Instant Remedies for Hypothyroidism

The Hypothyroidism Revolution

During Phase 1 of the Hypothyroidism Revolution Program, the magic begins to happen as you begin to notice many positive changes occurring. You will begin your progressive transition towards the ideal thyroid healing diet that will give your thyroid the big boost that it needs to help your cells produce more than enough energy for you. By the end of Phase 1, your energy levels will be rapidly on the rise and you will feel amazingly satisfied with zero food cravings. You will feel in control again as your mood drastically improves and any sign of depression and anxiety begin to disappear. Your family and friends are going to notice some major positive changes in you. You will also begin to experience many of the outer changes that come with improved thyroid function. Youre skin will begin to clear up and glow while your hair and nails will begin to look healthy again. As you ease into the thyroid healing diet, you will progressively remove the foods that suppress your thyroid, disrupt your hormone pathways, cause digestive upset and irritation, and cause toxic byproducts that congest your liver. At the same time, you will be progressively adding the foods that will be supplying your cells with the right balance and combination of nutrients that they need to thrive and produce endless amounts of energy. Continue reading...

The Hypothyroidism Revolution Summary

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Treatment of Hypothyroid States

As noted above, thyroid hormone extracts from sheep or cattle were the first treatments used that demonstrated efficacy in ameliorating the signs and symptoms of hypothyroidism. Several synthetic derivatives were introduced in the 1960s which quickly replaced desiccated thyroid tissue for the treatment of patients with thyroid disease. Among these are levothyr-oxine (Levoxyl, Levothroid, Synthroid), synthetic forms of thyroxine (T4) and liothyronine (Cytomel), and the synthetic levorotatory isomer of triio-dothyronine (T3). Moreover, in part due to the seminal work carried out by Prange and collaborators in the United States in the 1960s, the use of thyroid hormones in augmenting antidepressant response in depression was established.

Iodine deficiency disorders IDD

Iodine is needed to make thyroid hormones so prolonged iodine deficiency impairs thyroid function resulting in lower metabolic rate, lethargy, growth retardation and brain damage. Goitre occurs when the thyroid gland enlarges in an effort to capture more iodine from the blood. Diets in most places are low in iodine unless fortified foods or foods from the sea (which is rich in iodine) are commonly eaten. The iodine level of food is related to the level in the soil on which it is produced. So deficiency is often most severe in mountainous areas and flood plains where the soil has been leached. Where iodine deficiency exists, goitrogens (chemicals that reduce iodine uptake by the thyroid gland) make it worse. The toxin in Iodine deficiency is the single most common cause of mental retardation. It has different effects (see Table 9.6) according to the severity of deficiency and stage of the life cycle in neonates it causes stillbirth, low birth weight and, occasionally, hypothyroid...

Histology and Other Tumor Features

Classic PTC often has a large follicular component that may be mistaken for its follicular variant, a diagnosis that requires complete involvement of the tumor with malignant follicles that have cyto-logical features of PTC 22 . Diffuse sclerosing variant of PTC, which may be mistaken for Hashimoto's thyroiditis because it often presents as a diffuse goiter with fibrosis and positive antithyroid antibodies, is associated with some unfavorable features at presentation (large tumor and extensive lymph node metastasis) but also has a prognosis that is usually similar to that of classic PTC 30,31 . Oxyphilic (H rthle cell) PTC may have a more aggressive course than classic PTC 32 . Tall cell 33 and columnar cell 34 PTC variants, which typically occur in older patients, usually are large tumors that are often metastatic and fail to concentrate 131I. This tumor has a poor prognosis as does insular thyroid cancer, another subtype of thyroid cancer that may be...

Other signalling pathways

In addition to SCF and Epo, recent observations have shown that stimulation of the nuclear hormone receptors for dexa-methasone (glucocorticoid receptor) and oestrogen (oestrogen receptor) produces sustained proliferation of erythroid progenitors. Furthermore, the nuclear hormone receptors for thyroid hormone (c-ErbA thyroid hormone receptor), all-trans retinoic acid (retinoic acid receptor) and 9-a's-RA (RXR) were found to promote erythroid differentiation. Such observations are consistent with previous reports showing that patients with a wide range of endocrine disorders (hypothyroidism, hypopituitarism, Addison's disease and male hypogonadism) all have variable degrees of normochromic normocytic anaemia. It appears, therefore, that many hormones of the endocrine system can modify erythropoiesis.

Thyroid Hormone Therapy

Patients with thyroid cancer who have undergone total thyroid ablation require more T4 than those with spontaneously occurring primary hypothyroidism. In one study, for example, the average dose of T4 that resulted in an unde-tectable basal serum TSH concentration and no increase in serum TSH after thyrotropin-releasing hormone (TRH) was 2.7 0.4 (SD) mg kg day 180 .Younger patients needed larger T4 doses than older patients did and TSH suppression was more likely when the therapy had been prolonged. In a study of patients with thyroid cancer and other forms of hypothy-roidism, the dose of T4 needed to bring serum

Serum Thyroglobulin Tg

Paradigms for the follow-up of patients who appear to be free of tumor after total thyroidec-tomy and thyroid remnant ablation have shifted to performing neck ultrasonography and measuring Tg during TSH suppression and after rhTSH stimulation, or T4 withdrawal (which produces symptomatic hypothyroidism that many patients choose to avoid) 184,186 . These paradigms are used by many US physicians (Figures 1.10,1.11,and 1.12).Accurate serum Tg measurement is the cornerstone of this follow-up paradigm (Professor Spencer and Dr Fatemi

Nonparametric estimation in degradationrenewalfailure models

Some degradation processes are not non-reversible and degradation processes may be renewed. For example, the degradation of pancreas and thyroid can be defined by the quantities of secreted insulin and thyroidal hormone, respectively. By injection of insulin the degradation process of pancreas is (indirectly) renewed. By injection of thyroxine (case of hyperthyroid) or car-bimazole (case of hypothyroid) the degradation process of thyroid is (indirectly) renewed. If the value of hormone (for example, insulin) approaches a critical value, the risk of failure increases quickly.

Fine Needle Aspiration Cytology FNAC and Pathology

FNAC is an essential diagnostic procedure that is used in the planning of surgery. The cytology should be reported by a cytopathologist who has a special interest in thyroid disease and is a member of the MDT. An adequate sample is required and reports should be based on descriptive text, but should include a numerical coding as a guide towards specific further investigation or therapeutic action.

Thyroid Cancer Management Patterns of Care Studies

The author was involved with a recent study in the north of England which looked at all thyroid cancer patients diagnosed between 1998 and 1999 (234 patients) and examined responses from 48 consultants and 10 other healthcare professionals involved in treating thyroid cancer patients in 2001 and 2002. The conclusion was that prior to the publication of local and national guidelines, practice in this region was not very satisfactory. It was found that 18 of pathology results were incorrect. After review of histology, 18 of patients had a different prognosis and 8 had a different treatment plan as a result. FNA cytology was not widely used and experienced cytologists were not available 33 of patients were operated on by a surgeon who performed fewer than five surgical procedures for thyroid cancer a year. However, in 2001 half the surgeons questioned were operating on more than 20 cases of nonmalignant thyroid disease. Fewer than half the patients had satisfactory discussion that was...

Diagnosis and Management of Polycystic Ovary Syndrome

Differential diagnosis of PCOS includes nonclassic adrenal hyperplasia due to 21-hydroxylase deficiency, Cushing's syndrome, hyperprolactinemia, hypothyroidism, acromegaly or virilization due to an adrenal or ovarian neoplasm. The history alone may serve to distinguish the features of PCOS which is often perimenarchal in onset. However, a panel of endocrine tests is generally indicated to fully exclude the other causes of anovulation and or hirsutism (see Endocrine Evaluation).

Clarifying Mortality Rates

Attention to the quality of data regarding causes of death could provide insight into the mechanisms of preterm birth as well as the causes of fetal and early neonatal deaths. This approach would require clinicians to vigorously search for causes of death whenever a fetal or early neonatal death occurs. Petersson et al. (2004) found that 11.5 percent of fetal deaths that would have been characterized as unexplained were due to infections with parvovirus, cytomegalovirus, or enterovirus. Other possible causes that should be explored include thrombophilias (e.g., Factor V Leiden), fetomaternal hemorrhage, chorioamnionitis (which would include pathologic examination of the placenta and the umbilical cord), uterine anomalies, umbilical cord or placental anomalies, toxin or drug exposures, and maternal illness (e.g., diabetes, hypertension with or without preeclampsia, thyroid disease, and autoimmune diseases) (Gardosi et al., 2005). Because the most common condition associated with fetal...

