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This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of thyroid disorders? ​

Abstract ​

Thyroid disorders represent a significant global health challenge, affecting millions and imposing considerable economic burdens on healthcare systems. The thyroid gland plays a crucial role in regulating metabolism, growth, and development through the secretion of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3). Disruptions in hormone production can lead to hypothyroidism and hyperthyroidism, each associated with severe metabolic consequences. Understanding the mechanisms underlying these disorders is essential, as they involve intricate interactions among genetic, autoimmune, and environmental factors. This review discusses the anatomy and physiology of the thyroid gland, the mechanisms and causes of hypothyroidism—including autoimmune thyroiditis and iodine deficiency—and hyperthyroidism, focusing on Graves' disease and toxic adenomas. Genetic factors, such as hereditary syndromes and gene-environment interactions, are explored, along with the impact of environmental influences like medications, toxins, and nutritional factors on thyroid health. The findings emphasize the multifaceted nature of thyroid disorders and the need for comprehensive research to develop effective diagnostic and therapeutic strategies aimed at improving patient outcomes. By elucidating these mechanisms, this review seeks to enhance understanding and inform future research directions in the field of endocrinology.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Overview of Thyroid Function
    • 2.1 Anatomy and Physiology of the Thyroid Gland
    • 2.2 Hormonal Regulation and Feedback Mechanisms
  • 3 Hypothyroidism: Mechanisms and Causes
    • 3.1 Autoimmune Thyroiditis (Hashimoto's Disease)
    • 3.2 Iodine Deficiency and Other Environmental Factors
  • 4 Hyperthyroidism: Mechanisms and Causes
    • 4.1 Graves' Disease and Autoantibodies
    • 4.2 Thyroid Nodules and Toxic Adenomas
  • 5 Genetic Factors in Thyroid Disorders
    • 5.1 Hereditary Syndromes
    • 5.2 Gene-Environment Interactions
  • 6 Environmental Influences on Thyroid Health
    • 6.1 Impact of Medications and Toxins
    • 6.2 Nutritional Factors and Lifestyle
  • 7 Summary

1 Introduction ​

Thyroid disorders represent a significant global health challenge, affecting millions of individuals and imposing considerable economic burdens on healthcare systems. The thyroid gland, a small butterfly-shaped organ located in the neck, is crucial for regulating metabolism, growth, and development through the secretion of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3). Disruptions in thyroid hormone production can lead to a spectrum of disorders, primarily categorized into hypothyroidism, characterized by insufficient hormone production, and hyperthyroidism, marked by excessive hormone secretion. These conditions can lead to severe metabolic and physiological consequences, impacting overall health and quality of life [1][2].

The significance of understanding the mechanisms underlying thyroid disorders cannot be overstated. The pathophysiology of these conditions is multifaceted, involving intricate interactions between genetic, autoimmune, and environmental factors. For instance, autoimmune thyroiditis, exemplified by Hashimoto's disease, results from the immune system erroneously attacking the thyroid gland, leading to hypothyroidism. Conversely, Graves' disease is characterized by the production of autoantibodies that stimulate excessive thyroid hormone production, resulting in hyperthyroidism [3][4]. Additionally, environmental influences such as iodine deficiency, exposure to certain medications, and toxins play critical roles in the etiology of thyroid disorders [5][6].

Recent advances in research have highlighted the importance of genetic predispositions and environmental factors in the development of thyroid disorders. For example, genetic variations can significantly affect individual susceptibility to autoimmune conditions affecting the thyroid, and environmental elements such as dietary iodine levels and exposure to endocrine-disrupting chemicals can further modulate this risk [5][7]. Understanding these complex interactions is essential for developing targeted diagnostic and therapeutic strategies that can improve patient outcomes.

