Diagnosis of the classic form of Graves disease is easy and depends on the recognition of the cardinal features of the disease and confirmation by tests such as TSH and FTI. The differential diagnosis includes other types of thyrotoxicosis, such as that occurring in a nodular gland, accompanying certain tumors of the thyroid, or thyrotoxicosis factitia, and nontoxic goiter. Types of hypermetabolism that imitate symptoms of thyrotoxicosis must also enter the differential diagnosis. Examples are certain cases of pheochromocytoma, polycythemia, lymphoma, and the leukemias. Pulmonary disease, infection, parkinsonism, pregnancy, or nephritis may stimulate certain features of thyrotoxicosis. Treatment of Graves disease cannot yet be aimed at the cause because it is still unknown. One seeks to control thyrotoxicosis when that seems to be the major indication, or the ophthalmopathy when that aspect of the disease appears to be more urgent. The available forms of treatment, including surgery, drugs, and 131-I therapy, are reviewed. There is a difference of opinion as to which of these modalities is best, but to a large degree guidelines governing choice of therapy can be drawn. Antithyroid drugs are widely used for treatment on a long- term basis. About one-third of the patients undergoing long-term antithyroid therapy achieve permanent euthyroidism. Drugs are the preferred initial therapy in children and young adults. Subtotal thyroidectomy is a satisfactory form of therapy, if an excellent surgeon is available, but is less used in 2016. The combined use of antithyroid drugs and iodine makes it possible to prepare patients adequately before surgery, and operative mortality is approaching the vanishing point. Many young adults, are treated by surgery if antithyroid drug treatment fails. Currently, most endocrinologists consider RAI to be the best treatment for adults, and consider the associated hypothyroidism to be a minor problem. Evidence to date after well over five decades of experience indicates that the risk of late thyroid carcinoma must be near zero. The authors advise this therapy in most patients over age 40, and believe that it is not contraindicated above the age of about 15. Dosage is calculated on the basis of 131-I uptake and gland size. Most patients are cured by one treatment. Hypothyroidism.occurs with a fairly constant frequency for many years after therapy and may be unavoidable if cure of the disease is to be achieved by 131-I.. Many therapists accept this as an anticipated outcome of treatment. Thyrotoxicosis in children is best handled initially by antithyroid drug therapy. If this therapy does not result in a cure, surgery may be performed. Treatment with 131-I is accepted as an alternative form of treatment by some physicians, especially as age increase toward 15 years. Neonatal thyrotoxicosis is a rarity. Antithyroid drugs, propranolol and iodide may be required for several weeks until maternally-derived antibodies have been metabolized. The physician applying any of these forms of therapy to the control of thyrotoxicosis should also pay heed to the patients emotional needs, as well as to his or her requirements for rest, nutrition, and specific antithyroid medication. Consult our FREE web-book http://WWW.ENDOTEXT.ORG for complete coverage on this and related topics.

We note that there are currently available 2 very extensive Guidelines on Diagnosis and Treatment of Graves DiseaseThe 2016 ATA guideline http://online.liebertpub.com/doi/pdfplus/10.1089/thy.2016.0229 (270 pages), and the AACE 2011 version on Hyperthyroidism and other Causes of Thyrotoxicosis (65 pages)https://www.aace.com/files/hyperguidelinesapril2013.pdf. Both are well worth reviewing.

The diagnosis of Graves disease is usually easily made. The combination of eye signs, goiter, and any of the characteristic symptoms and signs of hyperthyroidism forms a picture that can hardly escape recognition (Fig -1). It is only in the atypical cases, or with coexisting disease, or in mild or early disease, that the diagnosis may be in doubt. The symptoms and signs have been described in detail in the section on manifestations of Graves disease. For convenience, the classic findings from the history and physical examination are grouped together in Table 1a and 1b.These occur with sufficient regularity that clinical diagnosis can be reasonably accurate. Scoring the presence or absence and severity of particular symptoms and signs can provide a clinical diagnostic index almost as reliable a diagnostic measure as laboratory tests(1).

Occasionally diagnosis is not at all obvious.In patients severely ill with other disease, in elderly patients with apathetic hyperthyroidism, or when the presenting symptom is unusual, such as muscle weakness, or psychosis, the diagnosis depends on clinical alertness and laboratory tests.

