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. Read more...

The Natural Thyroid Diet Summary

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Author: Louise O'Connor
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The author presents a well detailed summery of the major headings. As a professional in this field, I must say that the points shared in this manual are precise.

This ebook does what it says, and you can read all the claims at his official website. I highly recommend getting this book.

The Hypothalamic PituitaryThyroid Axis

Thyroid hormones play an important role in normal growth and development of the maturing human. In the adult, thyroid hormones maintain metabolic homeostasis by regulating oxygen consumption, body weight and intermediate metabolism. Thyroid function is under hypothalamic-pituitary control. Thus, thyroid hormones are produced by the thyroid gland in response to stimulation by thyroid-stimulating hormone (TSH) produced by the anterior pituitary. TSH, in turn is regulated by the hypothalamic peptide, thyrotropin-releasing hormone (TRH). The function of the entire complex is modified by the availability of the thyroid hormones in a typical negative feedback manner leading to the concept of a functional unit, the hypothalamic-pituitary-thyroid (HPT) axis. This chapter focuses on the ontogenesis and functional anatomy of the hypothalamic-pituitary system first, and the thyroid gland itself. Emphasis is placed on the molecular aspects regarding the morphogenesis of the functionally linked...

Papillary and Follicular Thyroid Cancer

Derived from follicular epithelial cells, papillary and follicular thyroid cancers comprise the majority of thyroid malignancies and have the best prognosis of the various thyroid cancers however, they account for nearly 70 of all thyroid cancer deaths (Table 1) (8). They are the only tumors that respond to radioiodine (131I) therapy and that synthesize and secrete thyroglobulin (Tg), a sensitive tumor marker, which in the absence of normal thyroid tissue identifies small amounts of persistent tumor that can be promptly treated. About 5 of papillary cancers are inherited as an autosomal dominant trait, the gene for which is still unknown (10,11). They have a less favorable prognosis than sporadic papillary cancer (12,13), unless they occur in the setting of certain syndromes such as familial adenomatous polyposis (Gardner's syndrome), for example, in which thyroid cancer occurs at a young age as bilateral, multicentric tumors with an excellent prognosis, particularly those with...

Anaplastic Thyroid Cancer

In the past, ATC comprised about 5-10 of thyroid cancers (24) but in recent years has accounted for about 2 of all thyroid cancers (8). In a review of 475 patients with this disease reported in six large studies, the mean age was 65 yr, with only a slight female predominance (24). ATC is almost never seen before age 20 yr. It evolves from well-differentiated tumors (24) which may slowly transform into ATC (25). One report, for example, described a 61-yr-old man who developed follicular cancer pulmonary metastases 12 yr after initial surgery, which transformed over several years into ATC (as shown by serial biopsies ) (26). Some appear to arise de novo (27), but many are well-differentiated tumors that slowly transform into ATC (24). One study (28) found elements of differentiated cancer in almost 90 of ATC specimens, which often came from persons previously treated for well-differentiated thyroid cancer, underscoring an important adverse effect of late or incomplete treatment of...

The Role of Thyroid Radiation in Causing Thyroid Cancer External Irradiation

The only environmental factor known to increase the risk of thyroid cancer is irradiation. The risk of developing papillary thyroid cancer after therapeutic external radiation, used in the past to treat children with benign head and neck conditions, is well known (30). Exposure before the age of 15 yr poses a major risk that becomes progressively larger with increasing doses of radiation between 0.10 Gy (10 rad) and 10 Gy (1000 rad). The incidence of thyroid cancer begins increasing within 5 yr of exposure and continues unabated for 30 yr, after which it begins to decline (30). After thyroid radiation exposure, females are more likely than males to develop thyroid cancer, and it is more prevalent among those with a family history of thyroid cancer (30). Radioiodine-Induced Thyroid Cancer Most early studies suggested that 131I was unlikely to induce thyroid cancer (31). A large U.S. study, for example, reported a slight elevation of thyroid cancer mortality following treatment of...

Causes of Death from Thyroid Cancer

Most patients who succumb to thyroid cancer die either from pulmonary metastases or local invasion of tumor. One large study (48) found a single cause aTumor stage in patients in whom diagnosis was delayed longer than 1 yr compared with those in whom the diagnosis was made within 12 mo of the presenting manifestations of papillary or follicular thyroid carcinoma. Data from ref. 9. aTumor stage in patients in whom diagnosis was delayed longer than 1 yr compared with those in whom the diagnosis was made within 12 mo of the presenting manifestations of papillary or follicular thyroid carcinoma. Data from ref. 9.

Thyroid Disease during Pregnancy

The prevalence of hyperthyroidism is around 5 per 1,000 and hypothyroidism about 3 per 1,000 in women. As the conditions are generally much more common in the female it is to be expected that they will appear during pregnancy. Developments in our understanding of thyroid physiology 1 and immunology 2 in pregnancy as well as improvements in thyroid function testing 3 have highlighted the importance of recognising and providing appropriate therapy to women with gestational thyroid disorders. Before considering the clinical entities occurring during and after pregnancy it is useful to briefly review thyroid physiology and immunology in relation to pregnancy.

FollowUp of Papillary and Follicular Thyroid Cancer

Performing a whole-body scan and measuring serum Tg is the standard of care in the follow-up of patients with differentiated thyroid cancer (1,84), although DxWBS before 131I therapy is usually unnecessary. The panel of experts that formulated the National Cancer Center guidelines for thyroid cancer could not reach consensus on recommending a DxWBS in lieu of RxWBS during evaluation (39). A retrospective study (85) of 76 patients undergoing follow-up after initial thyroid ablation found that two consecutive negative DxWBSs had a greater likelihood of predicting relapse-free survival than did one such study however, serum Tg was not measured under TSH stimulation, which is a considerably more sensitive test than DxWBS (86,87). A study of 256 patients (88) found that a 2-5-mCi 131I DxWBS performed 6 mo to 1 yr after thyroid ablation did not correlate with the serum Tg but only confirmed the completeness of thyroid ablation, suggesting that DxWBS is unnecessary in this setting patients...

Medullary thyroid cancer

MTC accounts for about 4 of all thyroid malignancies (8). Sporadic MTC is more frequent in women, with a female male ratio of 1.5 1, whereas familial MTC occurs with equal frequency in both sexes. Only about 10-20 of MTC cases occur as familial tumors the others are sporadic and may occur at any age but usually are detected later in life than familial MTC. The median age, for instance, of patients with sporadic MTC in one large study was 51 yr, compared with 21 yr for those with familial tumors (89). The diagnosis is made even earlier now with genetic testing.

Fetal Thyroid Development and Function

The fetal thyroid begins concentrating iodine at 10-12 weeks of gestation and is under control of fetal pituitary thyroid-stimulating hormone (TSH) by about 20 weeks of gestation 19 . Despite the fetus not possessing a functioning thyroid in early pregnancy there is good evidence that thyroid hormone is important in the development of many organs including the brain. It is now well accepted that maternal circulating T4 crosses the placenta into the fetus at all stages of pregnancy, first shown by Vulsma et al. 20 . The precise mechanism of placental T4 transport is not clear but the important role of both the type 2 and type 3 deiodinase enzymes, both expressed in the placenta, has been recognised. Type 2 deiodinase is also located in the uterus and other parts of the genital tract and may have a role in fetal implantation 21 . In the fetus it is expressed in the brain and its action supplies that developing organ with T3. Type 3 deiodinase (D3), which degrades thyroid hormones, is...

Hyperthyroidism and Pregnancy

Subacute thyroiditis causes such as hyperemesis gravidarum, toxic multinodular goitre, toxic adenoma and subacute thyroiditis may occur. It should be noted that most women with nausea and vomiting in pregnancy do not have hyperthyroidism. Rarer causes include struma ovarii, hydatidiform mole and one reported case of a TSH receptor mutation activated only during pregnancy 27 (table 3). The clinical suspicion of hyperthyroidism may not be obvious as symptoms of tachycardia, sweating, dyspnoea and nervousness are seen in normal pregnancy as are cardiac systolic flow murmurs. The diagnosis should always be confirmed by estimation of circulating thyroid hormone concentrations. It should be noted that serum thyroxine (both total and free) varies during normal gestation. Recent national and internationally agreed guidelines suggest that laboratories should be encouraged to develop normal ranges for total but more particularly free T4 and T3, as well as TSH after the 1st trimester during...

Effects of Hyperthyroidism on Mother and Child

Congestive heart failure and thyroid storm may also occur and the risk of pre-eclampsia is significantly higher in women with poorly controlled hyperthyroidism and low birth weight may be up to nine times as common. Neonatal hyperthyroidism, prematurity and intra-uterine growth retardation may be observed. A retrospective review documented a 5.6 incidence of fetal death or stillbirth in 249 pregnancies from hyperthyroid mothers and a further 5 fetal and neonatal abnormalities. Women with thyroid hormone resistance who, despite being euthyroid, had high levels of circulating T4 had a significantly increased miscarriage rate compared to euthyroid unaffected couples 30 . However, a recent study of women with subclinical hyperthyroidism, comprising 1.7 of women, showed no significant adverse pregnancy outcomes suggesting that treatment of this condition in pregnancy is not warranted 31 . Nevertheless, there is no doubt that overt clinical and biochemical hyperthy-roidism should...

Management of Graves Hyperthyroidism

Guidelines for measurements of thyroid-stimulating hormone-receptor antibodies in a pregnant woman with Graves' disease (reproduced from Laurberg et al. 37 , with permission from the Society of the European Journal of Endocrinology) allay fears which are commonly present in these women. The patient's thyroid status should be checked frequently to minimise risk of miscarriage should she be hyperthyroid at the time of conception. If treatment had been commenced with methimazole or carbimazole a change to propylthiouracil (PTU) is recommended to reduce the admittedly rare occurrence of aplasia cutis 35 and the equally rare methimazole embryopathy 36 reported following the administration of the former drugs. The patient may have been rendered euthy-roid by partial thyroidectomy or radioiodine therapy. However, if these procedures are performed the patient may require thyroxine therapy (with a requirement for an increase in dose and monitoring during gestation) in addition, there...

Thyroid Function in the Newborn and Infant

The thyroid gland is an endocrine organ of vital importance for the neonate since normal thyroxine concentrations are essential for the normal neurodevelopment of the newborn and subsequently the infant and child. The recent advances in our understanding of fetal thyroid hormone physiology have also shown the importance of the placental transfer of maternal thyroid hormones and the normal function of the fetal thyroid gland for normal brain development of the fetus with subtle differences in the outcome of the term newborn as opposed to the preterm newborn.