This review aims to provide a comprehensive overview of the mechanisms underlying various thyroid disorders, organized into several key sections. First, we will discuss the anatomy and physiology of the thyroid gland, emphasizing its hormonal regulation and feedback mechanisms. Following this, we will explore the mechanisms and causes of hypothyroidism, including autoimmune thyroiditis and environmental factors such as iodine deficiency. The subsequent section will focus on hyperthyroidism, examining the roles of Graves' disease, thyroid nodules, and toxic adenomas.

We will then delve into the genetic factors associated with thyroid disorders, discussing hereditary syndromes and gene-environment interactions that influence disease development. The review will also address environmental influences on thyroid health, highlighting the impact of medications, toxins, and nutritional factors on thyroid function. Finally, we will summarize the key findings and discuss the implications for future research and clinical practice in the field of endocrinology [5][6].

By elucidating the mechanisms underlying thyroid disorders, this review seeks to enhance our understanding of these complex conditions and inform future research directions and clinical practices aimed at improving patient care and outcomes in thyroid health.

2 Overview of Thyroid Function ​

2.1 Anatomy and Physiology of the Thyroid Gland ​

Thyroid disorders encompass a range of conditions that significantly impact endocrine function and overall health. The thyroid gland, a butterfly-shaped organ located in the neck, plays a critical role in regulating metabolism, growth, and development through the secretion of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3). Understanding the mechanisms underlying thyroid disorders involves examining both the anatomical and physiological aspects of the thyroid gland, as well as the genetic, environmental, and autoimmune factors that can disrupt its function.

Anatomically, the thyroid gland consists of two lobes connected by a thin isthmus, and it is richly vascularized, which is essential for its hormone production and secretion. The gland is composed of follicular cells that synthesize and secrete thyroid hormones and parafollicular cells (C cells) that produce calcitonin, which helps regulate calcium levels in the blood. The production of thyroid hormones is primarily stimulated by thyroid-stimulating hormone (TSH), secreted by the pituitary gland, which itself is regulated by thyrotropin-releasing hormone (TRH) from the hypothalamus.

Physiologically, the synthesis of thyroid hormones involves the uptake of iodine from the bloodstream, which is a crucial component for hormone production. Iodine deficiency can lead to hypothyroidism and goiter formation due to the overstimulation of the thyroid gland by TSH. Conversely, excessive iodine can lead to hyperthyroidism. The hormones produced by the thyroid gland exert widespread effects on metabolism, influencing processes such as protein synthesis, carbohydrate metabolism, and lipid metabolism, which are critical for maintaining energy balance and metabolic homeostasis.

Several mechanisms can lead to thyroid disorders:

  1. Autoimmune Mechanisms: Autoimmune diseases, such as Hashimoto's thyroiditis and Graves' disease, are significant contributors to thyroid dysfunction. In Hashimoto's thyroiditis, the immune system attacks thyroid tissue, leading to hypothyroidism. Conversely, Graves' disease results in the overproduction of thyroid hormones due to the stimulation of the thyroid gland by autoantibodies. The autoimmune processes are thought to involve genetic predispositions and environmental triggers that lead to dysregulation of immune tolerance [4].

  2. Genetic Factors: Genetic predisposition plays a crucial role in the development of thyroid disorders. Conditions like congenital hypothyroidism often stem from genetic abnormalities affecting thyroid development, including dysgenesis, which can manifest as agenesis, hypoplasia, or ectopy of the thyroid gland [8]. Studies have identified specific genetic mutations that can lead to these developmental issues, highlighting the complex interplay between genetics and thyroid function [7].

  3. Environmental Influences: Environmental factors, including exposure to certain trace elements, can significantly impact thyroid health. For instance, an imbalance in essential trace elements like iodine, selenium, and zinc can disrupt thyroid hormone synthesis and secretion, leading to conditions such as hypothyroidism and autoimmune thyroiditis [5]. Additionally, environmental contaminants and dietary factors have been implicated in altering thyroid function and increasing susceptibility to thyroid diseases [6].

  4. Hormonal Interactions: Thyroid hormones interact with various other hormonal systems, including the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-pituitary-gonadal (HPG) axis. Dysregulation of these systems can influence thyroid function and contribute to disorders. For example, stress and adrenal dysfunction can lead to alterations in thyroid hormone levels [9].

