Causes of Multinodular Nontoxic Goiter
Multinodular nontoxic goiter develops from the natural heterogeneity of thyroid follicular cells amplified by unidentified trophic stimuli, with iodine deficiency being an important but not sole contributing factor. 1
Primary Pathophysiologic Mechanisms
The fundamental process of goiter formation operates through mechanisms innate to hereditary and acquired heterogeneity among thyroid cells themselves, independent of iodine deficiency. 2 This represents a benign neoplastic process arising through mechanisms common to all benign endocrine tumors. 2
Cellular-Level Causes
Thyroid follicular cell heterogeneity is the foundational cause, where genetically diverse thyroid cells respond differently to growth stimuli, leading to episodes of proliferating micronodules that evolve into multinodular goiter over time. 1
Clonal and polyclonal nodule growth occurs within the same gland, demonstrating that multiple independent cellular populations contribute to nodule formation. 2
Somatic mutations may develop in individual nodules, though these are more characteristic of autonomous functioning nodules rather than nontoxic goiter. 1
Environmental and Nutritional Factors
Iodine-Related Causes
Iodine deficiency is the most important environmental factor globally, affecting 500-600 million people worldwide and greatly enhancing the incidence of multinodular goiter. 3, 1
Severe iodine deficiency causes goiter and hypothyroidism because thyroid activity increases to maximize iodine uptake and recycling, but iodine concentrations remain too low for adequate thyroid hormone production. 3
Iodine deficiency increases the risk of developing autonomous thyroid nodules that become unresponsive to TSH control. 3
However, low intrathyroidal iodine concentration is a secondary rather than primary event in goiter pathogenesis, occurring in both endemic and sporadic goiter. 2
Micronutrient Deficiencies
Iron deficiency impairs thyroid metabolism and contributes to goiter development. 3
Selenium deficiency affects thyroid function as deiodination of T4 to T3 depends on Type 1 5'-deiodinase, a selenoenzyme. 3
Non-Iodine Dependent Factors
Genetic and Constitutional Factors
Prominent genetic predisposition exists for multinodular goiter development, explaining familial clustering. 2
Female sex is a significant risk factor, with multinodular goiter being more common in women, particularly in their fifth and sixth decades. 3, 4
Advancing age increases goiter incidence, with typical development occurring over many years. 3, 5
Acquired and Environmental Factors
Previous external irradiation exposure increases the risk of nodular goiter formation. 5
Unidentified trophic stimuli beyond TSH contribute to the proliferative episodes that drive goiter growth. 1
Environmental and acquired factors beyond iodine status play roles in goiter development, though specific mechanisms remain incompletely understood. 6
Important Clinical Considerations
Sporadic nodular goiter occurs in 4-6% of American adults despite adequate iodine intake, demonstrating that iodine deficiency alone does not explain all cases. 1
The inverse relationship between goiter size and serum TSH indicates that TSH elevation is not the primary driver of growth in established multinodular goiter. 2
Autonomous growth patterns develop in many multinodular goiters, with nodules growing independently of TSH stimulation. 2
Superimposed iodine shortage enhances the incidence and shifts clinical appearance toward younger ages by adding TSH-mediated growth stimulation to an already activated growth-regulating network. 2