Biochemistry and Immunology

Patients with a toxic adenoma, toxic multinodular goiter, Hashimoto's thyroiditis, or relapsed Graves' disease after subtotal thyroidectomy need not be investigated further with regard to the nature of the nodule, unless there are worrying features on palpation or there is a clear history of recent increase in size. Patients with abnormal thyroid function should be referred routinely to an endocrinologist. Thyroid antibodies (antithyroid peroxidase and antithyroglobulin antibodies) are useful to identify patients with autoimmune thyroid disease, but the results of these tests are not necessary in making a decision about referral.

Diagnostic Frameworks for General Practice

'The masqueraders can be grouped into primary and secondary groups. The primary (most common) masqueraders are depression, diabetes mellitus, drugs, anemia, thyroid disease, spinal dysfunction, and urinary tract infection. A secondary (less common) list includes chronic renal failure, HIV AIDS, rare bacterial infections (e.g. subacute bacterial endocarditis, tuberculosis), systemic viral infections (e.g. infectious mononucleosis, hepatitis A, B, C, D, E), neurological dilemmas (e.g. Parkinson's disease, multiple sclerosis), connective tissue disorders (e.g. systemic lupus erythe-matosus, polymyalgia rheumatica).

Where to Refer Patients with Possible Thyroid Cancer

Euthyroid patients with a thyroid nodule may have thyroid cancer and should be referred to a member of a multidisciplinary thyroid cancer team if it is available. Patients with hyper- or hypothyroidism and a nodule or nodular goiter should be referred routinely to an endocrinologist.

Endocrinological Aspects

Thyroid disorders also strongly affect mood. A study to evaluate the prevalence of mental disorders in 93 inpatients affected by different thyroid diseases during their lifetimes, by means of standardized instruments, showed higher rates of panic disorder, simple phobia, obsessive-compulsive disorder, MDD, bipolar disorder and cyclothymia in thyroid patients than in the general population 54 . These findings may suggest either that thyroid abnormalities effect secondary mood changes, or that the co-occurrence of mental and thyroid diseases may be the result of common biochemical abnormalities. Lithium is known to interact with the thyroid axis and causes hypothyroidism in a subgroup of patients, which compromises its mood-stabilizing effects. Lithium was reported to alter thyroid hormone metabolism in the rat brain, and a study investigating whether these effects were mediated through regulation of thyroid hormone receptor (THR) gene expression found that chronic lithium treatment...

Evaluation of Clinical Risk Factors for Thyroid Cancer

A family history of benign thyroid disease will decrease and a family history of thyroid cancer will increase the suspicion of malignancy. Medullary thyroid cancer in the family will of course require measurement of serum calcitonin and dNa mutation analysis in the patient. Routine measurement of serum calcitonin in every patient with a thyroid nodule has been advocated as it detects about one case of medullary thyroid cancer in every 200 thyroid nodules 10,11 . The cost-effectiveness of this approach is, however, debated. A careful family history is furthermore important to discover rare syndromes associated with papillary or fol-licular thyroid cancer, which may have consequences for the patient and his family (Table 10.2). Familial clustering of differentiated thyroid cancer may not be as exotic as previously thought it accounts for approximately 5-10 of all papillary and follicular thyroid carcinomas 12 . A study among first degree relatives of cases (unselected nonmedullary...

Attention to Quality of Life

The physician in charge of the continuity in care of the thyroid cancer patient (likely the endocri-nologist) is instrumental in promoting compliance with the long-term follow-up and the required repeat investigations. Compliance can be enhanced by giving attention to many details which - although not determining the main outcome of the disease - may severely affect the patient's life. The cost of care should not be forgotten, as patients may have no or insufficient insurance 44 . The incidence of chronic xerostomia as a result of 131I-induced sialadenitis may decrease considerably with amifostine pretreat-ment 45 . During thyroid hormone withdrawal, hypothyroid symptoms are common such as fatigue, weight gain, peripheral edema, muscle cramps, skin dryness, anxiety, constipation, cold, depression, and impairment of memory and concentration these complaints are more pronounced in the elderly than in younger patients 45 . It is thus not surprising that quality-of-life questionnaires...

Preoperative Assessment

The new patient visit starts with the history. While almost all patients with thyroid cancer are euthyroid, surgery is performed on patients with large goiters who might be hypothyroid and occasionally on patients with hyperthy-roidism who are not amenable to medical control. Any previous neck operations must be understood in detail to elucidate the altered anatomy the surgeon will encounter. Important questions are used to delineate their clinical thyroid status (heat cold intolerance, skin changes, hair changes, cardiovascular status, and bowel changes) and also to investigate for possible multiple endocrine neoplasia (MEN) syndrome with vasoactive tumors of the adrenal glands. For cancer patients, a 1-year history of any excess iodine exposure, especially computed tomography (CT) scans, is obtained to assess how long postoperative radioactive iodine may need to be delayed. This will be checked with 24-hour urine iodine levels prior to administration of 131I. Present medications are...

Additional Clinical Studies

It is noteworthy that the proposal to use TSH-stimulated serum Tg as the only test in the postsurgical follow-up of thyroid cancer patients is not something new and only derived from experience with rhTSH. In addition, several authors have demonstrated the limited diagnostic value of 131I-WBS when patients are tested in the hypothyroid state. The first observation goes back to 1980, when serum Tg levels were found to be elevated in patients with nonfunctioning metastases 23 . More recently two large retrospective studies, one from Villejuif 24 and one from Pisa 25 , developed this concept further.

TgAbNegativeDTC Patients

It is well established that TSH stimulation enhances the sensitivity of using Tg measurements to detect disease 6,8,106,107 . Recently, rhTSH-stimulated Tg testing has become preferred to the practice of withdrawing thyroid hormone to raise endogenous TSH, with its attendant hypothyroid symptoms 108 . There is growing consensus that rhTSH-stimulated Tg testing is superior for detecting recurrent disease compared with diagnostic RAI imaging, even though the serum Tg response to rhTSH administration is only half of the response to the rise in endogenous TSH following thyroid hormone withdrawal 6,20,59,67,68,70,109,110 . There is a linear, approximate 10-fold relationship between the basal (THST) and 72-hour rhTSH-stimulated serum Tg concentrations of both normal control subjects and patients with DTC, as shown in Figure 18.4 6,72,111,112 . This is in accord with the factors known to influence the degree of TSH-stimulated Tg response, which include...

Prevention and Treatment

Newborn screening programs can detect certain disorders that will lead to mental retardation, including PKU, congenital hypothyroidism, galacto-semia, maple syrup urine disease, and other inherited metabolic disorders. Prenatal testing (such as amniocentesis and chorionic villi sampling) can be used to detect chromosomal disorders, including Down syndrome and sev

Six to 12Month Followup

The rationale for using rhTSH instead of L-T4 withdrawal for TSH stimulation is threefold. First, the sensitivity of rhTSH-stimulated serum Tg measurement has been amply demonstrated 13-23 . Second, rhTSH stimulation avoids the discomfort and quality-of-life impairment and decreases the safety risks associated with the hypothyroidism that is secondary to L-T4 withdrawal 15,24 . Third, use of rhTSH stimulation largely avoids the negative economic and professional consequences of that hypothyroidism. In patients with papillary thyroid carcinoma, neck lymph nodes are the most frequent site of recurrence, and almost the only site in patients with undetectable Tg during L-T 4 treatment 1,9,14,20,27,30 . Neck US should employ a probe containing a linear transducer of at least 7.5 megahertz, and results should be reported on a diagram. Lymph nodes are suspicious when they are hypoechogenic, lack an echogenic central line, have a round shape, and or have a hypervascularized appearance on...

Followup and Diagnosis of Persistent Disease

After the initial therapy has been performed, serum basal and pentagastrin-stimulated calci-tonin should be measured to verify the completeness of the treatment. The first control after surgery should be done 3 months after the surgical treatment, including physical examination, neck ultrasound and measurement of serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), calcitonin, and CEA. Measurement of FT3, FT4, and TSH are requested for monitoring the levothyroxine (L-T4) replacement therapy. Serum calcitonin and CEA measurement and neck ultrasound are necessary for follow-up of the medullary thyroid disease. Due to the prolonged half-lives, if performed too early, measurement of serum calcitonin may be misleading, especially if a high serum concentration was present preoperatively 66 (Figure 21.5). If basal calcitonin is undetectable, a pentagastrin

Medical History and Examination

The proband should first be identified as being either an affected or unaffected individual. The past medical history should be as complete as possible, giving specific reference to known preneoplastic lesions such as benign thyroid disease, goiter, adenomatous bowel polyps, and dysplastic nevi. Specific associated clinical features of cancer syndromes should be sought in either the probands, or in the cancers of the relatives. Such features might include, for example, a history of multinodular goiter, colonic polyps, epidermoid cysts, in a family segregating FAP-associated NMTC, or trichilemmomas and macrocephaly suggestive of Cowden syndrome. A personal or familial history of developmental delay might further indicate Cowden syndrome, as might a history of hamartomatous polyps or breast fibroadenomas, or uterine leiomyomas. Alternatively, a history of supernumerary or impacted teeth might indicate an underlying diagnosis of FAP, as might a history of duodenal or gastric polyps. A...