  5. Metabolic Factors: Thyroid hormones play a vital role in metabolic regulation, affecting energy expenditure and the metabolism of carbohydrates, fats, and proteins. Conditions such as obesity and metabolic syndrome can influence thyroid function, leading to a reciprocal relationship where thyroid disorders may exacerbate metabolic issues [3].

In summary, thyroid disorders arise from a complex interplay of anatomical, physiological, genetic, autoimmune, and environmental factors. Understanding these mechanisms is essential for developing effective diagnostic and therapeutic strategies for managing thyroid diseases. Further research is needed to elucidate the precise pathways and interactions involved in thyroid dysfunction, particularly in the context of emerging environmental and lifestyle factors that may contribute to the increasing prevalence of these disorders.

2.2 Hormonal Regulation and Feedback Mechanisms ​

Thyroid disorders encompass a range of conditions characterized by abnormal production or action of thyroid hormones (THs), which are critical regulators of numerous physiological processes, including metabolism, growth, and development. Understanding the mechanisms underlying these disorders involves exploring the hormonal regulation of the thyroid axis and the feedback mechanisms that govern thyroid function.

The thyroid gland synthesizes THs, primarily thyroxine (T4) and triiodothyronine (T3), which circulate in the bloodstream and exert effects on various tissues and organs. The regulation of thyroid hormone production is primarily mediated by the hypothalamic-pituitary-thyroid (HPT) axis. The hypothalamus secretes thyrotropin-releasing hormone (TRH), which stimulates the anterior pituitary to release thyroid-stimulating hormone (TSH). TSH, in turn, acts on the thyroid gland to promote the synthesis and release of T4 and T3. This process is tightly regulated through a negative feedback loop; elevated levels of circulating THs inhibit the release of TRH and TSH, thereby maintaining homeostasis [10].

Thyroid disorders can arise from various disruptions within this regulatory framework. For instance, primary hypothyroidism is often due to intrinsic thyroid dysfunction, such as autoimmune conditions like Hashimoto's thyroiditis, where the immune system attacks thyroid tissue, leading to decreased hormone production. This results in elevated TSH levels due to the lack of negative feedback from THs [2]. Conversely, hyperthyroidism may occur in conditions such as Graves' disease, where antibodies stimulate the thyroid gland to produce excess hormones, leading to suppressed TSH levels [2].

In addition to autoimmune mechanisms, thyroid disorders can be influenced by genetic factors and environmental exposures. Approximately 70% of thyroid disorders have a hereditary component, but environmental factors, including iodine intake and exposure to certain chemicals, can also significantly impact thyroid function and contribute to the development of autoimmune thyroid diseases [2].

Moreover, thyroid hormones play a crucial role in regulating cardiovascular function, with recent studies highlighting the importance of THs in the central regulation of blood pressure and heart rate through specific neuronal populations in the hypothalamus [11]. Disruptions in TH signaling can lead to cardiovascular manifestations associated with thyroid disorders, indicating a complex interplay between hormonal regulation and cardiovascular health [12].

The dynamics of thyroid diseases also involve the physiological delay in normalizing serum TSH levels following treatment. This delay is attributed to feedback mechanisms where the growth and recovery of the thyroid and pituitary glands lag behind the normalization of circulating THs, complicating the management of thyroid disorders [13].

In summary, the mechanisms of thyroid disorders are multifaceted, involving hormonal regulation through the HPT axis, feedback mechanisms that maintain TH homeostasis, and the influence of genetic and environmental factors. Understanding these mechanisms is crucial for developing effective treatment strategies for individuals with thyroid dysfunctions.

