Authors: Udaya M. Kabadi, MD, FRCP (c), FACP, FACE, Professor of Medicine, Department of Internal Medicine, Division of Endocrinology and Metabolism, University of Iowa College of Medicine, Iowa City. Mouin Abdallah, MD, Resident, Department of Internal Medicine, University of Iowa Healthcare, Iowa City.
Peer Reviewer: Daniel S. Duick, MD, Endocrinology Associates, Phoenix, AZ.
Editor’s Note—Goiter literally means the enlargement of the thyroid gland, independent of its cause. Historically, this terminology specifically was reserved for a visibly enlarged thyroid gland. During the past few decades of modern medical practice, the term has come to include both visible as well as palpable thyroid enlargement. An average thyroid normally weighs about 15 g. The gland is situated in the lower part of the anterior neck and partially is buried under the sternomastoid muscles. This complex arrangement often makes a normal gland non-palpable. Physicians may be faced with the diagnostic dilemma of possible thyroid disease even when thyroid barely is palpable. In fact, it may be the initial clue to the existence of an occult thyroid disorder.
This article will review the pathophysiologic processes leading to goiter formation and will provide a logical approach to the diagnosis and management of different entities, the end result of which is an enlarged thyroid gland.
Thyroid Physiology
First, it is helpful to review the normal thyroid physiology. Embryologically, the thyroid gland is derived from the epithelial cells of the pharynx. It is a bi-lobed structure lying anterior to the trachea. The connecting bridge is called the isthmus. The gland has a rich blood supply and is innervated by the sympathetic nervous system. The thyroid has evolved to specialize in synthesizing and secreting thyroxine (T4) and tri-iodothyronine (T3) into the circulation system. The regulatory process is thyroid stimulating hormone (TSH) dependent, which is secreted from the anterior pituitary and, in turn, is under the control of thyrotropin releasing hormone (TRH) from the hypothalamus. TRH and TSH both are regulated in a negative feedback loop by T4 and T3 in the circulation system.1
Thyroid hormone regulates a wide range of metabolic processes, including growth and development, reproduction, and metabolic enhancement. This regulatory function is its most important effect.
Histologically, the gland is composed of follicles that are the functional unit of thyroid hormone biosynthesis. Each follicle consists of thyrocytes arranged in spherical structure, their supporting mesenchymal tissue and cells, the endothelial cells of capillaries and fibroblasts. A few parafollicular, calcitonin secreting cells are located at the periphery of the follicles. The lumen of these follicles stores colloid enriched with thryoglobulin, a glycoprotein secreted through the apical membrane of the thyroid follicular cells. The thyroglobulin serves as a template for thyroid hormone biosynthesis.2
The key component of thyroid hormone biosynthesis is iodine, which is transported into the thyroid in its inorganic form, where it is oxidized by the thyroid peroxidase-H2O2 system and then used to iodinate the tyrosyl residues in thyroglobulin, producing monoiodotyrosine (MIT) and diiodotyrosine (DIT). Thyroid peroxidase is the key enzyme in thyroid hormone biosynthesis. Essentially, it serves three important functions: iodine oxidation, iodination of tyrosine residues, and coupling of iodothyronine molecules. Coupling of these iodinated tyrosyl intermediates produces T4 and T3. Hydrolysis from thyroglobulin releases these hormones into the circulation. The major hormone secreted by the thyroid gland is T4, along with smaller quantities of T3.
In peripheral tissues, T4 is converted into the active form of the T3 hormone, by the action of 5-iodothyronine deiodinase.3 Two different types of deiodinase enzymes have been characterized. Type I deiodinase predominantly is found in liver, kidney, and thyroid cells. It is the principal enzyme responsible for generation of T3 after monodeiodination of T4 in the periphery. Type II deiodinase primarily is found in brown fat, pituitary, and brain cells. It is responsible for regulating intracellular T3 concentration, such as in the brain where adequate concentration is required to optimize function.4 TSH is the major stimulus in thyroid hormone biosynthesis. It binds to the TSH receptor on thyroid cells, which structurally is related to the G-protein coupled receptor family, with a classic seven transmembrane domain.5
This hormone receptor interaction leads to an increased amount of cyclic adenosine monophosphate (cAMP) intracellularly, which promotes gene expression of thyroglobulin, thyroid peroxidase, protein iodination, thyroid hormone synthesis, secretion, and growth of thyrocytes.6 At a higher concentration of TSH, another mitogenic pathway, calcium-phosphotidylinisitol 1-4-5-phosphate, is activated, the net effect of which is enhanced iodination and hormone synthesis.7 The processes described above are so closely linked that a defect in any one component will impair hormone production or secretion along with consequent growth abnormality.
For years, it was believed that TSH was the only mitogenic stimulus to thyrocytes. However, recent in vitro studies have shown that TSH regulates the differentiation and function of thyroid cells and may induce hypertrophy but not hyperplasia. In contrast, locally produced growth factors, such as insulinlike growth factor (IGF-1) and epidermal growth factor (EGF), stimulate thyroid cell proliferation.8 More recently, in vivo thyroid volume studies have demonstrated that IGF-1 does not independently stimulate thyroid growth but promotes thyroid cell proliferation by potentiating the mitogenic action of TSH.9
Other researchers have argued that IGF-1 moderately increases the proliferation but actually potentiates the EGF stimulated growth by 100%.10 Despite these controversies, it is clear that TSH, in concert with these intermediary cytokines, exerts a powerful mitogenic effect. Other cytokines important in thyroid cell proliferation include transforming growth factor alpha (TGF-a), which also is believed to interact with EGF and its receptor. On the other hand, increasing concentration of intrathyroidal iodine antagonizes the effect of IGF-1 and EGF, and simultaneously stimulates transforming growth factor-beta (TGF-b), which inhibits thyroid cell proliferation.11 A very fine balance in hormone-cytokine interaction is required for thyroid growth differentiation and proliferation.