Clinical Management of NMTC Families

In patients with PTC, a family history should be extracted with special reference to family members with either NMTC or PRN. Presence of either of these should suggest a familial PTC syndrome. If such a familial PTC syndrome is identified, the first-degree relatives should be screened for underlying thyroid disease. The optimum screening method has yet to be identified. Although indicated in families with MEN2A and MEN2B, the value of prophylactic thyroidectomy has not been proven and should not routinely be recommended, not only since PTC is generally more indolent than medullary thyroid cancer, but also since no germline mutations can be unequivocally associated with affection status. There has yet to be formal consensus on the most effective screening program for PTC in high risk families. First-degree relatives of affected familial PTC kindred members should be assessed with a yearly physical examination of the thyroid gland, probably starting at the age of 20 years. The role of...

Anaplastic Thyroid Carcinoma

ATCs are usually large and widely invasive. Three major distinct microscopic morphological patterns exist (1) squamoid, (2) spindle cell, and (3) giant cell 47 . The tumor usually replaces a significant portion of the thyroid parenchyma, occasionally enough to cause thyroid failure (hypothyroidism). ATC is one of the most lethal human malignancies. It spreads aggressively and diffusely into the tissues of the neck. Distant dissemination usually occurs rapidly to lung, bone, liver, CNS, and other sites 44 .

History Taking and Physical Examination

The history-taking is important and should include questions about external irradiation to the head, neck, and upper chest. A history of goitrogen exposure should be also sought. Information regarding the rate of growth of the mass or masses, local or systemic symptoms, and hoarseness or dysphagia should be obtained. The family history should be explored for the presence of thyroid disease, hyper-parathyroidism, and features compatible with pheochromocytoma. Rapid painless growth of a nodule suggests the presence of carcinoma. Pain or tenderness in the thyroid gland is an unusual complaint in the context of a malignancy but may be severe in postviral (subacute) or suppu-rative thyroiditis. A rapidly enlarging nodule with transient pain suggests hemorrhage into a cyst.

Response to Thyroid Hormone Suppression Therapy

The rationale for thyroid hormone suppression therapy (THST) is based on evidence that TSH is the main stimulator of thyroid growth and function, at least in normal thyrocytes 60 . It is not clear whether long-term levothyroxine (L-T4) therapy to partially suppress TSH is effective in treating thyroid nodules, which are of course composed of neoplastic (not normal) thyroid tissue 61 . The use of high dose L-T4 to fully suppress TSH in patients with benign thyroid disease is neither beneficial nor completely safe 62 . Therefore, THST for unknown nodular thyroid disease is not recommended for pedi-atric patients.

The Genetic Connection

Other observations suggest an association with elevated homocysteine levels in some AD patients, perhaps related to a decreased level of folate (Chapter 15), prior viral infections, exposure to chemicals, or aluminum, or any correlation with neoplasms. However, still other data associate AD with head trauma, cardiovascular disease, and a less convincing association with thyroid disease (Chapter 12). There is a definite association of AD with Down syndrome.

Clinical Presentation of PMCT

PMCTs are frequently discovered as incidental findings on neck imaging for indications other than thyroid cancer. Unsuspected PMCTs also appear in surgical specimens from operations for benign thyroid disease or in search of a parathyroid adenoma. Occasionally, however, the patient notes a cervical mass that proves to be a metastatic lymph node. In the older literature, these lesions, often cystic, were referred to as lateral aberrant thyroid tissue. Sugitani et al. reviewed 34 patients with PMCTs, who presented with cervical nodes of 1 cm or greater 67 . Four of these patients later developed distant metastases and died of their disease. These observations contrasted with 156 patients with PMTC who presented without clinically apparent lymph node metastases. None of this latter group developed distant metastases and rarely had local recurrence. Factors associated with worse outcomes were lymph nodes greater than 3 cm in size and thyroid cancers that were

Management Options and Outcomes

The findings of Chow are essentially borne out in a retrospective study of 299 patients by Pellegriti et al. 75 . Included in this report are tumors measuring up to 1.5 cm, 18 patients with familial thyroid cancer, 122 with familial thyroid disease, 36 with concurrent Graves' disease, and 25 from an iodine-deficient area. Patient demographics were the same as in other studies. For purposes of comparison, the patients were placed into two groups those with non-incidental carcinoma (148 patients) mainly diagnosed by FNAB and those with incidental carcinomas (151 patients) after thyroidectomy for benign thyroid disorders. Two hundred and ninety-two patients underwent near-total or total thyroidectomy either as primary therapy (n 269) or as completion thyroidectomy (n 15) within 8 months of diagnosis. Seven patients had a lobectomy. The major findings in both groups were a surprisingly high incidence of multifocality, bilaterality, lymph node metastases, and extrathyroidal extension....

Diffuse Sclerosing Variant

The diffuse sclerosing variant of papillary cancer (DSPC) is rare, with an incidence of only 0.7-5.3 58,59 . It commonly affects young adults, with a female preponderance, and is important in the differential diagnosis of Hashimoto's thyroiditis. Histologically it is characterized by diffuse involvement of one or both lobes, fibrosis, squamous metaplasia, numerous psammoma bodies, and extensive lymphatic infiltration.

Other Emerging Therapies for Thyroid Cancer

Immunotherapy remains a major area of interest for thyroid cancer, and for a number of other malignancies 58,59 . The use of tumor vaccines with or without agents to enhance immune responses, or to induce thyroiditis in patients on chemotherapy using interferons, are avenues of potential treatment for thyroid cancer in the future. Chemoprevention is another alternative for thyroid cancer that remains relatively unexplored other than the use of iodide after accidental exposure to iodine isotopes. Chemo-preventive strategies could include administration of apoptotic-promoting agents after radiation exposure, to induce cell death and subsequent hypothyroidism. Or low doses of other agents that are shown to be radiation sensitizers. Finally, cyclooxygenase-2 inhibitors have been utilized as chemopreventive agents for malignancies such as colon cancer with high levels of cyclooxygenase-2 activity. Thyroid cancers also have been shown to have high levels of cyclooxygenase-2 expression and...

Serum methylmalonate and homocysteine levels

Homocysteine exists in plasma as single molecules, as two molecules linked together (homocystine) and as mixed homo-cysteine-cysteine disulphides. Serum homocysteine levels are raised in both early cobalamin and folate deficiency, but they may be raised in other conditions, e.g. chronic renal disease, alcoholism, smoking, pyridoxine deficiency, hypothyroidism therapy with steroids, cyclosporin and other drugs. Levels are

General Surgery Residency Training

Parathyroid Surgery Distribution

Harness et al. evaluated the operative experience of graduating general surgery residents in the USA in an attempt to characterize what baseline level of training general surgeons have obtained for thyroid, parathyroid, and adrenal surgery 5 . They found extremely varied levels of experience for all three endocrine glands, including the thyroid (Figure 11.2) 1,5 . The average number of thyroidectomies performed by graduating chief residents ranged from 10.8 (1986-1987) up to 15.2 (1998-1999). Despite the limited experience treating thyroid disease, it still made up an average of two thirds of the total operative endocrine experience in resi

Ablation of Residual Normal Thyroid Tissue

In the management of differentiated thyroid cancer (DTC) ablation of thyroid remnants with 131I aims to destroy all residual normal thyroid tissue. Total (or near-total) thyroidectomy will permit this to be achieved with a modest administered activity. Remnant ablation after lobectomy is more difficult and a repeat administration may be required. Ablation of a large remnant may cause radiation thyroiditis with neck pain and swelling. Furthermore thyroid-stimulating hormone (TSH) levels may fail to rise above 30mU L following hormone withdrawal, resulting in suboptimal 131I uptake. To optimize radioiodine uptake by both residual normal thyroid and cancer, TSH stimulation is mandatory and dietary iodine should be restricted for one month before and for several days after ablation. Dietary restriction of iodine intake to 50 mg per day can increase the 131I uptake twofold after ablation 31 . Iodized salt, dairy products, eggs, and seafood should be avoided 32 . Iodine-rich contrast media...