Fetal Thyroid Function and Maternal Thyroid Hormones

The onset of active fetal thyroid function (FTF) coincides with full maturation of the pituitary portal vessels at 16-20 weeks of gestation 1 . Before the period of FTF, the neocortex of the fetal brain undergoes important phases of development which are largely dependent on the presence of thyroxine (T4) and triiodothyronine (T3) 1, 2 . Low concentrations of T4 and T3 are present in early embryonic and fetal tissue before the onset of FTF in concentrations that are directly influenced (especially the T4 levels) by those in the maternal circulation 3-14 . When maternal T4 and T3 concentrations are abnormally low in the first trimester, fetal brain development is adversely affected and there is a defect in the histogenesis and cerebral cortex cytoarchitecture, defective neuronal migration at the beginning of fetal neocorticogenesis, and a defective cortical expression of several genes in the fetal brain such as neuroendocrine-specific protein A 15, 16 . At the time of neural tube...

Maternal Fetal Unit and the Function of the Fetal Thyroid Gland

Grows and obliterates the exocoelomic cavity (fig. 1b) considerably changing the maternal-fetal exchange pathways. From the 11 to 12th weeks of gestation and onward, maternal nutrients, including thyroid hormone, are transferred by the placenta directly into the fetal circulation. The placenta plays an important role in the development and function of the thyroid gland in the fetus. The placenta produces various hormones that can influence the fetal thyroid gland (e.g. chorionic gonadotropin, TRH). The most important role of the placenta though is in regulating the passage of hormones and drugs, from the mother to the embryo, which influence the fetal thyroid gland. For many years its was unknown how the very small amounts of maternal T4 which are allowed to pass the placental barrier (sometimes as low as 1 of the maternal concentrations in the first trimester) can play such a major role in the normal fetal physiology of the developing brain and fetal tissues. The answer came from...

Action of the Thyroid Hormones

The action of the thyroid hormones in the adipose tissue, the liver, the heart, the muscles and the bones are expressed during neonatal but not fetal life. It is not known whether this delay in the action of the thyroid hormones in these tissues is related to the maturation of the thyroid hormone signaling pathway at a molecular level or related to the maturation of thyroid hormone metabolism. The actions of the thyroid hormones, which are specific to each individual tissue, depend on the prevalent isoform of the thyroid hormone receptor (TR) which is expressed in each tissue and on cofactors at the site of action of the thyroid hormones. The highest concentrations of TRs are found in developing neurons and in various regions in the brain of the fetus and the neonate such as cortex, cerebellum, and visual and auditory cortices. There are many indications that the TR 1 isoform of the receptor is the one which promotes, via T3, the vital development of the central nervous system in the...

Thyroid Synthesis in the Full Term Newborn

During the birth process many changes occur in the function of the thyroid gland in the full-term neonate. The most dramatic change is the abrupt increase in TSH which takes place in the first 30min after parturition which can reach levels of 60-70 mlU l. This increase causes a major stimulation of the thyroid gland with an increase in T4 in the serum by about 50 and a 3- to 4-fold increase in T3 within 24h 36, 37 . Studies in experimental animals have shown that the increase in TSH is a consequence of the relative hypothermia that exists in the environment outside of the uterus. The increase in T3 occurs not only because TSH levels increase but also because of an increase in the action of type I deiodinase during birth. The high levels of reverse T3 (rT3) decrease relatively quickly during the neonatal period. The increase in the action of type II deiodi-nase causes an increase in T3 in the adipose tissue of the neonate which is necessary for thermogenesis and the synthesis of...

Thyroid Synthesis in the Pre Term Newborn

The function of the thyroid gland in the pre-term neonate reflects the immaturity of the hypothalamic-pituitary-thyroid axis which corresponds to the week of gestation of the pre-term neonate. There is a gradual increase in the concentration of TSH, TBG, T3 and T4 during gestation 42, 43 . After parturition there is an increase in T4 and TSH just as in full-term neonates, but the increase is much smaller in pre-term neonates than what it is in the full-term neonates and there is a dramatic decrease in the concentration of T4 during the following 1-2 weeks 44 . This decrease in T4 is more important in low birthweight and significantly premature neonates (< 1.5 kg and < 30 weeks of gestation) where the level of T4 may not be detectable 44, 45 . In most cases though total T4 is influenced and not FT4 as much since TBG is low in pre-term neonates due to immaturity of the liver. Another reason for the fall in T4 in pre-term neonates is the reduced storage of iodine which exists due to...

Function of the Thyroid Gland in the Neonate and Infant

After the large increase in the serum concentrations of the thyroid hormones and TSH which occur during the first days of neonatal life there is a gradual decrease in the levels of T4, T3 and TSH during the life of the neonate and infant. The most important difference between this period and adult life is that there is a larger production and utilization of T4 in the neonates and infants. The neonates produce 5-6 xg kg day of T4 with a gradual decrease during the first years of life to reach levels of 2-3 xg kg day of T4 at 3-9 years of age. This is in contrast to adults who produce 1.5 xg kg day of T4 42 . The weight of the neonatal thyroid gland is a good indicator of maternal iodine intake during pregnancy. On an adequate maternal iodine intake, the weight of the neonatal thyroid is less than 1.5 g 48 . Due to the increased turnover of iodine and consequently of thyroglobulin in the early neonatal period, decreased iodine intake will bring about an increased consumption of reserve...

Treatment of overt hyperthyroidism

Patients with overt hyperthyroidism from Graves' disease or from toxic mul-tinodular goiter should clearly be treated. One therapeutic option for patients with Graves' disease is medical management with methimazole (MMI) or pro-pylthiouracil (PTU), both of which decrease thyroid hormone synthesis. Therapy with one of these drugs will induce long-term remission of Graves' disease in about half of all patients, although those patients with large goiters are less likely to remain euthyroid (70). Since remission of the hyperthyroidism caused by toxic multinodular goiter almost never occurs, therapy with MMI or PTU is only given prior to definitive therapy, as described below. Side effects of both of these medications include rash or urticaria. More seriously, agranulocytosis occurs in approximately 0.3 of patients (71). Patients starting on these medications should be cautioned to discontinue them and call their physician if they develop fever, rash, jaundice, arthralgia, or sore throat....

Screening For Thyroid Disease

People with type 1 diabetes are at higher risk for autoimmune thyroid disease most frequently the thyroid is underactive (Hashimoto's thyroiditis), but it can also sometimes be overactive (Graves' disease). Your doctor will check you for thyroid disease when you are first diagnosed with type 1 diabetes and then every one to two years. Thyroid abnormalities also increase with age, and your doctor therefore may do thyroid tests periodically even if you have type 2 diabetes. Check you for thyroid problems

Genomic and Nongenomic Actions of Thyroid Hormones

As mentioned above, the biological activity of thyroid hormones is largely exerted by T3 and is determined by the intracellular T3 concentration, which is Most thyroid hormone actions are initiated by an interaction of T3 with specific nuclear receptors, which act largely as transcription factors exerting a modifying effect on the expression of a variety of genes, the genomic actions. However, extranuclear processes may also contribute to the overall biologic actions of thyroid hormones 88-90 . These effects occur rapidly and are shown to be unaffected by inhibitors of transcription and translation suggesting that thyroid hormones may also mediate non-genomic actions reviewed in 91 . The heart is a major target organ for thyroid hormone action, and the T3 effects are shown to be mediated by both nuclear and extranuclear mechanisms leading to enhanced velocity of cardiac contraction and increased speed of diastolic relaxation reviewed in 92 .

The Thyroid and Autoimmunity in Children and Adolescents

Thyroid autoimmunity is the commonest disease process to affect thyroid function. The prevalence of thyroid autoimmunity increases throughout life, with a possible decline in frequency in the very old as a 'healthy survivor' effect. The mere presence of thyroid autoimmunity, as demonstrated by the presence of thyroid autoantibodies or focal thyroiditis, for example, does not equal thyroid disease, since the majority of people with focal thyroiditis do not become hypothyroid 1 . On the other hand, as far as we know the formation of thyroid-stimulating antibodies (TSAb) leads to Graves' disease in the great majority of subjects, even if in rare cases their levels may oscillate and be associated with a fluctuating clinical course. After a brief review of the basic immunological mechanisms which underlie autoimmune thyroid diseases, this chapter will focus on the comparatively few studies which have looked specifically at the pathogenic mechanisms in these disorders in children and...

Mechanisms of Thyroid Autoimmunity

It is well established that a complex interplay of diverse environmental and genetic susceptibility factors interact in predisposing an individual to autoimmune thyroid disease (fig. 1). Moreover, the contribution that each factor makes varies from patient to patient, and as yet there are no clear genotype-phenotype correlations. We have shown that polymorphisms in the thyroid stimulating hormone receptor (TSH-R) are associated with Graves' disease but not autoimmune Clinical autoimmune thyroid disease Clinical autoimmune thyroid disease Fig. 1. Interaction of factors predisposing to autoimmune thyroid disease. hypothyroidism 2 . The other known genetic loci associated with thyroid autoimmunity, namely HLA, CTLA-4 and PTPN22, are shared between these 2 thyroid conditions, as well as many other autoimmune diseases reviewed in 3 . Several environmental factors have been delineated but some of these remain controversial and of unknown action, such as smoking and stress 4, 5 . Evidence...

Genetic and Other Causes of Congenital Hypothyroidism

CH represents a heterogeneous group of thyroidal and non-thyroidal disorders (fig. 1), leading to decreased or absent thyroid hormone action and clinical sequelae. In 70-80 of the cases thyroid dysgenesis is found due to agenesis (30 ), ectopic gland (48 ) or hypoplastic, eutopic gland (5 ) 3 . A normal (11 ) or enlarged thyroid gland (6 ) is observed in children with disorders of thyroid hormone synthesis. Up to 15 of cases with CH occur on a hereditary basis (table 1), while the remaining majority of cases are considered sporadic forms. Isolated thyroid dysgenesis may be caused by inactivating ('loss-of-function') mutations of the TSH receptor (TSHR) (fig. 2). CH in association with various complex syndromes is found in patients carrying mutations of thyroid transcription factors PAX8, TITF1, TITF2 or the stimulatory G protein a-subunit Gene Protein Heredity Thyroid Associated

Resistance to Thyroid Hormone in Childhood

Occasionally, a patient is seen in the clinic with apparent hypo- and or hyperthyroid symptoms but with conflicting results of thyroid function tests they have a nonsuppressed or even slightly increased TSH inappropriate for the invariably increased free T4 in serum. This combination of hormone levels can have several causes but there are two major ones namely a TSH-producing pituitary adenoma and resistance to thyroid hormone (RTH). The latter will be the subject of this chapter. The basic problem in RTH is a decreased sensitivity of tissues to thyroid hormone. The decreased sensitivity is also present in the pituitary, where it leads to a blunting of the feedback of thyroid hormone on the pituitary. This in turn results in the above mentioned increased secretion of TSH and thereby of T4. As will be explained below, the insensitivity is caused by mutations in the thyroid hormone receptor beta isoform that reduce thyroid hormone binding affinity. This does not just lead to a...

