The Natural Thyroid Diet

The Natural Thyroid Diet

The Natural Thyroid Diet can help you get the nutrition your thyroid needs. And when your thyroid is working better you will have more energy and it becomes much easier to lose weight. Find out why soy foods can actually harm your thyroid. Discover why going gluten free may not be a perfect dietary solution. Identify & treat the underlying factors that are driving your thyroid problem. Find out how to get a real medical diagnosis with specific pathology tests. How to assess your thyroid activity at home with a simple testing procedure. Find out which specific nutrients help enhance natural thyroid activity. Discover why iodine is such a critical mineral for the thyroid. Reduce thyroid stress & skyrocket your metabolism with a few simple activities. Learn about reverse T3 dominance & how to treat this common thyroid problem. How to detox your home to reduce the toxic load on your thyroid. Find out how to interpret the medical test results from your doctor. Get a natural thyroid diet with actual daily meal plans and food lists. Continue reading...

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Molecular Basis Of Thyroid Cancer

Kirsch, Matthias Black, Peter McL. (ed.) Angiogenesis in Brain Tumors. 2003. ISBN 1-4020-7704-1. Keller, E.T., Chung, L.W.K. (eds) The Biology of Skeletal Metastases. 2004. ISBN 1-4020-7749-1. Kumar, Rakesh (ed.) Molecular Targeting and Signal Transduction. 2004. ISBN 1-4020-7822-6. Verweij, J., Pinedo, H.M. (eds) Targeting Treatment of Soft Tissue Sarcomas. 2004. ISBN 1-4020-7808-0. Finn, W.G., Peterson, L.C. (eds.) Hematopathology in Oncology. 2004. ISBN 1-4020-7919-2. Farid, N., (ed) Molecular Basis of Thyroid Cancer. 2004. ISBN 1-4020-8106-5.

Types Of Primary Thyroid Lymphoma

Staging of primary thyroid lymphomas Stage I El Primary thyroid lymphoma (PTL) with or without perithyroidal soft tissue extension. Stage IE PTLs with involvement of lymph nodes on the same side of the diaphragm. Stage iTIE PTLs with involvement of lymph nodes on both sides of the diaphragm. Stage IV E PTLs with dissemination to other extranodal sites. MALT type. Others seen include MZBL of MALT type with large cell (blastic) transformation (mixed MZBL and diffuse large B cell lymphoma DLBCL ), DLBCL without MZBL and a miscellaneous, heterogenous group usually consisting of single case reports of a wide variety of lymphomas that can occur in lymph nodes and any other extranodal site. These include Hodgkin's disease, follicular lymphoma, intravas-cular lymphomatosis, anaplastic large cell lymphoma and T-cell lymphomas (35-42). These will not be dealt with, as their occurrence in the thyroid is the same as any other extra-nodal site or lymph node for that matter. The high-grade...

Papillary Lesions Of Thyroid

The papillary hyperplastic nodule of the thyroid is usually identified in girls, usually teenagers in and around the age of menarche. These present as solitary nodules and it is unusual for them to be associated with clinical hyperfunction, although that might occur. These lesion are distinguished from papillary carcinoma in that they are totally encapsulated, often show central cystic change, have subfollicle formation in the centres of broad oedematous papillae, and do not show nuclear features of papillary carcinoma (Figure 6). Although one analysis of clonality has suggested that these are polyclonal hyperplasias (56), the detection of or TSH receptor activating mutations in such nodules suggests that they are neoplasms (18-22). Their behaviour is almost always benign. Some have advocated the name papillary adenoma for these tumours while scientifically appropriate, this term carries historical connotations that some feel are unacceptable (5). In adults, one can have a similar...

Oncogenes And Thyroid Tumors Tyrosine kinase receptors

Growth factors act on the target cell through interaction with specific membrane receptors, some of which belong to the family of tyrosine kinase receptors. The genes encoding these receptors are frequently involved in the pathogenesis of human cancers, including thyroid cancer. Whenever uncontrolled activation of a tyrosine kinase receptor gene occurs, either through overexpression or activating mutations, increased responsiveness to growth factors or ligand-independent gene activation ensues, both of which then activate the signaling pathways downstream. Three tyrosine kinase receptor genes are known to be associated with the pathogenesis of papillary thyroid cancer the met gene through overexpression and the ret and trk genes through gene rearrangements. molecular basis of Ret PTC rearrangements. The ret proto-oncogene is a 21-exon gene located on chromosome 10q11-2 that encodes a membrane tyrosine kinase receptor. The ret receptor together with the glial cell line-derived...

Thyroid Follicular Hyperplasia And Neoplasia

Situ Follicular Neoplasia

Follicular nodules are the most commonly encountered problems in the surgical pathology of the thyroid. These lesions can be classified along the full spectrum of thyroid pathology from hyperplastic nodules to benign follicular adenomas and malignant fol-licular carcinomas. Sporadic nodular goitre is characterised by numerous follicular nodules with heterogeneous architecture and cytology, features that have suggested a hyperplastic rather than neoplastic pathogenesis (7-10). The gland may be distorted by multiple bilateral nodules and can achieve weights of several hundred to a thousand grams, but this disorder is often identified as a dominant nodule in what clinically appears to be an otherwise normal gland. Histologically, the nodules are irregular some are poorly circumscribed while others are surrounded by scarring and condensation of thyroid stroma, creating the appearance of complete encapsulation. They are composed of follicles of variable size and shape. Some follicles are...

Thyroid function in critical illness

Laboratory measurements of thyroid function in critically ill patients are frequently abnormal and are always difficult to interpret. The most common abnormality is low T3 syndrome. Most patients exhibiting this condition have a normal total thyroxine level and should be considered euthyroid. Low T 3 is probably due to deficient T4 uptake by the tissues and thus reduced peripheral conversion of T 4 to T3 (responsible for 80 per cent of total T3 production). The enzyme which catalyzes the conversion (5'-monodeiodinase) is inhibited by glucocorticoids. In low T 4 and T3 syndrome those exhibiting the lowest plasma T4 levels have the highest mortality. Despite normal levels of free hormone, postmortem analysis has shown low tissue T4 levels in brain, lung, liver, and kidney, but normal T4 levels in myocardium and skeletal muscle. These abnormalities are commonly grouped together under the term 'sick euthyroid syndrome' ( Rolih aD d O b rJ 9.95.).

Ras Mutations In Thyroid Cancer

A metastatic tumor is the end result of a complex series of steps involving multiple gene products. Work performed over the past decade has identified a number of gene products with putative roles in the initiation and progression of thyroid tumorigenesis. Mutations in Gsa (gsp) and the TSH receptor have been identified in hyperfunctioning adenomas. Ras mutations are prevalent in follicular carcinomas (see below). Mutations in ret, trk and met were identified in papillary carcinomas. Aberrant DNA methylation, leading to loss of expression of the p16 tumor suppressor gene, has been described in both types of cancer. Finally, mutations in p53 appear to play a role in the final dedifferentiation process. The reader is referred to several excellent recent reviews regarding the molecular basis of thyroid cancer (Jhiang, 2000 Gimm, 2001 Puxeddu et al., 2001 Fagin, 2002). Early reports revealed that Ras mutations were particularly prevalent in benign follicular adenomas and follicular...

Role Of Cellular Ras In Thyroid Cells

TSH regulates the function and proliferation of thyroid follicular cells, highly specialized epithelial cells that synthesize, store and secrete thyroid hormones. Thyroid hormone biosynthesis requires the expression of cell type specific gene products, including the TSH receptor, thyroperoxidase, thyroglobulin and the sodium iodide symporter (Damante et al., 1994). TSH regulates the expression of these genes in part through effects on thyroid-specific transcription factors such as TTF-1, TTF-2 and Pax-8 (Missero et al., 1998). The proliferation of thyroid cells is TSH-dependent (for recent reviews, see Medina et al., 2000 Kimura et al., 2001). However, for the most part, TSH acts together with insulin or IGF-I and serum to stimulate sustained proliferation. The effects of TSH on function and proliferation are reproduced by cAMP elevating agents and analogs. Positive growth regulation by cAMP is one of the unique features of thyroid cells and stands in marked contrast to the growth...

Sustained Ras Activity And Thyroid Cell Proliferation

The identification of activating Ras mutations in thyroid tumors prompted studies of the consequences of sustained Ras activity in thyroid cells. Early gene transfer studies revealed the oncogenic potential of Ras in thyroid cells in vitro. Stable expression of activated H- or K-Ras in FRTL-5 cells was fully transforming. Ras-expressing cells exhibited hormone-independent proliferation, anchorage-independent growth and formed tumors in nude mice (Fusco et al., 1987). In contrast to these results, rat thyroid PC-CL3 cells were only partially transformed by Ras. In vivo studies demonstrated that Ras activation was insufficient for tumor formation. When injected into adult Fischer rats, a K-Ras retrovirus induced the formation of differentiated thyroid carcinomas only in goitrogen-treated animals (Portella et al., 1989). Similarly, targeted expression of activated K-Ras to the thyroid gland stimulated hyperplasia and adenoma formation, but only in rare instances tumor formation, which...

Sustained Ras Activity And Thyroid Differentiation

Ras transformation suppressed differentiated gene expression in rat thyroid cells (Avvedimento et al., 1985 Fusco et al., 1987 Francis-Lang et al., 1992). Intrigu-ingly, H- and K-Ras impaired differentiation in different ways. H-Ras transformation was associated with the loss of Pax-8 and TTF-2 expression, and inactivation of TTF-1 possibly through decreased phosphorylation (Francis-Lang et al., 1992 Velasco et al., 1998). In contrast, TTF-1 expression was abolished in K-Ras transformed cells (Francis-Lang et al., 1992). K-Ras has also been shown to impair the nuclear localization of PKA, thereby preventing PKA-mediated phosphorylation of nuclear transcription factors (Gallo et al., 1995). Ras-transformed human cells retain their differentiated phenotype (Lemoine et al., 1990 Gire et al., 2000), a finding consistent with the occurrence of Ras mutations in differentiated thyroid tumors. It should be noted that de-differentiation is not an obligate response ofrat thyroid cells to...

Ras And Thyroid Cell Survival

Although stable expression of activated Ras in thyroid cells confers hormone and anchorage-independent proliferation, it also renders cells more sensitive to apoptosis. The effects of Ras on apoptosis are not limited to rat thyroid cells. Human thyroid cells immortalized by temperature-sensitive SV40 large T antigen underwent rapid cell death following expression of activated Ras at the restrictive temperature (Burns et al., 1993). Exposure to the phorbol ester tumor promoter TPA stimulated apoptosis in human thyroid cells expressing activated H-Ras (Hall-Jackson et al., 1998). Moreover, inhibition of PI3K activity induced apoptosis in H-Ras-expressing human thyroid cells, suggesting that clonal expansion induced by Ras requires PI3K activity to suppress apoptosis (Gire et al., 2000). Together these findings indicate that apoptosis is a conserved response to acute expression of activated Ras in thyroid cells. The relative ease with which rat and human thyroid cells are selected to...

