**2. Etiology and pathophysiology**

Thyroid hormones affect the function of virtually all organ systems of the body; these are critical determinants of brain and somatic development in infants and of metabolic activity in adults. The thyroid gland is regulated to a large extent by the delicate balance between the hypothalamus, pituitary, and thyroid. Thyrotropinreleasing hormones (TRH) are secreted by the hypothalamus which stimulates the secretion of the thyroid-stimulating hormone (TSH), by the pituitary gland. TSH is a major regulator of the thyroid gland which after binding to its receptor on plasma membrane stimulates each and all steps of thyroid hormone synthesis and secretion.

Goiter is an etiologically and pathogenetically complex disease. The specific role of TSH in its pathogenesis has not been unraveled. It has been variously defined and characterized by the increased volume of the thyroid gland with the formation of multiple nodules. Although a number of definitions exist, the most accepted is the thyroid gland weighing over 20–25 g or a volume of over 19 ml in females and 25 ml in males [8].

Grossly, MNG reveals a heterogeneous array of solid/cystic and mixed nodules. Cystic nodules are typically defined as a cystic component >50%. Typically, pathogenesis of MNG thyroid can be attributed to three main processes: diffuse follicular hyperplasia, focal nodular proliferation, and eventual acquisition of functional autonomy. Development of goiter especially in conditions of iodine deficiency or Hashimoto's disease seems to be TSH driven. However, in addition to TSH, several other growth factors, both TSH dependent and independent, have been known to play a role in the pathogenesis of MNG by influencing thyroid follicular cell growth. Chronic stimulation of follicular cells primarily due to TSH leads to follicular hyperplasia, which usually then enters a resting phase leading to the formation of colloid goiter [9]. This long-standing diffuse goiter may develop into MNG with the potential of autonomy in certain nodules. The role of genetic factors especially in nontoxic MNG is not clear, but some role has been suggested by twin studies, family history, female preponderance, etc. [10]. Certain mutations like those affecting the activation of camp cascade (e.g., TSH-r mutations) which stimulates growth and function mutation in genes encoding thyroglobulin (Tg), thyroid peroxidase (TPO), dual oxidase 2 (THOX2), the sodium-iodide symporter gene (SLC5A5), Pendred syndrome gene (SLC26A4), the TSH receptor gene (TSHR gene), the iodotyrosine deiodinase (DEHAL 1), and the thyroid oxidase 2 gene (THOX2) have been found to be responsible in certain cases for the formation of nodules in a patient with MNG [10]. Familial MNGs have been found to be strongly associated with mutations in the miRNA processing gene DICER1 [11]. Environmental factors have also been incriminated in causation of MNG possibly by aggravating the expression of heterogeneity causing the thyroid to grow and perhaps leading to its autonomy. Naturally occurring goitrogens are thought to work by different

**101**

*Multinodular Goiter*

Cassava, sweet potato,

Cruciferous vegetables: cabbage, cauliflower, broccoli, turnips

sorghum

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.90325*

Malnutrition Vitamin A deficiency

*Adapted and modified from Medeiros-Neto and Knobel [48].*

*Natural goitrogens associated with goiter prevalence.*

**Goitrogens Agent Action**

Millet, soy Flavonoids Impairs thyroperoxidase activity

Seaweed (kelp) Iodine excess Inhibits release of thyroidal hormones

Selenium Selenium deficiency Accumulates peroxides and causes

Inhibits iodine thyroidal uptake

Increases TSH stimulation, Reduces hemedependent thyroperoxidase thyroidal

deiodinase deficiency; impairs thyroid

Glucosinolates Impairs iodine thyroidal uptake

activity

hormone synthesis

Cyanogenic glucosides metabolized to thiocyanates

Babassu coconut, mandioca Flavonoids Inhibits thyroperoxidase

Iron deficiency

mechanisms, leading to impaired thyroid hormone synthesis or thyroid growth (**Table 1**). For example, iodine-rich substances like seaweed and cruciferous and cassava may impair iodine uptake [12]. In addition to this protein energy malnutrition and deficiency of other nutrients like iron and selenium, vitamin a may also be associated with thyroid enlargement if present with iodine-deficient state. The nonfunctioning nodules in nontoxic MNG may over time evolve into larger autonomous nodules, leading first to a smoldering subclinical hyperthyroid state which may then progress to overt hyperthyroidism [13]. The Marine Lenhart disease is functioning

Toxic MNG is a result of activating somatic mutation of the TSH receptor gene that leads to diffuse hyperplasia of thyroid follicular cells independent of TSH regulation [14–16]. MNG with thyrotoxicosis is also known as Plummer's disease. Toxic MNG presented with clinical features similar to other causes of thyrotoxicosis except ophthalmopathy. Incidence of thyrotoxicosis in MNG is related to the duration of the presence of MNG. So it's more common in elderly people who are harboring MNG for a long time. Hormone profile in toxic MNG is seen with sup-

Graves' disease is an autoimmune disorder caused by anti-TSH receptor antibody. These antibodies interact with TSH receptor and cause increased thyroid hormone synthesis and secretion [17]. Many risk factors have been found in causation of Graves' disease including high iodine intake and stress [18, 19]. Several drugs have also been implicated in etiology of Graves' disease including lithium,

thyroid nodules associated with Graves' disease.

pressed TSH along with normal or elevated thyroid hormones.