3 Hypothyroidism: Mechanisms and Causes ​

3.1 Autoimmune Thyroiditis (Hashimoto's Disease) ​

Hashimoto's thyroiditis (HT) is recognized as the most prevalent autoimmune thyroid disorder, primarily leading to hypothyroidism. The pathogenesis of Hashimoto's thyroiditis is multifaceted, involving a combination of genetic, epigenetic, and environmental factors that contribute to the loss of immunological tolerance and subsequent autoimmune attack on thyroid tissue.

Genetic susceptibility plays a crucial role in the development of HT, with numerous susceptibility genes identified that influence the immune response and thyroid function. Environmental factors also significantly impact the onset of the disease, with several studies highlighting the influence of iodine intake, vitamin D deficiency, selenium deficiency, and viral infections such as Epstein-Barr Virus (EBV) and Human parvovirus B19 on the risk of developing autoimmune thyroiditis [14].

The pathophysiological mechanisms underlying HT include the presence of autoantibodies against thyroid-specific antigens, particularly thyroid peroxidase (TPO) and thyroglobulin [15]. The disease is characterized by lymphocytic infiltration of the thyroid gland, leading to the destruction of thyroid follicles and gradual atrophy and fibrosis [16]. Histologically, HT is marked by features such as lymphoplasmacytic infiltration, formation of lymphoid follicles with germinal centers, and parenchymal atrophy [17].

Moreover, the role of chemokines and cytokines in the immune-pathogenesis of autoimmune thyroid diseases has been well-documented. These mediators are crucial in orchestrating the inflammatory response that characterizes HT [16]. The immune response in HT is primarily driven by both humoral and cellular immunity, with T and B cells playing significant roles in the inflammatory process [18].

In addition to the direct autoimmune mechanisms, there is emerging evidence suggesting that certain microorganisms may influence the pathogenesis of Hashimoto's thyroiditis. For instance, Helicobacter pylori and Hepatitis C virus have been implicated in the exacerbation of thyroid autoimmunity, possibly through mechanisms such as molecular mimicry or by inducing a heightened immune response [19].

The clinical manifestations of Hashimoto's thyroiditis are predominantly related to the resulting hypothyroidism, which can lead to a variety of systemic symptoms. Treatment typically involves the administration of synthetic levothyroxine to manage the hypothyroid state resulting from the autoimmune destruction of thyroid tissue [16].

In summary, the mechanisms underlying Hashimoto's thyroiditis involve a complex interplay of genetic predisposition, environmental triggers, and immune-mediated destruction of thyroid tissue, leading to hypothyroidism. Understanding these mechanisms is essential for developing targeted therapeutic strategies and improving patient outcomes.

3.2 Iodine Deficiency and Other Environmental Factors ​

Thyroid disorders, particularly hypothyroidism, are influenced by a variety of mechanisms and environmental factors, with iodine deficiency being a predominant cause globally. Iodine is essential for the synthesis of thyroid hormones, and both its deficiency and excess can lead to significant health issues.

Iodine deficiency early in life is known to impair cognition and growth, while in adults, it is a key determinant of thyroid disorders. Severe iodine deficiency can lead to goitre and hypothyroidism. In this scenario, the thyroid gland attempts to increase its activity to maximize iodine uptake and recycling; however, the iodine concentrations remain insufficient for adequate thyroid hormone production. Conversely, in cases of mild-to-moderate iodine deficiency, the thyroid can often compensate for low iodine intake and maintain euthyroidism. However, this chronic stimulation of the thyroid may result in an increased prevalence of toxic nodular goitre and hyperthyroidism. When iodine intake is subsequently increased, such as through iodized salt, there may be a transient increase in the prevalence of hyperthyroidism due to the normalization of thyroid activity and a reduction in nodular autonomy. Moreover, increased iodine intake can be associated with a slight rise in subclinical hypothyroidism and thyroid autoimmunity, although the long-term implications of these changes remain uncertain[20].