Papillary Thyroid Cancer

Papillary thyroid cancers appear as firm, unencapsulated, or partly encapsulated tumors. Extension beyond the capsule has been reported in 8 to 32 of the cases (9). PTCs may be partly necrotic and some undergo cystic degeneration. PTC is often multifocal when it occurs in a single thyroid lobe and occurs in bilateral lobes in 20 to 80 of the cases (12). Lymph-node metastatic involvement is found in 15 to 80 of the cases depending on the extent of lymph node dissection and examination of the surgical specimen. From the ipsilateral thyroid lymph node chains they may spread to more distant lymph node groups to the upper mediastinal nodes. Vascular invasion is rare and distant metastases (mostly to lungs) are observed in 5 to 10 of the cases, mostly as a result of lymphatic spread (11). Lymph node metastases as the first clinical finding in patients with PTC are not uncommon. The mean 10-year survival rates in PTC are 80 to 90 , with optimal treatment. Papillary Thyroid Cancer Variants...

Follicular Thyroid Cancer

Follicular thyroid cancer is an epithelial carcinoma showing evidence of follicular cell differentiation but lacking the diagnostic features of papillary carcinoma (11). It tends to be more common in regions with iodine deficiency and in patients older than 50 years. Ten-year survival rates are lower than in PTC ranging from 60 to 70 . It usually presents as a solitary thyroid tumor. The diagnosis of malignancy depends on the presence of blood vessel and or capsular invasion. Histologic Follicular Thyroid Cancer Variants Hurthle Cell Carcinoma (Oncocytic Carcinoma or Oxyphilic Variant Follicular Thyroid Cancer)

Thyroid abnormalities

In unselected major depression, thyroid hormone levels are usually normal, but there may be abnormalities of the thyrotropin (thyroid-stimulating hormone) response to thyrotropin-releasing hormone. The thyrotropin response is blunted in a significant number of patients, but this effect is poorly understood and has few accepted clinical associations. In contrast, a subgroup of patients may show an enhanced thyrotropin response with normal thyroid hormone levels (referred to as grade II hypothyroidism). These associations and the use of thyroid hormones in treatment suggest that there is more to be learned in this area (see Chapter4. .5.7).

Altered Expression Of The Retinoic Acid Receptors In Thyroid Cancer

Retinoic acids (RAs) are essential for many biological processes including proliferation, development, differentiation, carcinogenesis, and apoptosis. These biological effects are mediated through their receptors (RARs). The retinoids, both the natural and synthetic analogs, have been shown to be effective in preventing several cancers in experimental animals and in reversing pre-neoplastic lesions in humans (20, 21). Whether the retinoids could be effective in re-differentiating thyroid cancer cells to be amenable to radioiodide or TSH-suppressive T4 therapy has prompted several investigators to study the expression of RAR in cancer cell lines and tissues. Using Northern blot analysis, del Senno found that the expression of RARa mRNA was lower in thyroid carcinoma cells than in normal thyroid follicular cells. Moreover, del Senno demonstrated that RA reduces the proliferation and function of thyroid follicular cells (22, 23). These findings were confirmed in a larger study. Using...

Abnormalities Of Thyroid Hormone Receptors In Thyroid Cancer

The thyroid hormone receptors (TRs) mediate the pleiotropic activities of the thyroid hormone (T3) in growth, development, and differentiation and in maintaining metabolic homeostasis. The two TR genes, and are located on human chromosomes 17 and 3, respectively. Alternative splicing of the primary transcripts gives rise to five major TR isoforms (al, a2, (31, 32, and (33). TRal, TR 31, TR(32, and differ in their lengths and amino acid sequences at the amino terminal A B domain, but they bind T3 with high affinity to mediate gene regulatory activity. By contrast, TRa2, which differs from the other TR isoforms in the C-terminus, does not bind T3, and its precise functions have yet to be elucidated. The expression of TR isoforms is tissue-dependent and developmentally regulated (1, 2). Abnormal expression and somatic mutations of TRs in thyroid cancer Similar to the expression levels reported for ER, PR, and RAR, an altered expression of TRs was detected in thyroid carcinomas....

Pituitarythyroid axis

Thyroid-stimulating hormone stimulates the preferential release of thyroxine (T 4) from the thyroid gland. T4 is then peripherally deiodinated into its active metabolite tri-iodothyronine (T3) or into reverse T3 (rT3) which is thought to be biologically inactive. Both T4 and T3 exert feedback inhibition at the pituitary and hypothalamic level. Critical illness is characterized by a low T 3 or 'sick euthyroid syndrome'. In mild and severe illness T3 production is rapidly decreased by inhibited conversion of T4 to T3. There is then a reciprocal increase in the inactive thyroid metabolite rT 3. With more sustained illness T4 levels may also fall because of reduced T4 binding to its carrier proteins leading to accelerated metabolism. More importantly, thyroid-stimulating hormone secretion is also suppressed for example, the normal night-time surge in thyroid-stimulating hormone is not present in patients with sick euthyroid syndrome and the response of thyroid-stimulating hormone to...

Pathophysiological consequences of hyperthyroidism

Thyroid hormone exerts its effects directly via specific nuclear receptors and through central activation of the sympathoadrenal system. The increased basal metabolic rate, often exacerbated by pyrexia due to impaired thermoregulation, is associated with an increase in oxygen consumption and carbon dioxide production and a hyperdynamic circulation. Consequently, patients are at risk of developing arrhythmias and myocardial ischemia, while respiratory muscle weakness may lead to ventilatory failure. Thyroid hormones influence the concentration and distribution of various neurotransmitters. Neurological complications of severe hyperthyroidism include irritability and tremor, delirium, stupor, and seizures. The myopathy of hyperthyroidism may cause weakness of the striated muscles of the pharynx, resulting in dysphagia, as well as affecting the eye, resulting in ophthalmoplegia. Proximal muscle weakness is common and may be the dominant manifestation in some individuals.

Specific antithyroid treatments

Propylthiouracil impedes formation of thyroid hormone and prevents conversion of thyroxine to the metabolically active hormone tri-iodothyronine. The recommended dose is propylthiouracil 200 mg every 6 h by mouth or nasogastric tube if the patient is unable to take oral medication. An alternative is carbimazole 15 mg orally every 6 h. In very severe cases potassium iodide or Lugol's iodine may be required, but their administration should be delayed for approximately 1 h following the first dose of propylthiouracil. This is to minimize the possibility of massive hormone release following iodination. Dosing schedules vary, but potassium iodide 60 mg orally three times daily, or potassium iodide saturated solution (eight drops every 6 h orally), or sodium iodide 1 g intravenously twice daily are appropriate. Alternatively, Lugol's iodine can be administered as ten drops of a solution containing 130 mg ml iodine diluted in milk or water twice daily. Lithium carbonate may be useful in...

Measures to control the effects of hyperthyroidism

Propranolol (80 mg orally or 1-2 mg intravenously as required) blocks the b-adrenoreceptor effects of thyroxine and is particularly useful for reducing sinus tachycardia. It also impairs conversion of thyroxine to tri-iodothyronine and inhibits release of thyroid hormone. Propranolol is contraindicated in patients with cardiac insufficiency or air-flow limitation, although newer more specific b-blockers such as atenolol can be used in patients with congestive cardiac failure, bronchospasm, or peripheral vascular disease. Rapid atrial fibrillation should be managed by standard protocols involving digoxin administration (up to 1.5 mg as a loading dose) following correction of hypokalemia and anticoagulation. Thyrotoxicosis accelerates the metabolism of digoxin. Conversely, patients with thyrotoxicosis are more sensitive to warfarin because vitamin-K-dependent clotting factors are metabolized more rapidly. Verapamil may also be useful in this setting to reduce the ventricular rate....

Thyroid hormone therapy

Choice of thyroid hormone (thyroxine or tri-iodothyronine), its optimal dose, and the route of administration remain controversial. To exert its full biological effect, thyroxine must be converted into tri-iodothyronine by an enzymatic step involving 5'-deiodinase. thyroid-stimulating hormone, free tri-iodothyronine, and free thyroxine is not clinically useful during intensive care treatment. Nevertheless, if it is done it could show a rapid increase of plasma free thyroxine and a slower increase of free tri-iodothyronine, whereas thyroid-stimulating hormone levels decrease only after a few weeks. The goal of the maintenance treatment is to normalize the thyroid-stimulating hormone plasma levels which takes several months ( M lioiti, Lal 1995).

Differentiated thyroid cancer

Management is similar for all cases and commences with radical thyroidectomy preserving parathyroid and recurrent laryngeal nerve function. Low risk patients (those with small intrathyroidal papillary or micro-angioinvasive minimally invasive follicular tumours) are sometimes managed by thyroid lobectomy but most clinicians prefer the radical approach for all patients. Radioiodine therapy (40-80 mCi 1500-3000 MBq) to ablate the thyroid remnant follows the operation. This rids the body of all iodine avid normal thyroid, obviating the risk of future second tumours (papillary) and rendering the subsequent screening programme (both thyroglobulin and radioio-dine) more sensitive and specific for detecting relapse. External beam radiotherapy is delivered to the neck where the tumour was locally invasive at operation (giving a dose of 5000 cGy in 5 weeks via a well executed, CT planned, three field MV photon plan in a shelled patient, the volume being parallel to a straight cervical spine)....

Albert A Driedger and Thomas J McDonald Thyroid Anatomy and Physiology Embryology and Anatomy

The normal thyroid gland begins as a primitive diverticulum at the base of the tongue in the third week of gestation and grows caudally toward its ultimate position anterior to the thyroid cartilage. In the adult it forms a butterfly-shaped structure weighing about 20 grams. Some thyroid tissue may remain along the thyroglossal duct to form a pyramidal lobe or a thyroglossal thyroid remnant in post-natal life. In rare cases the thyroid fails to descend and forms at the base of the tongue (lingual thyroid) where it may present as a mass. The thyroid originates near the formation site of the aortic sac, and for this reason accessory thyroid tissue may be found in the mediastinum. The normal thyroid is made up predominantly of follicular cells whose function is the production, storage and secretion of thyroid hormone. These cells are able to trap iodine and produce thyroxine by about the 11th week of gestation. The follicular cells, possibly under the influence of TSH, arrange themselves...