Viruses Affecting the Thyroid

The effect of viruses on the thyroid is an area that has been underresearched there are few reports of specific viruses being associated with thyroid disease. Both acute and subacute thyroiditis have long been thought to have a viral etiology, but no specific association has been found despite numerous studies measuring broad spectra of viral antibodies in paired serum samples. However, an association between antibodies reactive with microsomal and or thyro-globulin fractions of thyroid tissue has been found in 20-40 of congenital rubella sera. Thyroid function was found to be abnormal (showing both hypo- and hyperthyroidism) in 5 of all congenitally infected children being restricted to those with thyroid autoantibodies. The finding of rubella virus antigen in a biopsy of thyroid tissue from a 5-year-old boy with congenital rubella and Hashimoto's thyroiditis suggests that virus may persist in the tissue even though no virus is isolated. It is interesting to note that there is a...

Regulation Of Thyroid Function

Effects of Thyroid-Stimulating Hormone Although the thyroid gland can carry out all of the steps of hormone biosynthesis, storage, and secretion in the absence of any external signals, autonomous function is far too sluggish to meet bodily needs for thyroid hormone. The principal regulator of thyroid function is the thyroid-stimulating hormone (TSH), which is secreted by thyrotropes in the pituitary gland (see Chapter 38). It may be recalled that TSH consists of two glycosylated peptide subunits including the same -subunit that is also found in FSH, and LH (Chap. 38). The -subunit is the part of the hormone that confers thyroid-specific stimulating activity, but free -subunits are inactive, and stimulate the thyroid only when linked to a-subunits in a complex three dimensional configuration. Thyroid-stimulating hormone binds to a single class of heptihelical G protein-coupled receptors (see Chapter 2) in the basolateral surface membranes of thyroid follicular cells. The TSH receptor...

Thyroid Hormones In Blood

More than 99 of thyroid hormone circulating in blood is firmly bound to three plasma proteins. They are thyroxine-binding globulin (TBG), transthyretin (TTR), and albumin. Of these, TBG is quantitatively the most important and accounts for more than 70 of the total protein-bound hormone (both T4 and T). About 10-15 of circulating T4 and 10 of circulating T3 is bound to TTR and nearly equal amounts are bound to albumin. TBG carries the bulk of the hormone even though its concentration in plasma is only 6 of that of TTR and less than 0.1 of that of albumin because its affinity for both T4 and T3 is so much higher than that of the other proteins. All three thyroid hormone binding proteins bind T4 at least 10 times more avidly than T3. All are large enough to escape filtration by the renal glomerular membranes and little crosses the capillary endothelium. The less than 1 of hormone present in free solution is in equilibrium with bound hormone and is the only hormone that can escape from...

Physiologic Effects Of Thyroid Hormones

One of the most striking effects of thyroid hormones is on bodily growth (see Chapter 44). Although fetal growth appears to be independent of the thyroid, growth of the neonate and attainment of normal adult stature require optimal amounts of thyroid hormone. Because stature or height is determined by the length of the skeleton, we might anticipate an effect of thyroid hormone on growth of bone. However, there is no evidence that T3 acts directly on cartilage or bone cells to signal increased bone formation. Rather, at the level of bone formation, thyroid hormones appear to act permissively or synergistically with growth hormone, insulin-like growth factor (see Chapter 44), and other growth factors that promote bone formation. Thyroid hormones also promote bone growth indirectly by actions on the pituitary gland and hypothalamus. Thyroid hormone is required for normal growth hormone synthesis and secretion. The importance of the thyroid hormones for normal development of the nervous...

Treatment of Hyperthyroidism Due to Graves Disease in Children

Yale Pediatric Thyroid Center, Department of Pediatrics, Yale University School of Medicine, New Haven, Conn., USA Total thyroidectomy is an effective treatment of Graves' disease, with a low rate of disease recurrence. Long-term complications include recurrent laryn-geal nerve paresis in 2 or more of individuals, permanent hypoparathy-roidism in 1 or more, and hypertrophic and non-hypertrophic scars. Surgery is the preferred definitive treatment for the very large thyroid gland and when the individual is considered too young for 131I. When used at doses that deliver 150 Gy, or more (> 150 xCi 131I g thyroid tissue), radioactive iodine is an effective cure for Graves disease and is associated with few acute side effects. Potential long-term adverse side effects, including thyroid cancer and genetic damage, have yet to be observed in individuals treated as children or adolescents with 131I.

Regulation Of Thyroid Hormone Secretion

As already indicated, secretion of thyroid hormones depends on stimulation of thyroid follicular cells by TSH, which bears the primary responsibility for integrating thyroid function with bodily needs (Chapter 38). In the absence of TSH, thyroid cells are quiescent and atrophy, and, as we have seen, administration of TSH increases both synthesis and secretion of T4 and T3. Secretion of TSH by the pituitary gland is governed by positive input from the hypothalamic hormone thyrotropin-releasing hormone (TRH) and negative input from thyroid hormones. Little TSH is produced by the pituitary gland when it is removed from contact with the hypothalamus and transplanted to some extrahypotha-lamic site, and disruption of the TRH gene reduces the TSH content of mouse pituitaries to less than half that of wild-type litter mate controls. Positive input for thyroid hormone secretion thus originates in the central nervous system by way of TRH and the anterior pituitary gland. TRH increases the...

Childhood Hyperthyroidism

Hyperthyroidism occurs much less commonly in children than hypothyroidism, yet is a far more virulent condition 7, 8 . In children the most common cause of childhood thyrotoxicosis is Graves' disease, which is characterized by diffuse goiter, hyperthyroidism and occasionally ophthalmopathy 6, 9-11 . Other causes of childhood hyperthyroidism include toxic nodules, toxic multinodular goiters, acute and subacute thyroiditis, and the ingestion of thyroid hormone 6, 9-11 . Untreated, hyperthyroidism is associated with excessive activity, tremor, tachycardia, flushing, palpitations, accelerated linear growth, weight loss, impaired skeletal mineralization, and poor school performance 6, 9-11 . Because Graves' disease, toxic nodules and toxic multinodular goiters only rarely spontaneously resolve within a short period, treatment of hyper-thyroidism is essential. Current treatment options include the use of radioactive iodine, surgery, and antithyroid medications.

Immunopathogenesis of Thyroid Eye Disease

The orbital fibroblasts are widely viewed as the target cells of the autoimmune attack in GO. During the early stages of the disease, macrophages, highly specialized T cells, mast cells, and occasional plasma cells infiltrate the orbital connective, adipose, and muscle tissues 4, 5 . Activation of T cells directed against a thyroid follicular cell antigen(s) that then recognizes and binds to a similar antigen(s) in orbital tissue is a probable but yet unproven theory 2 . The orbital fibroblasts do express functional TSH receptors (TSH-R). This recent finding has led to the currently favored view that the TSH-R is the long sought after shared antigen between the thyroid and the orbit and that the TSH-R is the autoantigen involved in GO. Indeed, cytokine-induced differentiation of a particular subset of orbital fibroblasts into adipocytes is associated with increased TSH-R expression and adipogenesis 16 . A causative role of stimulating TSH-R antibodies (TSI) in the development of GO is...

Parathyroid Glands And Parathyroid Hormone

Human beings typically have four parathyroid glands, but as few as two and as many as eight have been observed. Each gland is a flattened ellipsoid measuring about 6 mm in its longest diameter. The aggregate mass of the adult parathyroid glands is about 120 mg in men and about 140 mg in women. These glands adhere to the posterior surface of the thyroid gland or occasionally are embedded within thyroid tissue. They are well vascularized and derive their blood supply mainly from the inferior thyroid arteries. Parathyroid glands are comprised of two cell types (Fig. 6). The chief cells predominate and are arranged in clusters or cords. They are the source of PTH and have all of the cytological characteristics of cells that produce protein hormones rough endoplasmic reticulum, prominent Golgi apparatus, and some membrane-bound storage granules. The oxyphil cells, which appear singly or in small groups, are larger than chief cells and contain a remarkable number of mitochondria. Oxyphil...

Imaging of the Normal and Affected Thyroid in Childhood

Imaging has undergone major advances over the past three decades and has revolutionized the evaluation of patients with thyroid disease. However, the use of thyroid imaging is in general not evidence-based, and there have been few cost-benefit evaluations of medical imaging 1 . The thyroid gland can be evaluated by several imaging techniques (1) radionuclide imaging, and (2) nonisotopic imaging comprising (a) ultrasonography (US) (b) computed tomography (CT), and (c) magnetic resonance imaging (MRI). A recent development has been the combination of PET (positron emission tomography) and CT for oncologic imaging. Each has advantages and limitations, and there is no absolute clinical indication for performing any of them in the majority of patients 1, 2 . In this chapter emphasis will be on the clinical use of US in childhood.

Pseudohypoparathyroidism

Resistance to thyroid-stimulating hormone (TSH) is also common in this disorder. Pseudo-PHP typically occurs in families with PHP-Ia and is characterized by phenotypic abnormalities similar to those of patients with PHP-Ia, but these individuals demonstrate normal regulation of calcium and phosphate homeostasis. This disorder also involves inactivating mutations of GNAS1, but hormone resistance is thought to be suppressed by paternal imprinting (i.e., the GNAS1 gene is inherited from the father and the mutant copy is suppressed in selected tissues) (51). PHP-Ib is characterized by resistance to PTH, no resistance to thyrotropin, and absence of features of AHO. This disorder is thought to occur by mutation in or near GNAS1 (52). Gsa activity is normal in individuals with PHP-Ib (Table 5).

