Intrahepatic hypothyroidism in MASLD: Role of liver-specific thyromimetics including resmetirom

Background and aims Thyroid hormones are important regulators of hepatic lipid homeostasis and whole-body energy expenditure. Recent evidence suggests that euthyroid individuals with metabolic dysfunction-associated steatohepatitis (MASH) develop intrahepatic hypothyroidism that promotes progression of MASH. Methods A literature search was performed with Medline (PubMed), Scopus and Google Scholar electronic databases from inception till March 2024, using the following keywords: hypothyroidism and nonalcoholic fatty liver disease; MASLD and thyroid function; intrahepatic hypothyroidism; TRβ agonists; and resmetirom. Relevant studies were extracted that described pathogenesis of MASH in the context of thyroid functions. Results In euthyroid individuals with MASH, there is decreased conversion of prohormone thyroxine (T4) to bioactive tri-iodothyronine (T3) and increased conversion of T4 to inactive metabolite reverse T3 (rT3). Consequently, reduced levels of T3 results in impaired intrahepatic TRβ signaling, a state of intrahepatic hypothyroidism, which promotes progression of MASH. Hepatic TRβ activation leads to metabolically beneficial effects in the liver including mitochondrial fatty acid uptake and β-oxidation, mitochondrial biogenesis, increasing surface low-density lipoprotein (LDL) receptor density and lowering of circulatory LDL-cholesterol. In recent years, selective thyroid hormone mimetics that exhibit TRβ-selective binding and liver-selective uptake have been designed. Resmetirom, a liver-specific thyromimetic, improves intrahepatic TRβ signaling and in clinical trials significantly improved liver inflammation, fibrosis and lipid profile in patients with MASH. Conclusions In euthyroid individuals with MASH, development of intrahepatic hypothyroidism results in further progression of the disease. In clinical trials, resmetirom treatment results in a significant improvement in steatosis, inflammation and fibrosis and is the first drug approved by the US Food and Drug Administration (FDA) for the treatment of noncirrhotic MASH with moderate to advanced fibrosis.