Impaired Thyroid Hormone Sensitivity is Associated with Increased Risk of Liver Fibrosis in Euthyroid Population: A Cross-Sectional Analysis of NHANES

Abstract

The interplay between liver fibrosis and thyroid function remains incompletely understood, particularly regarding thyroid hormone sensitivity. Thus, this study aims to explore the relationship between liver fibrosis and thyroid hormone sensitivity in euthyroid US individuals. This study involved 4,678 euthyroid participants from the National Health and Nutrition Examination Survey 2007–2012. Key clinical parameters were extracted, including thyroid-stimulating hormone, free and total thyroxine, and liver function-related data. Thyroid hormone sensitivity was assessed by three indices: the Thyroid Function Quotient Index, Thyroid-Stimulating Hormone Index, and Thyrotrophic Thyroxine Resistance Index. Multiple regression analyses and machine learning models were performed to evaluate the relationships between liver fibrosis and thyroid sensitivity indices. Participants with advanced liver fibrosis indicated by fibrosis index 4 (FIB-4) demonstrated significantly impaired thyroid hormone sensitivity indicated by Thyroid Function Quotient Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid-Stimulating Hormone Index. Then, the logistic regression and restricted cubic spline analysis indicated that Thyroid Function Quotient Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid-Stimulating Hormone Index were risk factors for liver fibrosis (odds ratio>1, p<0.05). Furthermore, we developed machine learning models using random forest and Boruta’s algorithm identifying thyroid hormone sensitivity indices, Thyroid-Stimulating Hormone Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid Function Quotient Index as key predictors for liver fibrosis. Mediation analysis indicates that uric acid is a weak mediator between thyroid hormone sensitivity and liver fibrosis. This study reveals that impaired thyroid hormone sensitivity is a risk factor for liver fibrosis progression in euthyroid individuals. These findings uncover a potential molecular link between thyroid hormone signaling and the development of liver fibrosis, warranting further investigation.