Multiple extrathyroidal factors and intrathyroidal enzymatic cascades are postulated to explain the phenomenon of goiter formation. IGF-1 and fibroblast growth factor are linked to receptor plus protein kinase. Thyroid stimulating hormone and thyroid stimulating immunoglobulins (TSI) bind to a common receptor with activation of cAMP, whereas adenosine triphosphate (ATP), acetylcholine, and TSH exert their effect via enhancement of phosphotidylinositol triphosphate pathway. The common end results of these biochemical alterations are protein synthesis, cell differentiation, and goiter formation.12 Pathophysiologic causes of goiters include hormonal factors, intrinsic inflammation, and tumors. (See Table 1.)
|
TSH Dependent Goiterogenesis
Worldwide, iodine deficiency is the single most common cause of goiter.13 The classic concept regarding the mechanisms of iodine deficiency goiter is based on reduced thyroid hormone biosynthesis, leading to increased production of TSH, stimulating thyroid growth. Conversely, an excess amount of iodine can inhibit the release of thyroid hormone from the gland and ultimately lead to elevated TSH concentration with consequent goiter formation. Therefore, the recommended daily allowance of iodine is 100 mg per day for adults and adolescents, 60-100 mg per day for children, and 35-40 mg per day for infants.
The classic example of iodine deficiency goiter is endemic goiter, which, as the name implies, is common in iodine-deficient areas of the world. The pattern of circulating thyroid hormones in clinically euthyroid adults in the area of severe iodine deficiency is characterized by low serum T4, elevated TSH, and normal or supernormal T3 values primarily reflecting a compensatory adaptation by the thyroid gland, via the minor effect of increased peripheral conversion of T4 to T3. Moreover, persistent severe iodine deficiency results in an extreme thyroid failure as found in myxedematous endemic cretinism, characterized by lowering of both T4 and T3 and dramatically increased TSH.14 Other non-toxic sporadic goiters include simple, colloid, or idiopathic goiters, reflecting the similar hyperstimulation by TSH during a period of suboptimal thyroid hormone production along with local growth factors and the effect of goiterogens.15
Goiterogens are naturally occurring substances that can promote thyroid growth. (See Table 2.) Certain foods, especially cassava and other foods containing cyanoge glycosides, convert to free cyanide and then to thiocyanate after hydrolysis in the gut. Thiocyanate is a known inhibitor of iodine transport and also can interfere with the organification process, leading to reduced thyroid hormone concentration and elevated TSH. Other inhibitors with similar properties include perchlorate, chlorate, and periodate, and a high concentration of iodine.16
Iodine trapping and organification defects are not the only mechanisms responsible for goitrogenesis. Drugs have been shown to increase the incidence of goiter and include:
- sulfonamides, methimazole, and propylthiouracil (sulfonamides), which block the organic binding of iodine and coupling of iodothyronines to form T4 and T3;
- lithium and excessive iodine, which inhibit thyroid hormone secretion by blocking thyroglobulin proteolysis and the release of thyroid hormones from the colloid follicles.
Moreover, other drugs, such as central nervous system-acting drugs (i.e., phenobarbital, benzodiazepines), calcium channel blockers (i.e., nifedipine, nicardipine), and steroids including spironolactone, disrupt thyroid hormone economy by increasing the peripheral metabolism of thyroid hormone through an induction of hepatic microsomal enzymes, which ultimately leads to increased TSH concentration.17
Dyshormonogenesis is the inability of the thyroid gland to produce physiologically adequate amounts of T4 and T3. The defects conceptually can be assigned to one of the traditional categories of dyshormogenesis (i.e., defects of iodine trapping, organificiation, coupling, thyroglobulin synthesis, or deiodination). Iodine transport defect is characterized by impaired iodine transport mechanism reflected by low radioactive iodine uptake. Other tissues capable of transporting iodine (e.g., salivary glands and gastric mucosa) also may exhibit the same defective process.
An organification defect has been defined in only a few patients and includes qualitative or quantitative abnormalities of the thyroid peroxidase system along with structural alteration of amino acid sequence in the thyroglobulin molecule that serves as the iodine acceptor. The clinical presentations include a mild defect in organification associated with sensory nerve deafness (Pendred’s syndrome) and goitrogenesis. The uptake of iodine in the condition is unaffected. Rather, it remains enhanced as manifested by a high uptake of iodine-123(123I). The pathophysiology is believed to be lack of retention of iodine by thyroid follicular cells reflected by complete extrusion of 123I by subsequent administration of perchlorate, which competes with iodine for the thyroidal trapping mechanism. In iodothyrosine coupling defects, thyroid cells contain little or no T4 and T3 but abundant MIT and DIT. The exact defect is unknown, but its postulated mechanism includes the presence of abnormal thyroid iodoproteins, usually iodoalbumin, and inefficiency of thyroid peroxidase activity that ultimately leads to hypothyroidism and intense thyroid stimulation by TSH.
