Pathophysiology of Multinodular Goitre
Multinodular goitre (MNG) is one of the most common thyroid disorders encountered in clinical practice. It is characterized by an enlarged thyroid gland with multiple nodules that vary in size and function. While many MNGs are benign and non-toxic, some evolve into toxic multinodular goitre, leading to hyperthyroidism. Understanding the pathophysiology of MNG provides insights into its clinical presentation, natural history, and management.
Normal Thyroid Physiology
The thyroid gland regulates metabolism through the synthesis and release of thyroid hormones—thyroxine (T4) and triiodothyronine (T3). These hormones are produced under the influence of thyroid-stimulating hormone (TSH) secreted by the pituitary gland. Iodine uptake, thyroglobulin synthesis, and coupling of iodotyrosine residues within the colloid are all essential steps in thyroid hormone production.
When thyroid hormone levels fall, the hypothalamic-pituitary-thyroid axis responds by increasing TSH secretion, stimulating thyroid growth and hormone synthesis.
Pathogenesis of Multinodular Goitre
The development of multinodular goitre is a multifactorial and progressive process, influenced by both environmental and genetic factors.
1. Chronic TSH Stimulation
Prolonged, mild TSH stimulation—often due to iodine deficiency—is a key driver in goitre formation. In low-iodine environments, thyroid hormone synthesis is inefficient, leading to compensatory TSH elevation. This sustained stimulation induces follicular hyperplasia and hypertrophy, gradually enlarging the gland.
2. Heterogeneous Follicular Response
Not all thyroid follicular cells respond uniformly to TSH. Some clones acquire autonomous growth advantages through mutations in growth-regulating genes. Over time, these clonal expansions form distinct nodules.
3. Somatic Mutations and Growth Autonomy
Somatic mutations in the TSH receptor (TSHR) and G protein alpha subunit (Gsα) are frequently found in autonomous nodules. These mutations cause constitutive activation of cyclic AMP (cAMP) signaling, allowing the nodule to grow and function independently of TSH regulation.
4. Role of Growth Factors and Cytokines
Local growth factors such as insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), and fibroblast growth factors (FGFs) contribute to the hyperplastic process. Reactive oxygen species (ROS) and cytokine-induced inflammation may further stimulate proliferation and nodule formation.
5. Colloid Accumulation and Degenerative Changes
As nodules enlarge, they undergo colloid accumulation, hemorrhage, fibrosis, and cystic degeneration, giving rise to the heterogeneous echotexture often seen on ultrasound. Over time, the gland becomes lobulated and asymmetric.
Evolution from Diffuse to Multinodular Goitre
The early stage of MNG is often a diffuse, non-toxic goitre. With time, uneven growth and differential responsiveness of follicles lead to the development of nodules. Eventually, some nodules acquire functional autonomy, leading to toxic multinodular goitre, where excess thyroid hormone is produced despite suppressed TSH levels.
Genetic and Environmental Influences
While iodine deficiency remains the predominant environmental factor, other contributors include:
– Goitrogens (e.g., thiocyanates in certain foods)
– Female predominance, suggesting hormonal modulation
– Familial clustering, indicating a genetic predisposition
– Aging, which increases the chance of somatic mutations and oxidative stress
Microscopic and Molecular Features
Histologically, MNG shows:
– Variable-sized follicles with colloid-rich and colloid-poor regions
– Areas of fibrosis, calcification, and cystic degeneration
– Hyperplastic and involutional nodules coexisting
On a molecular level, heterogeneity arises from different genetic mutations in separate nodules, supporting the theory that MNG represents a mosaic of independent clonal proliferations rather than a uniform process.
Clinical Implications
Understanding MNG pathophysiology aids in:
– Differentiating benign nodular growth from malignancy
– Explaining variable thyroid function (from euthyroid to hyperthyroid)
– Guiding therapeutic approaches—surgery, radioiodine ablation, or observation
Because each nodule may behave differently, careful evaluation through ultrasound and fine-needle aspiration cytology (FNAC) remains critical.
Conclusion
Multinodular goitre represents a culmination of chronic TSH stimulation, heterogeneous follicular hyperplasia, and somatic mutations leading to nodular growth and autonomy. Its evolution is gradual, shaped by environmental, hormonal, and genetic influences. Recognizing these mechanisms is essential for clinicians in tailoring patient-specific management strategies.