Pathogenesis of toxic thyroid adenomas and nodules: relevance of activating mutations in the TSH-receptor and Gs-alpha gene, the possible role of iodine deficiency and secondary and TSH-independent molecular mechanisms

Summary

In iodine deficiency areas, activating mutations in the TSH receptor and Gs-alpha gene are found in the majority of toxic thyroid adenomas and in some toxic goiter nodules. Since TSH receptor and Gs-alpha gene mutations are very rare in areas with high iodine supply, iodine deficiency has been suspected to favor the occurrence of these mutations by yet unknown pathways. However, TSH receptor and Gs-alpha gene mutations alone are not sufficient to cause toxic adenomas and nodules. There is compelling evidence that other secondary and cAMP-independent mechanisms, including enhanced expression of various growth factors, their corresponding receptors and of signaling proteins, may affect the mutated cell and thus promote cell proliferation and in turn generation of the tumor.

In iodine deficiency areas, nodular goiters and, as a consequence, hyperfunctioning nodules and adenomas are highly prevalent.

Although these tumors represent only a minor fraction of all goiter nodules, they are a frequent cause of hyperthyroidism. In contrast, in regions with sufficient iodine intake of the population these thyroid diseases are relatively rare (Hamburger, 1987). Recent findings of activating mutations in the TSH receptor (TSHr) and Gs-alpha gene in toxic adenomas and nodules have spawned new insights into the pathogenesis of these tumors (Derwahl, 1996; Derwahl et al., 1996). The fact that these mutations have only been detected in toxic adenomas and nodules from iodine deficiency areas has been taken as evidence that iodine deficiency per se has a pathogenetic role in the generation of toxic adenomas and nodules by enhancing mutational events in follicular mother cells.

This review critically addresses the question whether an activating mutation of the TSHr or Gs-alpha gene is by itself a sufficient cause for generating toxic adenomas and goiter nodules.

At least two alternatives must be considered. Firstly, an activating TSHr or Gs-alpha mutation may be an initial event that is secondarily amplified and modulated by other growth-promoting events that finally lead to tumor formation. Secondly, activating mutations may only account for hyperfunc-tion of a cell, while its excessive proliferation may be due to processes independent of the mutation itself. Furthermore, the question may be discussed how iodine deficiency may influence the generation and propagation of toxic thyroid adenoma and nodular goiter growth.

Key words

Toxic thyroid adenoma - pathogenesis - iodine deficiency - growth factors