A deiodinase defect clinically is recognized by the presence of endogenous iodotyrosines in the urine or excretion of parenterally administered labeled MIT or DIT. Normal generation of MIT and DIT depends on proteolytic cleavage of these molecules from thyroglobulin. Deiodinase is the principal enzyme involved in the deoidination reaction in thyroid follicles to reclaim iodine for future thyroid hormone synthesis. A deoidinase defect results in insufficient iodotyrosine metabolism and functional iodine deficiency state.
It would be expected to find hypothyroidism with elevated TSH values in these settings, but most patients with dyshormogenesis and goiter are found to be euthyroid at the time of evaluation, reflecting adequacy of thyroid adaptation. Multiple factors work in concert to produce goiterogenesis. These include period of relative thyroid hormone deficiency with elevated TSH, increased TSH sensitivity, goiterogens, and hereditary factors. The other TSH-dependent cause is resistance to thyroid hormone, which can be either generalized or selectively affecting the pituitary gland. The resistance is caused by mutations of thyroid hormone receptor gene, leading to defective intracellular thyroid receptors with reduced receptor affinity for T3. Both of these types of resistance are characterized by elevated TSH and goiterogenesis.18-21
TSH Independent Goiterogenesis
In the past few years, research into the structure of the TSH receptor and its association with different thyroid conditions has revolutionized the understanding of goiterogenesis. Studies have found a lack of specificity and an absence of down regulation of TSH receptor in conditions like TSHoma, Grave’s disease, and gestational thyrotoxicosis.22
Furthermore, expression of an endogenously active mutant receptor has been described as accounting for autonomy, gain of function, and hyperthyroidism with the formation of toxic nodules or toxic adenoma within a goiter. The mutation in this condition has been mapped into the carboxyl half of the TSH receptor.23 The TSH receptor itself has been identified in the induction of the autoimmune process, in addition to two different autoantibodies—thyroid stimulating immunoglobulin (TSI) and TSH binding inhibiting antibodies (TBIAb).24 Hyperthyroidism in Grave’s disease results from TSI directed against the TSH receptors, with chronic hyperstimulation of cAMP cascade. TSI is responsible for growth and hyperfunction of thyrocytes, which is characteristic of this disease.25 Autoimmune thyroid disease results from the interaction of genetic susceptibility and either host or environmental factors.
Other important antibodies in chronic thyroiditis include anti-thyroid peroxidase antibodies, anti-thyroglobulin antibodies, and TSH receptor-blocking antibodies.26 It recently has been shown that iodine depletion reduces autoimmune thyroid disease expression and iodine repletion leads to augmentation of autoimmunity. The exact pathophysiology largely is unknown, but it is believed that a defect in iodine processing may result in elevated levels of oxygen and iodine radicals leading to thyroid cell disruption and induction of autoantigenic response.27 Other investigators found an inappropriate expression of human leukocyte antigen (HLA) class II molecules, which can present as exogenous and intrinsic autoantigens to the appropriate T cells. A defective suppressor T cell and a consequent activation of helper T cells leads to autoantibody and cytokine production by the thyroid gland. TSH and interferon gamma induce the expression of class II molecules.28 Therefore, it appears that excess iodine induces thyroid cell auto antigenicity in genetically susceptible individuals and could be an initiating event in autoimmune thyroid destruction with consequent hypothyroidism and TSH elevation leading to goiter formation.
Goiters also manifest during pregnancy, as well as at the onset of puberty and menopause. In the United States, the incidence of clinically detected goiter in pregnancy is estimated to be 5-6%. Most of these cases are due to autoimmune thyroid disease mediated by antithyroperoxidase antibodies, as well as thyroid gland blocking antibodies. A marginally low iodine intake in the face of elevated fetal iodine requirement should be kept in mind when evaluating goiter during pregnancy.29 On the other hand, there is strong evidence that maternal human chorionic gonadotropin (HCG) can interact with and stimulate the thyroid both in vivo and in vitro, and this phenomenon is attributed to HCG having the identical alpha subunit as TSH. In early pregnancy, when HCG concentrations are highest, T4 is elevated because of the increased thyroid hormone binding globulin concentration caused by excessive circulatory estogen along with low TSH concentration, exhibiting an inverse correlation between the two. These findings suggest that HCG has the same stimulatory effect as TSH and that it may be the cause of physiologic goiter during pregnancy.30,31
Goiters also are noted to occur during puberty and around menopause. These goiters are attributed to a sudden rise of follicle stimulating hormone (FSH) and luteinizing hormone (LH), which stimulate the thyroid growth because they possess the same alpha subunit as TSH. The incidence of clinically enlarged thyroid gland in acromegalics is 25-53%. The sensitivity of detection is as high as 80% if sophisticated techniques like ultrasound are employed. It is well established that thyroid gland in acromegaly has an increased amount of collagen synthesis and formation of new follicules. Researchers have found a positive correlation between the plasma IGF-1 (the principal mediator of growth hormone effects) and thyroid volume in acromegaly.32 The authors believe that IGF-1 along with EGF and TSH may work in concert to bring about this effect.
