INTRODUCTION: Familial clustering of goiters mostly with an autosomal dominant pattern of inheritance has repeatedly been reported. Moreover, other environmental and etiologic factors are likely to be involved in the development of euthyroid goiter. Therefore, a multifactorial etiology based on complex interactions of both genetic predisposition and the individuals' environment is likely. METHODS: The line of events from early thyroid hyperplasia to multinodular goiter argues for the predominant neoplastic (i.e., originating from a single mutated cell) character of nodular structures. Etiologically, relevant somatic mutations are known in two thirds of papillary and follicular thyroid carcinomas and hot thyroid nodules. In contrast, the somatic mutations relevant for benign cold or benign isocaptant thyroid nodules which constitute the majority of thyroid nodules are unknown. RESULTS: The nodular process is triggered by the oxidative nature of thyroid hormone synthesis or additional oxidative stress caused by iodine deficiency or smoking. If the antioxidant defense is not effective, this oxidative stress will cause DNA damage followed by an increase of the spontaneous mutation rate which is a substrate for tumorogenesis. CONCLUSIONS: Therefore, the hallmark of thyroid physiology--H(2)O(2) production during hormone synthesis--is very likely the ultimate cause for the frequent mutagenesis in the thyroid gland. Because iodine deficiency increases the oxidative burden, DNA damage and mutagenesis could provide the basis for the frequent nodular transformation of endemic goiters.
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