Fine Needle Aspiration Cytology

Fine-needle aspiration should be performed on any solitary or dominant nodule more than 10 mm in diameter or in nodules as small as 8 mm with highly suspicious ultrasonographic characteristics. Where the nodule is palpable it can be aspirated under direct palpation in the first instance. In some places in Europe and the USA and in Japan, ultrasound guidance is used for all lesions. However, in view of the additional resource required, many centers would reserve its use for cases where standard FNA yields nondiagnostic material. It is also especially useful in complex cysts, in lesions that are difficult to palpate or are impalpable, and in targeting the dominant nodule(s) in multinodular goiter. Aspiration should be carried out by a clinician with an interest in thyroid disease, trained in good practice and performing aspirates regularly. This can be a cytopathologist, surgeon, endocrinologist, or radiologist. The cytopathol-ogist reporting the FNA should also have an interest in...

Thyroid Papillary Carcinoma In Hla Identical Sibs

Levi F, Franceschi S, La Vecchia C, et al. Previous thyroid disease and risk of thyroid cancer in Switzerland. Eur J Cancer 1991 27(1) 85-88. 52. Preston-Martin S, Bernstein L, Pike MC, Maldonado AA, Henderson BE. Thyroid cancer among young women related to prior thyroid disease and pregnancy history. Br J Cancer 1987 55(2) 191-195.

HPT Axis Dysfunction in Patients with Primary Psychiatric Disorders

Excluding patients with primary endocrine disorders, a considerable amount of data has revealed an elevated rate of HPT axis dysfunction, predominantly hypothyroidism, in patients with major depression. More than 25 years ago, research groups led by Prange and Kastin demonstrated that approximately 25 of patients with major depression exhibit a blunted TSH response to TRH 8, 9 . Presumably this is due to hypersecretion of TRH from the median eminence, which leads to TRH receptor down-regulation in the anterior pituitary resulting in reduced sensitivity of the pituitary to exogenous TRH. This hypothesis seems plausible in the light of evidence showing elevated TRH concentrations in the CSF of drug-free depressed patients 10 . Depressed patients have also been shown to have an increased occurrence of symptomless autoimmune thyroiditis (SAT), defined by the abnormal presence of antithyroglobulin and or antimicro-somal thyroid antibodies consistent with grade 4 hypothyroidism 11 . HPT...

Cancer Predisposition Syndrome Associated Nonmedullary Thyroid Cancer

The lifetime risk for breast cancer in Cowden syndrome is around 40 37,40 , and the risk for thyroid cancer is around 10 36,37 . These thyroid cancers are typically follicular, but occasionally papillary. Benign thyroid abnormalities such as adenomatous goiter and hyper-or hypothyroidism are common, and a variety of benign tumors of muscular and neuronal origin have been described. Because Cowden syndrome is rare, the overall contribution of the disorder to the total burden of thyroid cancer is small.

Non Syndromic Familial Nonmedullary Thyroid Cancer

NMTC in Association with Benign Thyroid Disease Role of MNG1 There is evidence that some forms of NMTC may be caused by a predisposition to developing multinodular goiter (MNG) or other forms of benign thyroid disease. A high incidence of benign thyroid disease was documented in a number of families segregating NMTC 4 . This is supported by systematic studies of risks of thyroid disease in cancer in relatives of patients with NMTC. The risk of benign thyroid disease is increased three- to fourfold in relatives of patients with thyroid disease or NMTC 50,51 . Furthermore, the risk of NMTC is elevated up to fivefold in individuals with a history of benign thyroid disease 3,52 . Based on a survey of 159 patients, Ron et al. 3 estimated that about 20 of thyroid cancers are attributable to a prior history of benign thyroid disease. Taken together, these observations suggest the existence of relatively common disease-causing alleles conferring a high risk of benign thyroid disease (usually...

Well Differentiated Thyroid Carcinoma

After surgery and 131I thyroid remnant ablation, a diagnostic WBS is recommended to assess the need for further RAI therapy this should be performed 9-12 months after the remnant ablation and in conjunction with measurement of serum Tg 66 . In preparation for the diagnostic RAI WBS, patients are made hypothyroid over a period of 6 weeks. This is achieved through the implementation of various protocols to abrogate the deleterious effects of this prolonged iatrogenic hypothyroid state. We recommend the administration of L-triiodothy-ronine (liothyronine, L-T3) at 1.0-1.2 mg kg per day, divided into two or three doses, for the first 4 weeks of the 6-week treatment with the hypo-thyroid preparation. To increase the affinity of any thyroid tissue for RAI, a low iodine diet may be instituted (daily iodine content of about 50-75 mg) for the 2-3 weeks before the scan 66 . Patients who take L-T4 after thyroidectomy should discontinue it and start L-T3 for 4 weeks, as described above. L-T3 is...

Radioactive Iodine 131I Therapy Thyroid Remnant Ablation

More recently, 131I remnant ablation has been done after intramuscular administration of recombinant human thyrotropin-a (rhTSH, Thyrogen), which stimulates thyroidal 131I uptake and Tg release while the patient continues thyroid hormone (T4) therapy, thus avoiding symptomatic hypothyroidism 125 . Although now approved only for diagnostic use, rhTSH, 0.9 mg, has been given intramuscularly every day for 2 days followed by 1110 to 3700 MBq (30 to 100 mCi) 131I on the third day and RxWBS about 5 days later. This protocol has been shown to successfully prepare patients for 131I remnant ablation. At the present time, the drug is approved in Europe and is likely to be approved in late 2005 for this purpose in the USA. Complete ablation, defined as an absence of uptake on an 85 MBq (5 mCi) 131I diagnostic whole-body scan (DxWBS) image about one year later, was achieved in over 84 of patients prepared

Normal Distribution of 18FDG

Difficult to recognise as normal tissue if there has been previous surgery or radiotherapy that may distort the anatomy, resulting in asymmetric activity or even unilateral uptake on the unaffected side. Adenoidal tissue is not usually noticeable in adults but may show marked uptake in children. Another area of lymphoid activity that is commonly seen in children is the thymus. This usually has a characteristic shape (an inverted V) and is therefore not usually mistaken for anterior mediastinal tumour (Fig. 14.2). Clinical reports vary as to the incidence of diffuse uptake of 18FDG in the thyroid 16-18 . This may be a geographical phenomenon, because its presence is more likely in women and has been correlated with the presence of thyroid autoantibodies and chronic thyroiditis 18 .

Maternal thyrotoxicosis

Chart For Tsh And Ft4 Results

This inCludes a current or past history of maternal thyrotoxiCosis, espeCially those treated with surgery or radioiodine (who may now be CliniCally hypothyroid). ThyrotoxiCosis is nearly always due to Graves' disease and persisting thyroid stimulating antibodies renders the baby at risk of neonatal thyrotoxi-Cosis. Co-existing inhibiting antibodies may Cause neonatal hypothyroidism. - Birth Cord blood for fT4, TSH, TSH reCeptor antibodies (although the results are not usually available in the first few days of life when thyrotoxiCosis or hypothyroidism is usually deteCted, it is useful for the long term management of thyrotoxiCosis) and examine for sign of thyrotoxiCosis Initial eu- or hypothyroidism may be followed by thyrotoxicosis. This may S have central hypothyroidism (low fT4, low TSH) caused by an elevated fT4 s Maternal or familial 22 thyroid disease HISTORY OF MATERNAL HYPOTHYROIDISM

Differential Diagnosis of Dysthymic Disorder

Mood Disorder Due to a General Medical Condition. Depressive symptoms consistent with dysthymia occur in a variety of medical conditions. These disorders include stroke, Parkinson's disease, multiple sclerosis, Huntington's disease, vitamin B12 deficiency, hypothyroidism, Cushing's disease, pancreatic carcinoma, HIV and others. Rule out with history, physical exam and labs as indicated.

Complications of Radioiodine Treatment

Radioiodine therapy is well tolerated and usually lacks serious complications. Patients may experience nausea and vomiting, especially during the first 24 hours after administration prophylactic use of metoclopramide 10mg 30 minutes prior to 131I is therefore recommended 90 . Radiation thyroiditis may occur within the first week and last for several days after ablation The radiation dose delivered by 131I to each organ is difficult to estimate from established mathematical models uptake by metastases may modify the dose delivered to a given organ and the hypothyroid status at the time of iodine administration decreases renal clearance of 131I, thereby increasing the body retention of iodine by a factor of 2-4. Liberal fluid intake, frequent micturition, and use of laxatives will promote iodine excretion and reduce radiation exposure.