The diagnosis of Graves Disease does not only depend on thyrotoxicosis. Ophthalmopathy, or pretibial myxedema may occasionally occur without goiter and thyrotoxicosis, or even with spontaneous hypothyroidism. While proper classification can be debated, these patients seem to represent one end of the spectrum of Graves Disease. Thus we are usually making two coincident diagnoses:1)- Is the patient hyperthyroid? and 2)- Is the cause of the problem Graves disease ?.

Family history of any thyroid disease, especially Graves disease

TSH and FT4 assay-Once the question of thyrotoxicosis has been raised, laboratory data are required to verify the diagnosis, help estimate the severity of the condition, and assist in planning therapy. A single test such as the TSH or estimate of FT4 (free T4) may be enough, but in view of the sources of error in all determinations, most clinicians prefer to assess two more or less independent measures of thyroid function. For this purpose, an assessment of FT4 and sensitive TSH are suitable. As an initial single test, a sensitive TSH assay may be most cost-effective and specific. TSH should be 0 .1 U/ml in significant thyrotoxicosis, although values of .1 .3 are seen in patients with mild illness, especially with smoldering toxic multinodular goiter in older patients(1.1). TSH can be low in some elderly patients without evidence of thyroid disease. TSH can be normal or elevated only if there are spurious test results from heterophile antibodies or other cause, or the thyrotoxicosis is TSH-driven, as in a pituitary TSH-secreting adenoma or pituitary resistance to thyroid hormone. Measurement of FT4 or FTI (Free thyroxine index)is also usually diagnostic.The degree of elevation of the FT4 above normal provides an estimate of the severity of the disease. During replacement therapy with thyroxine the range of both FTI and fT4 values tend to be about 20% above the normal range, possibly because only T4, rather than T4 and T3 from the thyroid, is providing the initial supply of hormone. Thus many patients will have an fT4 or FTI above normal when appropriately replaced and while TSH is in the normal range. Except for this, elevations of fT4 not due to thyrotoxicosis are unusual, and causes are given in Table 3.

Of course the Total T4 level may normally be as high as 16 or 20 g/dl in pregnancy, and can be elevated without thyrotoxicosis in patients with familial hyperthyroxinemia due to abnormal albumin, the presence of hereditary excess TBG, the presence of antibodies binding T4 , the thyroid hormone resistance syndrome, and other conditions listed in Table 3. The T4 level may be normal in thyrotoxic patients who have depressed serum levels of T4 -binding protein or because of severe illness, even though they are toxic. Thus, thyrotoxicosis may exist when the total T4 level is in the normal range. However measurement of FT4, FT3 (Free T3), or FTI (Free Thyroxine Index) usually obviates this source of error and is the best test. In the presence of typical symptoms, one measurement of suppressed TSH or elevated fT4 is sufficient to make a definite diagnosis, although it does not identify a cause. If the fT4 is normal, repetition is in order to rule out error, along with a second test such as serum FT3. And it should be noted that in much of Europe FT3 is the preferred test, rather than FT4, and serves very well.

A variety of methods for FT4 determination have become available, including commercial kits. Although these methods are usually reliable, assays using different kits do not always agree among themselves or with the determination of FT4 by dialysis. Usually T4 and T3 levels are both elevated in thyrotoxicosis, as is the FTI (Free Thyroxin Index), or an index constructed using the serum T3 and rT3U levels, and the newer measures of FT3.

T3 and FT3 ASSAY-The serumT3 level determined by RIA is almost always elevated in thyrotoxicosis and is a useful but not commonly needed secondary test. Usually the serum T3 test is interpreted directly without use of a correction for protein binding, since alterations of TBG affect T3 to a lesser extent than T4. Any confusion caused by alterations in binding proteins can be avoided by use of a FT3 assay or T3 index calculated as for the FTI. Generally the FT3 assay is as diagnostically effective as the FT4. In patients with severe illness and thyrotoxicosis, especially those with liver disease or malnutrition or who are taking steroids or propranolol, the serum T3 level may not be elevated, since peripheral deiodination of T4 to T3 is suppressed (T4 toxicosis). A normal T3 level has also been observed in thyrotoxicosis combined with diabetic ketoacidosis. Whether or not these patients actually have tissue hypermetabolism at the time their serum T3 is normal is not entirely certain. In these patients the rT3 level may be elevated. If the complicating illness subsides, the normal pattern of elevated T4 , FTI, and T3 levels may return(5,6). Elevated T4 levels with normal serum T3 levels are also found in patients with thyrotoxicosis produced by iodine ingestion(7).