Intrinsic Abnormalities
Infections of the thyroid gland are rare causes of goiterogenesis. The infection usually involves pyogenic microorganisms, disseminating from a septic focus or from piriform a sinus fistula.33,34 On rare occasions, the gland can be infected by tuberculosis, coccidiodomycosis or other fungal infections, especially in immunocompromised hosts.35,36 However, a more common form of infection of the thyroid gland with resultant goitrous swelling is subacute viral thyroiditis.
Thyroid cancer is the seventh most common cancer in the country, with roughly 23,000 new cases in 2003. Cancers usually present as solitary goiterous nodules. These neoplasms can be classified as primary, originating within the thyroid tissue, or secondary to metastasis from distant sites. Primary carcinoma of the thyroid further is classified as differentiated thyroid cancer (follicular or papillary), medullary thyroid cancer, undifferentiated or anaplastic carcinoma. Other less common cancers include Hurthle cell carcinoma, squamous cell carcinoma, lymphoma, and sarcoma. Secondary metastasis to the thyroid gland arises from carcinomas of the kidney, breast, lung, colon, stomach, and pancreas, as well as melanoma.37
Thyroid cancer is a multifactorial phenomenon with multiple genetic lesions involved in its pathogenesis. Research in molecular pathophysiology of thyroid carcinomas has revealed changes in the RET (REarranged during Transfection) proto-oncogene and its relation to papillary carcinoma and medullary carcinoma. RET proto-oncogene encodes a tyrosine kinase receptor. Normal thyroid follicular cells do not express this gene. As a result of somatic rearrangement of chromosome 10, the tyrosine kinase portion of RET proto-oncogene is brought under the control of a promoter, driving the expression of tyrosine kinase at a higher level in the affected thyroid follicular cells. This rearrangement of chromosome 10 is called papillary thyroid carcinoma oncogene.38
A recent report demonstrated the same rearrangement in approximately 60% of papillary carcinoma of thyroid in children affected by the Chernobyl accident. This documents RET rearrangement as a direct consequence of radiation exposure.39 In familial medullary thyroid cancer (FMTC) and multiple endocrine neoplasia (MEN) type 2A, a germline mutation of RET proto-oncogene at codons 609, 611, 618, 620, and 634 has been identified, whereas in patients with MEN 2B, the mutation occurs at RET proto-oncogene codon 918.39 It is thought that expression of papillary thyroid carcinoma oncogene or RET proto-oncogene causes activation of the tyrosine kinase receptor, thereby initiating the transformation events.40 NTRK1 oncogene is another example of rearrangement of chromosome 10 found in papillary thyroid carcinoma causing stimulation of tyrosine kinase activity.41 Other researchers also have found expression of TGF-a with coexpression of its receptor as well as epidermal growth factor receptor (EGF-R) in papillary thyroid cancers, raising the possibility of autocrine stimulation by these cells.42 Other interesting findings include Ras point mutation in follicular carcinoma, p53 point mutation in anaplastic carcinoma, and differentiated thyroid carcinomas with stage III and IV reflecting an unfavorable prognosis.43-45 Other researchers have found significant association of Ras gene activation in the metastatic capacity of follicular carcinoma, poorly differentiated carcinoma, and undifferentiated carcinomas.46 Most of the discoveries related to genetic alterations still are unfolding, promising better understanding in a few years.
Miscellaneous Causes
Cigarette smoking is associated with an approximately 10-fold increase in goiter frequency, most likely due to a combination of increased sympathetic stimulation of the thyroid gland and possibly an iodine deficiency state caused by thiocynate inhalation.47 Finally, some chronic conditions, such as chronic renal diseases and acute hepatic diseases, demonstrate significant increase in thyroid volume, the exact mechanism of which has not been clarified.
Researchers have suggested an increased expression of TGF-a in these settings. TGF-a is known to bind the EGF receptor. Therefore, research seems to indicate that these growth factors interact with their receptors to promote thyroid cell proliferation, inducing goiter formation.48 TSH and IGF-1 can’t be implicated because normal values of TSH, along with reduced expression of IGF-1, have been documented in these conditions.49-50
Goiter represents a final outcome of different pathophysiologic processes from very indolent iodine deficiency to agressive thyroid cancers. (See Table 1.) The appropriate management rests on a thorough understanding of these different phenomena. Moreover, greater understanding of these pathophysiologic processes likely will lead to appropriate diagnosis and management.
Management
Although the pathophysiology of the goiter is exhaustively complex and involves several etiologic factors, the assessment and treatment in clinical practice is much simpler. (See Figure 1.) The first step in the assessment is determining the presence of thyroid dysfunction. Detailed patient background, including family history, and a thorough physical examination—the processes frequently overlooked in current clinical practice— provide invaluable information in the documentation of thyroid dysfunction as well as the nature of the goiter and its local and systemic effects.
Many symptoms and signs of thyroid dysfunction are vague and nonspecific, especially in the early stages and in the elderly. (See Tables 3 and 4.) Therefore, simultaneous determination of both the serum-free T4 and TSH concentrations provides the functional diagnosis. For anatomic diagnosis, ultrasound examination is used. Though used less frequently, radiotracer imaging, computerized axial tomography (CAT) scan, magnetic resonance imaging (MRI), and positron emission tomography (PET) scan can assist in defining functional status or ascertaining the anatomic nature of the goiter and structural integrity of the adjacent organs.
