Thyroid function in Gunn rats with genetically altered thyroid hormone catabolism

Abstract

Abstract. Due to a congenital deficiency in uridine diphosphate glucuronosyl transferase (UDP-GTase), Gunn rats display an impaired biliary elimination of both bilirubin and thyroid hormones, resulting in hyperbilirubinaemia and hyperthyroxinaemia. They also present a pigmented thyroid gland. In order to assess the effect of the hyperthyroxinaemia on the regulation of the thyroid function, the [125I]thyroid uptake and distribution into soluble proteins, the [127I]thyroid soluble content, the levels of circulating T4, total and free, T3, reverse T3 (rT3) and TSH as well as the TSH response to TRH have been determined in Gunn (G) and Wistar (W) rats aged 3 to 56 weeks. Gunn rats possess a goitre with increased soluble [127I]-iodine content. The [125I]thyroid uptake and incorporation into soluble proteins were similar in both strains, but the DIT fraction was higher, whereas the MIT, T4 and T3 fractions were lower compared to control rats. Total thyroxinaemia was greatly increased in Gunn rats as expected (G:5.1–9.1 vs W:3.1–4.6 μg/dl) whereasfree thyroxinaemia was increased only by 25–50%. The differences in total-T4 and bilirubin serum levels between Gunn and Wistar rats 6 to 56 weeks old were found to be in direct correlation. In addition, Gunn rats presented normal serum T3 levels, but increased rT3 (G: 0.10–0.45 vs W:<0.03–0.27 ng/ml) and TSH (G:0.33–0.75 vs W:0.11–0.43 ng/ml) serum levels. The TSH response to TRH was however normal, but the return to basal values was delayed in comparison to Wistar rats. Evolution of thyroid parameters with age was similar in both strains, i.e. opposite variations in T3 and rT3 serum values during the post-natal period and decreasing serum T4 concentrations, pituitary TSH content and TSH response to TRH during the adult life. In conclusion, the association of hyperthyroxinaemia with decreased T3/rT3 serum ratio suggests that Gunn rats may have, in addition to the impaired biliary excretion of iodothyronines, a modified T4 deiodination pattern with probably increased rT3 formation. A diminished T4 availability and/or a decreased T4 to T3 conversion in the thyrotrophe cell might explain the normal TSH response to TRH. These data reflect a partial peripheral resistance to the hyperthyroxinaemia, which may represent an adaptation mechanism.