T3 Toxicosis Since 1957, when the first patient with T3 thyrotoxicosis was identified, a number of patients have been detected who had clinical thyrotoxicosis, normal serum levels of T4 and TBG, and elevated concentrations of T3 and FT3[8]. Hollander et al [9] found that approximately 4% of patients with thyrotoxicosis in the New York area fit this category. These patients often have mild disease but otherwise have been indistinguishable clinically from others with thyrotoxicosis. Some have had the diffuse thyroid hyperplasia of Graves disease, others toxic nodular goiter, and still others thyrotoxicosis with hyperfunctioning adenomas. Interestingly, in Chile, a country with generalized iodine deficiency, 12.5% of thyrotoxic subjects fulfilled the criteria for T3 thyrotoxicosis [10]. Asymptomatic hypertriiodothyronemia is an occasional finding several months before the development of thyrotoxicosis with elevated T4 levels [11]. Since T4 is normally metabolized to T3, and the latter hormone is predominantly the hormone bound to nuclear receptors, it makes sense that elevation of T3 alone is already indicative of thyrotoxicosis.

Thyroid Isotope uptake-In patients with thyrotoxicosis the RAIU (Radioactive Iodine Uptake) at 24 hours is characteristically above normal. In the United States, which has had an increasing iodine supply in recent years, the upper limit of normal is now about 25% of the administered dose. This value is higher in areas of iodine deficiency and endemic goiter. The uptake value at a shorter time interval, for example 6 hours, is as valid a test and may be more useful in the infrequent cases having such a rapid isotope turnover that uptake has fallen to normal by 24 hours. If there is reason to suspect that thyroid isotope turnover is rapid, it is wise to do both a 6- and a 24-hour RAIU determination during the initial laboratory study. As noted below, rapid turnover of 131-I can seriously reduce the effectiveness of 131-I therapy. Similar studies can be done with 123-I and also technetium. Because of convenience, and since serum assays of thyroid hormones and TSH are reliable and readily available, the RAIU is now infrequently determined unless 131-I therapy is planned.. It is however useful in patients who are mildly thyrotoxic for factitia thyrotoxicosis, subacute thyroiditis and painless thyroiditis in whom RAIU is low, thus confirming thyrotoxicosis in the absence of elevated RAIU. This may include patients with brief symptom duration, small goiter, or lacking eye signs, absent family history, or negative antibody test result. Obviously other causes of a low RAIU test need to be considered and excluded. Tests measuring suppressibility of RAIU are of historical interest(13-15)

Thyroid IsotopeScanning-Isotope scanning of the thyroid has a limited role in the diagnosis of thyrotoxicosis. It is useful in patients in whom the thyroid is difficult to feel or in whom nodules (single or multiple) are present that require evaluation, or rarely to prove the function of ectopic thyroid tissue. Nodules may be incidental, or may be the source of thyrotoxicosis (toxic adenoma), or may contribute to the thyrotoxicosis that also arises from the rest of the gland. Scanning should usually be done with 123-I in this situation, in order to combine it with an RAIU measurement.

Thyroid Ultrasound- US exam of the thyroid is sometimes of value in diagnosis. For example, if a possible nodule is detected on physical exam. It also may confirm hypoechogenicity or intense vascularity of Graves disease if a color Doppler flow exam is done.

Antithyroid Antibodies Determination of antibody titers provides supporting evidence for Graves disease. More than 95% of patients have positive assays for TPO (thyroperoxidase or microsomal antigen), and about 50% have positive anti-thyroglobulin antibody assays. In thyroiditis the prevalence of positive TG antibody assays is higher. Positive assays prove that autoimmunity is present, and patients with causes of thyrotoxicosis other than Graves disease usually have negative assays. During therapy with antithyroid drugs the titers characteristically go down, and this change persists during remission. Titers tend to become more elevated after RAI treatment.

