Development of nodular goitre most likely proceeds in two phases, that involve global activation of thyroid epithelial cell proliferation (e.g. as the result of iodine deficiency or other goitrogenic stimuli) leading to hyperplasia and a focal increase of thyroid epithelial cell proliferation causing thyroid nodules. So far, the most common stimulus for focal proliferation is a somatic mutation.
Two driving pathogenetic events have to be considered (Figure 1): first, iodine deficiency causing an increase in thyroid cell numbers (true hyperplasia) as observed in animal models. Second, H2O2 production and free radical formation, which occurs physio logically during thyroid hormone synthesis, may damage genomic DNA. Thus in a mouse model, the spontaneous mutation rate in the naive thyroid gland has been found to be almost ten times higher than in other organs.
Fig1. Interaction of extrinsic and intrinsic factors contributing to the development of nodular goitre. Note that the pathogenic influence of several goitrogenous components (e.g. selenium deficiency, pregnancy) will be aggravated with coexisting iodine deficiency. The two elementary molecular pathomechanism are increased cell proliferation, leading to hyperplasia/ goitre and in addition with oxidative stress leading to increased mutagenesis and nodule formation.
Both processes provide a mutagenic milieu, in which the like lihood of somatic mutations is increased. Whether these somatic mutations lead to thyroid nodular disease critically depends on the affected gene and most likely the environmental selection fac tors (e.g. iodine deficiency; Figure2). A proof of principle for this concept is the evolution of a toxic adenoma from a somatic thyroid- stimulating hormone (TSH) receptor mutation. Other examples include the origin of papillary thyroid cancer based on BRAF mutations or RET/ PTC rearrangements. These somatic mutations have been found already in microscopic lesions of thyroid autonomy and papillary microcarcinoma, respectively. Besides the driving mutation, increased growth factor production and auto- and paracrine action of secreted growth fac tors (e.g. IGF- 1) has been found in monoclonal thyroid tumours and may further propel nodule development.
Fig2. Pathogenesis of nodular goitre in an iodide deficiency environment. According to current concepts the development of nodular goitre proceeds in two phases, that involve: (1) adaptive increase in thyroid epithelial cell proliferation and function, providing a mutagenic milieu with increased likelihood for occurrence of somatic mutations; and (2) clone expansion to a macroscopic thyroid nodule by growth advantage of cell clone with somatic mutation and propagation in persisting iodine deficiency.
The development of polyclonal thyroid lesions in an NTG is less clear and putatively is linked to exogenous factors (e.g. intrathyroidal production of growth factors such as IGF- 1), which act on the naturally functional and morphological heterogeneous thyroid follicles.
