Animal models of nonthyroidal disease.

Abstract

Rats bearing transplantable Walker 256 carcinoma provide an opportunity to assess thyroid function and activity during an interval of time when the tumor has not affected growth rate. Rats with tumor have decreased serum T4 and T3 concentration and decreased serum FT4 and FT3 as well. These changes are due to a decrease in binding of iodothyronines by the serum binding proteins, an increase in the fractional rate of T4 metabolism and a decrease in thyroidal secretion. The decrease in activity of the thyroid gland appears to be due to reduced sensitivity of the thyroid to circulating TSH. Despite decreased serum FT4 and FT3 concentrations, serum TSH remains normal, not increased as would be anticipated in a hypothyroidal animal. Nevertheless, a further experimental decrease in serum T4 and/ or T3 from the already reduced serum iodothyronine levels of the tumor bearing rat results in a normal increment in serum TSH. Thus, TSH secretion appears to be regulated normally despite decreased concentrations of pituitary nuclear T3. This finding suggests that tumor bearing rats have greater than normal sensitivity to T3 in their regulation of TSH secretion. Rats with Walker 256 carcinoma have decreased concentrations of hepatic nuclear T3 receptors and a decrease in T3 specifically bound to the receptors. The fractional occupancy of hepatic nuclear receptors appears relatively normal. The dose-response of alpha-GPD in relation to fractional nuclear T3 receptor occupancy appears shifted up and to the left in tumor bearing rats, whereas the curve for ME is shifted down to the right. The appearance rates of these enzymes are described by similar functions. These findings suggest that postreceptor factors in tumor bearing rats may result in augmentation of some and depression of other biologic responses to thyroid hormones. If the results of these studies are extended to sick patients, they may provide a possible mechanism whereby patients maintain the euthyroid clinical state despite a decrease in serum T3. Thus, postreceptor factors may enhance those thyroidal responses which characterize the euthyroid clinical state. Moreover, attenuation of other thyroidal responses related to conservation of protein may provide a distinct adaptive advantage to the patient with nonthyroidal illness with or without decreased food consumption.