Environmental factors also play a significant role in the development of thyroid disorders. Autoimmune thyroid disease (AITD), which is the most prevalent autoimmune disease worldwide, is often linked to both genetic predispositions and environmental influences. Iron deficiency, for instance, has been shown to impair the activities of thyroid enzymes, disrupt immune function, and potentially exacerbate autoimmune conditions, including AITD. The modern lifestyle, characterized by exposure to various environmental stressors, may further heighten the risk of autoimmune disorders and thyroid dysfunction[21].

In iodine-replete areas, the most common causes of hypothyroidism are often autoimmune in nature, such as Hashimoto's thyroiditis. This autoimmune condition leads to chronic inflammation of the thyroid gland, resulting in reduced hormone production. Factors contributing to the risk of developing hypothyroidism include genetic predisposition, prior neck surgery, radiation exposure, pregnancy, and certain medications. The prevalence of spontaneous hypothyroidism varies, with estimates ranging from 1% to 2%, and it is notably more common in older women[22].

In summary, the mechanisms behind thyroid disorders, particularly hypothyroidism, involve a complex interplay of iodine availability, autoimmune processes, and environmental factors. Iodine deficiency remains a significant concern globally, and its correction is crucial for preventing thyroid dysfunction. However, careful management is necessary to avoid the potential adverse effects associated with excessive iodine intake, which can also lead to thyroid disorders[23][24][25].

4 Hyperthyroidism: Mechanisms and Causes ​

4.1 Graves' Disease and Autoantibodies ​

Graves' disease (GD) is a prominent autoimmune disorder characterized by hyperthyroidism, resulting from the production of autoantibodies that stimulate the thyrotropin receptor (TSHR). The pathophysiological mechanisms underlying GD involve several key components, including the generation of thyroid-stimulating autoantibodies (TSAbs), the aberrant activation of immune cells, and genetic predispositions.

The primary mechanism of hyperthyroidism in GD is the presence of autoantibodies that act as agonists to the TSHR, leading to excessive thyroid hormone production. These autoantibodies mimic the action of TSH, causing the thyroid gland to be hyperstimulated, which results in thyrocyte hyperplasia and increased synthesis of thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3) [26]. This autoimmune response is often associated with clinical manifestations such as goiter and, in some cases, Graves' ophthalmopathy, where the same autoantibodies may affect orbital tissues due to the cross-reactivity with insulin-like growth factor 1 receptor (IGF1R) [26].

The etiology of GD is multifactorial, involving genetic susceptibility and environmental triggers. There is evidence suggesting a strong genetic component to the disease, as familial clustering and a high sibling recurrence risk have been observed [27]. The disease is particularly prevalent among women of reproductive age, with a population prevalence of approximately 1-2% [27].

At the cellular level, the induction of GD is associated with the aberrant function of immune cells, particularly natural killer (NK) cells and T lymphocytes. NK cells may play a crucial role in the interplay between thyroid hormones and immune regulation in the progression of GD [28]. Moreover, the activation of Th1 lymphocytes leads to the production of pro-inflammatory cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which are involved in perpetuating the autoimmune process [29].

Furthermore, research has demonstrated that certain immunoglobulin heavy chain variable region genes contribute to the development of TSAbs, suggesting a genetic basis for the immune response seen in GD [30]. The role of regulatory T cells (Tregs) has also been highlighted, as they may influence the transition from hyperthyroid states to hypothyroidism in some patients [31].

In summary, the mechanisms underlying Graves' disease encompass the production of TSHR autoantibodies that stimulate thyroid hormone synthesis, the involvement of immune cells in the autoimmune process, and the genetic factors that predispose individuals to this condition. The complexity of these interactions emphasizes the need for ongoing research to further elucidate the pathophysiology of GD and to develop more targeted therapeutic strategies.

4.2 Thyroid Nodules and Toxic Adenomas ​

Hyperthyroidism is primarily characterized by the overproduction of thyroid hormones from the thyroid gland, leading to a state of thyrotoxicosis. The mechanisms underlying hyperthyroidism are multifaceted, with several distinct etiologies contributing to the disorder. The most prevalent causes include autoimmune hyperthyroidism, specifically Graves' disease (GD), toxic multinodular goiter (TMNG), and toxic thyroid adenoma (TA).