Radiopharmaceuticals for the Assessment of Thyroid Function

Much of modern Nuclear Medicine began with the challenges presented by the thyroid gland. It was known prior to the era of radioactive isotopes that the thyroid gland concentrated iodine. For instance, Dr. Plummer's introduction of Lugol's iodine to block release of thyroid hormone in preparation of thyrotoxic patients for surgery at the Mayo Clinic in the early 1920s reduced the post-surgical mortality from 11 to < 1 within a year. When, in the late 1930s, it became possible to produce radioactive isotopes of iodine with cyclotrons, they were first used to study the

Scanning of the Thyroid

Radionuclide imaging of the thyroid is a direct extension of the clinical examination. It is important for the nuclear physician to be familiar with the setting in which the examination is being requested. Patients may be self-medicating with vitamins, kelp or other substances containing iodine and it is recommended to defer the examination for several weeks after discontinuation of these substances (Table 1). Clinical examination of the patient while under the camera allows correlation of palpable features with those of the scan. This ought always to be done by the physician who will report the examination and who should be aware of the presenting complaint, the relevant clinical history and laboratory data. A positive family history will increase the pre-test likelihood for multinodular goitre and Graves's disease. A complaint of pain predisposes toward thyroiditis. A history of radiation exposure with a symptomatic mass increases the probability of a malignancy. Thyroid imaging is...

Table 3 Classification of thyroid cancer

Medullary carcinoma of the thyroid Adapted from Biddinger P and Nikiforov YE. Pathologic features of thyroid tumors. In Thyroid Cancer. Fagin JA (ed.) Kluwer Academic Publishers. 1998. large component of radioiodine isotopes, in the Marshall Islands following atmospheric nuclear weapons testing was that exposed persons developed thyroid nodules and an increased incidence of cancers after several decades. It was anticipated at the time of the Chernobyl nuclear reactor accident, which also released a large amount of iodine isotopes, that there would be an increase in the number of thyroid cancers but the rising incidence within only five years was surprising at the time. In retrospect, this early appearance was predictable as it merely reflects the progressive broadening of the Gaussian distribution of risk on account of the very large exposed population to that event. In the 15 years since the Chernobyl accident, it appears that the population at highest risk of developing thyroid...

Follicular Cell Derived Thyroid Cancers

The discussion of thyroid cancer RAI therapy must be grounded in the risk factors for recurrence of disease presented by the diagnosis. There are many clinical schemes for evaluating risk, such as AMES, where Such a scheme is helpful in evaluating the post-surgical risk of thyroid cancer recurrence and essential in guiding discussions with the patient concerning post-surgical treatments or ongoing surveillance. Other risk assessment protocols exist,

Table 3 Simplified lowiodine diet typically used for 1014 days prior to radioiodine scanning or therapy for thyroid

Accurate preoperative detection of distant metastases is typically not possible with these cancers underscoring the importance of RAI imaging to detect extent of metastatic disease and the difficulty inherent in imaging them while the thyroid gland is in place. Thus, the definitive discussion of prognosis must often await ablation of remnants with RAI and post-therapy scanning.

Thyroid emergencies Thyrotoxic crisis

Presents as an exacerbation of the clinical features of hyperthyroidism (e.g. pyrexia, hyperdynamic circulation, heart failure, confusion). There is usually a precipitating factor such as infection, surgery, ketoacidosis, myocardial infarction or childbirth. It may present with exhaustion in the elderly with few features of hyperthyroidism. The diagnosis is confirmed by standard thyroid function tests.

Medullary Thyroid Carcinoma

Medullary thyroid carcinoma (MTC) is a rare tumor of the thyroid gland. It was recognized as an unique entity by Hazard in 1959 (Hazard, J. B. et al., 1959) previously it was often classified as undifferentiated thyroid carcinoma. MTC comprises approximately 5-10 of all thyroid malignancies. At variance with other thyroid malignancies, deriving from the follicular thyroid cells, MTC arises from parafollicular C cells (Williams, E. D., 1966). C cells derive from the neural crest and are able to secrete the hormone calcitonin (CT), a specific tumor marker for MTC. Calcitonin is in fact a useful marker in the follow up of treated patients and was used for screening the individuals predisposed to the hereditary form of the disease. RET analysis has now replaced CT testing to diagnose MEN2 carrier state. In 1959, Hazard and coworkers first recognized medullary thyroid carcinoma as a distinct tumor (Hazard, J. B. et al., 1959). Sipple first described the association of medullary thyroid...

Ret Activation In Inherited And Sporadic Medullary Thyroid Carcinomas

The correlation between the various RET mutations and the development of thyroid carcinomas has been proved in fibroblast (Santoro, M. et al., 1995 Borrello, M. G. et al., 1995) and in a variety of different transgenic models (Asai, N. et al., 1995 Michiels, F. M. et al., 1997 Reynolds, L. et al., 2001 Acton, D. S. et al., 2000).

Endocrinopathies Congenital hypothyroidism

Congenital hypothyroidism is associated with mental retardation and may be associated with decreased motor activity at birth, hoarse cry, and difficulty with feeding. It is rarely diagnosed at birth from clinical assessment alone, but it is recognized from new-born screening tests with confirmation by measurement in blood samples. Symptoms of hypothyroidism may not be clearly detected until the second month of life. The overall prevalence is 1 in 4000 live births. Neurological and learning disorders associated with untreated congenital hypothyroidism include attention-deficit disorder, hearing loss, speech defects, ataxia, and abnormal muscle tone. (35 Rapid diagnosis in infancy is essential to prevent these complications. Without treatment, severe neurological dysfunction ensues. With initiation of oral thyroid hormone treatment (levothyroxine in a single daily dose of 8 to 10 pg kg per day) in the first 6 weeks of life, IQ is in the normal range. If treatment is delayed until 3 to 6...

Thyroid Hormone Activation and Inactivation by Selenodeiodinases

In humans, the major pathway in the metabolism of the thyroid hormones consists of the removal of iodine or deiodination. Three deiodinase isoenzymes, encoded on three distinct genes, catalyze the reductive deiodination. All three enzymes contain the rare amino acid seleno-cysteine. The essential trace element selenium therefore plays an important role in thyroid hormone economy. The three deiodinases have differing tissue distributions, substrate preferences, and Km values. This arrangement allows for control of thyroid hormone action at the cellular level. The source and quantity of T3

Mechanisms Of Action Of Thyroid Hormones

Thyroid hormone mechanisms of action can be classified into two types (1) genomic or nuclear and (2) nongenomic, including effects at the plasma membrane and mitochondria. Genomic effects involve modification of gene transcription, are mediated only by T3, and require at least several hours to detect. Nongenomic actions are generally rapid in onset and occur in response to T4 and some T4 metabolites (e.g., rT3,T3, and T2).

Genomic Actions of Thyroid Hormones

Thyroid hormone receptors are members of a super-family of nuclear receptors that includes receptors for estrogen, glucocorticoid, mineralocorticoid, retinoic acid, 9-cis-retinoic acid (retinoid X), and vitamin D. Similar to the mechanism of action of lipophilic steroid hormones, the lipophilic T3 binds to a protein receptor to form a complex and the hormone-receptor complex binds to an appropriate hormone response element on DNA to alter the transcription of specific genes. The current view of the mechanism of thyroid hormone action differs from that for steroid hormones, however, in three major ways (1) There are apparently no cytosolic receptors for thyroid hormones. (2) The nuclear TRs can bind to DNA nucleotide sequences in the regulatory region of thyroid hormone-responsive genes in the absence of thyroid hormone binding. (3) In the absence of T3 binding, TR bound to these specific areas of DNA may repress or promote the transcription of the associated thyroid hormone-responsive...

Nongenomic Actions of Thyroid Hormone

The nongenomic actions of thyroid hormone are increasingly recognized as physiologically significant. Nongenomic actions may be observed within minutes of stimulation and respond to a range of thyroid hormone metabolites (T4, T3, rT3, T2). The magnitude of nonge-nomic actions is usually only a few fold in contrast to the multifold genomic actions. The nongenomic actions (Table 65.2) may involve interactions with components of the cellular signal transduction pathways, such as cyclic adenosine monophosphate (cAMP), phosphatidyl inositol, and protein kinases. Examples include effects on cellular respiration, cell morphology, vascular tone, and ion homeostasis. Possible nongenomic targets of thyroid hormone include the plasma membrane, cy-

Euthyroid Multinodular Goiters

Although surgery may be the first-line treatment of significantly enlarged euthyr-oid multinodular goiters, RAI has also been used. In the setting of nonhyperfunc-tional thyroid tissue, there are greater concerns that nonablative therapy with RAI would predispose residual thyroid tissue to develop thyroid cancer. The actual risk of cancer from RAI, used to treat euthyroid goiters, is not known. RAI may be more preferable in patients older than 65 years, in whom contraindications to surgery are more common, and the risk of developing fatal and nonfatal cancer from RAI may be negligible (24). Doses of 3.7 to 4.625 MBq (100-125 mCi) per gram of estimated thyroid tissue have been used for the treatment of euthyroid goiters. More than 90 of patients can be expected to demonstrate a decrease in goiter size with an average reduction of 40 at one year (25). Tracheal compression may also improve significantly, both symptomatically and radiographically (26). However, caution should be exercised...

Congenital hypothyroidism

This results from loss of thyroid function, usually due to failure of the thyroid gland to develop correctly. The incidence is 1 in 3500 to 4000, which may be higher in Asian families, being 1 in 918 in the north-west of England. Neonates are usually normal at birth. Prior to the establishment of neonatal screening programme, hypothyroidism used to be a major cause of mental retardation. (59 If the condition remains untreated, neonates develop lethargy, difficulty with feeding, constipation, enlargement of the tongue, and umbilical hernia. As the development of the brain and normal growth are dependent upon normal levels of thyroid hormone, congenital hypothyroidism leads to growth retardation and mental retardation. Treatment with thyroxine needs to begin as soon as the diagnosis is made even a delay of 6 months can lead to significant reduction in the IQ. (6,9

Drugs Used In The Treatment Of Hyperthyroidism

Treatment of hyperthyroidism is directed at reducing the excessive synthesis and secretion of thyroid hormones. This may be accomplished by inhibiting thy-roidal synthesis and secretion with antithyroid drugs, by reducing the amount of functional thyroid tissue, or by both. Unfortunately, only a small proportion of patients treated with antithyroid drugs obtain long-term remission of their hyperthyroidism. Ablative therapy is often necessary. Since many of the signs and symptoms of hy-perthyroidism reflect increased cellular sensitivity to adrenergic stimulation, a p-adrenergic antagonist is often used adjunctively. Propranolol (Inderal), the most widely used p-adrenoceptor blocker, is effective in ameliorating many of the manifestations of thyrotoxicosis. It may reduce thyrotoxicosis-induced tachycardia, palpitations, tremor, sweating, heat intolerance, and anxiety, which are largely mediated through the adrenergic nervous system. Propranolol may also impair the conversion of T4 to...