The paradigm of goiter management is determined by the state of thyroid function. The major objective is to maintain euthyroid state and normalize or reduce the size of the goiter. In the presence of hyperthyroidism, determining the cause is important because the treatment may vary based on the etiology. Once again, a detailed history and a thorough physical examination assist in defining the etiology. Diffuse goiter with eye signs or pretibial myxedema indicates presence of Grave’s disease. A bumpy surface or discrete nodules denote multinodular toxic goiter; a single palpable nodule may suggest a presence of a toxic adenoma. Similarly, a tender gland with history of a viral prodrom suggests a diagnosis of subacute thyroiditis. However, radioiodine 123I thyroidal uptake and imaging is the most useful objective test in confirming the etiology in most hyperthyroid subjects. Ancillary tests (i.e., determination of anti-thyroid antibodies, TSI, thyroglobulin) may assist in defining the etiology and help in planning appropriate treatment of hyperthyroidism.
Determining the cause is paramount in planning the appropriate treatment. The radioiodine dose is almost three times higher in the presence of multinodular toxic goiter of the same size as compared to Grave’s disease. In the presence of subacute thyroiditis, transient administration of beta-adrenergic blocker to ameliorate manifestations of hyperthyroidism and non-steroidal anti-inflammatory drugs to curtail inflammation and pain may suffice, because this disorder is self-limiting, lasting for 12-15 weeks, with total resolution in most subjects. There are multiple strategies for the management of hyperthyroidism.51
In contrast, the determination of the cause of hypothyroidism with or without presence of a goiter rarely is crucial in treatment, which consists of oral administration of L-thyroxine in most subjects irrespective of the cause. The adequacy of the daily LT4 dose is established by normalization of serum TSH concentration in primary hypothyroidism. However, in subjects with central hypothyroidism, daily LT4 dose is adjusted to attain and maintain normal serum free T4 and free T3 concentrations with simultaneous improvement in clinical manifestations. For a detailed description of hormone replacement therapy in hypothyroidism, readers are referred to another review.52
In the presence of a euthyroid state confirmed by normal serum-free T4 and TSH concentrations, management is determined by several factors, including pathophysiologic etiology, structural characteristics, impact of the goiter on adjacent structures, and cosmetic concerns of the subject. (See Figure 2.) In the presence of iodine deficiency, documented frequently by a reliable nutritional history especially in an endemic area and confirmed by low serum and urine iodine concentration in non-endemic environment, therapy is simple and inexpensive. Oral iodine supplementation in an appropriate daily dose results in the resolution of goiter in most subjects.
Iodine deficiency is extremely rare in most Western countries because of supplemental iodine in foods, including common table salt. In these populations, the most common etiology of goiter, especially of diffuse variety in euthyroid adults and adolescents, appears to be autoimmune thyroiditis, as documented by presence of antithyroid (i.e., anti-thyroperoxidase and/or anti-thyroglobulin antibodies). These antibodies also frequently are present in subjects with multinodular goiter, especially in the elderly. In this population, superimposition of autoimmune thyroiditis in the presence of multinodular goiter of prolonged duration is more likely since the thyroid glands tend to develop nodularity with aging.53
The presence of nontoxic goiter in subjects with autoimmune thyroiditis may be attributed to inflammation and lymphocytic infiltration of the thyroid gland. Alternatively, dyshormonogenesis secondary to reduced organification of iodine induced by decreased intrathyroidal content of peroxidase enzyme or inhibition of its activity by antithyroperoxidase antibody also may contribute to goiter development. Dyshormonogenesis secondary to lack of or inhibition of one or multiple intrathyroidal enzymes in their activity of congenital origin likely is the most prominent cause of goiters in newborns and children.
Thus, in the presence of a non-toxic simple diffuse or multinodular goiter of either autoimmune variety or with an uncertain etiology, recurrent follow up at a 6-12 month interval for a change in size or structure of the thyroid gland without any specific intervention may be adequate, especially in the absence of manifestations of encroachment of adjacent structures or for cosmetic reasons. Surgical intervention is the preferred therapeutic option if a prompt reduction in gland size is required. These circumstances include presence of dysphagia secondary to compression of esophagus, hoarseness of voice due to involvement of recurrent laryngeal nerve, dyspnea or sensation of choking secondary to encroachment of trachea, or presence of tracheomalacia.
Surgery also is a preferred option in the presence of substernal extension of the goiter, especially if further enlargement during follow-up observation with or without LT4 administration is noted. Finally, surgery also is recommended for psychological reasons for fear of the unknown (i.e., malignancy) or for cosmetic reasons. An alternative option is radioiodine therapy, which can help achieve a gradual decrease in the size of the goiter.
The rationale of LT4 administration includes suppression of the thyroid gland and usually is achieved by administration of LT4 in a dosage required to induce suppression of serum TSH level both directly and indirectly via inhibition of TRH, (which works well for simple goiter, but is variable for multinodular goiter).54,55 A slightly higher daily LT4 dose in comparison to the one used for management of primary hypothyroidism is required because the appropriate serum TSH concentration to be attained and maintained in this setting is significantly lower (0.05-0.5 microunits per liter) than that attained in primary hypothyroidism (1.0-2.0 microunits per liter as recommended by the American Thyroid Association. The usual initial daily LT4 dose is 100 mcg in subjects younger than 50 years old, whereas in subjects between the ages of 50-65, the preferred daily initial dose is 50 mcg in absence of history of cardiovascular disease. Finally, the initial daily LT4 dose in subjects older than 65 years of age, or all other subjects irrespective of age with a history of cardiovascular disease, often is 25 mcg to reduce side effects.