**3. Types of goiter**

**3.2 Graves' disease**

**3.1 Toxic MNG**


#### **Table 1.**

*Goiter - Causes and Treatment*

supplementation [7].

secretion.

in males [8].

are usually large and nodular.

**2. Etiology and pathophysiology**

250 mcg for pregnant and lactating women, and 90 mcg for children <2 years of age that can be easily obtained by iodized salt, processed food, and milk products [6]. Prevalence of goiter still remains 4–7% in the United States even after iodine

Goiter can be classified as solitary or multiple, diffuse or nodular, and toxic or nontoxic on an anatomical and functional basis. The nontoxic goiter is due to abnormalities of iodine supplies or metabolism without any abnormal thyroid function. In children goiter tends to be smaller and diffuse, whereas in older people they

Thyroid hormones affect the function of virtually all organ systems of the body; these are critical determinants of brain and somatic development in infants and of metabolic activity in adults. The thyroid gland is regulated to a large extent by the delicate balance between the hypothalamus, pituitary, and thyroid. Thyrotropinreleasing hormones (TRH) are secreted by the hypothalamus which stimulates the secretion of the thyroid-stimulating hormone (TSH), by the pituitary gland. TSH is a major regulator of the thyroid gland which after binding to its receptor on plasma membrane stimulates each and all steps of thyroid hormone synthesis and

Goiter is an etiologically and pathogenetically complex disease. The specific role of TSH in its pathogenesis has not been unraveled. It has been variously defined and characterized by the increased volume of the thyroid gland with the formation of multiple nodules. Although a number of definitions exist, the most accepted is the thyroid gland weighing over 20–25 g or a volume of over 19 ml in females and 25 ml

Grossly, MNG reveals a heterogeneous array of solid/cystic and mixed nodules. Cystic nodules are typically defined as a cystic component >50%. Typically, pathogenesis of MNG thyroid can be attributed to three main processes: diffuse follicular hyperplasia, focal nodular proliferation, and eventual acquisition of functional autonomy. Development of goiter especially in conditions of iodine deficiency or Hashimoto's disease seems to be TSH driven. However, in addition to TSH, several other growth factors, both TSH dependent and independent, have been known to play a role in the pathogenesis of MNG by influencing thyroid follicular cell growth. Chronic stimulation of follicular cells primarily due to TSH leads to follicular hyperplasia, which usually then enters a resting phase leading to the formation of colloid goiter [9]. This long-standing diffuse goiter may develop into MNG with the potential of autonomy in certain nodules. The role of genetic factors especially in nontoxic MNG is not clear, but some role has been suggested by twin studies, family history, female preponderance, etc. [10]. Certain mutations like those affecting the activation of camp cascade (e.g., TSH-r mutations) which stimulates growth and function mutation in genes encoding thyroglobulin (Tg), thyroid peroxidase (TPO), dual oxidase 2 (THOX2), the sodium-iodide symporter gene (SLC5A5), Pendred syndrome gene (SLC26A4), the TSH receptor gene (TSHR gene), the iodotyrosine deiodinase (DEHAL 1), and the thyroid oxidase 2 gene (THOX2) have been found to be responsible in certain cases for the formation of nodules in a patient with MNG [10]. Familial MNGs have been found to be strongly associated with mutations in the miRNA processing gene DICER1 [11]. Environmental factors have also been incriminated in causation of MNG possibly by aggravating the expression of heterogeneity causing the thyroid to grow and perhaps leading to its autonomy. Naturally occurring goitrogens are thought to work by different

**100**

*Natural goitrogens associated with goiter prevalence.*

mechanisms, leading to impaired thyroid hormone synthesis or thyroid growth (**Table 1**). For example, iodine-rich substances like seaweed and cruciferous and cassava may impair iodine uptake [12]. In addition to this protein energy malnutrition and deficiency of other nutrients like iron and selenium, vitamin a may also be associated with thyroid enlargement if present with iodine-deficient state. The nonfunctioning nodules in nontoxic MNG may over time evolve into larger autonomous nodules, leading first to a smoldering subclinical hyperthyroid state which may then progress to overt hyperthyroidism [13]. The Marine Lenhart disease is functioning thyroid nodules associated with Graves' disease.
