Nontoxic Multinodular Goiter Theories of Pathogenesis and Thyrocyte Regulation

The pathogenesis and hence the treatment of multinodular goiter are debatable. If a goiter were simply induced by uninhibited TSH stimulation, one might expect it to be a diffuse goiter. Early studies by Taylor suggested a "natural" progression from diffuse toward multinodular.104 Indeed, TSH levels are in general not elevated in sporadic goiters. Studer and Ramelli105 suggested that newly generated follicles involve thyrocyte clones that may retain the ability to concentrate iodine (hot nodules) or that have lost that ability (cold nodules). This phenomenon, coupled with an impairment of blood supply during growth, may lead to areas of fibrotic regression and dystrophic calcification indicative of a degenerate multinodular goiter.105

Changes in follicular function are probably due to environmental factors, such as the local iodine supply,'06 failing blood supply to an active goiter,107 and the relative aging of cellular components, which has been shown in the aging mouse thyroid as a transformation of normally functioning follicles into irreversibly cold follicles.108

Genetically separable thyrocyte clones probably also generate nodular heterogeneity. This in itself does not explain all the features of a multinodular goiter, in particular the natural tendency toward autonomous nodule formation or the variability of metabolic function such as TSH-inducible adenosine monophosphate activity within the goiter.109110

Moreover, multinodular goiters have unique growth patterns with variable iodine turnover and demonstrate growth that is discordant with radioscintigraphic function, which separates their behavior from that of other types of goiter. The cells from human multinodular goiters in tissue culture have variable TSH dependence, with cells with equivalent growth potential clustering near one another. Presumably, the clones with inherent growth potential respond to strong extrathyroidal stimuli (such as TSH or epidermal growth factor) and differ from the clones with low mitotic activity that respond to weak stimuli (such as endemic iodine fluctuation or the activity of local goitrogens) over very prolonged periods.

Further evidence, although controversial, has implicated a putative set of thyroid growth-stimulating immunoglobulins (TSIs) in multinodular goiter development, which are thought to act independently of the TSH but through the TSH receptor.101111"113 We believe most evidence suggests that TSIs work through the TSH receptor. The newly generated follicles are then integrated into the growing goiter by cellular adherence to the dominant follicle, by papillary protrusion into the follicular lumen, and by the formation of daughter follicles. All of these processes incorporate cellular groups with widely differing iodinating capacities and TSH responsiveness"4 but with individual follicular similarity in terms of ultrastructure, metabolic activity, and receptor expression.115116

It is believed that in addition to differences in follicular activity, variable interregional DNA concentration per unit volume of goiter weight may reflect variability in stromal content. Factors affecting the elastic connective tissue framework of the goiter may alter the capacity of the developing capillary network to keep pace with the metabolic requirements of expanding follicular cohorts. This effect ultimately changes the shape of the enlarging goiter as well as its overall function and level of degeneracy.117118

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