Hyperthyroidism in pregnancy

Thyroid function should be assessed in women with hyperemesis gravidarum. Women known to have Graves' disease may decide on definitive treatment of their condition prior to becoming pregnant. If Graves' disease is diagnosed during pregnancy, it is important to use the smallest dose of antithyroid drugs by reviewing regularly to maintain maternal concentrations of free thyroid hormone and thyroid-stimulating hormone within their respective normal ranges. This is to avoid fetal hypothyroidism and goiter. Most recommend that carbimazole should be discontinued 4 weeks before the expected date of delivery to avoid any possibility of fetal hypothyroidism at the time of maximum brain development. If subtotal thyroidectomy is necessary because of poor drug compliance or hypersensitivity, it is most safely performed in the middle trimester. Radio-iodine is contraindicated because it invariably induces fetal hypothyroidism. If antithyroid agents are given postdelivery, breast feeding is not...

Treatment Of Children With Hyperthyroidism

Exposure of nonablated thyroid tissue to radiation. However, thyroidectomy carries a small risk of hypoparathyroidism and recurrent laryngeal nerve damage. The success of surgery depends on the experience of the surgeon. With external radiation exposure, there is a known risk of thyroid cancer in children that may decrease with increasing age at exposure (62). Studies of radiation exposure related to fallout from nuclear weapon testing in the Marshall Islands and the Chernobyl disaster have also shown higher rates of thyroid cancer in children (63). However, less is known regarding the risk of thyroid cancer following the medical use of RAI in children, and a comprehensive study of thyroid and nonthyroid cancer risks in this setting has not been performed. At prescribed activities of 3.7-7.4 MBq (100-200 pCi) per gram of thyroid tissue, one study did not detect an increased incidence of thyroid cancer in children (64). However, definitive long-term data on the oncogenic effects of...

Abnormal Expression Of Estrogen And Progesterone Receptors In Thyroid Cancer

Thyroid carcinoma is more common in women than in men (5). For 2003, the estimate of new cases of thyroid cancer has a female predominance with a 2.9 1 ratio (6). This predominance suggests that estrogens may play a critical role in the development of thyroid carcinoma. In the past two decades, efforts have been made to demonstrate the presence of estrogen receptors (ERs) in thyroid tumors and to correlate tumor malignancy with ER expression. Using a dextran-coated charcoal method and analysis by the method of Scatchard, Miki et al. did not detect ER in the cytosol of normal thyroids, but they found a significantly higher ER in the neoplastic and hyperplastic thyroid tissues (7). Using different biochemical methods, Mizukami et al. (8) and Yane et al. (9) also showed a higher expression of ER in neoplastic thyroid lesions than in normal thyroids or in adjacent normal tissues. Lewy-Trenda examined 72 thyroid glands for the expression of ER by using immunochemical assays with anti-ER...

The hypothalamicpituitarythyroid axis

It has been recognized for more than a century that adult patients with hypothyroidism exhibit profound disturbances in CNS function, including cognitive impairment and depression. In more recent years, attention has focused on more subtle alterations of the hypothalamic-pituitary-thyroid ( HPT) axis in depressed patients. Hypothyroidism is most frequently subclassified as in four grades as follows. Grade 1 hypothyroidism is classic primary hypothyroidism (increased thyroid-stimulating hormone ( TSH), decreased peripheral thyroid hormone concentrations, and an increased TSH response to thyrotrophin-releasing hormone (TRH)). Grade 2 hypothyroidism is characterized by normal, basal thyroid-hormone concentrations, but an increase in basal TSH concentrations and an exaggerated TSH response to TRH. Grade 3 hypothyroidism can only be detected by a TRH-stimulation test patients have a normal basal thyroid hormone and TSH concentrations, but an exaggerated TSH response to TRH. Grade 4...

Radiationassociated Thyroid Tumors

The thyroid gland is highly sensitive to radiation during childhood, the excess relative risk per Gray being 7.7, and 88 of thyroid cancers occurring in these subjects being attributable to radiation. The irradiated thyroid gland is thus an adequate model for the study of radiocarcinogenesis. Several epidemiological studies have suggested a familial predisposition to developing a thyroid carcinoma after irradiation. Firstly, approximately 3-5 of patients with thyroid cancer, without previous exposure to radiation, have a familial history of the same disease (29). Secondly, when both individuals in sibling pairs were irradiated, the occurrence of thyroid tumors was concordant more often than would have been expected by chance. Thirdly, patients with one radiation-induced tumor (thyroid, salivary, neural, parathyroid) are more likely to develop another tumor than patients with comparable risk factors but who had never had a tumor. This predisposition may Epidemiological studies have...

Experimental Induction Of Thyroid Tumors

Methods for inducing thyroid tumors in animals can be subdivided into two groups according to the mechanism of action. The first group comprises methods based on the application of substances with a direct oncogenic effect on thyroid cells, i.e., proper carcinogenic agents. The methods in the second group aim primarily at establishing a hormonal imbalance that, in turn, will lead to tumor development. Such a division, however, is rather artificial. Some known carcinogenic agents with a direct mechanism of action may also produce profound and irreversible hormonal disturbances that lead to thyroid carcinogenesis. Vice versa, many of the agents used to disturb the hormonal balance may exert a direct carcinogenic effect. As a result of numerous investigations, a consistent concept of experimental thyroid tumor pathogenesis was established to explain the tumorigenic effect of antithy-roid drugs (Bielschowsky 1955). According to this concept, the first stage in the development of thyroid...

Gene Expression Profiling In Thyroid Cancer

A limited number of studies have reported on DNA microarray studies in thyroid cancer two on follicular tumors, one on papillary carcinoma (PTC) and only one that examined a range of benign and malignant thyroid disease. The numbers of samples analyzed in each study was small to moderate in size. Most of the studies quoted are, however, robust and pass muster for the stringent rules stipulated for reporting of gene expression studies (4). Papillary thyroid carcinoma Huang et al. (12) used oligonucleotide DNA chips containing more than 12,000 genes to profile 8 papillary carcinomas and matching normal thyroid tissue. They found the expression of 8 genes to be suppressed in 7 8 samples and that of 19 genes in 6 8 samples. The genes whose expression was suppressed fell in a number of categories tumor suppressor genes (e.g. bcl-2, gas-1 and fos-B), thyroid metabolism (e.g. dio-1, dio-2, tpo), cell adhesion (dpt and fgl-2), fatty acid binding (apo-B and fabp-4) and signal transduction...

Physiological Effects Of Thyroid Hormones

There is no discrete target tissue for thyroid hormones virtually every cell in the body is affected by thyroid hormones in some way. These hormones are intimately involved in the maintenance of normal function in virtually every cell type, including cellular responsiveness to other hormones, to the availability of metabolic substrates, to growth factors, and so on. Thyroid dysfunction can produce dramatic changes in the metabolism of proteins, carbohydrates, and lipids at the cellular level that can have repercussions for the operation of the cardiovascular, gastrointestinal, musculoskeletal, reproductive, and nervous systems. Some of the clinical manifestations of thyroid dysfunction are presented next in the discussions of hypothyroid and hyperthy-roid states.

Clinical Manifestations of Hypothyroidism

During the perinatal period, there is an absolute requirement for thyroid hormone for the development and maturation of the nervous and musculoskeletal systems. In the perinatal nervous system, thyroid hormone plays a critical role in normal growth of the cerebral and cerebellar cortices, the proliferation of axons, the branching of dendrites, synaptogenesis, myelination, cell migration, and so on. Thyroid hormone also plays a major role in the maturation of bone. A deficiency of thyroid hormone in early life leads to both delay in and abnormal development of epiphyseal centers of ossification (epiphyseal dysgenesis). Hypothyroidism-induced impairment of linear growth can lead to dwarfism in which the limbs are disproportionately short in relation to the trunk with the apparent bone age retarded in relation to chronological age. The hallmarks of infantile hypothyroidism (e.g., retardation of mental development and growth) become manifest only in later infancy and are largely...

Naturally Existing CD4CD25 T Cells as Peripheral Barrier to Autoimmune Thyroiditis

As we have hypothesized earlier and discussed above, there is a clonal balance of regulatory T cells and autoreactive T cells, with the former keeping the latter in check in normal, susceptible individuals (Kong et al., 1982). This hypothesis has certainly been borne out by transfer experiments in which CD4+CD25- T cells, transferred without CD4+CD25+ T cells, mediated the development of several autoimmune diseases including thyroiditis (Sakaguchi et al., 1995). The depletion of CD4+CD25+ T cells also enabled resistant mice to respond to induction of autoimmune gastritis (McHugh and Shevach, 2002). We have postulated that such a natural barrier to autoimmune thyroiditis development represents the first level of regulatory influence, while mTg-induced resistance to withstand EAT induction represents the second level of regulation (Kong et al., 1989). With the identification of CD4+CD25+ regulatory T cells as mediators of induced resistance, we examined if naturally occurring regulatory...

Hypothalamopituitarythyroid HPT axis

Clinical disorders of thyroid function are known to cause alteration in mood. Classically, patients with hypothyroidism frequently report features similar to depression and, while usually more closely linked to feelings of anxiety, depressive reactions are also sometimes seen in hyperthyroid patients. In depression, several abnormalities in thyroid function have been described. Figure 2.2 shows the axis, and Table 2.2 lists the abnormalities described. While not entirely consistent, the blunted thyroid-stimulating hormone (TSH) response to thyrotrophin-stimulating hormone (TRH) could be due to hypersecretion of TRH that causes downregulation of pituitary TRH receptors. Table 2.2 Thyroid axis abnormalities in depression relating to Figure 2.2 Given the suggestions of subclinical hypothyroidism in depression, albeit in a minority, it is natural to ask about the effects of thyroid hormone treatment. A recent review found six randomised, controlled trials, and concluded that thyroid...

Biological Basis Of Iodine Accumulation In Thyroid Tissue

The sodium iodide symporter (NIS) is responsible for the specificity of RAI for thyroid tissue. This transmembrane protein transports iodide against an electrochemical gradient via a sodium-dependent active transport mechanism by which two sodium ions are transported along with one iodide ion (4). Synthesis of this protein is regulated by activation at the thyrotropin receptor (5). Following the characterization of the NIS gene in 1996, much research has been directed toward understanding the role of the NIS in autoimmune and malignant thyroid disease. The NIS protein is most abundantly expressed in thyroid tissue, although it is also present in glandular and mucosal tissue, choroid plexus, ciliary body of the eye, and placenta. Normal NIS protein expression is limited to the basolateral membrane in a small percentage of thyroid follicular cells at any one time (6). However, in autoimmune thyroid disease, thyrotropin receptor-mediated activation by stimulating auto-antibodies...

