Natural History of Goitre Formation
Goitre formation follows a progressive natural history characterized by continuous growth over time, with evolution from euthyroid to hyperthyroid states in many cases, driven primarily by chronic iodine deficiency and local growth factor dysregulation. 1, 2
Pathophysiology and Evolution
The development of goitre involves a complex interplay beyond the classical TSH-driven model:
Iodine deficiency remains the predominant cause worldwide, affecting over 90% of the 200 million patients with goitre globally, with endemic prevalence reaching approximately 25% in countries without systematic iodine supplementation 3
Growth factor regulation plays a critical role: intrathyroidal iodine depletion leads to increased production of proliferation-stimulating factors (IGF-I and EGF) while simultaneously decreasing proliferation-inhibiting factors (TGF-beta), resulting in thyroid cell proliferation independent of TSH alone 3
TSH primarily regulates differentiation and function of thyroid cells and may induce hyperplasia, but does not directly cause cell proliferation—challenging the classical concept that TSH is the sole driver of goitre formation 3
Progressive Disease Course
The natural history demonstrates predictable progression patterns:
Continuous growth is the hallmark feature, with most intrathoracic goitres showing ongoing enlargement over time 1
Functional evolution occurs from euthyroidism toward hyperthyroidism in many patients, particularly those with nodular disease 1
Morphological transformation progresses from diffuse to nodular patterns, with nodular disease requiring evaluation for malignancy risk (though malignancy rates are not higher than cervical goitres) 1, 4
Pulmonary function deterioration develops even in asymptomatic individuals with substernal extension 1
Clinical Presentation Patterns
Patients may present across a spectrum:
Asymptomatic presentation is common, with goitre discovered incidentally on examination or imaging 2
Compressive symptoms including cough, dysphagia, and respiratory compromise develop as the gland enlarges 2
Thyroid dysfunction symptoms may emerge, with hypothyroid or hyperthyroid features depending on the underlying etiology and disease stage 2
Risk Factors and Modifiers
Several factors influence goitre development and progression:
Hereditary factors play an important role beyond environmental influences 4
Environmental goitrogens, smoking, and deficiencies of selenium and iron contribute to goitre formation 4
Geographic location determines iodine availability, with endemic goitre persisting in regions lacking prophylactic supplementation 3
Management Implications Based on Natural History
Given the progressive nature of goitre:
Active intervention is recommended rather than observation alone, because the natural history demonstrates continuous growth and functional deterioration 1
Total or near-total thyroidectomy followed by levothyroxine substitution represents the therapy of choice for intrathoracic goitres, with complications only slightly more prevalent than cervical goitres 1
Radioactive iodine offers an alternative for secondary intrathoracic goitres, achieving approximately 40% size reduction at one year with improved respiratory function and quality of life 1
Recombinant human TSH can augment radioiodine-related shrinkage by 30-50% when used off-label, with rare and mild side effects beyond hypothyroidism 1
Levothyroxine suppression alone is not recommended for goitre shrinkage, though it may prevent further growth in some cases 1, 2
Diagnostic Evaluation Framework
Based on the progressive natural history:
TSH measurement serves as the appropriate first test for all patients with goitre 2
Thyroid ultrasound should be performed in all patients as an extension of physical examination to characterize nodules and guide biopsy decisions 2
Radionuclide scanning is indicated when TSH is suppressed to differentiate toxic etiologies 2
CT imaging is superior for evaluating substernal extension and tracheal compression in intrathoracic goitres 5