Department for Endocrinology and Nephrology, University of Leipzig, Liebigstrasse 20, D-04103, Leipzig, Germany.
Langenbecks Arch Surg. 2011 Dec;396(8):1127-36. doi: 10.1007/s00423-011-0788-5. Epub 2011 Apr 14.
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.
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.
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.
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.
家族性甲状腺肿的聚集主要表现为常染色体显性遗传模式。此外，其他环境和病因因素可能参与了甲状腺功能正常的甲状腺肿的发展。因此，可能基于遗传易感性和个体环境的复杂相互作用的多因素病因。
从早期甲状腺增生到多结节性甲状腺肿的一系列事件表明结节结构具有主要的肿瘤性质（即源自单个突变细胞）。从病因学上讲，已知两种三分之一的甲状腺乳头状癌和滤泡状癌以及热结节中有相关的体细胞突变。相比之下，与良性冷结节或良性等摄碘性甲状腺结节相关的体细胞突变是未知的，而后者构成了大多数甲状腺结节。
结节过程是由甲状腺激素合成的氧化性质或碘缺乏或吸烟引起的额外氧化应激引发的。如果抗氧化防御无效，这种氧化应激会导致 DNA 损伤，随后自发突变率增加，这是肿瘤发生的底物。
因此，甲状腺生理学的标志——激素合成过程中的 H2O2 产生——很可能是甲状腺中频繁突变的最终原因。由于碘缺乏会增加氧化负担，因此 DNA 损伤和突变可能为地方性甲状腺肿的频繁结节转化提供基础。