Endocrine 18321 Thyroid Function

Primary hypothyroidism is a common late effect observed in cancer survivors who received head and neck radiation (Kaplan et al. 1983 Halperin et al. 1999). The occurrence of thyroid dysfunction is related, primarily, to the dose of radiotherapy administered but is also influenced by the age and gender of the patient and the time elapsed since the end of treatment (Sklar et al. 2000). Many cases of subclinical primary hypothy-roidism have been described in neuroblastoma patients following the administration of 131I-metaiodo-benzylguanidine (131 I-MIBG Garaventa et al. 1991 Picco et al. 1993 Picco et al. 1995 Van Santen et al. 2002). The reported incidence is 50-80 despite thyroid protection with high doses of potassium iodide before, during, and after the 131I-MIBG (Picco et al. 1995 Van Santen et al. 2002). Optimal prophylaxis against the thyroidal damage induced by radio-iodi-nated substances is still unknown (Van Santen et al. 2002). In our cohort, 23 of the patients developed...

Drugs And The Thyroid Gland

The thyroid gland secretes two hormones that regulate protein synthesis, enzyme activity, and stimulate mitochondrial oxidation. These are thyroxine (T4) and triiodothyronine (T3). The thyroid gland secretes 20 of the circulating T3. The remaining 80 comes from degradation of T4 hormone. Approximately 40 of T4 is degraded and becomes T3. A decreased amount of T3 and T4 is produced in a condition called hypothyroidism. This is caused by a disorder of the thyroid gland or a secondary lack of TSH secretion. Hyperthyroidism is an increase in circulatory T4 and T3 caused by an overactive thyroid gland or an excessive output of thyroid hormones. Primary hypothyroidism is characterized by a decrease in T4 and an increase in TSH levels. Primary hypothyroidism is caused by acute or chronic inflammation of the thyroid gland, radioiodine therapy, excess intake of antithyroid drugs, and surgery. Hypothyroidism is treated by administering levothyroxine sodium (Levothroid, Synthroid), which...

Medullary Thyroid Cancer

Increased genetic knowledge has also changed our approach to thyroid cancer. Medullary thyroid cancer (MTC) is a well-established component of multiple endocrine neoplasia syndrome type 2a (MEN 2a) or type 2b (MEN 2b). Previously, family members at risk for MEN 2 underwent annual screening for elevated calcitonin levels however, this only detected MTC after it developed. In 1993 it was identified that mutations in the RET proto-oncogene were present in almost all cases of MEN 2a and 2b. Now family members of MEN patients can be screened for the presence of a RET mutation. Those without the mutation need not undergo additional screening, whereas those with the mutation should undergo total thyroidectomy at a young age (6 years for MEN 2a, infancy for MEN 2b).49

Spontaneous Thyroid Tumors In Animals

Roe (1965) defined a spontaneous thyroid tumor as a neoplasm that had developed without any influence exerted by internal or external carcinogens. Data on the incidence of spontaneous thyroid tumors in animals are contradictory. McCoy (1909) and Woolley & Wherry (1912) were the first to systematically investigate thyroids of animals. They searched for tumors in 23,000 and 100,000 wild rats, but failed to detect them. In 1917, Bullock and Rhodenburg firstly described nine tumors found in 4,300 rats in 1926, Slye at al detected 12 so-called carcinomas in 51,700 mice. They are seen more often in laboratory rats, but have a predilection for older animals. Many of these tumors are derived from the C-cell component of the thyroid gland. Lindsay et al (1968) coined the term naturally occurring carcinoma of the rats thyroid for these medullary tumors. In the following years, many studies described spontaneous tumors in various rat strains For example, van Dyke (1944) reported on nine...

Preoperative Evaluation Of Thyroid Nodules

Thyroid nodules are extremely common with prevalence rates approaching 50-60 of adults under 60 years old. Because only approximately 5 of thyroid nodules are malignant, accurate pre-operative characterization of thyroid nodules is critical in selecting patients appropriate for surgical thyroidectomy. Fine needle aspiration (FNA) is the single most important diagnostic procedure in the evaluation of thyroid nodules. Table 1. Molecular markers for thyroid nodules and lymph nodes Potential diagnostic markers for thyroid nodules and lymph nodes Telomerase Galectin-3 Thyroid peroxidase Thyroglobulin Oncofetal fibronectin ret PTC oncogenes PaxH PPARy oncogene B-Raf mutations Nm23 For small, solid nodules, experienced cytopathologists can accurately distinguish most benign nodules and papillary cancers. However, cytological features do not distinguish benign from malignant follicular neoplasms, and cystic papillary thyroid cancers are a common cause of false negative results. Importantly,...

Future Of Animal Models Investigating Thyroid Carcinogenesis

In the last 75 years, very different models investigating thyroid carcinogensis have been developed. The concept of initiation and promotion of carcinogenesis is well demonstrated by the studies reviewed in this chapter. The initiation step may be produced by diverse agents, including ionizing radiation and many classes of carcinogens. The action of these agents is promoted by raising the level of trophic stimulation (TSH), which can also be achieved in a variety of ways (for instance goitrogen therapy or low-iodine diet). All these models successfully described the changes in morphology and function of thyrocytes during carcinogenesis. However, the time in which these kind of models were used is over. Therefore, in the last ten years, such studies were published only sporadically. The molecular basis of thyroid neoplastic processes involved in experimental tumors is now being elucidated by investigations of the changes associated with developing tumors, and also by the reconstruction...

Nis Expression In Thyroid Cancer

Given that most thyroid cancers exhibit decreased or absent radioiodide accumulation, the prevailing expectation for a long time was that NIS expression would be found to be decreased or absent in cancerous thyrocytes. The first investigations addressing this issue, carried out using RT-PCR and showing lower mRNA levels in cancerous than in normal thyrocytes, seemed to confirm these expectations (24-28). RT-PCR is an easy-to-perform and very effective technique to detect mRNA expression even in very small tissue samples. However, determinations of mRNA levels by either RT-PCR or Immunoblot analyses may provide satisfactory quantitative and qualitative information on NIS protein expression and some posttranslational modifications, but not on subcellular distribution. The subcellular localization of NIS is particularly significant because, as pointed out earlier, NIS is functional only when it is properly targeted to the plasma membrane. Hence, immunohistochemical analysis ofNIS...

Adverse Effects Of Treatment With Thyroid Hormone

In patients with longstanding hypothyroidism and those with ischemic heart disease, rapid correction of hypothyroidism may precipitate angina, cardiac arrhythmias, or other adverse effects. For these patients, replacement therapy should be started at low initial doses, followed by slow titration to full replacement as tolerated over several months. If hypothyroidism and some degree of adrenal insufficiency coexist, an appropriate adjustment of the corticosteroid replacement must be initiated prior to thyroid hormone replacement therapy. This prevents acute adrenocortical insufficiency that could otherwise arise from a thyroid hormone-induced increase in the metabolic clearance rate of adrenocortical hormones.

Aberrant Thyroid Tissue

Thyroid tissue rarely appears in sites outside of its embryonic development. The subglottic area of the larynx and upper trachea are places where aberrant t hyroid tissue (ATT) may be found 36 , especially between the lower border of the cricoid cartilage and the upper ring of the trachea. According to different reports, intraluminal thyroid tissue occurs anywhere between the glottis and the bifurcation of the trachea, as a broad-based, smooth, rounded mass protruding from the left subglottic posterolateral wall 305, 345 . It has been pointed out that two-thirds of patients are middle-aged women from regions of endemic goitre 22, 36 . Intralaryngotracheal thyroid is a rare lesion. Only about 125 cases were described up to 1998 327 . Waggoner divided intralaryngotracheal thyroid tissue into false and true aberrant thyroids. The former is likely to arise in the pre- or neonatal period, when the thyroid gland could grow into incompletely formed laryngotracheal cartilages that remain in...

Thyroid USP and Thyroglobulin

Thyroid USP (Thyrar, Thyroid Strong, S-P-T) is derived from dried and defatted thyroid glands of domestic an imals (bovine, ovine, or porcine), while Tg (Proloid) is a partially purified extract of frozen porcine thyroid glands. Although used extensively in the past, these preparations are rarely used today. The total thyroid hormone content of thyroid glands and the ratio of T3 to T4 vary somewhat from one species to another. Thyroid USP preparations are therefore standardized on the basis of their iodine content. Much of the iodine in these preparations is in the metabolically inactive form of iodotyrosines. Thus, a given preparation may satisfy the USP iodine assay requirements and yet contain low amounts of T4 and T3. Thyrar (a beef extract) and Armour Thyroid tablets (a pork extract) are evaluated by additional biological assays to ensure consistent potency from one batch to another. The production of Proloid, which is a partially purified frozen porcine Tg preparation, is an...

Thyroglossal Duct Cyst and Ectopic Thyroid

Cysts and sinuses may be found along the course of the thyroglossal duct these cysts develop during the migration of the thyroid gland from the base of the tongue. The cysts are situated in the midline of the neck, usually below the hyoid bone. A fistula may develop from an infected cyst. The thyroid begins to develop during the 4th week of gestation when the embryo is about 2-2.5 mm long 126 . It is an endodermal derivative composed of two small lateral anlagen and the more substantial median anlage from the foramen caecum at the base of the tongue. Because of elongated cephalad embryonic growth rather than active descent, the orthotopic pre-tracheal location of the thyroid is caudal to the foramen caecum 126 . Thyroglossal duct cysts range in size from 0.5 to 4 cm in diameter. They can be either unilocular or mul-tilocular and usually contain mucoid material if the cyst is not infected or mucopurulent material or pus if it is. The type of epithelium lining the cyst varies from one...

Thyrotoxic Crisis or Thyroid Storm

Thyrotoxic crisis, thyroid storm, or accelerated hyper-thyroidism is an extreme accentuation of thyrotoxicosis. Although uncommon, this serious complication of hy-perthyroidism usually occurs in association with Grave's disease and occasionally with toxic multinodular goiter. If unrecognized, it is invariably fatal. Thyroid storm is usually abrupt in onset and occurs in patients whose preexisting thyrotoxicosis has been treated incompletely or not at all. Thyrotoxic crisis may be related to cytokine release and an acute immunological disturbance caused by a precipitating condition, such as trauma, surgery, diabetic ketoacidosis, toxemia of pregnancy, or parturition. Although the serum thyroid hormone levels may not be appreciably greater than those in uncomplicated thyro-toxicosis, the clinical picture is severe hypermetabolism with fever, profuse sweating, tachycardia, arrhythmias, and so on. Pulmonary edema or congestive heart failure may also develop. With progression of the...