Graves' disease is an autoimmune condition caused by autoantibodies that stimulate the thyroid-stimulating hormone (TSH) receptor, leading to increased production of thyroid hormones. This hyperactivity results in elevated levels of free thyroxine (FT4) and free triiodothyronine (FT3), while serum TSH levels are typically suppressed. In patients with GD, characteristic laboratory findings include the presence of TSH-receptor autoantibodies[32].

Toxic multinodular goiter and toxic adenoma are other significant causes of hyperthyroidism. These conditions arise from somatic activating gain-of-function mutations that lead to autonomous production of thyroid hormones independent of TSH regulation. In TMNG, multiple nodules within the thyroid gland produce excess hormones, while TA typically refers to a single nodule that secretes thyroid hormones autonomously[32].

Additionally, less common etiologies include destructive thyroiditis, such as that induced by amiodarone, and factitious hyperthyroidism, which occurs due to the exogenous administration of thyroid hormones. In cases of destructive thyroiditis, the release of preformed thyroid hormones into circulation can lead to transient hyperthyroid symptoms[32].

The diagnostic approach to hyperthyroidism involves laboratory tests and imaging studies. Typical laboratory findings include low serum TSH and elevated levels of FT4 and FT3. Ultrasound imaging assists in evaluating the size and vascularity of the thyroid gland, as well as the characteristics of any thyroid nodules present. Thyroid scintigraphy, using either radioiodine or 99mTc-pertechnetate, is instrumental in characterizing the various forms of hyperthyroidism and guiding therapeutic decisions[32].

In summary, the mechanisms of hyperthyroidism are primarily linked to autoimmune processes, genetic mutations, and, in some cases, environmental factors. Understanding these mechanisms is crucial for effective diagnosis and treatment of the disorder, which may include antithyroid medications, radioactive iodine therapy, or surgical intervention, depending on the underlying cause and severity of the condition[2][33].

5 Genetic Factors in Thyroid Disorders ​

5.1 Hereditary Syndromes ​

Thyroid disorders encompass a range of conditions, many of which have significant genetic underpinnings. The most frequent cause of congenital hypothyroidism is thyroid dysgenesis (TD), which refers to a spectrum of developmental abnormalities of the embryonic thyroid. These abnormalities can range from complete absence of the thyroid gland (athyreosis) to a normally located but too small thyroid (hypoplasia), or an abnormally located thyroid gland (ectopy) [8].

The genetics of thyroid dysgenesis are complex and do not typically follow simple Mendelian patterns. Recent research indicates that distinct genetic forms of isolated or syndromic thyroid dysgenesis have been identified, suggesting a multifactorial inheritance model that includes monogenic, multigenic, and epigenetic mechanisms [8]. This complexity is underscored by findings that mutations in regulatory genes expressed in the developing thyroid are responsible for various forms of TD, demonstrating that TD can be a genetic and inheritable disease [7].

Additionally, studies utilizing genome-wide association studies (GWAS) have revealed numerous susceptibility loci associated with autoimmune thyroid diseases and thyroid cancer. For instance, genes related to autoimmune responses, such as human leukocyte antigen (HLA), protein tyrosine phosphatase, non-receptor type 22 (PTPN22), and cytotoxic T-lymphocyte associated protein 4 (CTLA4), have been implicated [34]. Furthermore, GWAS have identified associations for thyroid function-related traits, such as thyroid stimulating hormone (TSH) and free thyroxine (T4) levels, which are also partly genetically determined [34].

The relationship between genetic factors and environmental influences is particularly significant in the context of autoimmune thyroid disorders. Although hereditary factors account for a substantial proportion of thyroid disorders—approximately 70%—environmental factors also play a crucial role, particularly in individuals predisposed to autoimmune conditions [2]. The interaction between genetic predisposition and environmental triggers may lead to the development of disorders such as Hashimoto's thyroiditis and Graves' disease.

