Liver, Portal, and Systemic Thyroid Hormone Concentrations in End-Stage MASH Reveal Distinct Roles for T3/rT3 Ratio and T4

Abstract

Background: The liver is a central organ in thyroid hormone (TH) metabolism, mediating the conversion of thyroxine (T4) to bioactive triiodothyronine (T3) via type 1 deiodinase and the clearance of reverse T3 (rT3). Selective thyromimetics targeting the TH receptor beta in the liver are in development and, recently, are FDA-approved for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). To unravel TH metabolism during MASH in patients, we aim to determine specific alterations in TH concentrations in both the liver and circulation in patients with end-stage MASH. Methods: In this cross-sectional study, liver tissue, portal plasma, and systemic plasma were collected intraoperatively from 12 patients with MASH cirrhosis undergoing liver transplantation and 12 living liver donors serving as healthy controls (fibrosis stage F0-F1). Total T4, T3, and rT3 were quantified by liquid chromatography-tandem mass spectrometry. Results: Patients with MASH cirrhosis exhibited substantially lower total T3 and T4 across all three compartments, with elevated rT3 in portal and systemic plasma. The T3/rT3 ratio, a functional index of deiodinase-mediated TH metabolism, was markedly suppressed (-65% to -83%). For disease discrimination, hepatic T3 demonstrated the strongest capacity (body mass index [BMI]-adjusted odds ratios [OR] = 0.009, 95% confidence intervals [CI]: 0.001-0.190; p < 0.001), followed by the systemic T3/rT3 ratio (BMI-adjusted OR = 0.045, 95% CI: 0.001-0.328; p < 0.001). Within the MASH cohort, systemic T4 correlated inversely with model for end-stage liver disease score (r = -0.867, adjusted p = 0.005) and Child-Pugh score (r = -0.760, adjusted p = 0.033), confirmed as the predominant severity correlate by multivariable regression independent of BMI (standardized beta = -0.744, adjusted p = 0.004). Conclusions: This study characterized TH metabolism in human end-stage MASH, which provides direct tissue-level evidence supporting intrahepatic hypothyroidism. The systemic T3/rT3 ratio and hepatic T3 potently discriminate MASH from healthy liver, while total systemic T4 tracks disease severity within established cirrhosis. Our findings suggest that distinct TH parameters serve complementary roles as biomarkers in diagnosis and prognosis.