Insufficient TSH Stimulation of 131I Uptake

After thyroidectomy, 131I uptake by thyroid remnants and metastases is increased by high serum TSH levels. To maximize the therapeutic effect of 131I, one must closely adhere to a protocol that ensures serum TSH reaches levels of at least 30 mIU L. This may be done by administering oral T3 (liothyronine, Cytomel) alone for 4 weeks then withdrawing it for 2 weeks, after which the patient is hypothyroid and the serum TSH usually is about 70 mIU L, but it ranges from just over 30 to nearly 300mIU L, depending upon the size of the thyroid remnant 47 . T3 may be withdrawn for 4 weeks, which raises the TSH even further, but careful studies 47 show that this does not improve 131I uptake by remnants or tumors more than that achieved with 2 weeks' withdrawal of T3. Another way to do this is to simply withdraw thyroid hormone therapy and to measure serum TSH levels several times a week. One recent study 45 found that serum TSH concentrations reached more than 30 mU L 8 to 26 days (14.2 4.8...

Maintenance of Surgical Decision Making

As the optimal surgical treatment for thyroid disease is often debated, it provides an excellent example of how clinical decision-making requires sound knowledge of accepted guidelines, as well as an understanding of the controversies and the study results which support or refute the various treatment options. This allows one to tailor treatment for individual patients. Although controversial, the current trend for treatment of selected benign and most malig nant thyroid disease is towards more extensive surgery, such as near-total or total thyroidec-tomy 37-39 . When used to treat thyroid malignancies, these operations may involve central and or lateral lymph node dissections, the indications for which are also a source of controversy. With an active clinical practice and ongoing hands-on research in this field, specialist surgeons treating thyroid disease are most adept at making these difficult clinical decisions.

Effects on Male Fertility

Following 131I administration, sources of radiation to the testes are the blood, bladder, gut, and functioning metastases close to the testes. Another source of testicular irradiation is derived from organified 131I, which is incorporated into a variety of iodoproteins. These have relatively long half-lives and produce continuous blood-borne irradiation for weeks 16 . The MIRD to the testes is 0.085cGy 37MBq (1mCi) in euthyroid adults 7 . Theoretical models taking into account the hypothyroid status of the patients, which decreases renal clearance of iodine resulting in a more prolonged exposure, suggested a higher testicular dose in the order of 0.5-1 cGy 37MBq 17 . Thus the cumulative radiation dose following a standard ablation iodine activity of 3 GBq (81 mCi) is approximately 40-80 cGy. Using thermoluminescent dosimetry (TLD) we measured the dose in 14 patients the mean dose to each testis was 6.4cGy, 14.1 cGy, and 21.2cGy following administration of 3, 5.5 and 9.2GBq (81, 149...

Psychological Aspects of Thyroid Cancer

An Italian study used a standardized instrument (structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders - III - Revised) to evaluate the lifetime prevalence of psychiatric disorders in 93 inpatients with different thyroid diseases. They found higher rates of several psychiatric disorders in thyroid patients than in the general population. These authors suggest that underlying biochemical abnormalities may explain the cooccurrence of psychiatric disorder and thyroid diseases 14 . Following treatment for thyroid cancer, patients are required to undergo regular monitoring of their disease status for the rest of their lives. The morbidity associated with lifetime surveillance is highlighted in a number of studies 13,19,20 . Surveillance generally involves thyroid hormone withdrawal followed by body scanning. The induced hypothyroid state results in symptoms of fatigue sleep disturbance impaired psychomotor skills reduced ability to concentrate anorexia...

Disorders of the HPT Axis

Disorders of the HPT axis lead to numerous psychiatric manifestations, ranging from mild depression to overt psychosis. Numerous conditions can lead to hypothyroid states, also known as myxoedema, including CNS causes of decreased TSH or TRH secretion, severe iodine deficiency, thyroid surgery, drugs, or autoimmune disorders. The most common cause of hypothyroidism is Hashimoto's thyroiditis, which is due to autoimmune destruction of thyroid tissue. Regardless of the aetiology, hypothyroidism leads to a number of clinical manifestations, including slowed mentation, forgetfulness, decreased hearing, cold intolerance and ataxia. Decreased energy, weight gain, depression, cognitive impairment or overt psychosis (myxoedema madness'') may also result. Due to the overlap of symptoms with clinical depression, thyroid hormone deficiency must be ruled out in the evaluation of patients with depression. Hypothyroidism is frequently subclassified into the following four groups Grade 1...

Discriminative Evaluative And Predictive Instruments

Throughout the stages of scale development, validation and evaluation it is important to consider the intended use of the measurement scale. Guyatt, Feeny and Patrick (1993) draw attention to the need to distinguish between discriminative, evaluative and predictive instruments. Some scales are intended to differentiate between people who have a better QoL and those with a worse QoL these are discriminative scales. Other scales are intended to measure how much QoL changes these are evaluative scales. Scales may also be designed to predict future outcomes for patients. If an instrument is intended to be discriminative, it may be less important to include symptoms that are common to all patients and unlikely to differ between the various treatment groups. For example, fatigue is not only common for patients with thyroid disease but is also common amongst patients without the disease, and hence it might be considered an unimportant item in a purely discriminative instrument. However,...

Screening of Asymptomatic Individuals

A urinalysis could give a clue to urinary schis-tosomiasis (hematuria) in an asymptomatic child returning from a long stay in East Africa or another endemic area. Hepatitis C testing is sometimes recommended for foreign-born adoptees (Miller, 1999). Very young infants and some older children who did not have newborn screening testing might benefit from screening for conditions such as hypothyroidism, galactosemia, phenyl-ketonuria, and hemoglobinopathy. 'Routine' newborn screening (phenylketonuria, hypothyroidism, galactosemia, hemoglobinopathy, perhaps others)

Ultrasound Color Doppler Imaging and FDGPET

The increasing use of high resolution US and its identification of thyroid nodules never before suspected is not the only modality causing conundrums in the appropriate management of these discoveries. Now 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is unearthing unsuspected thyroid nodules. In one study, as many as 2.3 of patients without known thyroid disease had PET-positive thyroid lesions, 47 of which were malignant 65 . Kang et al. have published a retrospective review of their experience in patients undergoing FDG-PET for metastatic evaluation of non-thyroidal cancer (999 patients) versus a second group of healthy volunteers without known malignancy, undergoing cancer screening (331 subjects) 66 . Twenty-one focal type lesions were identified in this group of 1330 subjects (1.6 ). Thirteen were from the cancer patients and 8 from the volunteers. Fifteen of the 21 focal type lesions were evaluated by either US-guided core biopsy or surgical histology. Four of...

Obtaining Cytological Histological Diagnosis

Where the features are suggestive of malignancy. This is often not the palpable nodule. The needle is advanced through the tissues with US visualization in real time. The nondiagnostic sample rate is significantly reduced 18,19 . Deeper and smaller nodules can easily be sampled 20,21 . As a result the availability of US-guided biopsy is seen as important in centers treating thyroid disease 6,18,22-27 .

Potassium Iodide KI Prophylaxis

The life-time thyroid cancer risk in exposed children is estimated by WHO at 1 per Gy (1 per 100 rad) and, conversely the risk of severe side effects from a single administration of stable iodine is estimated at 10-7 9 . WHO therefore recommends an age-specific intervention level of 10 mGy (1Rad) for children and adolescents below the age of 18 years and for pregnant and for lactating women. WHO considers this to be justified because - even with the lower intervention level - some 2 to 5 extra thyroid cancer cases are expected to occur per 1 million children exposed per year 9 . For adults up to 40 years old, WHO follows the recommendation of IAEA for an intervention level of 100mGy (10 Rad). Because the risk of thyroid cancer is very small in adults over the age of 40, WHO recommends iodine blockade only in the event of very high exposure with more than 5 Gy (500 rad) that may lead to hypothyroidism. People with preexisting thyroid diseases - for example nontoxic nodular goiter or...

Differential Diagnosis

A comprehensive history and physical examination are indicated to rule out other possible causes of the emotional and physical symptoms of PMS. The differential diagnosis includes premenstrual molimina, hypothyroidism, perimenopause and major mood or anxiety disorders. Most ovulatory women experience some physical changes (e.g., breast tenderness, bloating, and food cravings) during the luteal phase. If these physical symptoms do not interfere with normal life functions, the term molimina can be applied. Hypothyroidism can share many of the same symptoms as PMS however there should be no cyclic variation. A thyroid stimulating hormone level is a sufficient screen, if warranted by clinical suspicion. There is also considerable overlap between the symptoms of perimenopause and those of PMS. Many women experience symptoms of emotional irritability, cyclic mastalgia, bloating and hot flashes as part of the perimenopause. It is likely that similar pathophysiologic factors mediate symptoms...