In summary, the mechanisms underlying thyroid disorders are multifaceted, involving complex genetic architectures that include monogenic, multigenic, and epigenetic factors, alongside significant environmental influences. This interplay complicates the understanding and management of thyroid disorders, necessitating a comprehensive approach that considers both genetic and environmental contributions.

5.2 Gene-Environment Interactions ​

Thyroid disorders are complex conditions influenced by various mechanisms, particularly genetic factors and gene-environment interactions. Genetic predisposition plays a crucial role in the development of autoimmune thyroid diseases, with research indicating that genetic factors are fundamental in dysregulating the immune system and enhancing susceptibility to these disorders. This genetic predisposition is often exacerbated by environmental factors, which can act as initiating or precipitating events in genetically predisposed individuals, leading to thyroid autoimmunity[35].

Environmental factors, including pollutants, ionizing radiation, and dietary influences, have been shown to impact thyroid function significantly. For instance, exposure to environmental contaminants such as heavy metals and endocrine-disrupting chemicals can disrupt thyroid hormone synthesis and action, contributing to thyroid dysfunction[36]. Moreover, specific dietary patterns, such as high consumption of animal fats, have been associated with increased production of thyroid autoantibodies, indicating a potential link between diet and autoimmune thyroid disorders[36].

The interplay between genetic susceptibility and environmental factors can lead to a cascade of immunological events. In autoimmune thyroid diseases, autoreactive T cells targeting thyroid autoantigens are crucial in the induction and maintenance of thyroid damage. These autoreactive T cells can activate various effector systems, leading to tissue lesions through the secretion of lymphokines[35]. Furthermore, environmental factors may exacerbate the dysregulation of immune responses, resulting in a more pronounced autoimmune reaction[2].

The current understanding of the mechanisms underlying thyroid disorders highlights the necessity for comprehensive etiological research. Mendelian randomization has emerged as a valuable approach to elucidate these mechanisms, allowing researchers to explore the causal relationships between genetic variants and thyroid diseases, thereby addressing confounding factors typically present in observational studies[1].

In summary, thyroid disorders are influenced by a complex interplay of genetic factors and environmental exposures. The genetic predisposition affects immune regulation and organ susceptibility, while environmental factors can trigger or exacerbate autoimmune responses. This multifaceted relationship necessitates ongoing research to unravel the precise mechanisms and develop effective intervention strategies.

6 Environmental Influences on Thyroid Health ​

6.1 Impact of Medications and Toxins ​

Thyroid disorders are influenced by a variety of environmental factors, medications, and toxins, which can disrupt normal thyroid function through several mechanisms. The complexity of these interactions is highlighted in multiple studies that explore the pathogenesis of thyroid dysfunction.

Environmental factors such as pollution, dietary deficiencies, and exposure to endocrine-disrupting chemicals (EDCs) have been shown to significantly impact thyroid health. For instance, exposure to heavy metals like lead, mercury, and cadmium, as well as chemical pollutants such as polybrominated biphenyls and polycyclic aromatic hydrocarbons, is associated with increased thyroid autoantibody levels and thyroid dysfunction. These pollutants can provoke inflammatory responses and oxidative stress, which are critical pathways in the development of autoimmune thyroid diseases (AITD) [37].

Additionally, environmental contaminants like perchlorate, which disrupts thyroid hormone synthesis, have been shown to lower thyroid hormone levels [38]. Chemicals such as polychlorinated biphenyls (PCBs) and dioxins can interfere with the hypothalamic-pituitary-thyroid (HPT) axis, impacting hormone production and regulation. These substances may bind to thyroid transport proteins, displacing thyroxine and impairing thyroid function [39]. Furthermore, EDCs can mimic or disrupt the action of thyroid hormones at target tissues, leading to altered signaling pathways that affect thyroid hormone synthesis and secretion [40].