Antibodies to TSH-Receptor-Thyrotrophin receptor antibody (TRAb) assays have become readily available, and a positive result strongly supports the diagnosis of Graves disease(15.1). Determination of TRAb is not required for the diagnosis, but the implied specificity of a positive test provides security in diagnosis, and for this reason the assay is now widely used. The assay is valuable as another supporting fact in establishing the cause of exophthalmos, in the absence of thyrotoxicosis. High maternal levels suggest possible fetal or neonatal thyrotoxicosis. TRAb assays measure any antibody that binds to the TSH-R. Assays for Thyroid Stimulating Antibodies (TSAb,TSI) are less available, but are more specific for the diagnosis. Using current tests, both are positive in about 90% of patients with Graves disease who are thyrotoxic. Second generation assays becoming available use monoclonal anti-TSH-R antibodies and biosynthetic TSH-R in coated tube assays, are reported to reach 99% specificity and sensitivity(15.2,15.3,3). Although rarely required, serial assays are of interest in following a patients course during antithyroid drug therapy, and a decrease predicts probable remission(15.4).

Other Assays Rarely Used-General availability of assays that can reliably measure suppressed TSH has made this the gold standard to which other tests must be compared, and has effectively eliminated the need for most previously used ancillary tests. There are only rare causes of confusion in the TSH assay. Severe illness, dopamine and steroids, and hypopituitarism, can cause low TSH, but suppression below 0.1 /ml is uncommon and below 0.05 /ml is exceptional, except in thyrotoxicosis. Thyrotoxicosis is associated with normal or high TSH in patients with TSH producing pituitary tumors and selective pituitary resistance to thyroid hormone. If TSH, FT4, TRAb, and other tests noted above do not establish the diagnosis, it may be wise to do nothing further except to observe the course of events. In patients with significant thyroid hyperfunction, the symptoms and signs will become clearer, and the laboratory measurements will fall into line. Measurement of BMR, T3 suppression of RAIU, TRH testing, and clinical response to KI are of historical interest.

Graves disease must be differentiated from other conditions causing thyrotoxicosis. (Table -4).

Thyrotoxicosis factitia-Thyrotoxicosis may be caused by taking T4 or its analogs, most commonly due to administration of excessive replacement hormone by the patients physician. Hormone may be taken surreptitiously by the patient for weight loss or psychologic reasons. The typical findings are a normal or small thyroid gland, a low131-I uptake, a low serum TG, and, of course, a striking lack of response to antithyroid drug therapy. The problem can easily be confused with painless thyroiditis, but in thyrotoxicosis factitia, the gland is typically small.

Toxic nodular goiter is usually distinguished by careful physical examination and a history of goiter for many years before symptoms of hyperthyroidism developed. The thyrotoxicosis comes on insidiously, and often, in the older people usually afflicted, symptoms may be mild, or suggest another problem such as heart disease. The thyroid scan may be diagnostic, showing areas of increased and decreased isotope uptake. The results of assays for antithyroid antibodies, including TRAb, are usually negative. TMNG is typically produced by activating somatic mutations in TSH-R in one or more nodules, allowing them to enlarge and become functional even in the absence of TSH stimulation. (Interestingly, cats are well known to develop hyperthyroidism, with thyroid autonomy, often due to TSH-R gene mutations as seen in humans.(16))

Hyperfunctioning solitary adenoma is suggested on the physical finding of a palpable nodule in a otherwise normal gland, and is proved by a scintiscan demonstrating preferential radioisotope accumulation in the nodule. This type of adenoma must be differentiated from congenital absence of one of the lobes of the thyroid. Toxic nodules typically present in adults with gradually developing hyperthyroidism and a nodule > 3 cm in size. These nodules are usually caused by activating somatic mutations in the TSH-R, which endows them with mildly increased function, compared to normal tissue, even in the absence of TSH. These nodules are usually, but not always, monoclonal(17). In adults toxic nodules are very rarely malignant. Rarely, functioning thyroid carcinomas produce thyrotoxicosis. The diagnosis is made by the history, absence of the normal thyroid, and usually widespread functioning metastasis in lung or bones. Invasion of the gland by lymphoma has produced thyrotoxicosis, presumably due to thyroid destruction (18).