Description Surgical Thyroid Procedures

I hyroid cancer is the most common endocrine cancer, and the number of new cases in the United States is increasing annually by 3 per 100,000. Most thyroid nodules or tumors develop from thyroid follicular cells 95 of these nodules and tumors are benign. The remaining 5 of 896 Thyroid Cancer thyroid nodules or tumors are cancerous, and there are several forms of thyroid cancer. Papillary carcinoma is the most common form of primary thyroid cancer. It is also the slowest-growing thyroid cancer and is usually multifocal and bilateral in distribution. Papillary carcinoma metastasizes slowly into the cervical lymph nodes and the nodes of the mediastinum and lungs. Follicular cancer is the next most common form. It is more likely to recur than other forms it generally metastasizes to the regional lymph nodes and is spread by the blood to distant areas such as the bones, liver, and lungs. More than 90 of patients treated for either papillary or follicular carcinoma will live for 15 years or...

Rationale For Molecular Diagnostic Testing In Patients With Suspected Thyroid Cancer

The initial workup of a thyroid nodule consists of ultrasonography and if indicated a fine-needle aspiration biopsy (FNAB). Despite the fact that cytological examination of FNAB by an experienced pathologist provides the most accurate and cost-effective means of diagnosing thyroid neoplasms, in some situations, cyto-logical examination may not provide a conclusive diagnosis. For example, biopsy samples are cytologically found to be ''intermediate'' or ''suspicious,'' but most of these lesions are benign. In addition, preoperative diagnosis of lesions with follicular histology is difficult, and a consistent number of not otherwise specified ''follicular nodules'' are surgically resected more for diagnosis than therapeutic purposes. Because operation could be recommended only to those patients with a high risk of malignancy, the use of a molecular-based approach with detection of tissue- or tumor-specific mRNA transcripts may provide a more objective method to assure reliable diagnosis....

Medullary Thyroid Carcinoma

In medullary thyroid carcinoma (MTC), laboratory tests for preoperative diagnosis and postoperative follow-up are performed using basal as well as pentagastrin-stimulated serum calcitonin (CT), which is supplemented by estimation of serum levels of carcinoembryonic antigen (CEA). In contrast to papillary and follicular thyroid carcinoma, to date only a few studies have been published concerning the preoperative diagnosis of MTC using PCR-based methods. The reason for that discrepancy may be that patients with MTC are usually readily diagnosed by conventional cytology and serum calcitonin measurements. One study reported the preoperative diagnosis of MTC by RT-PCR using RNA extracted from leftover cells of FNAB. 7 As transcripts specific for MTC, calcitonin, carcinoembryonic antigen, and RET proto-oncogene mRNA, respectively, were used. In another study using identical primer sequences, calcitonin mRNA was found in all samples of FNAB derived from patients with MTC, but not in samples...

Molecular Analyses Of Peripheral Blood And Postoperative Surveillance Of Thyroid Carcinomas

Papillary and Follicular Thyroid Carcinoma The application of RT-PCR to detect circulating thyroid-specific mRNA in recurrent thyroid cancer was first reported in a study in which all patients with thyroid carcinoma and metastases were tested positive for circulating thyroglobulin (TG) mRNA, whereas patients without metastases were tested negative. 9 In a subsequent study, 10 circulating mRNA transcripts of TG, thyroid peroxidase (TPO), and RET PTC1 were used as tumor markers in patients with thyroid disease. Although there was a correlation between existence of these transcripts in peripheral blood and diagnosis of thyroid carcinoma, TG and TPO mRNA transcripts could be detected in the peripheral blood of all control subjects as well as in several human cell lines when PCR assay sensitivity was increased. Finally, an optimistic study was published, 11 which reported an RT-PCR assay to detect blood-borne TG mRNA that was more sensitive than the conventional TG serum assay. However, in...

Hypothyroidism Introduction

Hypothyroidism is the result of inadequate thyroid hormone production to maintain body processes. It may be the result of congenital thyroid abnormality and therefore present in infancy or it may become notable during the first two years of life. It appears later when production is inadequate to maintain body processes as rapid growth increases the need for hormones. Acquired causes of the condition may be thyrotoxicosis, thyroidectomy, irradiation, infections, and dietary deficiency of iodine. Secretions of the thyroid gland include thyroid hormone (thyroxine, T4 and triiodothyronine, T3) which are bound to proteins in the blood (thyroxine-binding globulin, TBG) and thyrocalcitonin (maintains calcium levels in blood). The hormones are controlled by the thyroid-stimulating hormone (TSH) that is secreted by the anterior pituitary gland. Treatment of hypothyroidism is by thyroid hormone replacement, which involves prompt intervention in the infant and gradually increasing amounts of...

Thyroid And Cancers Of The Head And Neck

Thyroid cancer is generally associated with a favorable prognosis. However, advanced local involvement and distant metastases incur significant mortality. Curative resection improves the prognosis in advanced thyroid cancer (21). Thyroid cancers that have invaded the esophageal wall as far as the muscular layer require a full thickness resection, although cancers that invade only the adventitia can be managed with a simple shaving (22). Although CT and MRI are able to detect esophageal invasion, these modalities are insufficient for a precise determination of depth. Because the thyroid is near the esophagus, the gland can be detected by EUS through the esophageal wall. EUS has been used successfully for diagnosing depth and extension of thyroid cancer (see Fig. 10). A study published recently compared EUS with esophagography and MRI in 59 patients in whom esophagopharyngeal invasion by thyroid cancer was suspected (large tumors with poor mobility). The diagnostic specificity and...

Papers Mri Of Normal Thyroid Gland

Lingual Thyroid Vallecula Mri

Medullary carcinoma appearing as a heterogeneous and enlarged left thyroid lobe with ipsilateral lymph node metastasis lateral to the jugular vein. The trachea is displaced slightly to the right. Thyroid nodules often appear as low density lesions but CT cannot differentiate benign nodules from papillary and follicular carcinomas. As with US, calcifications are easily detected and invasive growth into surrounding structures, as well as lymph node metastases (neck and mediastinum), can be revealed by CT (fig. 29) 138 . MRI offers excellent anatomic resolution and generation of images in multiple planes. Conventional T1- and T2-weighted imaging is highly sensitive but just as nonspecific as US and CT in differentiating benign thyroid nodules from carcinomas. Sensitivity does not increase with additional gadolinium-enhancement but primary thyroid lymphoma enhances less than other solid thyroid tumors 147 . MRI can distinguish solid from cystic nodules (fig. 30) 132 . Like CT, it...

Incidence and death rates of thyroid cancer and lymphoma

About 17,000 new cases of thyroid cancer are diagnosed annually in the United States, making it about 14th in incidence among malignancies (6). It occurs at all ages but is most common among middle-aged and postmenopausal women (Fig. 1). The lifetime risk of developing thyroid cancer is about 1 (0.65 for women and 0.25 for men) (7), and death rates are less than 10 (1200 deaths occurred among 135,000 thyroid cancer patients in 1998) (6). However, both the incidence and mortality rates vary substantially among the different forms of thyroid cancer (Table 1) (8). To appreciate the impact of early treatment, one must know the survival rates with different types of thyroid malignancy. Although death rates are usually low, cell type and tumor stage substantially alter outcome (Table 1). Prognosis is determined by many variables, but a patient's fate largely depends on three things the gross and histologic characteristics of the tumor, the patient's age and general health, and prompt...

Thyroid Disease in Turner Syndrome

An association between Turner syndrome (TS) and thyroid disease was first suggested by Atria et al. 1 in 1948 when they reported post mortem findings of a small thyroid gland with lymphocytic infiltration in a young woman with Turner syndrome. Many authors reported on a higher prevalence of hypothyroidism and an association with positive thyroid antibodies in TS patients (table 2) 2, 6, 7, 24, 29, 32, 37 . Hypothyroidism is found in up to 35 of TS patients. Thyroid autoimmunity seems to be even more common in females with Turner syndrome with a prevalence of up to 52 15 . A positive family history was reported by Wilson et al. 37 . This group found an increased incidence of thyroid antibodies in patients with TS and their first degree relatives. The incidence of thyroid antibodies was 30 in patients compared to 1.7 in an age matched control group and 22 in the mothers of the TS patients (vs. 6.6 in the controls). Larissa et al. 21 found a preferential parental segregation of...

Antithyroid Drug Therapy

Medical treatment in the first half of the century consisted of bed rest, quinine, and iodine in the form of Lugol's solution 98 . Partial thyroidectomy was used to provide permanent cures 98 . With the advent of thiouracil and propylthiouracil (PTU) in the mid-1940s, medical therapy of Graves' improved PTU and MMI reduce thyroid hormone synthesis by inhibiting the oxidation and organic binding of thyroid iodide 100, 101 . These medications are not curative. Rather, they palliate the hyperthyroid state until it spontaneously resolves or definitive treatment is rendered. In contrast to oral iodine therapy (see below), thiouracil drugs do not prevent thyroid gland hyperplasia. Thus, thyroid enlargement may occur during therapy. The thyroid gland may become softer and the outlines of the gland more difficult to distinguish 99 . Because radioactive iodine is less effective in large than in small glands 59, 99, 107 , thyroid size should be continuously monitored for progressive thyroid...

Clinical Outcomes of Congenital Hypothyroidism

Children with CH may have selective deficits on visual, language, motor, attention and memory abilities 21 . Auditory brainstem evoked potentials were abnormal in 25 of early-treated patients with CH 22 . Recent studies have comprehensively analyzed the temporal patterns of thyroid hormone action in the developing brain 21 . Hypothyroidism in early pregnancy is related to impaired visual attention and processing as well as gross motor abilities. It has to be considered that syndromatic forms of CH due to functional defects of thyroidal transcription factors or the iodothyronine transporter (table 1) may adversely affect CNS development independent of circulating thyroid hormone levels. The long-term perspective for normal mental and neurologic development is poor for infants with CH not detected by newborn screening. Physical symptoms and growth may normalise when L-T4 treatment is started later but within the first months of life but infants with severe perinatal hypothyroidism...

Thyroid Disease in Diabetes Mellitus

The most frequent autoimmune disease in type 1 diabetes affects the thyroid. The etiology of autoimmunity in pancreas and thyroid is a T cell-mediated disease and seems to be due to common genetic susceptibility. Two immune regulatory genes (HLA human leukocyte antigen and CTLA-4 cytotoxic T lymphocyte-associated protein 4) contribute to the susceptibility for both diseases 5, 23 . This locus, also known as the IDDM 12 gene, seems to play a major role in development of autoimmune polyglandular syndrome type 2 (APS-2). Autoimmunthyroiditis describes a group of thyroid diseases with destruction of thyroid tissue due to an autoimmune reaction. Classification of these diseases is not consistent in the literature. Most frequently, Hashimoto thyroidi-tis with antibodies against thyroid antigens is found. These antibodies are directed towards thyroid peroxidase (TPO-Ab), thyreoglobulin (TG-Ab) and or TSH-receptor antigen (TRAK). Positivity for thyroid auto antibodies in children with type 1...