The daily LT4 dose then is titrated gradually to attain the desirable serum TSH concentration described earlier. The older the subject, the more gradual the titration, especially in the presence of cardiovascular disease. Moreover, careful monitoring for the presence of even subtle manifestations of hyperthyroidism is required to avoid untoward outcomes, including cardiovascular manifestations in the short term and osteoporosis in the long term.
The response to suppressive L thyroxine therapy may be assessed by physical examination. The assessment based on palpation alone, however, may be misleading since nodules may appear prominent because of the suppression of the remaining part of the gland. Therefore, ultrasound examination prior to initiation and at about one year following LT4 administration is more helpful in definitive objective documentation of the size of the goiter and must be conducted. Many goiters, especially the diffuse ones, begin shrinking by two months and continue to recede with maximum response being noted by 12 months of LT4 suppressive therapy. However, the response to LT4 suppressive therapy is gradual and variable. Simple diffuse goiters are relatively more responsive, apparently because they are more TSH dependent. Alternatively, multinodular goiters most likely are more resistant because the hot nodules are autonomous in nature, whereas cold or nonfunctioning nodules are TSH independent. Thus, both types of nodules are not highly responsive to TSH suppression. Therefore, the response rate for multinodular goiters hovers around 50%. It is much higher (almost 70-80%) for diffuse goiters.54-55 Finally, LT4 suppressive therapy must be used in subjects following surgical resection or radioiodine ablation to maintain euthyroid state and prevent or delay anticipated recurrence as shown in several studies, although there is conflicting data.56-60
More recently, some investigators have proposed radioiodine ablation as a noninvasive alternative therapy.60-62 Available data indicate a successful and prompt reduction in size of multinodular goiters in almost 90% of subjects with minimal side effects. This therapy may be advantageous in all subjects, but especially in the elderly since a major surgical procedure could be avoided. However, the radioiodine (131I) dose required is extremely high (³100 mCi), especially in multi-nodular goiters, and, therefore, close monitoring is required for assessment of the side effects (i.e., bone marrow suppression in the immediate post-therapy period and radiation thyroiditis, acute airway obstruction, and dysphagia) in the intermediate period of 2-6 weeks following therapy. Finally, there may be a slight increase (0.5%) in the incidence of thyroid cancer in the long term, requiring future follow-up assessment. Finally, radioiodine administration following IM recombinant TSH administration for 2-3 days as performed in subjects with thyroid cancer may help in increasing the radioiodine uptake by the thyroid gland, reducing the dose of radioactive iodine (131I) with further decline in prevalence of side effects. However, this procedure requires further testing before being put into clinical practice.
The assessment and management of solitary or a prominent nodule (> 1.0 cm) in a multinodular goiter is distinctively different. As with other goiters, a detailed history and a thorough physical examination may provide clues as to the diagnosis. (See Table 5.)
|
Prior history of neck radiation or family history of thyroid cancers, including medullary carcinoma may point to a prompt fine-needle aspiration. Similarly, a hard nodule with decreased mobility on swallowing, especially in the presence of cervical lymphadenopathy, raises a very high suspicion of cancer and once again calls for prompt fine-needle aspiration. A determination of serum thyroid hormone concentrations, especially TSH, offers definitive clues. In the presence of subnormal TSH, radioactive iodine or Tech 99 imaging is likely to show the nodule to be hot or functioning, requiring a specific therapeutic intervention such as surgery or radioiodine ablation without fine-needle aspiration. In the presence of elevated TSH, management should follow the guidelines of treatment of primary hypothyroidism.52
With normal thyroid hormone concentrations, fine-needle aspiration is an important, initial cost-effective intervention to access the histology and formulate a definitive treatment.63 It is fortunate that 80% of these nodules are benign and the appropriate recommendation is continued observation or LT4 suppression therapy with yearly evaluation for change in size or structural integrity using ultrasound examination.54,55 TSH suppressive therapy is less successful when compared to treatment of other goiters, with resolution of the nodule in approximately 20% of subjects.54,55 Moreover, many of these nodules regress spontaneously, and the subjects concerned must be made aware of this possibility to avoid unnecessary major surgery or even radioiodine ablation.
In summary, goiter management is dictated by the pathophysiology, functional status, and the nature of the goiter; its impact on adjacent structures; and cosmetic concerns of the patient. The most important strategies involve continued recurrent observation with or without LT4 suppressive therapy used either as initial therapy or used following surgical intervention or radioiodine ablation.
References
1. Brent G. Thyroid hormones. In: Conn PM, Melmed S, eds. Endocrinology Basic and Clinical Principles. Totowa, NJ: Humana Press; 1997:291-306.
2. Braverman LE, Utiger RD, eds. Werner and Ingbars the Thyroid. 2nd ed. Philadelphia: JB Lippincott; 1996.
3. Fisher DA. Physiological variation in thyroid hormones: Physiological and pathological considerations. Clin Chem 1996;42:135-139.
4. Ganong WF. The thyroid gland. In: Review of Medical Physiology. 18th ed. Norwalk, CT: Appleton & Lange;1997:296-311.
5. Tonacchera M, Van Sande J, Parma J, et al. TSH receptor and disease. Clinical Endocrinology 1996;44:621-633.
6. Laurent E, Mockel J, Van Sande J, et al. Dual activation by thyrotropin of the phospolipase C and cyclic AMP cascade in human thyroid. Mol Cell Endocrinol 1987;52:273-278.
