Xinru Zhang1, Zhixiong Ying2, Tonguç U. Yilmaz3, Piter J. Bosma2, Maarten E. Tushuizen4, Anita Boelen1, Eveline Bruinstroop5
(1) Department of Laboratory Medicine, Endocrine Laboratory, Research Institute Amsterdam Gastroenterology Endocrinology & Metabolism (AGEM), Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
(2) Department of Gastroenterology and Hepatology and Tytgat Institute for Liver and Intestinal Research, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
(3) Department of Organ Transplantation, Acıbadem Mehmet Ali Aydınlar University, Atakent Hospital, Istanbul, Turkey.
(4) Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands.
(5) Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, Research Institute Amsterdam Gastroenterology Endocrinology & Metabolism (AGEM), Amsterdam UMC, Amsterdam, The Netherlands.
Background and aims
Metabolic dysfunction-associated steatohepatitis (MASH) cirrhosis is linked to impaired thyroid hormone (TH) signaling. Animal studies showed decreased hepatic TH availability, but the exact changes in humans are currently unknown. We aimed to determine the systemic and intrahepatic TH concentrations in patients with end-stage MASH compared to healthy liver donors.
Methods
We measured total triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3) via LC-MS/MS in liver tissue and plasma from patients with MASH cirrhosis (n = 12) undergoing transplantation and matched healthy donors (n = 12). In addition, we analyzed correlations between TH concentrations and Model for End-Stage Liver Disease (MELD)/Child-Pugh scores.
Results
MASH patients exhibited significantly lower T3 and T4 and markedly higher rT3 concentrations in both liver tissue and plasma compared to healthy donors. Consequently, the T3/rT3 ratio, as a surrogate marker for type 1 deiodinase (DIO1) activity, was profoundly decreased. Plasma T3 and T3/rT3 ratio showed strong negative correlations with MELD and Child-Pugh scores.
Conclusion
End-stage MASH features severe hepatic hypothyroidism and systemic TH changes resembling non-thyroidal illness syndrome (NTIS). The systemic T3/rT3 ratio is a robust non-invasive biomarker of disease severity with potential as a mechanistic endpoint for clinical trials in decompensated MASH cirrhosis.