Pendrins Function in the Thyroid

The exact mechanism by which pendrin functions in the thyroid is still debated. Based on homology with sulfate transporters, it was initially hypothesized that 29 reported that pendrin is responsible for iodide efflux from the follicular cells into the colloid. They also report that in the thyroid, iodine is transported in exchange for chloride, whereas in other tissues, it is hypothesized that pen-drin's main function is to transport chloride through exchange with other anions In normal thyroid, pendrin is expressed at low levels on the apical membrane of follicular cells. Thyroids from patients with Graves' disease display a similar, albeit more extensive, expression of pendrin when compared to normal thyroid tissue, especially in areas with increased proliferation of the follicular cells. In contrast, immunohistochemical staining was absent and mRNA levels were significantly lower in papillary carcinoma when compared to normal and other neoplastic diseases of the thyroid. These...

Diagnostic WorkUp of Congenital Hypothyroidism

A positive newborn screening result calls for immediate diagnostic work-up. Information on maternal medication or morbidity should be obtained to assess the infant's prenatal thyroid status. Clinical examination should be performed to document signs and symptoms of CH and possible associated malformations. There is an increased risk for other congenital anomalies (8.4 ), including cardiovascular, musculoskeletal and CNS malformations 3 . Confirmatory serum measurements of TSH and T4 are required, along with thyroid hormone binding proteins and serum free T4. In cases of maternal autoimmune thyroid disorder, assessment of TSHR blocking antibodies may indicate a transient form of CH. Thyroglobulin levels tend to be high in dyshormonogenesis and low in thyroid agenesis. Thyroid ultrasono-graphy and or thyroid scan are considered optional for management of CH 1 but are necessary to clarify the underlying source of CH, to distinguish between thyroid aplasia, ectopy or inborn errors of T4...

Metabolism Of Thyroid Hormones

Because T4 is bound much more tightly by plasma proteins then T3, a greater fraction of T3 is free to diffuse out of the vascular compartment and into cells where it can produce its biological effects or be degraded. Consequently, it is not surprising that the half-time for disappearance of an administered dose of 125I-labeled T3 is only one-sixth of that for T4, or that the lag time needed to observe effects of T3 is considerably shorter than that needed for T4. However, because of the binding proteins, both T4 and T3 have unusually long half-lives in plasma, measured in days rather than seconds or minutes (Fig. 7). It is noteworthy that the half-lives of T3 and T4 are increased with thyroid deficiency and shortened with hyperthyroidism. Although the main secretory product of the thyroid gland and the major form of thyroid hormone present in the circulating plasma reservoir is T4, abundant evidence indicates that it is T3 and not T4 that binds to the thyroid hormone receptor (see...

Thyroid Hormone Transport

More than 99 of the circulating thyroid hormone is bound to plasma proteins but can be liberated with great rapidity for entry into cells. The thyroid hormone-binding proteins are comprised of thyroxine-binding globulin (TBG), transthyretin (TTR or thyroxine-binding prealbumin), human serum albumin (HSA) and lipoproteins. Their functions are most probably to ensure a constant supply of TH to the cells and tissues by preventing urinary loss 3 , protect the organism against abrupt changes in thyroid hormone production and degradation, protect against iodine deficiency 2 and target the amount of TH delivery by ensuring a site-specific, enzymatic alteration of TBG 4 . TBG has by far the highest affinity for T4, the result of which being that TBG binds 75 of serum T4, whereas TTR binds 20 and HSA 5 2 . Some of the properties of the binding proteins are displayed in table 1. Table 1. Some properties and metabolic parameters of the prinicpal thyroid hormone-binding proteins in serum...

Hypothyroidism in Infancy Childhood and Adolescence

The child with severe primary hypothyroidism may develop enlargement of the cella tursica. After radiologic examination, the detected mass represents hypertrophy and hyperplasia of thyrotrophs in response to lack of negative feedback by thyroid hormones 43 . In laboratory evaluation they have high levels of TSH with low levels of T4. Measurement of TSH and thyroid hormones, antithyroid antibodies namely thyroperoxidase (TPOAb) and thyroglobulin (TGAb) should be obtained. The presence of the antibodies permits the diagnosis of autoimmune thyroiditis. A hypothalamic cause vs. pituitary origin of the hypothyroidism with low serum free T4 and TSH levels can be distinguished by TRH testing. In children with hypothalamic hypothyroidism the peak serum TSH response to TRH is often delayed beyond 30 min, and the TSH response may be prolonged with serum TSH values that remain elevated for 2-3 h. In hypopituitarism, there is little or no TSH response to TRH. Thyroid hormone resistance is...

Primary prevention of hypothyroidism

Primary prevention of disease focuses on risk factor identification and modification. Risk factors may stem from genetic predispositions and environmental exposures. There is a genetic predisposition to the most common cause of hypothyroidism, autoimmune thyroiditis, which occurs approximately tenfold more frequently in women than men and affects approximately one in seven female children of affected women. However, autoimmune thyroiditis appears to be a polygenic disorder (8) for which there can currently be only general predictions of disease risk. A number of other rare monogenic disorders causing hypothyroidism have been described. Familial combined pituitary hormone deficiencies (9) and isolated thyrotropin (TSH) deficiency (10) cause central hypothyroidism. The thyroid gland may be congenitally resistant to TSH action as the result of a mutation in the TSH receptor (11), its related Gsa subunit (12), or the TSH p-subunit (13). Inherited defects in thyroid hormone biosynthesis...

Tertiary prevention of hypothyroidism Avoiding Complications

Potential complications of recognized hypothyroidism and its treatment are preventable with sustained thyroxine therapy and appropriate clinical and laboratory monitoring. Myxedema coma is a life-threatening syndrome of multisystem organ failure resulting from prolonged profound thyroid hormone deficiency, usually with superimposed sepsis, drug intoxication, or an ischemic vascular event (52). Anecdotally, the hypothyroid patient who is elderly or has a history of previous noncompliance, other systemic illness, alcohol abuse, social isolation, and economic deprivation is at greatest risk. A second potential complication in hypothyroid patients who are suboptimally treated is persistence of risk factors for atherosclerosis. In this setting, the serum low-density lipoprotien cholesterol (53) concentration may remain elevated. In one small trial of patients with treated hypothyroidism and ischemic heart disease undergoing follow-up coronary catheterization after angioplasty, the patients...

Mechanism Of Thyroid Hormone Action

As must already be obvious, virtually all cells appear to require optimal amounts of thyroid hormone for normal operation, even though different aspects of cellular function may be affected in different cells. Thyroid hormones are quite hydrophobic and may either diffuse across the cell membrane or enter target cells by a carrier-mediated transport process. T3 formed within the target cell by deiodination of T4 appears to mix freely with T3 taken up from the plasma and to enter the nucleus, where it binds to specific receptors (see Chapter 2). Thyroid hormone receptors are members of the large family of nuclear hormone receptors and bind to specific nucleotide sequences (thyroid response elements or TREs) in the genes they regulate. Unlike most other nuclear receptors, thyroid hormone receptors bind to their response elements in the absence of hormone. They bind as monomers or as homodimers composed either of two thyroid hormone receptors, or they may form heterodimers with other...

The thyroid gland

HCG may suppress thyroid-stimulating hormone (TSH) in early pregnancy because they share a common a-subunit. The thyroid remains normally responsive to stimulation by TSH and suppression by tri-iodothyronine (T3). There is a threefold rise in the thyroid's clearance of iodine, allowing the absolute iodine uptake to remain within the non-pregnant range. Thyroid-binding globulin concentrations double during pregnancy, but other thyroid-binding proteins do not increase. Overall, free plasma T3 and thy-roxine (T4) concentrations remain at the same levels as outside pregnancy (although total levels are raised) and most pregnant women are euthyroid. Free T4 may fall in late gestation 17 . Calcitonin, another thyroid hormone, rises during the first trimester, peaks in the second and falls thereafter, although the changes are not large. It may contribute to the regulation of 1,25 dihydroxyvitamin D.

Thyroid lymphoma

Primary thyroid lymphoma is an uncommon but life-threatening disorder that often poses a major diagnostic dilemma because it is encountered so infrequently. Typically it arises in the setting of Hashimoto's thyroiditis, sometimes in patients with long-standing hypothyroidism. The neoplasm may go unrecognized for several months until the patient develops airway obstruction symptoms, and when it does become apparent that it is a malignancy, an erroneous diagnosis of ATC is sometimes made. It is important to identify the tumor as a thyroid lymphoma since its prognosis is much better than that of ATC. Nevertheless, many patients continue to die from this tumor because the diagnosis is often delayed, which is challenging because when it is diagnosed at an early stage it has an excellent prognosis.

Hypothyroidism

Early diagnosis and treatment of hypothyroidism is the exception rather than the rule. Despite its high prevalence (1-3) and potential consequences, hypothyroidism is typically diagnosed in clinical settings at an advanced and often longstanding stage or is incidentally detected during a wide-ranging evaluation for nonspecific complaints. Even when hypothyroidism should be anticipated, such as in patients who have received neck irradiation (4) or amiodarone therapy (5), its recognition is often delayed. Only in neonates, for whom universal thyroid function testing is mandated in most industrialized societies, is hypothyroidism identified early and treated promptly. Application of the principles of preventive medicine to hypothyroidism has occurred slowly, except in the worldwide efforts to prevent dietary iodine deficiency disorders, including endemic goiter, hypo-thyroidism, and cretinism (6).

Thyroid Hormones

The thyroid hormones are a-amino acid derivatives of tyrosine (Fig. 3). The thyronine nucleus consists of two benzene rings in ether linkage, with an alanine side chain FIGURE 2 Histology of the human thyroid. Simple cuboidal cells (arrows) make up the follicles. C, thyroid colloid (thyroglobulin), which fills the follicles. (From Borysenko M, Beringer T. Functional histology, Boston Little, Brown, 1979, p. 312.) FIGURE 2 Histology of the human thyroid. Simple cuboidal cells (arrows) make up the follicles. C, thyroid colloid (thyroglobulin), which fills the follicles. (From Borysenko M, Beringer T. Functional histology, Boston Little, Brown, 1979, p. 312.)

