Increased Hepatic Fat Content in Patients with Resistance to Thyroid Hormone Beta

“26 Consistent with these mouse observations, linkage studies showed that humans bearing THR-β loss- of-function variants had greater hepatic fat content on ultrasound than relatives with wild-type alleles, 27 interrupting the expected positive relationship between BMI and hepatic fat accumulation.”

“In one study, patients with THR-β mutations had increased liver fat (as assessed by controlled attenuation parameters using transient elastography) compared with their unaffected family members, while controlling for body mass index.(37) All participants belonged to the same family, lived on the same small island and…”

“…hypertriglyceridemia, insulin resistance, and non-alcoholic fatty liver disease, increased prevalence of attention-deficit disorder, and reduced colour vision and hearing 46,47 reflecting the important roles of THRβ1 in the adult liver and THRβ2 in the development of brain, retina, and cochlea.”

“Humans bearing loss-of-function mutations in the THRβ gene show thyroid hormone resistance [30] and a higher risk for liver steatosis [31].”

“com both hypothyroidism and thyroid hormone receptor b mutations in mice and humans increase NAFLD risk [8,9].”

“[39] In the next section, we will discuss in more detail how TH is involved in hepatic lipid metabolism and in cholesterol metabolism.”

“[78,79]”

“19 On the contrary, other authors supported that resistance to THs, indirectly evaluated by the calculation of the thyrotroph T4 sensitivity index, was higher in euthyroid patients with biopsy-proven MASLD and advanced fibrosis than in those without hepatic fibrosis or with minimal fibrosis.”

“13 Preclinical studies and results in humans have, therefore, supported the importance of THR-β in hepatic steatosis and stimulated interest in developing THR-β agonists as potential treatments for MASLD.”

“75 These studies also demonstrate the critical role of THR b in the liver to maintain normal lipid metabolism and prevent the development of MASLD in humans.”

“provided evidence that impairments in liver TRb signaling due to mutations in the THRB gene can lead to hepatic steatosis, which indicates the influence of TH on lipid metabolism in the liver (24).”

“In contrast, other studies found that an increase in the amount of the THR-β receptor increases the sensitivity of the liver tissue to the T3 hormone, improving mitochondrial function, β-oxidation, and slowing the progression of the disease.”

“Linkage studies have shown similarity in mice and humans in that humans bearing THR-B loss-of-function variants had greater hepatic fat content on ultrasound [29,36].”

“Likewise, humans bearing loss-of-function mutations in the THRB gene are at much higher risk for liver steatosis [29].”

“34 In human studies, low-dose TH as well as two liver-specific THR β specific agonists VK-2809/MB-07811 and resmetirom (MGL-3196) have shown significant efficacy in resolving MASLD/MASH.”

“Chaves et al. demonstrated that impairments in liver TR β signaling due to THRB gene mutations can lead to hepatic steatosis, indicating the influence of TH on lipid metabolism in the liver [22].”

“Among the metabolic dysfunctions, we should also acknowledge that intramyocellular and intrahepatic lipid accumulation [123] cause MASLD [124], whereas data regarding insulin resistance in RTH β are conflicting [123,125]; nevertheless, diabetes and high fasting glucose were highly prevalent (11”

“Therefore, THR influenced the accumulation of fat more that age and obesity [17].”

“Chaves et al. demonstrated that the nuclear receptor THRB plays a significant role in hepatic steatosis, highlighting the influence of thyroid hormone on lipid metabolism in the liver [34].”

“Research shows that the impaired signaling of thyroid hormone (TH) and thyroid hormone receptor beta (TR β ) in the liver can trigger hepatic steatosis [1].”

“14,15 That TC concentrations fall promptly after the administration of T3 in patients with RTH b 28 suggests resistance to the thyroid hormone action in the liver and a status of hypothyroidism in the organ.”

“For example, mutations in the thyroid hormone receptor beta (THRb) gene [83], the rs17618244 G > A β-Klotho (KLB) variant [84], germline hedgehog pathway [85], and polymerase I and transcript release factor [86], can also induce the occurrence of fatty liver.”

“Impairment of THR b 1 signaling may disrupt beta-oxidation of free FA, or disturb several metabolic processes including lipophagy, lipase activity, and mitochondrial function [40].”

“37 To elucidate the function of THR in lipid homeostasis, Araki et al created gene mutant mice with specific suppression of THR-α and THR-β.”

“Conversely, refractoriness to TH action in the liver, which expresses mainly TR β , may in part mediate the dyslipidemia [raised low-density lipoprotein cholesterol (LDL), triglycerides] and hepatic steatosis (9– 11) associated with RTH β .”

“It is characterized by elevated, circulating thyroid hormones with nonsuppressed TSH, dyslipidemia, and hepatic steatosis [2, 3], reflecting refractoriness to hormone action within the hypothalamic-pituitary-thyroid axis and liver, which are known to express mainly TR β .”

“Supporting this, individuals with mutations in THR-β, and thus resistant to T3, also show liver steatosis (Chaves et al. 2021).”

“Resmetirom was granted accelerated approval by the United States Food and Drug Administration (FDA) in 2024 and a conditional marketing authorization by the European Medicines Agency (EMA) in 2025 [8, 11, 13].”

“Notably, patients with mutations in the THRβ gene that reduce TH binding affinity also experience higher lev - els of hepatic steatosis and more liver fibrosis compared to controls [ 63].”

“Yet, despite systemic thyrotoxicosis, patients exhibit reduced TH action in TR b - predominant tissues, including liver and pituitary, and often develop dyslipidemia, insulin resistance, and non-alcoholic fatty liver disease (Chaves et al., 2021).”

“[ 27 ] Thus, despite some clear clinical effects on glucose metabolism and insulin sensitivity, the systemic regulation of glucose by TH and the THR is inadequately and incompletely understood.”

“In addition, RTHβ has also been associated with metabolic disturbances which may further increase cardiovascular risk [3, 12, 13].”