7. Corvilan B, Laurent B, Lecomte M. Role of cyclic 3-5 monophosphate and the phosphatidylinositol-ca++ cascade in mediating the effects of thyrotropin an diodine in hormone synthesis and secretion in human thyroid slices. J Clin Endocrinol Metab 1994;79:152-159.
8. Gartner R, Bechtner G. Advances in pathogenesis of goitre. Thyroidology 1990;2:93-98.
9. Cheung NW, Lou JC, Boyages SC. Growth hormone does not increase thyroid size in the absence of thyrotropin: A study in adults with hypopituitarism. J Clin Endocrinol Metab 1996;81: 1179-1183.
10. Bechtner G, Potscher C, Gartner R. Role of autocrine and paracrine factors in thyroid follicle growth. Thyroidology 1992;4:1-5.
11. Jockenhovel F, Olbricht T. Questions and answers on the epidemiology and etiology of goiter. Z Gesamte Inn Med 1993;48: 565-574.
12. Dumont JE, Lamy F, Roger P, et al. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiological Reviews 1992;72: 667-696.
13. Kelly FC. Goitre. World Health Organization, Geneva. 1960;44: 227-234.
14. Delange F. The disorders induced by iodine deficiency. Thyroid 1994;4:107-128.
15. Hennemann G. Non toxic goiter. Clin Endocrinol Metab 1979;8: 167-179.
16. Gaitan E. Goitrogens in food and water. Annu Rev Nutr 1990;10: 21-39.
17. Capen CC. Pathophysiology of chemical injury in the thyroid gland. Toxicol Lett 1992;64-65 Spec No:381-388.
18. Niepomniszcze H, Degroot LJ, Hagen GA. Abnormal thyroid peroxidase causing iodine organification defect. J Clin Endocrinol Metab 1972;34:607-616.
19. Kusakabe T. A goitrous subject with structural abnormality of thyroglobulin. J Clin Endocrinol Metab 1972;35:785-791.
20. Lissitzky S, Bismuth J, Jaquet P, et al. Congenital goiter with impaired thyroglobulin synthesis. J Clin Endocrinol Metab 1973;36:17-29.
21. Barsano CP, Degroot LJ. Dyshormonogenetic goiter. Clin Endocrinol Metab 1979;8:145-165.
22. Hoermann R. Stimulation of thyroidal and extrathyroidal thyrotropin receptors. Exp Clin Endcrinol Diabetes 1996;104:88-91.
23. Van Sande J, Parma J, Tonacchera M, et al. Somatic and germline mutations of the TSH receptor gene in thyroid diseases. J Clin Endocrinol Metab 1995;80:2577-2585.
24. Tamai H, Hirota Y, Kasagi K, et al. The mechanism of spontaneous hypothyroidism in patient with Graves’ disease after antithyroid drug treatment. J Clin Endocrinol Metab 1987;64:718-722.
25. Orgiazzi J, Williams DE, Chopra IJ, et al. Human thyroid adenyl cyclase-stimulating activity in immunoglogulin G of patient with Graves’ disease. J Clin Endocrinol Metab. 1976;42:341-354.
26. Mestmann JH, Goodwin M, Montoro MM, Thyroid disorders of pregnancy. Endocrinol Metab Clin North Am 1995;24:41-71.
27. Kennedy RL, Darnel J. The role of hCG in regulation of the thyroid gland in normal and abnormal pregnancy. Obstet Gynecol 1991;78:298-307
28. Ballabio M, Poshychinda M, Ekins RP. Pregnancy induced changes in thyroid function: Role of human chorionic gonadotropin as putative regulator of maternal thyroid. J Clin Endocrin Metab 1991;73:824-831.
29. Miyakawa M, Saji M, Tsushima T, et al. Thyroid volume and serum thyroglobulin levels in patients with acromegaly: Correlation with plasma insulin like growth factor 1 levels. J Clin Endocrinol Metab 1998;67:973-978.
30. Hofbauer LC, Spitzweg C, Tammen AR, et al. Infectious thyroiditis as initial manifestation of embolizing endocarditis of the aortic valve. Dtsch Med Wochenschr 1996;121:369-374.
31. Houghton DJ, Gray HW, MacKinzie K. The tender neck: Thyroiditis or thyroid abcess? Clin Endocrinol (oxf). 1998;48: 521-524.
32. Winkler S, Wiesinger E, Graninger W. Extrapulmonary tuberculosis with paravertebral abcess formation and thyroid involvement. Infection 1994;22:420-422.
33. Lambert M. Thyroid dysfunction in HIV infection. Baillieres Clin Endocrinol Metab 1994;8:825-835.
34. Burch HB. Evaluation and management of the solid thyroid nodule. Endocrinol Metab Clin North Am 1995;24:663-709.
35. Pierotti MA, Santoro M, JenkinsRB, et al. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC. Proc Natl Acad Sci USA. 1992;89:1616-1620.
36. Pisarchik AV, Ermak G, Fomicheva V, et al. The RET/PTC1 rearrangement is a common feature of Chernobyl associated papillary thyroid carcinoma from Belarus. Thyroid 1998;8:133-139.
