OR01-06 Resistance to Thyroid Hormone Beta Is Associated with an Increase in Hepatic Fat Measured by Transient Elastography (Fibroscan®) with Controlled Attenuation Parameter (CAP)

Abstract

Hepatic regulation of lipid metabolism is dependent on thyroid hormone receptors (TRs) with TRβ as the predominantly expressed TR isoform in the liver. Patients with resistance to thyroid hormone (RTH) harboring mutations in the THRB gene have loss-of-function of TRβ. Thus, we investigated whether these patients can present with alterations in the lipid homeostasis.We evaluated hepatic fat content and metabolic parameters in patients bearing the R243Q mutation of THRB gene (n=21) and in their non-affected (WT) first degree relatives (n=22). All participants belonged to the same family, lived in the same small island, therefore exposed to similar environmental conditions. Family members with disorders known to affect lipid metabolism as well as a history of drinking habits of more 30 g alcohol/day were excluded. Whenever possible, medications were suspended one month before the tests. Hepatic fat content was estimated by transient elastography (FibroScan®, TE) with controlled attenuation parameter (CAP) as a noninvasive marker of hepatic steatosis. Measurements of CAP and metabolic parameters were carried after an overnight fast. The observers were blinded to the status of the patients.There were no significant difference between the two groups, RTHβ and WT respectively, in age (mean±SD) 36±11 years (range 18-55) and 34±9 years (19-59) and body mass index, BMI, 21.9 Kg/m2 (14.2-31.7) and 23.8 Kg/m2 (18.9-37.7). CAP values were significantly higher in RTHβ patients when compared to those measured in their WT relatives, 263±21 dB/m and 218.7±43 dB/m, respectively (P<0.001). Measurements of CAP correlated positively with age and BMI in the WT group (r=0.56; P<0.05 and r=0.59; P<0.05 respectively) but not in the group of RTHβ (r=0.19; P>0.05 and r=0.21;P>0.05. The lipid profile was not significant difference between the two group regarding total cholesterol (165±27 and 175±30 mg/dl), LDL cholesterol (103±16 and 113±29 mg/dl) and tryglicerides (115±45 and 108±43mg/dl). However, the HDL cholesterol was significantly lower in RTHβ patients (40±8 and 52±10 mg/dl; P<0.006). Glycemia, insulin levels and HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) were within the normal range and showed no significant differences between the two groups.In conclusion, RTHβ was associated with hepatic steatosis indicating that the TRβ dependent signaling of thyroid hormone plays an important role in lipid homeostasis. This finding further emphasizes the rational for the development of thyroid hormone analogues selective for TRβ which may offer alternatives for treatment of lipid-associated hepatic disorders without generating cardiac toxicity or accelerated bone loss.