsy-proven euthyroid NAFLD population.
In the present study, our results indicated that both TSH and FT3 levels were independently correlated with advanced fibrosis, even after adjusting for metabolic factors. However, we failed to find an association between advanced fibrosis and serum FT4 level. Higher levels of FT3-induced advanced fibrosis may be related to the expression of iodothyronine deiodinase (DIO), which is increased in obese people and animals, and accelerates the conversion from FT4 to FT3 [
], which may accelerate the progression of NAFLD. Studies have also confirmed that higher FT3 levels are strongly linked to metabolic risk factors that participate in NAFLD, such as TGs, blood glucose, and insulin [
. We also found that FT3 levels were correlated with BMI, WC, TC, and LDL-C levels in the present study. However, the causal relationship between FT3 level and advanced fibrosis remains unclear.
We further explored the role and mechanism of the hypothalamus–pituitary–thyroid (HPT) axis in regulating circulating THs. Disorders caused by metabolic abnormalities are often accompanied by the dysregulation of the HPT axis [
]. In Laclaustra et al. first reported that the TFQI was better in assessing sensitivity to THs than the TSHI and TT4RI. This study also indicated that higher TFQI values were significantly related to metabolic syndrome, diabetes, and diabetes-related mortality [
]. Recently, a cross-sectional study conducted by Lai et al. also reported that higher TFQI and FT3/FT4 values were positively correlated with dyslipidemia and NAFLD [
]. These studies provide an explanation for the link between thyroid dysfunction and metabolic disorders. However, to the best of our knowledge, the present study is the first to evaluate the relationship between sensitivity to THs and the risk of advanced fibrosis among patients with NAFLD.
In addition to the HPT axis, abnormal peripheral DIO activity is associated with the prevalence of metabolic disorders. As mentioned earlier, the upregulation of peripheral DIO activity in obese subjects leads to increased conversion of FT4 to FT3, accelerating the progression of NAFLD [
. In this study, our results also showed that the incidence of advanced fibrosis increased in NAFLD patients with an increased FT3/FT4 ratio. Previous studies have confirmed that higher FT3/FT4 levels are positively correlated with metabolic disorders, such as obesity, elevated BP, and FBG levels [
Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects.
]. Consistent with our results, a Lifelines Cohort Study found that the prevalence of NAFLD significantly increased with elevated FT3/FT4 in a population with euthyroidism [
Since various metabolic risk factors accelerate the occurrence and progression of NAFLD, we speculate that sensitivity to THs may be a potential predictor of advanced liver fibrosis. In this study, TFQI, TSHI, TT4RI, and FT3/FT4 were used, and all of these variables were found to be significantly positively associated with higher risks of advanced fibrosis. Few studies have focused on the relationship between TFQI and NAFLD-related fibrosis, and the exact mechanisms remain unclear.
The strengths of the present study are that all participants were diagnosed with NAFLD by liver biopsy, and thyroid parameters were measured under the same facilities and conditions. However, this study has several shortcomings. First, this cross-sectional study was insufficient to assess the causal relationship between the thyroid parameters and advanced fibrosis. Second, the participants in this cohort were all Chinese individuals from a single medical center; therefore, the conclusions of this study may not be applicable to other populations. Thirdly, the total number of cases was small, because only patients with biopsy-proven euthyroid NAFLD were included to ensure the accuracy of the study. Finally, individuals without NAFLD were not included and analyzed in this study. Therefore, further multicenter prospective studies are required to confirm our results.
5. Conclusions
In conclusion, this study showed that FT3/FT4, TT4RI, TSHI, and TFQI were positively associated with advanced fibrosis in euthyroid NAFLD patients. This study provides evidence that TFQI combined with age, WC, TGs, and LDL-C levels may be a novel predictor of advanced liver fibrosis. Therefore, older patients with NAFLD with lower central sensitivity to THs and dyslipidemia should be treated to prevent the progression of liver fibrosis. However, extensive studies are necessary to confirm our results and reveal their potential mechanisms.
Funding
This work was funded by the Natural Science Foundation of Tianjin City (No. 20JCYBJC01150) and Tianjin Health Science and Technology Project (No. TJWJ2021QN063).
Declaration of Competing Interest
None declared.
References
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Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
Association between thyroid dysfunction and lipid profiles differs according to age and sex: results from the Korean national health and nutrition examination survey.
Association between thyroid hormone levels and advanced liver fibrosis in patients with type 2 diabetes mellitus and non-alcoholic fatty liver disease.
Triiodothyronine and free thyroxine levels are differentially associated with metabolic profile and adiposity-related cardiovascular risk markers in euthyroid middle-aged subjects.
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