Preparation for Ablative 131I Therapy

Ablative 131I therapy may still be favored in that it improves the diagnostic accuracy of serum thyroglobulin and 131I total body scan for remaining tumor tissue after total ablation of the thyroid gland 22 . The internist-endocrinologist can play an important role in the preparation for 131I treatment. For the efficacy of 131I ablation depends on how much of the administered 131I dose is taken up by remaining thyroid tissue, which is greatly stimulated by high serum TSH and low serum inorganic iodide concentrations. The endocri-nologist should see to it that at the time of 131I ablation the serum TSH is elevated (arbitrarily up to at least 25-30 mU L) and the serum iodide is definitely not high but preferably low. After (near) total thyroidectomy simply withholding T4 treatment will ensure high TSH levels after 4-6 weeks, the usual time for 131I ablation. If for any reason the interval between surgery and planned 131I treatment is longer, it is prudent to start T4 treatment in order...

Maintenance of Technical Surgical Skills the Volume Outcome Relationship

The results from Sosa et al. must be considered in light of the differences in the patient populations. Surgeons who operated on more than 100 patients with thyroid disease per year were performing more total thyroidectomies (versus lobectomy), treating more malignant (versus benign) conditions and had a significantly younger patient population than the lower volume surgeons 22 .The finding that the highest volume group treated the more challenging and complex patient population may support one of two views First, that the small difference in recurrent laryngeal nerve injury rates and the absence of difference in the hypoparathyroidism rates are biased towards the null, that is, that the difference in complication rates would be greater if the lower volume surgeons performed more complex cases.

Effects on Female Fertility

High serum FSH luteinizing hormone (LH) values in women with temporary amenorrhea following radioiodine therapy indicate temporary ovarian failure 5 . Contributing factors are not known. Both psychological stress leading to hypothalamic amenorrhea and hypothyroidism have been implicated. However, in most cases amenorrhea appears 1-3 months after treatment when the patient is on thyroxine replacement. This interval also excludes an action of radioactivity on the maturing follicle, possibly suggesting an effect on the oocytes involved in future cycles. After radioiodine administration, sources of radiation to the ovaries are the blood, bladder, gut, and functioning metastases close to the ovaries. Based on the Medical Internal Radiation Dose (MIRD) estimate, the dose received by each ovary is 0.14cGy 37MBq (1 mCi) 7 . However, the ideal MIRD model subject is morphologically bigger than the average patient and the kinetic model used applies to euthyroid patients iodine-treated patients...

Harmful Effects of Radioiodine

High doses of radioiodine (more than 5 Gy) may lead to necrosis and apoptosis of thyroid cells thus inducing hypothyroidism. In the case of a nuclear reactor emergency, exposure to high radiation doses sufficient to cause hypothy-roidism may only occur in people within very close proximity to the nuclear power plant. After the Chernobyl reactor catastrophe, hypothy-roidism occurred in very few people, only those working at the nuclear power plant at the time of the incident. Smaller doses of radiation (in the range of less than 1 Gy), however, may induce thyroid cancer, especially in vulnerable populations such as unborn or young children. Radiation from any source - including ingested or inhaled radioisotopes - can damage DNA and thus induce tumors. The health effects of the use of radioactive iodine isotopes for diagnosis and treatment of thyroid diseases in adults have been well studied, showing no significant consequences with respect to the induction of thyroid cancer 5 ....

Thyroid Remnant Ablation

More recently, a prospective, randomized clinical trial has been conducted in the USA, Canada, and Europe regarding the ablation of thyroid remnants in patients with well-differentiated thyroid cancer who had recently undergone total or near-total thyroidectomy. After surgery, a total of 63 patients were randomized to receive thyroid ablation with 100 mCi 131I aided by rhTSH while euthyroid (n 33) or by thyroid hormone withdrawal while hypothyroid (n 30). The efficacy of the ablation regimens was assessed 8 months later ( 1 month) using rhTSH-stimulated 4mCi radioio-dine scanning and stimulated serum Tg levels. As a primary endpoint, the definition of successful remnant was a negative neck scan (no visible uptake, or if visible, less than 0.1 uptake in the thyroid bed) 8 1 months following the ablation treatment. Moreover, stimulated serum Tg levels also were used to assess the success of remnant ablation, and a Tg cutoff level of 2 ng mL was proposed as a widely accepted and...

Treatment of Recurrent and Metastatic Disease

The British Thyroid Association recommends withdrawal of thyroxine (T4) 4 weeks before radioiodine, or triiodothyronine (T3) 2 weeks before so that endogenous TSH levels rise to above 30mU L, thereby optimizing iodine uptake 50 . This will induce symptomatic hypothyroidism, which may result in lethargy, cognitive impairment, or depression. Quality of life may be significantly impaired and many patients are unable to drive or work. This symptomatic period may be shortened by substitution of T3 for T4 4 weeks with discontinuation of T3 14 days prior to admission. If patients are unable to tolerate hypothyroidism, 131I may be given following rhTSH stimulation, with continuation of thyroid hormone replacement, although it remains unlicensed for this purpose. Retention of radioiodine is reduced due to rapid clearance in the euthyroid state, whereas renal excretion is reduced when thyroid hormone withdrawal is performed 51 . This may result in higher activities of radioiodine being...

The Thyroid and Iodine

Iodine is an essential component of the iodine-containing thyroid hormones thyroxine (T4) and triiodothyronine (T3). Severe iodine deficiency (intake less than 50 mg day) causes mental retardation, cretinism, and endemic goiter. Even in developed countries such as Germany endemic goiter with thyroid enlarge ment and or nodules is still prevalent in approximately 30 of the adult population 2 . The daily supply of iodine should amount to 90 mg in children aged 0-7 years, 120 mg in children aged 7-12 years, 150 mg in adolescents and adults, and 200 g in pregnant and nursing women ( 3 ,http www.ICCIDD.org). In cases of iodine deficiency, the thyroid enlarges and more actively transports iodine from the bloodstream, thus allowing uptake of sufficient iodine for the maintenance of normal thyroid function. In contrast, when the iodine supply is excessive (more than 500 mg day) the sodium iodide sym-porter (NIS) of thyrocytes is downregulated, thus inhibiting iodide transport from the...

Acute Complications

Radiation Thyroiditis Up to 20 of patients, usually those with a large thyroid remnant, given sufficient 131I to deliver about 500 Gy (50000 rads) develop thyroiditis 142 , which occurs less often when 1110 MBq (30mCi) of 131I is administered 143 . Within a week, painful swallowing, neck and ear pain, thyroid tenderness and swelling, and transient mild thyrotoxicosis may occur, which is usually transient, requiring no therapy.

Followup

Recombinant human TSH is now available and has an evolving role in the management of selected cases 19 . Recombinant human TSH (rhTSH) is used instead of stopping T3 or T4 prior to 131I scan or measurement of thyroglob-ulin, thus avoiding hypothyroidism with its debilitating symptoms. It is clearly indicated in patients who are unable to mount a TSH response to thyroid hormone withdrawal, and also those for whom an episode of hypothy-roidism is particularly undesirable, but may be used for any low risk patient for diagnostic purpose, provided serum Tg is undetectable on suppressive thyroxine therapy and anti-Tg antibodies are absent. Its potential therapeutic role has not yet been fully evaluated.

Summary

This chapter has reviewed the UK guidelines for the management of thyroid cancer and made reference to other available guidelines. The objective for clinicians involved in treating thyroid cancer must be to achieve lower recurrence rate and lower mortality rate. This will require early diagnosis and treatment, specialist management of patients by an MDT, adherence to guidelines, better detection of recurrence, and more effective treatment for progressive disease. In addition, clinicians should aim for improved wellbeing of the patient, and to that end consideration must be given to improving communication as well as the avoidance of hypothyroidism.

Initial Assessment

Colloid nodule Colloid cyst Follicular adenoma Multinodular goiter Malignancy Papillary Follicular Medullary Anaplastic Lymphoma Metastasis Hashimoto's thyroiditis Subacute thyroiditis Effect of prior operation or 131I therapy Thyroid hemiagenesis Parathyroid cyst or adenoma

History

Historical features that reduce the chance of a cancer include family history of Hashimoto's thyroiditis or autoimmune thyroid disease family history of benign thyroid nodule or goiter symptoms of hypothyroidism or hyper-thyroidism 7 . Living in an area of iodine deficiency increases the chance of multinodular goiter 8 .

Investigations

If the TSH is normal or elevated, the diagnosis then is between an autoimmune thyroiditis and other forms of nodule including cancer. Thyroid autoantibody assays (antithyroid per-oxidase and antithyroglobulin) will determine the presence of immune activity. Although cancers and Hashimoto's thyroiditis can coexist, this is rare 7 . Serum calcitonin would be added to the investigations performed if there is a family history of medullary thyroid carcinoma.