Thyroid scintigraphy

131I as radioiodine, 123I as sodium iodide, and 99mTc as sodium pertechnetate are the radionuclides used for scintigraphic visualization of the thyroid gland. Although 131I is cheap and readily available, its major disadvantages are its long physical half-life and a-emissions, resulting in a considerable radiation dose to the thyroid and the gastrointestinal tract. 123I has excellent physical properties for imaging and a physical half-life of 13 hours, but its use is limited due to its cost. 99mTc is trapped in the thyroid, but is not organified and washes out from the gland over time. The indications for thyroid scintigraphy in oncology are Follow-up after surgery for differentiated thyroid cancer. Thyroid scintigraphy with 99mTc and 123I can be used to assign probability of malignant disease on the basis of the functional status of the nodule. Hyperfunctioning nodules are almost always benign, but malignancy can be found in 4 of the hot nodules. The majority of non-functioning...

Lingual Thyroid

Ectopic lingual thyroid is a rare developmental anomaly due to failure of the thyroglossal duct to migrate cau-dally from the foramen caecum 13 . It is seen in females about four times more frequently than males and usually presents in middle age. The lingual gland is seen in the base of the tongue, deep to the foramen caecum. It is often asymptomatic, but may cause dysphagia, dyspho-nia or dyspnoea. Symptoms may coincide with puberty, pregnancy or the menopause due to hyperplasia secondary to raised levels of thyroid-stimulating hormone. In addition, any of the diseases involving the conventional thyroid gland, including inflammatory conditions, adenomas and carcinomas, can affect the ectopic thyroid tissue. Microscopy typically shows normal thyroid tissue. As many as 70 of patients with lingual thyroid have no other thyroid tissue present, so it is essential that pre-surgical evaluation includes appropriate imaging and assessment of function using 131I or 99mTc pertechne-tate.

The thyroid gland

The thyroid gland weighs about 25 g and is made up of two lobes joined by a bridge, situated on either side of the trachea (windpipe) in the throat (Fig. 5.7). It has a rich blood supply. It is responsible for secretion both of the thyroid hormones themselves, and the protein, thyroglobulin, which carries them in the circulation. The thyroid hormones are iodinated amino-acid derivatives Thyroid gland Thyroid gland Fig. 5.7 The anatomy of the thyroid gland.

Hypothyroidism

Hypothyroidism is usually the result of primary failure or ablation of the thyroid gland, hypothalamic dysfunction, pituitary dysfunction, autoimmune thyroiditis, or lithium therapy. Clinical manifestations of hypothyroidism include fatigue, cold intolerance, lethargy, weakness, weight gain, constipation, menstrual irregularities, hair loss, slow reaction time, oedema, delayed reflexes, and bradycardia. Hypothyroidism occurs in as many as 10 per cent of patients taking lithium lithium-induced hypothyroidism is much more likely to occur in women.( .5) The association between clinical hypothyroidism and depression is well known. Gold et al.(66) found that 5 per cent of a series of 250 patients with major depressive syndromes had at least subclinical hypothyroidism. In many patients with hypothyroidism, the depression responds to thyroid hormone replacement alone, (67) but the response may take a long time. When that is the case, antidepressants are indicated and efficacious. (65)

Hyperthyroidism

The most frequent clinical manifestations of hyperthyroidism are nervousness, diaphoresis, hypersensitivity to heat, palpitations, fatigue, weight loss, tachycardia, dyspnoea, and weakness 6.8) The most common causes include Graves' disease, toxic adenoma, and toxic multinodular goitre. (69> Less common causes include Hashimoto's thyroiditis, postpartum hyperthyroidism, and factitious hyperthyroid state. As with hypothyroidism, depressive and anxiety syndromes are the most common psychiatric conditions seen among patients with hyperthyroid states. It is not difficult to identify hyperthyroid patients, because the signs and symptoms are often dramatic. Fortunately, when patients have depressive or anxiety syndromes in the context of hyperthyroidism, and have no past histories of psychiatric disorders, the psychiatric symptoms resolve more than 90 per cent of the time when the hyperthyroidism resolves. This obviates the need for other psychiatric interventions unless antithyroid...

Thyroid Metastases

These disorders share in common increased thyroid hormone synthesis in the face of a low RAIU. Iodine-induced production of a hyperthyroid state is also known as the Jod-Basedow effect. Excessive iodine intake results from ingestion of iodine-rich foods, from over-the-counter pharmaceutical or health food store preparations, from radiological contrast media or from prescribed pharmaceuticals. Of particular note, amiodarone used for the treatment of cardiac arrhythmias, has complex effects on thyroid function producing a thyrotoxic state by overloading the patient with iodine (Jod-Basedow effect) or via stimulation of the immune system to produce a so-called silent thyroiditis state or even Graves' disease. The rare struma ovarii syndrome is characterized by uptake of radioiodine into a pelvic mass. Similarly, rare cases of thyrotoxicosis produced by massive thyroid cancer metastases, usually in bone, are characterized by an abnormal site of radioiodine uptake and these may be...

Thyroid Nodules

Goitres occur both endemically in regions characterized by iodine deficiency as well as sporadically in all populations. Common to all goitrogenic processes is an increase in the number of follicles. A number of factors, of which TSH is a major contributor, can stimulate growth of new follicles. Many patients with nontoxic goitres have thyroid-stimulating antibodies similar to those seen in Graves' disease. It is possible that at the outset of goitrogenesis the process is always, or nearly always, diffuse. The newly generated follicular cells may display heterogeneous growth potential and nodules develop from the most rapidly growing clones. The process is usually slow, requiring years or decades. The properties of the original cells, which give rise to nodules, tend to be maintained in their daughter cells thus, individual nodules in a multinodular goitre will display distinct behaviours. It is this morphological heterogeneity that gives rise to the presence of hot, warm and cold...

Thyroid Cancer

Although thyroid cancer accounts for less than 1 of all clinical cancers, it is the commonest form of endocrine malignancy and accounts for more deaths than all other endocrine cancers combined, excluding cancers of the reproductive tract. Thyroid neoplasms may arise from either the follicular endothelium or from the C cells (Table 3). The parafollicular C cells give rise to medullary carcinomas. Rarely, the thyroid may be the site of origin of a lymphoma or sarcoma. Primary tumors of kidney, breast, lung and melanomas can metastasize to the thyroid gland.

The Thyroid

DYSHORMONOGENESIS A variety of genetic defects could affect thyroid hormone synthesis, resulting in congenital hypothyroidism. Inability to transport iodide is caused by defects in the sodium-iodide symporter (NIS) (OMIM 601843) (70). In Pendred syndrome, characterized by congenital hypothyroidism with goiter and deafness, the defect lies in the step of organification of iodide, caused by mutations in the SLC26A4 gene (OMIM 605646) (71). Organification defects are also caused by mutations in thyroid peroxidase (TPO) (OMIM 606765) (72). 4.2. THYROID HORMONE RESISTANCE Generalized thyroid hormone resistance is characterized by a reduced effect of T4 and T3 because of mutations in the thyroid hormone receptor-P (THRP) (OMIM 190160). Patients typically have elevated levels of T4 and T3 with an inappropriately normal TSH. Most patients are clinically euthyroid, although some could have symptoms of hypothyroidism because of the lack of thyroid hormone effect. The majority of patients...

Thyroid

Weakness occurs in 20 of thyrotoxic patients. Shoulder girdle weakness is more marked than pelvic. Reflexes are brisk, fasciculation and atrophy may be present. Distinction must be made from motor neuron disease. These is always clinical evidence of thyrotoxicosis in these patients. Diagnosis is confirmed by thyroid function studies. Muscle enlargement in limbs and tongue often occur. There is always clinical evidence of hypothyroidism in these patients. Diagnosis is confirmed by thyroid function tests and response to thyroid hormone therapy is excellent.

Hypothyroid States

Hypothyroidism refers to the exposure of body tissues to a subnormal amount of thyroid hormone. This can result from a defect anywhere in the HPTA. As a consequence of the lack of thyroid hormone, a wide variety of physiological and clinical disturbances involving virtually every organ system may result. Primary hypothyroidism results from an inability of the thyroid gland itself to produce and secrete sufficient quantities of T4 and T3 and accounts for most cases of hypothyroidism. In iodine-sufficient areas of the world, the most common cause of primary hypothyroidism is chronic autoimmune thyroiditis (Hashimoto's thyroiditis). Other causes of primary hypothyroidism include spontaneous degeneration of glandular tissue (idiopathic hypothyroidism), thyroid ablation with radioactive iodine uptake (131I), and total or subtotal surgical thyroidectomy. Primary hypothyroidism is accompanied by an elevation in pituitary TSH secretion and circulating TSH levels. An enlargement of the...

Thyroid Gland

The two lobes of the thyroid (THIE-ROYD) gland are located near the lower part of the larynx, as shown in Figure 50-5. The thyroid gland produces and secretes the hormones thyroxine (thie-RAHKS-een) and triiodothyronine (TRIE-ie-oh-DOH-THIE-roh-NEEN). Both of these hormones are derived from the same amino acid and are synthesized with iodine atoms. Thyroid-stimulating hormone (TSH) regulates the release of the thyroid hormones. Release of TSH from the anterior pituitary is regulated primarily by a releasing hormone as well as release-inhibiting hormones secreted by the hypothalamus. The thyroid hormones help maintain normal heart rate, blood pressure, and body temperature. They stimulate enzymes that are associated with glucose oxidation and oxygen consumption, generating heat and increasing cellular metabolic rates. They also promote carbohydrate usage over fat usage for energy. The thyroid gland is important to human development because thyroid hormones promote the development of...

Silent Thyroiditis

This form of thyroiditis is dominated by the pathological picture of a prominent lymphocytic infiltration of the gland. The evidence to date suggests that silent thyroiditis is a variant of lymphocytic thyroiditis. Both have a predilection to occur in the post-partum period but are also common in the non-pregnant state. In contrast to subacute thyroiditis, the clinical features are usually (but not invariably) milder. There is usually less or no pain in the cervical region and less or no thyroid tenderness, despite, at times, acute enlargement of the thyroid. There are minimal if any systemic symptoms and the thyrotoxic symptoms, if present, may be quite mild. The subsequent evolution in the thyroid biochemical abnormalities has a similar clinical course to that of subacute thyroiditis. However, in contrast to subacute thyroiditis, patients with silent thyroiditis often have recurrences and up to one-half of the patients may develop permanent hypothyroidism in the future.