Keywords

thyroid hormone sensitivity - liver fibrosis - uric acid - TFQI - FIB-4

• References

• 1 Huang DQ, El-Serag HB, Loomba R.. Global epidemiology of NAFLD-related HCC: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol 2021; 18: 223-238
• 2 Paik JM, Golabi P, Younossi Y. et al. Changes in the global burden of chronic liver diseases from 2012 to 2017: the growing impact of NAFLD. Hepatology 2020; 72: 1605-1616
• 3 Younossi ZM, Koenig AB, Abdelatif D. et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016; 64: 73-84
• 4 Devarbhavi H, Asrani SK, Arab JP. et al. Global burden of liver disease: 2023 update. J Hepatol 2023; 79: 516-537
• 5 Miao L, Targher G, Byrne CD. et al. Current status and future trends of the global burden of MASLD. Trends Endocrinol Metab 2024; 35: 697-707
• 6 Mao X, Zhang X, Lai R. et al. Glucagon-like peptide 1 receptor agonist and reduced liver and non-liver complications in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease: a target trial emulation study. Clin Mol Hepatol 2025; 31: 1084-1099
• 7 Yao X.. Letter: Methodological concerns regarding GLP-1RA effects on MASLD outcomes. Clin Mol Hepatol 2025;
• 8 Tsochatzis EA, Newsome PN.. Non-alcoholic fatty liver disease and the interface between primary and secondary care. Lancet Gastroenterol Hepatol 2018; 3: 509-517
• 9 Zoncapè M, Liguori A, Tsochatzis EA.. Non-invasive testing and risk-stratification in patients with MASLD. Eur J Intern Med 2024; 122: 11-19
• 10 Galán-Puchades MT.. Use of liver imaging and biopsy in clinical practice. N Engl J Med 2017; 377: 2295-2297
• 11 Varughese R, Rahman S.. Endocrine dysfunction in primary mitochondrial diseases. Endocr Rev 2025; 46: 376-396
• 12 Boelen A, Kwakkel J, Fliers E.. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev 2011; 32: 670-693
• 13 Luongo C, Dentice M, Salvatore D.. Deiodinases and their intricate role in thyroid hormone homeostasis. Nat Rev Endocrinol 2019; 15: 479-488
• 14 Sinha RA, Bruinstroop E, Yen PM.. Actions of thyroid hormones and thyromimetics on the liver. Nat Rev Gastroenterol Hepatol 2025; 22: 9-22
• 15 Zheng Y, Wang S, Wu J. et al. Mitochondrial metabolic dysfunction and non-alcoholic fatty liver disease: new insights from pathogenic mechanisms to clinically targeted therapy. J Transl Med 2023; 21: 1-21
• 16 Sinha RA, Singh BK, Yen PM.. Thyroid hormone regulation of hepatic lipid and carbohydrate metabolism. Trends Endocrinol Metab 2014; 25: 538-545
• 17 Chen P, Hou X, Wei L. et al. Free triiodothyronine is associated with the occurrence and remission of nonalcoholic fatty liver disease in euthyroid women. Eur J Clin Invest 2019; 49: e13070
• 18 Manka P, Bechmann L, Best J. et al. Low free triiodothyronine is associated with advanced fibrosis in patients at high risk for nonalcoholic steatohepatitis. Dig Dis Sci 2019; 64: 2351-2358
• 19 Qin Z, Muhanhali D, Ling Y.. Impaired thyroid hormone sensitivity increases risk of cardiovascular events in patients undergoing coronary angiography. J Clin Endocrinol Metab 2024; 109: 1550-1564
• 20 Laclaustra M, Moreno-Franco B, Lou-Bonafonte JM. et al. Impaired sensitivity to thyroid hormones is associated with diabetes and metabolic syndrome. Diabetes Care 2019; 42: 303-310
• 21 Cholankeril G, Kramer JR, Chu J. et al. Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease. J Hepatol 2023; 78: 493-500
• 22 Hagström H, Talbäck M, Andreasson A. et al. Repeated FIB-4 measurements can help identify individuals at risk of severe liver disease. J Hepatol 2020; 73: 1023-1029
• 23 Berzigotti A, Tsochatzis E, Boursier J. et al. EASL clinical practice guidelines on non-invasive tests for evaluation of liver disease severity and prognosis – 2021 update. J Hepatol 2021; 75: 659-689
• 24 Chang M, Chang D, Kodali S. et al. Degree of discordance between FIB-4 and transient elastography: an application of current guidelines on general population cohort. Clin Gastroenterol Hepatol 2024; 22: 1453-1461.e2
• 25 Anstee QM, Berentzen TL, Nitze LM. et al. Prognostic utility of fibrosis-4 index for risk of subsequent liver and cardiovascular events, and all-cause mortality in individuals with obesity and/or type 2 diabetes: a longitudinal cohort study. Lancet Reg Health Eur 2023; 36: 100780
• 26 Zhang T, Nikouline A, Lightfoot D. et al. Machine learning in the prediction of trauma outcomes: a systematic review. Ann Emerg Med 2022; 80: 440-455
• 27 Li W, Zeng L, Yuan S. et al. Machine learning for the prediction of cognitive impairment in older adults. Front Neurosci 2023; 17: 1158541
• 28 Xiang LL, Cao YT, Sun J. et al. Association between thyroid function and nonalcoholic fatty liver disease: a dose-response meta-analysis. Front Endocrinol (Lausanne) 2024; 15: 1399517
• 29 Li Z, Wu X, Chen Z. et al. Association between low-normal thyroid function and advanced liver fibrosis in metabolic dysfunction-associated fatty liver disease patients: a retrospective cohort study. Gastroenterol Rep (Oxf) 2024; 12: goad076
• 30 Kim D, Kim W, Joo SK. et al. Subclinical hypothyroidism and low-normal thyroid function are associated with nonalcoholic steatohepatitis and fibrosis. Clin Gastroenterol Hepatol 2018; 16: 123-131.e1
• 31 Chao G, Zhu Y, Bao Y.. A screening study of high-risk groups for liver fibrosis in patients with metabolic dysfunction-associated fatty liver disease. Sci Rep 2024; 14: 23714
• 32 Dietrich JW, Landgrafe-Mende G, Wiora E. et al. Calculated parameters of thyroid homeostasis: emerging tools for differential diagnosis and clinical research. Front Endocrinol (Lausanne) 2016; 7: 57
• 33 Liu X, Liu D, Tan C. et al. Gut microbiome-based machine learning for diagnostic prediction of liver fibrosis and cirrhosis: a systematic review and meta-analysis. BMC Med Inform Decis Mak 2023; 23: 294
• 34 Sinha RA, Singh BK, Yen PM.. Direct effects of thyroid hormones on hepatic lipid metabolism. Nat Rev Endocrinol 2018; 14: 259-269
• 35 Harrison SA, Bashir MR, Guy CD. et al. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2019; 394: 2012-2024
• 36 Harrison SA, Taub R, Neff GW. et al. Resmetirom for nonalcoholic fatty liver disease: a randomized, double-blind, placebo-controlled phase 3 trial. Nat Med 2023; 29: 2919-2928
• 37 Harrison SA, Bedossa P, Guy CD. et al. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis. N Engl J Med 2024; 390: 497-509
• 38 Yang X, Lin Y, Huang J. et al. Serum uric acid levels and prognosis of patients with non-alcoholic fatty liver disease. Sci Rep 2024; 14: 5923
• 39 He J, Ye J, Sun Y. et al. The additive values of the classification of higher serum uric acid levels as a diagnostic criteria for metabolic-associated fatty liver disease. Nutrients 2022; 14: 3587
• 40 Desideri G, Bocale R, D’Amore AM. et al. Thyroid hormones modulate uric acid metabolism in patients with recent onset subclinical hypothyroidism by improving insulin sensitivity. Intern Emerg Med 2020; 15: 67-71
• 41 Wen X, You H, Wei L. et al. Correlation between impaired sensitivity to thyroid hormones and serum uric acid in female patients with obesity and after laparoscopic sleeve gastrectomy. Endocr Pract 2024; 30: 417-423
• 42 Wan X, Xu C, Lin Y. et al. Uric acid regulates hepatic steatosis and insulin resistance through the NLRP3 inflammasome-dependent mechanism. J Hepatol 2016; 64: 925-932