Thyroidectomy

Surgery is the oldest form of definitive therapy of Graves' disease with the Nobel Prize in Physiology and Medicine awarded to Koker in 1909 for developments in this field 90 . Whether total or subtotal thyroidectomy should be performed has been the focus of past and recent debate. The higher relapse rates seen with subtotal thyroidectomy have resulted in the recommendation that total thyroidectomy is the procedure of choice for Graves' disease 68, 91, 92 . New surgical techniques, such as minimally invasive thyroidectomy and minimally invasive video-assisted thyroidectomy have recently been described 93 . Whereas it can take several months for the hyperthyroid state to remit after 131I treatment, the hypothyroid state occurs much sooner after surgery, being dependent on the clearance of circulating thyroid hormone. Following subtotal thyroidectomy, relief of hyperthyroidism is achieved in about 80 of children and adults, and hypothyroidism develops in about 60 of individuals 94, 95 ....

TSHthyroid axis

Acute illness or trauma induces alterations in thyroid hormone equilibrium within hours. Although serum TSH usually remains normal, circulating T3 rapidly drops, partly due to reduced conversion of T4 to T3 and or increased turnover of thyroid hormones. The extent of the T3 drop within 24 hours reflects the severity of illness (Schlienger et al 1991, Rothwell & Lawler 1995). Serum reverse T3 (rT3) levels increase partly due to reduced rT3 degradation. In animal models hepatic nuclear T3 receptors appear to decrease in number and occupancy. The absence of a TSH elevation in the presence of low circulating T3 levels suggests that there is also an altered feedback setting at the hypothalamic pituitary level. Experimental data indicate that reduced TRH gene expression as well as enhanced nuclear T3 receptor occupancy within the thyrotrophs may be involved (Kakucska et al 1994, St Germain & Galton 1985). The mechanism responsible for the low T3 syndrome remains speculative. Increased...

The hypothalamus and pituitary gland

And the rapidly rising hCG suppresses secretion of both follicle-stimulating hormone and luteinizing hormone, thus inhibiting ovarian follicle development by a blunting of response to gonadotrophin-releasing hormone (GnRH). Thyroid-stimulating hormone (TSH) secretion responds normally to hypothalamic thyrotropin-releasing hormone (TRH also synthesized in the placenta). Adrenocorti-cotropic hormone (ACTH) concentrations rise during pregnancy, partly because of placental synthesis of ACTH and of a corticotrophin-releasing hormone (CRH) and do not respond to normal control mechanisms.

Intracellular Receptors

To reach intracellular receptors, agonists must get across the plasma membrane. The steroid hormones and vitamin D (see Chapters 40, 43, and 45-47) are derivatives of cholesterol and readily diffuse through the lipid bilayer of the plasma membrane because they are highly lipid soluble. Similarly, the thyroid hormones (see Chapter 39), which are a-amino acids, have large nonpolar constituents and penetrate cell membranes both by diffusion and to some extent by carrier-mediated transport. Retinoic acid (vitamin A) is also quite lipid soluble, as is the gas nitrous oxide (NO). With the exception of the soluble form of guanylyl cyclase, which is an intracellular receptor for NO (see Chapter 17), all of the known intracellular receptors belong to the nuclear receptor superfamily of transcription factors that includes receptors for the steroid hormones, thyroid hormone, vitamins D and A, and derivatives of Nuclear receptors enhance or repress expression of some genes in a manner that is...

Estrogen Is Required For Breast Development And Tumorigenesis

Like the other steroids, E2 is lipophilic and enters cells and their nuclei primarily by diffusing through plasma and nuclear membranes. Once in the nucleus, E2 encounters proteins known as ERs, because they bind E2 with high affinity and specificity. Until relatively recently, only one ER gene (now called the ERa) was thought to be present in either humans or rodents. However, in 1996, a second species, or ERp, was isolated and cloned from rat prostate and ovary, closely followed by the human homolog in the same year (10,11). Both ERa and ERp are members of the steroid thyroid hormone nuclear receptor superfamily, and may be described as ligand-dependent nuclear transcription factors. Both proteins have the modular structure that typifies the nuclear receptor superfamily comprising six functional domains designated A-F, which include regions involved in steroid binding and interaction with DNA. The ERp gene shows a high degree of sequence homology with the ERa in its hormone-binding...

Age of Cancer Incidence

The sixth section examines the different patterns of incidence between the two sexes. Males have slightly more cancers early in life. From approximately age 20 to 60, females have more cancers, mainly because breast cancer rises in incidence earlier than the other major adulthood cancers. After age 60, during the period of greatest cancer incidence, males have more cancers than females, male incidence rising to about twice female incidence. The excess of male cancers late in life occurs mainly because of sharp rises in male incidence for prostate, lung, and colon cancers. Male cancers accelerate more rapidly with age than do female cancers for lung, colon, bladder, melanoma, leukemia, and thyroid. Female cancers accelerate more rapidly for the pancreas, esophagus, and liver, but the results for those tissues are mixed among samples taken from different countries.

Clinical manifestation

Multiple, protuberant, dark blue, compressible nodules large, cavernous lesions that may compress vital structures irregular blue macules or patches multiple gastrointestinal hemangiomas which may bleed, cause intussusception, volvulus, or bowel infarction other extra-cutaneous sites, including skull, central nervous system, thyroid, parotid gland, eyes, oral cavity, lungs, pleura, pericardium, musculoskele-tal system, peritoneal cavity, mesentery, kidney, liver, spleen, penis, vulva, and bladder

Mortality and Recurrence Rates

Mortality rates of differentiated thyroid cancer are low, less than 10 over three decades in our study (9) however, recurrence rates were 30 , and distant metastases or serious local recurrences often occurred years after initial therapy (Fig. 8) (9,20). Prognosis varies greatly, however, among subsets of patients. Age over 40 yr at the time of diagnosis is among the most important adverse prognostic factors that predict death from thyroid cancer. Mortality rates become progressively worse with advancing age, increasing at a particularly steep rate after age 60 yr (Fig. 1) (9,20). The best outcomes are in younger patients whose tumors concentrate 131I (53-55). Fig. 8. Recurrence of differentiated thyroid cancer according to time after initial therapy. (Data from ref. 9.) Fig. 8. Recurrence of differentiated thyroid cancer according to time after initial therapy. (Data from ref. 9.) are about 40 in children, compared with 20 in adults (9,55) the rate of pulmonary metastases in children...

Fetal Maternal Relationships

Thyroid Function during Pregnancy Pregnancy affects thyroid homeostasis. An increased excretion of iodine in the urine accounts for the increase in thyroid volume even in areas of moderate dietary iodine intake 4 . Some studies, however, do not show an increase in urinary iodine during pregnancy. In either case the increase in thyroid volume is the result of imbalance between the intake and increased requirements of iodine during pregnancy 5 . Iodine deficiency during pregnancy is associated with maternal goitre and reduced maternal thyroxine (T4) level. While thyroid size increases in areas of iodine deficiency it does not do so in those regions that are iodine sufficient even in moderate iodine-deficient regions urinary iodine excretion is higher in all trimesters than in non-pregnant women and may be causative in maternal goitre formation as assessed by ultrasound. The increase in thyroid volume already referred to is substantially greater in iodine-deficient areas. This...

Anorexia Nervosa DRG Categr 428

Weight is lost three ways in this condition by restricting food intake, by excessive exercise, or by purging either with laxatives or by vomiting. Initially, patients receive attention and praise for their extreme self-control over food intake, but as the illness progresses, this attention is replaced by worry and efforts to monitor the patient's food intake. The increased negative attention and attempts at control of the patient serve to reinforce the patient's need for control and contribute to the progression of the illness. Adverse consequences of anorexia nervosa include possible atrophy of the cardiac muscle and cardiac dysrhythmias, alteration in thyroid metabolism, and estrogen deficiencies (those with long-standing estrogen deficiencies may develop osteoporosis). Refeeding may lead to slowed peristalsis, constipation, bloating, and fluid retention. Mortality rates are as high as 10 to 20 , and only half of people with anorexia nervosa recover completely.

The Future Is Here Functional Foods

If your breakfast this morning included calcium-fortified orange juice and toast made with folate-enriched flour, you are a consumer of functional foods. Just what is a functional food As the fastest growing category of new food products, these are foods or food components to which manufacturers have added ingredients that are known or believed to promote health and prevent disease (see Chapter 4, What Do the Terms Fortified and Enriched Mean page 92). Although the name functional foods is new, the concept is not when it was discovered in the early part of the 20th century that some thyroid disease was caused by a deficiency of the mineral iodine, manufacturers began enriching table salt with iodine. Since that time, we have also seen vitamin D-for-tified milk, breakfast cereals fortified with a variety of vitamins and minerals, and the addition of preservatives that are themselves antioxidants to almost all processed foods (see Chapter 3, Cholesterol-Lowering Margarine, page 66). The...

Factors Affecting Prognosis

Prognosis is best with FMTC and MEN-2A. Early detection and treatment has a profound impact on the clinical course of MTC. When nodal metastases are not present, for example, the 10-yr survival rates are nearly similar to those in unaffected subjects, but they fall to about 45 when nodal metastases are present (89). Before 1970, MTC was usually diagnosed in the fifth or sixth decade. For the next 20 yr biologic markers assumed a preeminent role in diagnosis. With periodic calcitonin screening, affected members of MEN kindreds were usually identified in the second decade of life or earlier, when they usually had CCH or microscopic MTC confined to the thyroid (98). Nonetheless, the results of long-term studies using this approach are somewhat disappointing. One study comparing calcitonin measurement with genetic testing found 14 young gene carriers (18 of the 80 known gene carriers in the study) who had normal plasma calci-tonin levels, 8 of whom had undergone thyroidectomy at the time...

Gender Ethnicracial And Life Span Considerations

Primary cancers of the bone are more common in males and tend to occur in the late teen years or after age 60. Osteogenic sarcoma, or osteosarcoma, the most common kind of bone cancer, occurs mainly in teenagers. Metastatic bone cancer usually appears later in life since it accompanies other cancers, especially lung, breast, prostate, and thyroid cancer. Incidence of osteosarcoma is slightly higher in African Americans than in whites. Data from the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Pediatric Monograph 1975-1995 are as follows African Americans 5.2 cases per million per year (persons < 20 yr) and Whites 4.6 cases per million per year.

Clinical cancer genetic management

The two most serious, and established, component tumours in CS are breast cancer and non-medullary thyroid cancer for affected females and males. Endometrial cancer is now believed to be a component of CS as well. Patients with CS or those who are at risk of CS should undergo surveillance for these three cancers. Beginning in their teens, these individuals should undergo annual physical examinations, paying particular attention to the thyroid examination. Beginning in their mid-twenties, women with CS or those at risk of it should be encouraged to perform monthly breast self-examinations and to have careful breast examinations during their annual check-ups. The value of annual imaging studies is unclear as no objective data are available. Nonetheless, we usually recommend annual mammography and or breast ultrasounds performed by skilled individuals in at-risk women, beginning at age 30 years or 5 years younger than the earliest breast cancer case in the family, whichever is earlier....

