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

Abstract

Background: Thyroid hormone (TH) has important functions in controlling hepatic lipid metabolism. Individuals with resistance to thyroid hormone beta (RTHβ) who harbor mutations in the THRB gene experience loss-of-function of thyroid hormone receptor beta (TRβ), which is the predominant TR isoform expressed in the liver. We hypothesized that individuals with RTHβ may have increased hepatic steatosis. Methods: Controlled attenuation parameter (CAP) was assessed in individuals harboring the R243Q mutation of the THRB gene (n = 21) and in their wild-type (WT) first-degree relatives (n = 22) using the ultrasound-based transient elastography (TE) device (FibroScan). All participants belonged to the same family, lived on the same small island, and were therefore exposed to similar environmental conditions. CAP measurements and blood samples were obtained after an overnight fast. The observers were blinded to the status of the patients. Results: The hepatic fat content was increased in RTHβ individuals compared with their WT relatives (CAP values of 263 ± 21 and 218.7 ± 43 dB/m, respectively, p = 0.007). The CAP values correlated with age and body mass index (BMI) (age: r = 0.55, p = 0.011; BMI: r = 0.51, p = 0.022) in the WT first-degree relatives but not in RTHβ individuals, suggesting that the defect in TRβ signaling was predominant over the effects of age and obesity. Circulating free fatty acid levels were significantly higher in RTHβ individuals (0.29 ± 0.033 vs. 0.17 ± 0.025 mmol/L, p = 0.02). There was no evidence of insulin resistance evaluated by the homeostatic model assessment of insulin resistance in both groups studied. Conclusions: Our findings provide evidence that impairments in intrahepatic TRβ signaling due to mutations of the THRB gene can lead to hepatic steatosis, which emphasizes the influence of TH in the liver metabolism of lipids and provides a rationale for the development TRβ-selective thyromimetics. Consequently, new molecules with a very high TRβ affinity and hepatic selectivity have been developed for the treatment of lipid-associated hepatic disorders, particularly nonalcoholic fatty liver disease.

Keywords: hepatic steatosis; resistance to thyroid hormone beta; thyroid hormones; transient elastography.

FIG. 1.

More than 200 members of this family with RTHβ spanning six generations were identified. They were traced to a late 19th-century founder couple that served as the progenitor of 68 nuclear families. Family members belonging to the sixth generation are not drawn in this tree because it would increase the size of the figure behind acceptable limits. Furthermore, none of these individuals were included in the present study due to their young age (younger than 18 years). RTHβ, resistance to thyroid hormone beta.

FIG. 2.

(A) Values of liver stiffness obtained by TE in 21 (square) RTHβ individuals and 22 (circle) WT relatives. The difference between the means was not significant. Notably, 6 of 21 RTHβ individuals (28.6%) presented levels >7.5 kPa (upper limit of normal indicated by a horizontal line in this panel) compared with only 3 of 22 (13.6%) in the WT relatives (11,12). (B) The CAP values were significantly higher in the RTHβ individuals compared with those measured in their first-degree relatives (t-test; p < 0.007). CAP values >240 dB/m are very sensitive for hepatic steatosis (13,14). This cutoff is indicated in the panel as a horizontal line. (C) Age and BMI were not correlated (linear regression) with CAP values in individuals with RTHβ, indicating that loss of TRβ signaling is a strong and independent risk factor of hepatic steatosis. (D) In the WT first-degree relatives without impaired TRβ signaling, the CAP values were correlated (linear regression) with age and BMI (one outlier BMI value of >40 kg/m² was removed). Both correlations remained significant after adjustment for BMI and age, respectively. BMI, body mass index; CAP, controlled attenuation parameter; TE, transient elastography; TRβ, thyroid hormone receptor beta; WT, wild type.