Subacute Thyroiditis

Subacute thyroiditis (or de Quervain's disease) is a relatively uncommon form of thyroiditis characterized pathologically by the presence of extensive follicular cell destruction, extravasation of colloid and aggregation of histiocytes around colloid, coalescing into giant cells. There is strong but indirect evidence that this pathology may result as a reaction to a preceding viral infection, but immune mechanisms may also play a role. Patients often present with cervical pain, tenderness of the thyroid (at times exquisite), symptoms of thyrotoxicosis and in some cases, systemic symptoms of an inflammatory illness. Thyrotoxicosis results from an unregulated release of preformed thyroid hormone from an inflamed gland. As the thyroid gland is depleted of preformed hormone and the thyroiditis subsides, the serum T4 and T3 concentrations fall to normal and in some cases to subnormal levels, before recovery of the gland with normalization of function. The entire course of the illness may...

In The Thyroid Gland

Fig. 5.8 Biosynthesis of the thyroid hormones. Thyroxine (T4) and triiodothyronine (T3) are synthesised in the thyroid gland from tyrosine residues in the protein thyroglobulin. The conversion of T4 to T3, the active hormone, occurs mainly in peripheral tissues. Fig. 5.8 Biosynthesis of the thyroid hormones. Thyroxine (T4) and triiodothyronine (T3) are synthesised in the thyroid gland from tyrosine residues in the protein thyroglobulin. The conversion of T4 to T3, the active hormone, occurs mainly in peripheral tissues. they are formed from tyrosine residues within thyroglobulin, and iodine which is taken up avidly by the gland from the blood (Fig. 5.8). There are two thyroid hormones, known as thyroxine or T4 (with four iodine atoms per molecule) and triiodothyronine or T3 (with three iodine atoms). Both are secreted by the gland and present in blood, although it appears that T3 is the active hormone. Most tissues express the enzyme necessary to convert T4 to T3. Synthesis and...

KjfePi L r M r T vTfc SS

An unusual variant of papillary carcinoma is the hyalinizing trabecular tumour. This tumour was originally described by pioneers such as Zipkin in 1905 (109), Masson in 1922 (110), and Ward et al. in 1982 (111). The terminology hyalinizing trabecular adenoma (HTA) was defined by Carney et al. in 1987 (112). This lesion has also been designated paraganglioma-like adenoma of thyroid (PLAT) by Bronner et al (113) because of its unusual histologic pattern (Figure 12). Since the original descriptions, a malignant counterpart, hyalinizing trabecular carcinoma (HTC), has been described (114-116) and both HTA and HTC are now incorporated under the umbrella of hyalinizing trabecular tumors (HTT). Their main importance lies in the fact that they are sometimes mistaken for other entities such as paraganglioma or medullary carcinoma (112). Immunohistochemical stains for neuroendocrine markers will easily discriminate between HTT and paraganglioma or medullary carcinoma. However, it was noted that...

Mixed Follicularc Cell Lesions

Although controversial, mixed follicular-parafollicular cell carcinomas do occur (253) these rare monomorphous tumours are composed of cells showing dual differentiation (254,255). Composite tumors are composed of two intermixed well differentiated components, one showing thyroglobulin immunoreactivity and either papillary or follicular architecture and cytology, the other with calcitonin and CEA immunopositivity (81,256). The diagnosis of a mixed or composite tumor can be convincing only in cases where metastatic disease is identified, since the identification of thyroglobulin and calcitonin in a primary intrathyroidal tumor may represent the identification of a typical medullary thyroid carcinoma with trapped nontumorous elements containing thyroglobulin, or phagocytosis of thyroglobulin by medullary carcinoma cells. Moreover, the two tumours may occur separately in the same gland and metastasise together to a regional node (257,258).

Introduction And Historical Aspects

Primary thyroid lymphomas have been recognised for many years and have been documented from the 1940s and 1950s. It was deemed to be important to recognise this entity for it seems that about a third of the cases may be treated successfully with X-rays, followed by maintained thyroid medication (1). Thus, the importance of separating lymphomas from its mimics, namely, chronic thyroiditis and small cell carcinoma, was evident at an early stage because of the therapeutic implications. Indeed, the histological difficulty in separating lymphoma from chronic thyroiditis and small cell carcinoma, no doubt led to the under-diagnosis of lymphoma. Even 50 years and more ago, certain peculiarities of thyroid lymphoma were apparent to pathologists the predilection for elderly women, long survival and the tendency for similar lesions to occur in the gastrointestinal tract. These lymphomas were so characteristic that Brewer and Orr coined the term struma reticulosa to describe them (2). The fact...

Clinical Presentation

Women are more frequently affected than men with a ratio of 2.5 to 8.4 1. Most patients are in the 50 to 80 year age range. There is usually rapid enlargement of an already existing goitre, and the mass may extend extra-thyroidally. The rapid growth and extent of invasion may result in dysphagia, hoarseness and dyspnoea (3, 16, 21). Thyroid function is usually normal but hypothyroidism has been documented in a minority of cases (11, 22). If hypothyroidism is present, it is usually due to the preexisting thyroiditis and not due to the obliteration of thyroid parenchyma by the lymphomatous infiltrate. Very rare cases of hyperthyroidism have been encountered where rapid destruction of thyroid follicles with release of colloid and thyroid hormone into the circulation, have been implicated as causative (23, 24).

Nomenclature And Terminology

In the last 10 or so years lymphoma classification has undergone a major revision with the appearance of the Revised European-American Lymphoma (REAL) classification (25-27) and the subsequent World Health Organization (WHO) update, refinement and minor modification of the REAL classification (28-34). After Isaacson and Wright brought the concept of MALT and lymphomas arising therefrom to prominence, the terms MALT lymphoma or lymphoma arising in MALT or MALT-oma have been used. The advent of the REAL WHO classifications led to a re-appraisal, and these peculiar and characteristic lymphomas were categorized as extra-nodal marginal zone B-cell lymphomas (MZBL) of MALT-type. This is the prototype lymphoma occurring primarily in the thyroid. Variants and other common related lymphomas will be discussed.

The Epidermal Growth Factor Family

May alter pituitary production ofTSH as well as cell proliferation (17). TGFais thought to mediate estrogen-induced cell proliferation in several tissues (18-20). Estrogen stimulation has been implicated in thyroid tumorigenesis most aptly in rodents using a number of synthetic estrogenic compounds. Using a two-stage thyroid tumorigene-sis model, one week administration of N-bis(2-hydroxypropyl)nitrosamine, gonadec-tomized F344 rats of both sexes were implanted with fused pellets containing EB for 32 weeks (21). Thyroid gland weights were increased by EB pellet in a dose-dependent and increased the occurrence ofthyroid proliferative lesions in male and female animals. These data provide suggestive evidence for the potential significance of this growth factor in thyroid tumorigenesis. The common receptor of EGF and TGF-a, EGF-R, is a 170-kD plasma membrane tyrosine kinase product of the protooncogene v-erb 3. EGF-R is over-expressed in several types of human cancers that correlate with...

Vascular Endothelial Growth Factor

Producing folliculo-stellate cells of the pituitary (33). In one mouse model, estrogen-induced tumorigenesis was associated with parallel increases in the expression of a pituitary tumor transforming gene (PTTG) as well as FGF-2 (33). In turn, both PTTG and FGF-2 have been shown to be increased in mRNA expression in papillary thyroid cancer that was also associated with lymph nodal invasion and distant metastasis. These findings were upheld even after consideration of other known prognostic factors such as age and gender ofthe patient and size and type ofthe tumor (34). Similarly, increased concentrations of FGF-2 in the serum of patients with differentiated papillary thyroid carcinoma has also been reported (35). The expression of FGF-2 and one of its receptors FGFR1 was recently compared in differentiated thyroid cancers, normal thyroids, multinodular goiters, and Graves' disease specimens. The investigators noted that FGF-2 was significantly over-expressed in thyroid carcinomas...

Ras Regulation And Signaling

Ras signals through multiple downstream effectors including, but not limited to those illustrated here. In thyroid cells, Ras has been shown to signal through Raf-1, PI3K and RalGDS (shown in bold). 2000). Interaction between GTP-Ras and its first identified target, Raf-1, induces a conformational change that unmasks phosphorylation sites and anchors Raf-1 to the plasma membrane. Once this occurs, Raf-1 activity becomes Ras-independent. Active Raf binds to and phosphorylates MEK1 2 proteins, stimulating their kinase activity. MEK proteins are dual specificity serine threonine and tyrosine protein kinases that phosphorylate and activate MAPK1 2 (also referred to as ERK1 2), protein kinases that play important roles in many cellular processes including the regulation of gene expression. In a similar fashion, binding of GTP-Ras to the p110 catalytic subunit of PI3K stimulates lipid kinase activity, increasing the production of second messenger phosphoinositide (3,4) P2 (PIP2)...

Ras And Genomic Instability

One of the consequences of Ras mutations in human tumors is destabilization of the karyotype. Expression of activated Ras in a variety of established cell lines and tumor cells induces chromosomal aberrations including an enhanced frequency of gene amplification (Smith et al., 1995), chromosome losses and gains, aberrant chromosome segregation and centrosome amplification (Saavedra et al., 1999). Inducible expression of activated H-Ras in PC-CL3 cells stimulated the formation of micronuclei containing chromosomes and chromosome fragments (Saavedra et al., 2000). Micronuclei with whole chromosomes arise as a consequence of spindle disruption micronuclei containing chromosome fragments are typically generated by double strand DNA breaks. Although the effects of Ras on micronuclei formation were rapid, they were observed in only a small proportion of cells, perhaps due to the presence of wildtype p53 in these cells. This raises the interesting possibility that Ras predisposes thyroid...

Cell Cycle Deregulation And Apoptosis

Acute expression of activated Ras stimulated aberrant cell cycle progression followed by apoptosis in WRT cells (Cheng et al., 2003). Infection of quiescent cells with an adenovirus expressing activated H-Ras induced cell cycle progression into S phase. Rather than completing the cell cycle, the majority of Ras-expressing cells exhibited a protracted S phase and ultimately perished by apoptosis. The effects of Ras on cell cycle regulatory proteins were very different from the mitogens, TSH, insulin, and serum. Unlike mitogen treatment, which increased the expression of cyclins D1 and B, Ras rapidly decreased cyclin D1 expression, and failed to increase cyclin B expression. Excessive mitogenic signaling, for example through overexpression of E2F (Nahle et al., 2002), is a potent inducer of apoptosis, as is delayed cell cycle progression (Meikrantz et al., 1995). These findings suggest that the acute effects of Ras on thyroid cell cycle progression are aberrant, and induce an apoptotic...