Somatic PTEN alterations in sporadic tumours

It is not uncommon to find a high frequency of somatic mutations in a gene, X, in sporadic counterpart tumours that are components of an inherited cancer syndrome whose susceptibility gene is X. For example, germline mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2, which is characterized by medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (reviewed by Eng, 2000a). Somatic RET mutations have been found in 20-80 of sporadic medullary thyroid carcinoma (reviewed in Eng, 1999). The three sporadic counterpart tumours of CS are breast, thyroid and endometrial carcinomas. While a broad range of cancer cell lines harbour a high frequency of intragenic PTENmutations and homozygous PTENdeletions (Li et al., 1997 Teng et al., 1997), this does not hold for non-cultured neoplasias. While breast cancer can occur in up to 50 of females affected by CS, somatic intragenic PTEN mutations in non-cultured primary adenocarcinomas of the breast are very...

Sensorimotor Examination

Parkinson's disease, and normal pressure hydrocephalus. Dysarthria would alert the clinician to possible extrapyramidal disorders, bilateral strokes, de-myelinating disease, and motor neuron disease. Sensory abnormalities (e.g., peripheral neuropathy) may be associated with B12, other vitamin deficiency states, thyroid disease, or a paraneoplastic syndrome. Cerebellar signs might raise concerns about cerebrovascular disease, spinocerebellar degeneration, a paraneoplastic syndrome, and Creutzfeldt-Jakob disease. In Alzheimer's disease, especially early in its course, the sensorimotor examination tends to be relatively benign. Some researches have pointed out that the presence of extrapyramidal signs in patients with a profile otherwise consistent with Alzheimer's disease suggests a worse prognosis (33). Extrapyramidal signs may indicate the presence of Lewy body variant of AD (34). In general, if a patient with dementia presents with focal or multifocal neurological signs, the...

Differential diagnosis

A Low Thyroid RAIU Silent lymphocytic thyroiditis Subacute painful thyroiditis Drug-induced (amiodarone, lithium, interferon-a, interleukin-2 High-dose x-ray therapy Surgical manipulation Infarction of thyroid adenoma Thyrotoxicosis factitia Silent lymphocytic thyroiditis Subacute painful thyroiditis Drug-induced (amiodarone, lithium, interferon-a, interleukin-2 High-dose x-ray therapy Surgical manipulation Infarction of thyroid adenoma Thyrotoxicosis factitia Metastatic thyroid cancer Iodine-induced (hyperthyroidism) Struma ovarii (hyperthyroidism) uninodular toxic goiter is another major cause of hyperthyroidism, especially in areas of marginal iodine intake. The natural history of multinodular goiter (Plummer's disease) appears to be the gradual development of autonomy, leading first to subclinical and then to overt hyperthyroidism (19). The prevalence of thyroid nodularity generally increases with age, especially in women in one English postmortem study, 23 of women over age 60...

Early signs and symptoms

Physical findings in thyrotoxicosis may include hyperactivity, tachycardia or atrial fibrillation, systolic hypertension, warm, moist, smooth skin, stare and eyelid retraction, tremor, hyperreflexia, and muscle weakness (28). Goiter is not invariably present one study found that 37 of thyrotoxic patients over age 60 did not have thyroid enlargement (29). In Graves' disease, ophthalmologic findings may include exopthalmos, extraocular muscle dysfunction, periorbital edema, conjunctival chemosis and injection, and exposure keratitis (30). Pretibial myxedema is rarely seen in patients with Graves' disease and only when eye disease is also present.

Trials to determine best chemotherapy regimen

Chemotherapy to reduce the dose of cranial-spinal radiation. This effort is due to the very real risk of long-term deficits produced by the radiation to the cranial-spinal axis. There have been a number of studies that indicate that 30-35 Gy to the whole brain can produce deficiencies, including growth hormone, thyroid deficiencies and, more significantly, intellectual deficit, especially in children less than 7 years old.

Optimal Iodine Intake

These recommendations derive from consensus statements by several groups, including the International Council for Control of Iodine Deficiency Disorders, the World Health Organization, UNICEF, and the Food and Nutrition Board of the US National Academy of Sciences. The amounts are based on the following the calculated daily thyroid hormone turnover in euthyroidism, the iodine intake producing the lowest values for serum thyrotropin (TSH) and for serum thyroglobulin (TG), the amount of thyroid hormone replacement necessary to restore euthyroidism to athyreotic subjects, the iodine intake associated with the smallest thyroid volumes in populations, and the lowest incidence of transient hypothyroidism in neonatal screening with blood spot TSH. About 90 of iodine is eventually excreted in the urine. The median urinary iodine concentration in casual ('spot') samples, expressed as micrograms per liter ( g l), is currently the most practical biochemical laboratory marker of community iodine...

Treatment of subclinical thyrotoxicosis

Be treated with estrogen replacement and bisphosphonates and tachycardia with P-blockers. However, once a persistently suppressed TSH level has been documented, the goal of specific therapy is to normalize the serum TSH using small doses of MMI or PTU. Definitive therapy with 131I may be carried out, especially in patients with goiter, although large doses may be required in the setting of a normal 24-h RAIU. The thyroid 131I uptake may be enhanced by the prior administration of recombinant human TSH (78,79). Early therapy may be especially beneficial for patients with multinodular goiter, given an expected progression to overt hyperthyroidism (80). Treatment with antithyroid drugs has been shown to have a beneficial effect on osteoporosis in two small studies (81,82). Additionally, treatment of subclinical hyperthyroidism does seem to decrease the risk for atrial fibrillation (77). Some authors (16,35) advocate aggressive treatment for subclinical hyperthyroidism, whereas others...

Breast and ovarian cancer in other hereditary colorectal cancer syndromes

Cowden syndrome is a rare autosomal predisposition characterized by multiple hamartomas and a high risk of breast, thyroid and, perhaps, other cancers (Eng, 2000). These hamartomas can arise in tissues derived from all three embryogenic germ-cell layers. The cardinal features of this syndrome include trichilemmomas, which are hamartomas of the infundibulum of the hair follicle, and mu-cocutaneous papillomatous papules. Breast cancer develops in 20-30 of female carriers. Other tumours seen among patients with Cowden syndrome include adenomas and follicular cell carcinomas of the thyroid polyps and adenocar-cinomas of the gastrointestinal tract and ovarian cysts and carcinoma. Cowden syndrome is caused by germline mutations in the PTEN gene.

Second Major Decision Point Differential Diagnosis

Once the diagnosis of dementia has been made, the clinician needs to establish the most likely underlying etiology of the condition. Traditionally, this involves trying to rule out potentially treatable or reversible etiologies of dementia that may be identified by the workup discussed earlier. Specifically, one aims to exclude encephalopathies due to metabolic problems (e.g., thyroid deficiency) or side effects from medications, CNS infections, vitamin deficiencies, or structural lesions (e.g., hydrocephalus, tumor, subdural hematoma). These conditions tend to account for small percentage of patients presenting with dementia (36-38). When these conditions have been excluded, the two largest remaining disease categories are the degenerative dementias (of which Alzheimer's disease is by far the most common) and vascular dementia.

Clinical Description Presentation

Cowden syndrome displays a high level of variability in expression, both between and within families however, it usually presents in the third decade. Hamartomas are derived from all three germ cell layers. Those of the inner organs most commonly involve the breast (70 ) thyroid adenomas and multinodular goitres (40-60 ) gastrointestinal polyps (35-40 ) and can also be seen in the central nervous system and reproductive tract. The gastrointestinal polyps seen in CS are distinct from those seen in other hamartomatous syndromes, as they are more likely to be of ectodermal and or endodermal origin. 5 Dermatological manifestations are the most prevalent findings, with palmoplantar hyperkeratosis in 54 , trichilemmonmas (benign tumors of the hair follicle In addition to these benign findings, patients have an elevated risk for malignant tumors, most commonly in the breast (25-50 in females, and a small percentage of males) and thyroid, especially follicular thyroid carcinoma (3-10 )....

Altered Balance Between Natural Treg and Self Reactive T Cells as a Possible Cause of Autoimmune Disease

As environmental causes of autoimmune disease, a physical, chemical, or biological agent can cause autoimmune disease when it reduces natural CD25+CD4+ Treg in the periphery or affects their thymic production or function 7 for example, administration of cyclosporin A (CsA), infection with mouse T lymphotropic virus (MTLV), or low-dose fractionated X irradiations 46-49 . These autoimmune inductions can be attributed to specific immunological properties of natural CD25+CD4+ Treg. For example, natural CD25+CD4+ Treg recognizing self-antigens are continuously proliferating in the periphery and hence are more radiosensitive than other T cells 25, 50 . Inhibition of IL-2 production, for example by CsA, may reduce natural Treg in the periphery by affecting their thymic production or peripheral survival. In addition, the early period in life seems to be more susceptible to such environmental insults because it is relatively easy to deplete a small number of natural Treg in the periphery or...

Pathology and Histopathology

The intestinal phase of porcine enterovirus infections is generally not accompanied by histological changes, although atrophy of villi has been reported for recently weaned scouring pigs. Changes have been reported in the lung, liver, kidney, spleen, heart and in adrenal and thyroid glands. Teschen Talfan viruses have the ability to invade the central nervous system. The histological changes in Teschen disease are more severe than those of Talfan disease. These include varying degrees of neuronal degradation, neurono-phagia, lymphocytic perivascular cuffing and the development of focal areas of gliosis. The endoplasmic reticulum appears to be the target organelle in the infected degenerating neuron. Central nervous system changes are most prevalent in the gray matter of the spinal cord, with the cerebellum being the next most affected region. At the height of the disease the meninges above the cerebellum are severely infiltrated with lymphocytes. The pons and medulla oblongata are...

More Than Adequate Iodine Intake

Although not excessive, studies in more than adequate iodine intake (see table 4) following iodine prophylaxis, also pointed out the possible development of thyroid autoantibodies. Zois et al. 85 investigated the iodine status and the impact of iodine prophylaxis on the prevalence of autoimmune thyroiditis among schoolchildren in a formerly iodine-deficient community in northwestern Greece. The findings were compared to those obtained from a similar survey carried out 7 years previously in the same area. A total of 302 schoolchildren (12-18 years of age) from a mountainous area of northwestern Greece were examined for the presence of goiter, and blood and urine samples were collected for assessment of thyroid function, antithyroid antibodies and urinary iodine excretion. Median urinary iodine concentration in the children was 200 xg l. Thyroid function was normal in all but 7 children, who had subclinical hypothyroidism (2.5 ). Antithyroid antibodies (antithyroid peroxidase and or...