37. Gagel RF, Goepfert H, Callender DL. Changing concepts in the pathogenesis and management of thyroid carcinoma. 1996;46: 261-283.
38. Pierotti MA, Bongarzone I, Borello MG, et al. Cytogenetics and molecular genetics of carcinomas arising from thyroid epithelial follicular cells. Genes Chromosomes Cancer 1996;16:1-14.
39. Orr C, O’Dorisio T. Multiple endocrine neoplasia types 1, 2A, and 2B. In: Bar RS, ed. Contemporary Endocrinology: Early Diagnosis and Treatment of Endocrine Disorders. Totowa, NJ: Humana Press; 2003: 239-252.
40. Karga H, Lee JK, Vickery AL Jr, et al. Ras oncogene mutations in benign and malignant thyroid neoplasms. J Clin Endocrinol Metab 1991;73:832-836.
41. Zou M, Shi Y, Farid NR. P53 mutations in all stages of thyroid carcinomas. J Clin Endocrinol Metab 1993;77:1054-1058.
42. Simon D, Goretzki PE, Schafer C, et al. Molecular analysis of mutations in thyroid tumors with TGGE. Exp Clin Endocrinol Diabetes 1995;103:275-279.
43. Manenti G, Pilotti S, Re FC, et al. Selective activation of ras ocogenes in follicular and undifferentiated thyroid carcinomas. Eur J Cancer 1994;30A:987-993.
44. Rapoport B. Pathophysiology of Hashimoto’s thyroiditis and hypothyroidism. Annu Med 1991;42:91-96.
45. Sundick RS, Bagchi N, Brown TR. The role of iodine in thyroid autoimmunity: From chicken to humans: A review. Autoimmunity 1992;13:61-68.
46. Pujol-Borrell R, Todd I, Londei M, et al. New ideas in thyroid autoimmunity. Horm Res 1987;26:118-124.
47. Hegedus L. Thyroid size determined by ultrasound. Influence of physiological factors and non-thyroidal disease. Dan Med Bull 1990;37:249-263.
48. Gogusev J, Duchambon P, Stoermann-Chopard C, et al. De novo expression of transforming growth factor-alpha in thyroid gland tissue of patients with primary or secondary uraemic hyperparathyroidism. Nephrol Dial Transplant 1996;11:2155-2162.
49. Hegedus L, Anderson JR, Poulsen LR, et al. Thyroid gland volume and serum concentration of thyroid hormones in chronic renal failure. Nephron 1985;40:171-174.
50. Abdullah MS, Wild G, Jacob V, et al. Cytokines and the malnutrition of chronic renal failure Miner Electrolyte Metab 1997;23: 237-242.
51. Cooper DS. Lancet. Hyperthyroidism. The Lancet 2003;362: 459-468.
52. Clarke N, Kabadi U. Optimizing treatment of hypothyroidism. Treatment in endocrinology (In Press).
53. Kabadi UM. Thyroid disorders in the elderly. Invited review. Comp Therapy 1989;15:53-65.
54. Anderson PE, Hurley PR, Rosswick P. Conservative treatment and long term prophylactic thyroxine in the prevention of recurrence of multinodular goiter. Surg Gynecol Obstet 1990;171: 309-314.
55. Gharib H, Mazzaferri EL. Thyroxine suppressive therapy in patients with nodular thyroid disease. Ann Intern Med 1998; 128:386-394.
56. Geerdsen JP, Frolund L. Thyroid function after surgical treatment of nontoxic goiter. A randomized study of postoperative thyroxine administration. Acta Med Scand 1986;220:341-345.
57. Hegedus L, Hansen JM. Does prophylactic thyroxine treatment after operation for non-toxic goiter influence thyroid size? Br Med J (Clin Res Ed) 1987;28;294:801-803.
58. Bistrup C, Nielsen JD, Gregersen G, et al. Preventive effect of Levothyroxine in patients operated for non-toxic goiter: A randomized trial of one hundred patients with nine years follow-up. Clin Endocrinol (Oxf) 1994;40:323-327.
59. Hegedus L, Nygaard B, Hansen JM. Is routine thyroxine treatment to hinder postoperative recurrence of nontoxic goiter justified? J Clin Endocrinol Metab 1999;84:756-760.
60. Huysmans DA, Buijs WC, van de Ven MT, et al. Dosimetry and risk estimates of radioiodine therapy for large, multinodular goiters. J Nucl Med 1996;37:2072-2079.
61. Nygaard B, Hegedus L, Gervil M, et al. Radioiodine treatment of multinodular non-toxic goitre. BMJ 1993;307:828-832.
62. Wesche MF, Tiel-V Buul MM, Lips P, et al. A randomized trial comparing Levothyroxine with radioactive iodine in the treatment of sporadic nontoxic goiter. J Clin Endocrinol Metab 2001;86: 998-1005.
63. Kabadi UM. Thyroid nodule. Saudi Medical Journal, Invited Review. 1995;16:484-487.
Goiter literally means the enlargement of the thyroid gland, independent of its cause. Historically, this terminology specifically was reserved for a visibly enlarged thyroid gland. During the past few decades of modern medical practice, the term has come to include both visible as well as palpable thyroid enlargement. This article will review the pathophysiologic processes leading to goiter formation and will provide a logical approach to the diagnosis and management of different entities, the end result of which is an enlarged thyroid gland.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content