Conclusions And Perspectives

While the frequency of Ras mutations in human tumors is only 20 overall, constitutive signaling through Ras is a conserved feature of a much higher proportion of human tumors. Mutations giving rise to increased production of growth factors or sustained activation of growth factor receptors are frequent events in human tumors. Over the past year, mutations in a Ras effector, B-Raf, have been identified in several types of human cancer (Davies et al., 2002 Rajagopalan et al., 2002). Together, mutations that give rise to constitutive signaling through Ras-mediated pathways comprise a significant proportion of human tumors. The fundamental role of Ras in tumori-genesis is particularly evident in the thyroid gland where mutations in Ras, B-Raf and RET PTC have now been identified. Expression of activated Ras in thyroid cells in vitro elicits morphological transformation, sustained proliferation, apoptosis and genomic instability, hallmarks of human tumor cells (Figure 3). Despite the...

Function And Structure Of

Thyroid, both NIS and the Na+ K+ ATPase are located on the basolateral side of the thyroid follicular cells, facing the blood supply (20). Rat NIS (rNIS) is a 618-amino acid protein (relative molecular mass 65,196) (4) both human and pig NIS, which contain 643 amino acids each, are highly homologous (75.9 and 74.2 , respectively) to rNIS (6, 7). Based on extensive experimental testing, we have proposed a NIS secondary structure model with 13 transmembrane segments (Figure 1) (12). The amino and carboxy termini face extra- and intracellularly, respectively (10). NIS is a glycoprotein three of its Asp residues (225, 485, 497) are glycosylated in the endoplas-mic reticulum (21). However, glycosylation is not essential for proper NIS function, as indicated by the observation that a non-glycosylated NIS protein is properly targeted to the plasma membrane and displays transport activity with an identical Kmvalue ( 20-30 (iM) to that ofwild-type (WT) NIS (21). The ca 70-amino acid...

Understanding Nis Regulation In Health And Disease May Improve The Effectiveness Of Radioiodide Treatment

TSH and are the two main factors that regulate NIS expression TSH stimulates and I decreases it. Hence, TSH stimulation and I depletion ofresidual thyroid carcinoma tissue are the two most important modulators routinely used to optimize radioiodide treatment. To achieve maximum therapeutic effect, thyroidectomized patients must have TSH levels above 30 mU l and must have been on a low I diet for two weeks prior to initiation of radioiodide treatment (1). TSH has long been known to be a key regulator not only of NIS expression but also of thyroidal I uptake (i.e., NIS activity). No thyroidal NIS expression is observed in hypophysectomized rats (because of the lack of TSH), but thyroidal NIS expression is restored as early as 24 h after treatment with TSH. In intact (i.e., non-hypophysectomized) rats, treatment with the organification inhibitor propylth-iouracil causes elevated TSH levels, which in turn lead to higher NIS expression than in control animals (10). TSH regulates NIS...

Specific Considerations Related To Radioiodide Treatment

In the healthy thyroid gland, NIS mediates the active accumulation of whereas the mechanisms involved in efflux are poorly understood (see efflux pendrin and AIT below). I organification - i.e., the TPO-mediated iodination of the tyrosine residues on the thyroglobulin molecule - occurs on the colloidal surface of the apical membrane. lodinated thyroglobulin molecules remain in the colloid, surrounded by the thyroid epithelial cells, thus increasing the radioiodide retention time in the thyroid gland. In contrast, in thyroid cancer, the typical follicular architecture of normal thyroid tissue is not conserved, as the malignantly transformed epithelial cells lose their polarity (53). Hence, these cells display no well-defined colloidal space, and as a result, thyroglobulin leaks out into the extracellular space and the bloodstream. Most differentiated thyroid cancers exhibit TPO protein expression, but at levels lower than those considered normal (54-56) TPO gene mutations have also...

Concluding Remarks

The role of thyroidal transport in the treatment of thyroid cancer is difficult to overestimate. For over 60 years, the administration of radioiodide to thyroid cancer patients after thyroidectomy has been the most effective internal targeted anticancer radiotherapy available, on account of the unique specificity of NIS. Radioiodide therapy is not only effective and specific, it is also remarkably free of severe side effects. This article shows how, upon isolation of the NIS cDNA and the characterization of the NIS molecule, considerable strides have been made in our understanding of NIS regulation at all levels, including biosynthesis, biogenesis, half-life, targeting, and subcellular localization. These advances considerably increase our potential ability to manipulate the system to optimize the effectiveness of radioiodide treatment. In addition, the discovery that NIS is expressed endogenously in breast cancer has raised, for the first time, the realistic prospect of effectively...

Elements And Pathways Of Molecular Signaling Via Plasma Membrane Receptors In Tc

The par excellence thyroid-specific GPCR is the TSHR. It is a typical member of the GPCR family containing seven-transmembrane (TM) domain receptors, and transduces the signal of ambient TSH to the thyrocyte (9). Its ligand, TSH, upon binding onto TSHR activates thyroid function, proliferation and differentiation via activation of both G-protein- and inositol triphosphate (IP3) phospholipase C (PLC)-dependent pathways. The trophic role of the TSHR system is considered highly significant in fact, suppression of endogenous pituitary TSH production by thyroid hormone treatment in patients with TC following thyroidectomy is considered standard therapy in this malignancy, leading to decreased morbidity and mortality, at least for well-differentiated TC's (as reviewed in 10 ). TSH also possesses a lesser, inhibitory effect on TSHR signaling, as chronic stimulation of this system leads to down-regulation of TSHR expression (11). Additionally, TSH exposure can also desensitize TSHR-dependent...

Conclusions And Perspective

The study of gene expression by microarray technology (just as the earlier use of serial analysis of gene expression SAGE, 29 ) has yet to yield the answer to the proposition posited at the beginning of this chapter. While the protocols for performing gene expression are relatively easy, the analysis and interpretation of the results are time consuming and may be difficult to interpret in our current state of knowledge of functional genomics. Independent corroboration of differential expression is necessary by different techniques and, in our opinion, by replication in different sample sets in the same or independent laboratories. Some of the studies reviewed have limited themselves to circumscribed issues e.g overexpression of genes in two sets of tumors one benign and one malignant (13) and generalization from any of the studies is hampered by the small number of samples examined in each. Given the diverse pathways to malignancy it would be naive to adopt a candidate gene panel...

The Problem Of Tumor Classification

All the difficulties encountered in the classification of human thyroid tumors have to be faced in an attempt to classify thyroid tumors in animals, particularly in the rat. In early experiments, the well-known absence of clear-cut histological criteria for distinguishing reactive hyperplasia from neoplasia or benign from malignant tumorous growth has been reflected in publications describing corresponding lesions in the rat. In most cases, the authors have tried to apply the nomenclature of human pathology to the lesions observed in the rat thyroid. This approach has not only some easily recognizable advantages, but also some disadvantages. On the one hand, the use of similar terms would provide an opportunity for conducting a comparative analysis of Figure 1. Experimental thyroid tumors in rats induced by x-ray irradiation Low power view of a follicular adenoma with surrounding capsule (a), high power view of papillary carcinoma (b), follicular carcinoma (c) and squamous cell...

Molecular Markers Of Tumor Recurrence Or Progression

The use of highly sensitive molecular tests to identify recurrent or progressive disease using tissue and or tumor-specific markers have been used to detect metastases in bone marrow, lymph nodes, peripheral blood, and other sites. Methods employed include RTT-PCR amplification of tissue or tumor-specific transcripts or isolation of cancer cells directly using cell sorting. These approaches are particularly attractive for thyroid cancer because, in comparison to other solid tumors, initial therapy of thyroid cancer frequently results in the removal and ablation of all thyroid tissue, making both tumor and tissue-specific markers useful for early diagnosis. Several markers have been applied to nodes (Table 1) and peripheral blood (Table 2). The most common sites of tumor metastases in thyroid cancer are local-regional lymph nodes, particularly for papillary cancer. These metastases are frequently present at diagnosis and can be difficult to isolate and eradicate. Standard approaches to...

Future Perspectives Of Tsh Analogs

Produced in Chinese hamster ovary cells exhibits relatively low affinity to the TSH receptor that translates into limited clinical efficacy. Despite quite apparent advantages of TSH superactive analogs, further development and clinical trails of such analogs are now dependent on commitment of biotech industry for a relatively small thyroid market (Table 2). Clinical Differentiated thyroid cancer follow-up (TSH analog stimulated thyreoglobulin testing and radioiodinc scanning) Differentiated thyroid cancer treatment (TSH analog induced radioiodinc ablation) Large euthyroid goiter treatment (TSH analog induced radioiodinc ablation) TSH analog stimulation tests (testing thyroid reserve, identifying warm thyroid nodules, detecting thyroid hemiagenesis, etc.) Management of patients with TSH receptor mutations associated with low ligand binding, impaired receptor expression or coupling TSH receptor-mediated delivery of therapeutic agents to the thyroid cancer cell (Figure 5) Laboratory ' I...

Evidence For An Inherited Susceptibility To

It is reasonable to suggest that any malignancy may have a familial predisposition. Cancer is caused by multiple gene mutations that are acquired over time by the cancer progenitor cell. Although these are usually somatic mutations, it would not be surprising if the first gene mutation was inherited (germline mutation). Family members possessing this hypothetical gene mutation would be at increased risk for developing PTC. Such a hypothetical susceptibility gene could persist in the population. It takes years to decades for the thyroid cancer progenitor cell to develop into a malignancy, since it must acquire other necessary gene mutations. Even then the malignancy is slow A number of large kindreds with fPTC have been described 8-15 . These kindreds are further evidence for a familial predisposition to PTC. Against this interpretation, it can be argued that these kindreds represent the rare association of multiple sporadic thyroid carcinomas, and that the number of affected family...

Linkage Analysis And The Chromosomal Loci Of Putative Fptc Susceptibility Genes

A large kindred with f PTC and benign thyroid nodules with the distinct pathologic finding of eosinophilia (TCO) has been mapped to 19p13.2 with a maximum LOD score of 3.0 19 . Eosinophilia refers to the staining of the cytosol by eosin, is often caused by a large cytoplasmic population of mitochondria, and in the thyroid these are often referred to as Hurthle cells. Interestingly, other f PTC kindreds also link to this region (19p13), but the fPTC in these kindreds were not associated with eosinophilia 20 . Since the tumors of these fPTC kindreds are pathologically distinct, it is possible that there are two different susceptibility genes at this locus. Alternatively, there may be a single susceptibility gene this locus and an additional modifier gene contributes to the eosinophilia in one kindred. Table 1. Familial papillary thyroid carcinoma summary of linkage analyses Table 1. Familial papillary thyroid carcinoma summary of linkage analyses

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