Causes

Dementia may be reversible or irreversible. Reversible causes include brain tumors, subdural hematoma, slowly progressive or normal-pressure hydro-cephalus head trauma endocrine conditions (such as hypothyroidism, hypercalcemia, hypoglycemia) vitamin deficiencies (of thiamin, niacin, or vitamin B12) thyroid disease ethanol abuse infections metabolic abnormalities effects of medications renal, hepatic, and neurological conditions and depression. Irreversible dementia is more common in the elderly. Irreversible causes of dementia include diseases of the brain such as Alzheimer's, Parkinson's, Pick's, Creutzfeldt-Jakob, and Huntington's diseases human immunodeficiency virus (HIV) infection vascular dementia and head trauma.

Efficacy

And serum Tg responses were comparable between the two methods. Among patients with persistent or recurrent disease, 80 had concordant scans, 4 had superior rhTSH scans, and 16 had superior withdrawal scans. Serum Tg was detectable (> 2ng mL) in only 80 of these patients during L-T4 therapy and was detectable in 100 following both rhTSH and withdrawal. The peak serum Tg was usually observed 2-3 days after the last injection of rhTSH. The shorter duration of stimulation with rhTSH is likely to have an impact on Tg levels and radioiodine uptake. In fact, the serum Tg level attained following rhTSH stimulation was usually lower than following withdrawal, but Tg was still detectable in all patients with persistent or recurrent disease investigated this underlines why a sensitive IRMA method should be used and why all detectable serum Tg levels should be taken into account, even low levels. Furthermore, radioiodine uptake was also lower with rhTSH, and this was attributed both to a...

Tolerance

The usual signs or symptoms of hypothy-roidism, and its consequences for organ function in particular on the brain, heart, liver, and kidney it avoids the worsening of any associated disease, and also the hazards of any drug therapy induced by a decreased renal or hepatic function finally, modification of physiology induced by hypothyroidism is avoided and thus any 3. As a consequence, quality of life was maintained and was much better during rhTSH than during hypothyroidism. Patient preference for rhTSH over withdrawal is universal. Side effects were minimal, being observed in less than 10 of patients, and consisted mainly of mild and transient nausea and headache, and no patient developed detectable anti-rhTSH antibodies.

Thyroglobulin

Serum thyroglobulin (Tg) measurements are a cornerstone for managing patients with differentiated thyroid carcinomas (DTC). The clinical utility of serum Tg testing is predicated on the tissue-specific origin of circulating Tg protein (thyroid follicular cells). However, since the maturation and secretion of a mature Tg molecule is complex, it is not surprising that circulating Tg is heterogeneous, and that as tumors dedifferentiate they can lose their capability to synthesize, iodinate, and secrete conformation-ally normal Tg protein 1,2 . Consequently, current Tg immunometric assays (IMA), based on monoclonal antibodies with restricted epi-tope specificity, may only recognize a limited population of Tg isoforms secreted by a neoplasm 3,4 . It follows that specificity differences largely explain the wide method-to-method variability that precludes changing assays when serially monitoring DTC patients. Serum Tg concentrations should be interpreted relative to (1) the mass of thyroid...

Hyperthyroid States

Follicular cells to secrete excessive amounts of T3 and T4. In this state, the normal negative feedback exerted by T3 and T4 on TRH and TSH release is disrupted. The clinical manifestations of thyroid hormone excess are exaggerations of the normal physiologic effects of T3 and T4 they include diaphoresis, heat intolerance, fatigue, dyspnoea, palpitations, weakness (especially in proximal muscles), weight loss despite an increased appetite, hyperdefecation, increased psychomotor activity, and visual complaints. Psychiatric manifestations are also common and include anxiety (13 of unselected cases), depression (28 of patients) and cognitive changes (approximately 7 of patients). Psychotic manifestations and mania are less common, occurring in only 2 of unselected cases. Overall, psychiatric comorbidity is much less common in hyperthyroid states than it is in hypothyroid states 7 .

Pathologic

Chest wall lesions (following chest surgery, herpes zoster, nipple piercing) as well as prolonged nipple stimulation can increase serum PRL levels as well as cause galactorrhea. This occurs via a reduction in hypothalamic dopamine. Notably, routine breast exams are not associated with increased PRL. Chronic renal failure, due to a decreased clearance of PRL, can result in hyperprolactinemia. Renal transplant reverses it. Forty percent of patients with hypothyroidism have mildly elevated PRL levels, due to the increase in thyroid releasing hormone, which is also a PRL releasing factor. Some rare causes of ectopic hyperprolactinemia include small cell carcinoma of the lung as well as colorectal cancer. Liver cirrhosis can also cause an elevation of PRL, possibly secondary to decreased clearance.

Evaluation

Although prolactin is secreted in a pulsatile fashion, a random blood test usually suffices. If the prolactin is mildly elevated on initial evaluation (< 40 ng ml), it is prudent to repeat it prior to making a diagnosis of hyperprolactinemia. If the mild prolactin elevation is persistent on subsequent testing or if the initial level is greater than 40 ng ml, then a specific cause should be sought. A TSH level should always be checked to rule out primary hypothyroidism, as this can result in an elevated PRL level (due to the PRL stimulating effect of TRH). A renal panel should be checked, as compromised kidney function leads to decreased clearance of PRL. Brain imaging, using gadolinium enhanced MRI (preferred) or CT scanning is mandatory to rule out hypothalamic-pituitary lesions. Although microadenomas typically produce serum PRL levels less than 100 ng ml, while macroadenomas typically show levels greater than 100 ng ml, a serum level cannot distinguish between the two. For...

Methodology

Toxicity criteria developed by the WHO and the National Cancer Institute (NCI) provide guidelines for objectively and systematically categorizing adverse effects according to type and severity grade. NCI's Common Toxicity Criteria (CTC) are particularly useful for studies involving antineoplastic drugs but are equally applicable to other drug categories. The CTC organizes related adverse events alphabetically according to body system or disease. For example, the endocrine category includes specific adverse effects such as gynecomastia and hypothyroidism. Specific criteria are detailed for grading the severity of each adverse effect. The CTC can be accessed at the NCI's Cancer Theraphy Evaluation Program web site

Biochemical Indices

In general, there is no blood test that is of value in the initial diagnosis of WDTC or ATC. Nevertheless, serum-free thyroxine (free T4), total (or free) triiodothyronine (T3), and TSH determinations are helpful in determining the functional status of the thyroid gland. It should be mentioned that the degree of hyperthyroidism due to a toxic nodule may not be sufficiently severe to allow diagnosis on clinical grounds alone. Hypothyroidism should be excluded because, if secondary to chronic lymphocytic (Hashimoto's) thyroiditis, it can be associated with solitary or multiple nodules. Serum thy-roglobulin (Tg) levels can be elevated in patients with WDTC but are also elevated in a variety of benign thyroid disorders. Thus, the measurement of serum Tg is not helpful at the outset (unless of course one knows the diagnosis of TC) however, it is of great importance in the follow-up of patients with WDTC after initial therapy (see below).

Radionuclide Imaging

The traditional approach to evaluating patients with nodular thyroid disease has been radioisotope scintigraphy, aiming to classify nodules as cold, hot, or warm, depending on their ability to concentrate the isotope. Scanning can be done with 123I or technetium-99m pertechne-tate (99mTc). Unfortunately, the value of such scans is limited by their inability to reliably differentiate between benign and malignant disease. However, scintigraphy can rule out the presence of developmental anomalies, such as agenesis of a lobe (with compensatory hypertrophy of the contralateral lobe), presenting clinically as a solitary nodule. presents the greatest clinical problem in differentiating a benign from a malignant nodule, because such nodules can underlie TCs, chronic lymphocytic thyroiditis, cysts, follicular adenomas, abscesses, hypofunctioning nodular goiter areas, or embryonic defects 57 . The highest incidence of TCs occurs in patients with cold solitary nodules, but certainly not all cold...

Pathogenesis

In Graves' hyperthyroidism it is likely that thyroid damage leads to activation of autoimmune thyroid disease by activation of anti-receptor antibodies to the thyrotrophin receptor (TSH receptor). Eye disease is clinically evident in 40 of patients with Graves' disease but, in contrast, in only 3 of patients with Hashimoto's thyroiditis and very rarely with primary hypothyroidism. The high correlation between Graves' disease and orbital disease suggests a shared antigen, such as TSH receptor, thyroglobulin or thyroid peroxidase. Circulating activated T lymphocytes infiltrate the orbital tissues, where they release cytokines which, in turn, stimulate proliferation of fibroblasts and deposition of glycosaminoglycans (GAGs). Intense lymphocytic infiltration, fibroblast proliferation and perimysial oedema result in expansion of orbital contents and proptosis. Subsequent fibrosis of involved perimysial connective tissue results in varying degrees of muscular contracture.