Medications can also play a significant role in thyroid health. Certain drugs, including those containing iodine, have been implicated in the development of AITD. For example, interferon treatments have been associated with thyroid dysfunction [41]. Moreover, medications that affect the immune system can trigger autoimmune responses, leading to conditions such as Hashimoto's thyroiditis or Graves' disease [42].

Stress and infectious agents are additional environmental factors that contribute to thyroid disorders. Viral infections, particularly those caused by human parvovirus B19 and hepatitis C, have been linked to the pathogenesis of AITD [41]. Stress can also exacerbate existing thyroid conditions by altering immune responses and hormone levels [37].

In summary, the mechanisms underlying thyroid disorders involve a multifaceted interplay of environmental factors, medications, and toxins that disrupt normal thyroid function. This disruption occurs through inflammatory pathways, oxidative stress, interference with hormone synthesis and action, and alterations in immune responses. Understanding these mechanisms is crucial for developing preventive strategies and effective treatments for thyroid-related diseases.

6.2 Nutritional Factors and Lifestyle ​

Thyroid disorders are influenced by a complex interplay of genetic, environmental, and lifestyle factors. Environmental influences play a significant role in the pathogenesis of thyroid dysfunctions, particularly through exposure to various contaminants and dietary factors.

Environmental factors such as climate change, pollution, and exposure to endocrine-disrupting chemicals have been recognized as impactful on thyroid function and health. For instance, global warming can alter thyroid function, while living in iodine-poor areas and regions with high concentrations of heavy metals and radon poses threats to thyroid health. Specifically, areas with elevated nitrate and nitrite levels in water and soil have been shown to negatively affect thyroid function. Air pollution, particularly particulate matter, has been linked to worsened thyroid function and is considered carcinogenic. Chemicals like bisphenols, phthalates, and per- and poly-fluoroalkyl substances can mimic or disrupt thyroid hormone synthesis, release, and action on target tissues, further complicating thyroid health [36].

Nutritional factors are equally critical in maintaining thyroid health. Iodine intake is a key determinant of thyroid disease risk, with iodine deficiency being the most common cause of thyroid disorders globally. However, excessive iodine can lead to increased thyroid-stimulating hormone (TSH) levels while decreasing thyroid hormone levels [43]. The balance of other micronutrients such as selenium, iron, zinc, and vitamins D, B9, and B12 is also vital, as they act as cofactors in DNA replication and repair, impacting thyroid function [44].

Lifestyle factors, including smoking and body mass index (BMI), have been shown to correlate with thyroid hormone levels. Smoking typically leads to decreased TSH and increased levels of triiodothyronine (T3) and thyroxine (T4), while a higher BMI is positively associated with TSH levels [38]. Furthermore, dietary patterns, particularly the consumption of animal fats, may influence the production of thyroid autoantibodies, highlighting the importance of diet in thyroid health [36].

Overall, understanding the mechanisms by which environmental influences, nutritional factors, and lifestyle choices affect thyroid health is crucial for developing preventive strategies and effective management of thyroid disorders. This knowledge is essential for mitigating risks associated with thyroid dysfunction and improving health outcomes in affected populations [2][41].

7 Conclusion ​

The exploration of thyroid disorders reveals a complex interplay of anatomical, physiological, genetic, autoimmune, and environmental factors that contribute to their pathogenesis. The findings underscore the significant role of autoimmune mechanisms, particularly in conditions such as Hashimoto's thyroiditis and Graves' disease, which account for a substantial proportion of hypothyroidism and hyperthyroidism cases, respectively. The influence of genetic predisposition is profound, with numerous hereditary syndromes identified, alongside gene-environment interactions that further complicate the etiology of these disorders. Environmental factors, including iodine availability, exposure to pollutants, and lifestyle choices, also significantly impact thyroid health. Future research should focus on elucidating the intricate mechanisms underlying these interactions and their implications for prevention and treatment. By advancing our understanding of thyroid pathophysiology, we can develop targeted therapeutic strategies and improve clinical outcomes for individuals affected by thyroid disorders.

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