Primary Nursing Diagnosis

For secondary Cushing's syndrome from a pituitary tumor, the preferred option is a transsphenoidal adenectomy, a procedure that explores the pituitary gland to find microadenomas. It is successful in 20 to 70 of patients. A second option is the transsphenoidal hypophy-sectomy, a procedure that removes the entire pituitary gland and leads to a cure in 100 of the patients. It is usually used for more invasive tumors and requires lifelong hormone replacement (glucocorticoids, thyroid hormone, gonadal steroids, and antidiuretic hormone ADH ). A third alternative is bilateral total adrenalectomy, which cures the signs and symptoms of excess cortisol but does not decrease ACTH secretion. The patient requires lifelong replacement therapy with glucocorticoids and mineralocorticoids. If the patient has secondary Cushing's syndrome because of ectopic production of ACTH from a nonendocrine tumor, the first concern is to remove the source of the ectopic secretion of ACTH. If this is not possible,...

Hamartomatous Polyposis Syndromes

Cowden's disease and Bannayan-Ruvalcaba-Riley syndrome are related syndromes with autosomal-dominant inheritance and juvenile polyposis but with a much lower risk of gastrointestinal cancer. Cowden's disease consists of multiple hamar-tomatous polyps of the stomach, small and large bowel, and is related to a mutation of the PTEN tumor suppressor gene. The extraintestinal manifestations include multiple facial trichilem-momas, breast, and thyroid cancer. There does not appear to be an increased risk of gastrointestinal cancer in these patients (96-99). Bannayan-Ruvalcaba-Riley syndrome consists of hamartomatous gastrointestinal polyposis with macrocephaly, developmental delay and pigmented spots on the penis (91).

Transport Across the Cell Membrane

The deiodinases involved in T4 to T3 conversion and T4 and T3 degradation as well as the T3 receptors are located intracellularly. Therefore, both action and metabolism of thyroid hormones are intracellular events requiring transport of iodothyronines across the cell membrane. For a long time it was believed that TH diffused passively over the cell membrane, but recent years of research has made it increasingly clear that cellular transmembrane transport of TH is mediated by transporters, that these transporters determine the availability of iodothyronines to the intracellular sites for metabolism and action 19 , and that the TH transport is energy dependent 20 (fig. 1). Recently, specific transporters (organic anion transporters and amino acid transporters) known to facilitate cellular thyroid hormone uptake have been identified 20-22 . Hennemann and Visser 22 have defined requirements for (patho)physiological significance of thyroid These mediate uptake of iodothyronines and their...

Deiodination of Iodothyronines

Deiodination is the foremost pathway of thyroid hormone metabolism both in quantitative terms but also through activation of T4 by outer ring deiodination to T3, as well as inactivation of both T4 and T3 by inner ring deiodination reviewed in 50 . Three iodothyronine deiodinases (D1-D3) are identified as seleno cysteino-containing membrane proteins with their active enzymatic sites located in the cytoplasma. D1 and D2 convert T4 to T3, while D3 has only inner ring deiodination activity and inactivates T4 and T3 to rT3 and T2, respectively (fig. 1). D1 is expressed in liver, kidney and the thyroid, while D2 is expressed in the brain, pituitary, thyroid gland and skeletal muscle. In contrast to the rat, humans do not express D1 in the central nervous system. D3 is expressed in brain and fetal tissues, placenta and pregnant uterus. Other characteristics of the deiodinases are presented in table 3. D1 has both outer and inner ring deiodination activities, but appears particularly...

Receptor Specific Nuclear Actions Genomic Actions

Thyroid hormone receptors belong to a large superfamily of nuclear hormone receptors that include the steroid hormone, retinoic acid, vitamin D and peroxysomal proliferator receptors (PPARs). The receptors have a central DNA-binding domain and a carboxy-terminal ligand-binding domain (fig. 4). The two major isoforms, the thyroid hormone receptor a-1, a-2 (TRa) and (-1, (3-2, (3-3 (TR() have a high homology in these two domains, while the amino-terminal regions are more variable. Two thyroid hormone receptor genes located on chromosomes 17 and 3, respectively 89, 93-94 encoding for TRa and TR(, respectively. TRa-1, TRa-2, TR(-1 and TR(-3 are expressed widely, whereas TR( -2 is predominantly restricted to the hypothalamic pituitary axis in the negative feedback regulation of TSH. T3 binds to TR-a and TR-( resulting in nuclear gene expression. The receptors are ligand-regulatable transcription factors that recognize and interact with specific DNA sequences (thyroid hormone response...

Nongenomic Actions Extranuclear Actions

A number of T3 effects occur rapidly and are unaffected by inhibitors of transcription and protein synthesis. The site of these actions has been localized to the plasma membrane, cytoplasm and cellular organelles. The nongenomic actions often have a short latency. Cell culture studies suggest that thyroid hormones rapidly, and nongenomically regulate the Ca2+ ATPase enzyme, the Na+ channel via protein kinase C (PKC), the K+ channel via phosphatidyl-inositol 3 (PI3)-kinase, the Na+ H+ antiporter via PKC and mitogen-activated protein kinase (MAPK) 98 . The nongenomic actions thus presumably include the regulation of ion channels, oxidative phosphorylation and mitochondrial gene transcription and involve the generation of intracellular secondary messengers signaling pathways including induction of calcium, cyclic AMP or protein kinase signaling cascades 91, 98-100 . Recently, integrin aV 3, has been identified as a plasma membrane TH-binding site 101 . Furthermore, it has been shown that...

Summary and Conclusions

Deficient supply of e.g. iodine, and possibly also a protection of urinary loss of the smaller molecules of unbound TH compared to the bound forms 2 . The normal human organism has a high capacity for compensating to a maintained normal thyroid function by almost any reduction in the plasma binding proteins. Several transporters that mediate the cellular entry of TH have been identified, but most of them are not specific for thyroid hormones. Up to now only two truly TH-specific transporters have been found OATP1C1 with high preference for T4 and MCT8 with preference for T3 as the ligand 21 . Since delivery of TH to the cells is a crucial mechanism for subsequent TH action, abnormalities in these transporters probably result in disease, e.g. a described mutation in the MCT8 caused tissue-specific hypothyroidism in the brain with milder affection of other organs 39 . In both qualitative and quantitative terms, deiodination is by far the most important pathway of thyroid hormone...

Discharge And Home Healthcare Guidelines

GGoiter is the enlargement of the thyroid gland. It is usually a response to a thyroid hormone deficiency (primary hypothyroidism) that results in the hypersecretion of thyroid-stimulating hormone (TSH) from the anterior pituitary gland. Oversecretion leads to subsequent thyroid hypertrophy and hypervascularity. The body's response may compensate for thyroid hormone deficiency, leaving the patient asymptomatic. Goiter may also occur in conjunction with hyperthyroidism, known as Graves' disease. Finally, goiter may occur with the growth of thyroid tumors. Secondary hypothy-roidism occurs with TSH deficiency in the pituitary gland and is not associated with goiter. Most goiters are classified as simple (or nontoxic). They result from any enlargement of the thyroid gland that is not caused by an inflammation or a neoplasm. Simple goiters can be classified as sporadic or endemic and are not associated initially with either hyperthyroidism or hypothyroidism. Sporadic goiters occur after a...

Current and future therapies

The limited success achieved with diet exercise coupled with the realization that obesity is a chronic disease requiring lifelong treatment has fueled the intense drive to develop an effective drug therapy. Unfortunately, this attempt has received a lot of negative press for a variety of reasons, ranging from the inappropriate use of thyroid hormone, diuretics, and addictive sympathomimetics to the withdrawal of fenfluramine dexfenfluramine owing to associated valvular heart disease and pulmonary hypertension (88,89). Although a few have questioned the wisdom of using pharmacologic agents to treat obesity (90), most health care professionals and experts in this field lament the lack of safe and effective drug(s) to complement lifestyle modifications (diet exercise). Despite the many challenges inherent in this enterprise, recent advances in the understanding of the mechanisms pathways that regulate modulate appetite and energy expenditure (albeit studied mostly in rodents) have...

Debate on Newborn Screening Programs

Although both screening strategies detect CH of thyroidal origin, they may miss patients with central CH because T4 may be only moderately decreased and TSH is not elevated. In such patients, however, early diagnosis is crucial not only for early and appropriate thyroxine replacement (fig. 3), but Preterm infants with CH may have a delayed TSH increase owing to the immaturity of the hypothalamic-pituitary-thyroid axis, and may thus be missed by laboratory screening procedures. Therefore, a routine second screening between 2 and 6 weeks of age has been suggested in preterm neonates 14 leading to a reported additional 10 of cases.

Drugs that Increase Energy Expenditure

P-Adrenergic agonism has been recognized as an appropriate target since the resultant catecholamine release would be expected to increase metabolic rate and consequently energy expenditure. However, the adverse cardiac effects seen with thyroid hormone and other sympathomimetics such as ephedrine and caffeine have highlighted the potential dangers associated with this approach (8,11). Recently, a number of major pharmaceutical companies have filed patents on selective thyroid hormone receptor modulators, indicating renewed interest in this mechanism. It may well be that the selectivity of these new compounds will lead to an acceptable safety profile to complement their presumed efficacy. It is worth mentioning that p3-adrenergic receptor agonist research has yet to bear fruit, despite years of positive results in mice, confirming the adage that mice are neither men nor women.

Treatment Recommendations

To ensure optimal dosage and compliance, frequent evaluations of thyroid hormone serum levels are necessary. These tests should be obtained 2 and 4 weeks after L-T4 start, every 1-2 months during the first year of life, every 3-4 months between 1-3 years of age and 2-4 weeks after any change in dosage 1 . During L-T4 therapy, 4 or more episodes of elevated TSH (> 5mU l) after the age of 6 months were associated with inferior school performance 27 . These episodes may be caused by poor parental empowerment or impaired T4 bioavailability. The latter may be caused by inhibited intestinal uptake of T4 through soy or fiber and medications with iron or calcium, malabsorption or increased degradation by anticonvulsants. 10 Moreno JC, Bikker H, Kempers MJ, et al Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002 347 95-102. 12 Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S A novel syndrome combining thyroid and...

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