Thyroid cancer

a R Childhood exposure to radiation (papillary tumours). Medullary thyroid carcinomas may be familial and are associated with MEN syndrome type Ila or lib (20 cases). Lymphoma is associated with Hashimoto's thyroiditis. Medical Chemotherapy Thyroxine treatment to avoid hypothyroidism post surgery and to suppress residual tumour cells in papillary and follicular tumours. Doxorubicin chemotherapy is used in anaplastic tumours. Radiological 131I-radioiodine treatment for papillary tumour extending beyond the capsule, recurrences and metastasis. External radiotherapy for local recurrences. Anaplastic tumours are poorly responsive. From surgery Haemorrhage, recurrent laryngeal nerve damage, superior la-ryngeal nerve paresis, tracheomalacia, laryngeal oedema, hypoparathyroidism, hypothyroidism.

Females Males

Syndrome Albright

A number of factors can activate the hypothalamic production of GnRH, leading to stimulation of pituitary gonadotrophs and gonadal steroid production. Tumors can impinge on inhibitory neurons causing increased secretion of GnRH. A suspected malignancy should be followed by biopsy for identification. Benign tumors, such as hamartomas (hyperplastic malformations of the tuber cinerum which elaborate GnRH), can be successfully treated with GnRH agonist therapy. Long standing hypothyroidism can cause central precocity (usually associated with retarded bone age). Treatment will curtail symptoms. A careful history may illicit a previous history of an infectious process (i.e., meningitis), trauma, radiation, or developmental abnormalities (hydrocephalus). Ectopic gonadotropin production by tumors accounts for less than 0.5 of the causes of central precocity. The most common of these tumors include chorioepithelioma, dysgerminoma, and hepatoblastomas. All patients with delayed puberty should...

Thyroid Lymphoma

Primary thyroid non-Hodgkin's lymphoma (NHL) is uncommon, representing 4 of all thyroid cancers 1 . Only 2 of extranodal lymphomas arise within the thyroid. Secondary involvement is more frequent as a manifestation of generalized disease, which occurs in 10 of all lymphomas and leukemias 2 . The mean age at presentation is 60-70 years with a female male predominance of 3 1. Presentation before age 40 is rare. Preexisting Hashimoto's thyroiditis is a significant risk factor 3 and may be the result of chronic antigen stimulation. Radiation exposure is not associated with an increased risk. Typical presentation is with a rapidly enlarging thyroid mass associated compressive symptoms comprise dysphagia, dyspnea, stridor, hoarseness, and superior vena caval obstruction. A preceding history of goiter in association with hypothyroidism is characteristic. The thyroid mass is often fixed to underlying structures, with confluent cervical lymphadenopathy occurring in up to 50 of cases. Only 10...

Miscellaneous

Hypothyroidism considered to be a relatively mild nongenetic form of VWD, as opposed to having an inherited mutation involving the von Willebrand protein gene. Furthermore, hypothyroidism can result in an acquired form of VWD, which resolves with thyroid replacement. Decisions about what diagnostic studies should be performed in cases of abnormal vaginal bleeding need to be individualized. Table 4.3 provides a list of evaluative measures that should be considered, and most patients should at least have a complete blood cell count (CBC) that includes platelets if not done recently. In general, it is mandatory to rule out pregnancy with a serum or sensitive urine pregnancy test in anyone that could possibly be pregnant, regardless of contraceptive method or the specific bleeding pattern present. If pregnancy is not present, most premeno-pausal women should have their ovulatory status established. This may involve basal body temperature charting, serum progesterone determinations, or...

Sarcoma

Tivity to factor VIII-related antigen and keratin are common 27 . Cases have been described from the Alpine regions of Central Europe where iodine deficiency is common. An enlarging mass following a long history of goiter, with invasion of local structures and lymph node involvement (unusual with other sarcoma subtypes) is the typical presentation. Hemothorax from pleuropulmonary metastases may occur at presentation 24 . Prognosis is poor, with the majority dying of locoregional or metastatic disease. As with sarcoma at any site, surgery remains the definitive and potentially curative treatment comprising total thyroidectomy with excision of any locally involved tissue, along with neck dissection. This may be impossible in the majority of cases if tumor extends beyond the thyroid capsule and invades vital structures. Postoperative radiotherapy is indicated but the role of chemotherapy is yet to be established.

Histology

Thyroid Parafollicular Cell Hyperplasia

The definition of C-cell hyperplasia has changed over the years, especially after the introduction of RET genetic screening and the histological examination of apparently normal thyroid glands of mutated gene carriers that usually show an increased number of C cells. Studies of both human normal thyroid and thyroids affected by lymphocytic thyroiditis have demonstrated that one can see up to 50 C cells per 1 and 3 low power fields respectively, without correlation with any pathological status 98,113 . According to these findings, this is at present the most widely accepted definition of Several authors would like to distinguish two types of C-cell hyperplasia primary or neoplastic C-cell hyperplasia, which is related to the hereditary form of medullary thyroid carcinoma, and secondary or non-neoplastic C-cell hyperplasia, which may be observed in other thyroid diseases (thyroiditis and follicular or papillary microcarcinoma) and in about 20 of normal subjects 116,117 . However, the

Etiology

Iodine deficiency remains a worldwide problem, especially in Africa, Europe, and the eastern Mediterranean 22 . In these three areas, up to 56 of the general population, including children, are deficient (urinary iodine less than 100 mg L). Iodine deficiency may shift the histological type of thyroid malignancy from follicular to papillary. For example, in a formerly iodine-deficient area of Argentina with a stable population, the ratio of papillary to follicular carcinoma rose from 2.5 1 to 6.2 1 following the introduction of iodine prophylaxis 23 . The shift was noted in tumors both less than and greater than 1 cm in diameter. Marchesi et al. have reported papillary carcinoma in nine first-degree relatives from four families 51 . At least one family had a strong history of hypothyroidism and multinodular goiter. Four of the nine tumors found measured 1 cm or less and 44 were multifocal. Rios et al. discovered 59 thyroid carcinomas in a series of 672 patients operated on for...

Nodular Goiter

This disease develops as the result of absolute or relative deficiency of iodine intake. Goiter is defined as endemic in areas where more than 10 of the population is affected and sporadic when the incidence is less than that. Endemic goiter occurs in areas of iodine deficiency. Increased requirement for thyroid hormones, individual dietary insufficiency of iodine, ingestion of goitrogens, and subclinical levels of dyshormonogenesis may be important in the pathogenesis of the sporadic form. The pathological features are a combination of hyper-plastic and involutional change and nodule formation. The initial change is related to stimulation of secretion of thyroid hormones by pituitary thyroid-stimulating hormone (TSH) in response to an increased demand for thyrox-ine. This results in thyroid hyperplasia, with the development of increased numbers of small follicles with little storage of colloid. The follicular cells are columnar and may show pleomor-phism and mitotic activity. When...

Epidemiology

The prevalence of thyroid nodules increases with age. They are commoner in women than men and very common in areas of iodine deficiency. The prevalence of palpable thyroid nodules in most series is 3-7 5-8 and the annual incidence 0.1 7 . Using sensitive imaging techniques such as high resolution ultrasound, it has been shown that over 50 of all adults have thyroid nodules 9-11 . Similarly high prevalence of nodules has been noted in postmortem studies 12 . The malignancy rate of palpable solitary nodules is 5 with a range of 3.4-29 13 . Nearly half of all patients thought to have a solitary nodule by clinical examination are found to have multiple nodules on ultrasonography 14 . The incidence of malignancy in multinodular goiters is similar to that of solitary nodules 15,16 . Different pathologies presenting as thyroid nodules are shown in Table 7.1.

Prevalence

A lower incidence of PMCT was found in an autopsy study from a rural area of Greece not known for a high incidence of endemic goiter or iodine deficiency 13 . Thyroid glands from 160 subjects who died following accidents, suicide, or sudden death were examined. Twelve papillary tumors were discovered, nine of which were smaller than 1 cm, yielding a PMCT incidence of 5.6 . There was no preponderance of either sex in these nine. A much higher incidence of PMCT was found by Harach et al. 14 in a meticulous study of 101 consecutive autopsies in Finland. They found that 35.6 of thyroid glands had one or more PMCTs 66.7 were in nodular specimens and 64 measured less than 6 mm. There was no correlation between tumor size and age. Sixteen of the 36 glands containing tumors had multiple foci, many bilateral, and were found predominantly in males. In fact,64 of the PMCTs in this series were discovered in males. Since clinical papillary carcinomas are much more common in women, the authors...

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