Thyrotoxicosis associated with subacute thyroiditis is usually mild and transient, and the patient lacks the physical findings of long-standing thyrotoxicosis. If thyrotoxicosis is found in conjunction with a painful goiter and low or absent 131-I uptake, this diagnosis is likely. Usually the erythrocyte sedimentation rate (ESR) and CRP are greatly elevated, and the leukocyte count may also be increased. Occasionally the goiter is non-tender. Antibody titers are low or negative. Many patients have the HLA-B35 antigen, indicating a genetic predisposition to the disease. The rare TSH secreting pituitary adenoma will be missed unless one measures the plasma TSH level, or until the enlargement is sufficient to produce deficiencies in other hormones, pressure symptoms, or expansion of the sella turcica(19). These patients have thyrotoxicosis with inappropriately elevated TSH levels and may/or may not secrete more TSH after TRH stimulation. The characteristic finding is a normal or elevated TSH, and an elevated TSH alpha subunit level in blood, measured by special RIA. TRAbs are not present. Exophthalmos, and antibodies of Graves disease are absent. Family history is sometimes positive for a similar condition. Demonstration of a suppressed TSH level excludes these rare cases.

The category of patients with thyrotoxicosis and inappropriately elevated TSH levels also includes the rare persons with pituitary T3 resistance as a part of the Resistance to Thyroid Hormone syndrome caused by TH Receptor mutations. The syndrome of Pituitary Thyroid Hormone Resistance is usually marked by mild thyrotoxicosis, mildly elevated TSH levels, absence of pituitary tumor, a generous response to TRH, no excess TSH alpha subunit secretion [19,20, 21],and by TSH suppression if large doses of T3 are administered. Final diagnosis depends on laboratory demonstration of a mutation in the TR gene, if possible. Hyperthyroidism caused by excess TRH secretion is a theoretical but unproven possibiity.

Administration of large amounts of iodide in medicines, for roentgenographic examinations, or in foods can occasionally precipitate thyrotoxicosis in patients with multinodular goiter or functioning adenomas. This history is important to consider since the illness may be self-limiting. Induction of thyrotoxicosis has also been observed in apparently normal individuals following prolonged exposure to organic iodide containing compounds such as antiseptic soaps and amiodarone. Amiodarone is of special importance since the clinical problem often is the presentation of thyrotoxicosis in a patient with serious cardiac disease including dysrythmia. Amodarone can induce thyrotoxicosis in patients without known prior thyroid disease, or with multinodular goiter. The illness appears to come in two forms. In one the RAIU may be low or normal. In the second variety , which appears to be more of a thyroiditis-like syndrome, the RAIU is very suppressed, and IL-6 may be elevated. In either case TSH is suppressed, FTI may be normal or elevated, but T3 is elevated if the patient is toxic. Antibodies are usually negative.

An increasingly recognized form of thyrotoxicosis is the syndrome described variously as painless thyroiditis, transient thyrotoxicosis, or hyperthyroiditis. Its hallmarks are self-limited thyrotoxicosis, small painless goiter, and low or zero RAIU(22,23). The patients usually have no eye signs, a negative family history, and often positive antibody titers. This condition is due to autoimmune thyroid disease, and is considered a variant of Hashimotos Thyroiditis. It occurs sporadically, usually in young adults. It frequently occurs 3 12 weeks after delivery, sometimes representing the effects of immunologic rebound from the immunosuppressive effects of pregnancy in patients with Hashimotos thyroiditis or prior Graves Disease, and is called Post Partum Thyroiditis(22-25). The course typically includes development of a painless goiter, mild to moderate thyrotoxicosis, no eye signs, remission of symptoms in 3 -20 weeks, and often a period of hypothyroidism before return to euthyroid function. The cycle may be repeated several times. Histologic examination shows chronic thyroiditis, but it is not typical of Hashimotos disease or subacute thyroiditis and may revert to normal after the attack(26). In most patients, the thyrotoxic episode occurs in the absence of circulating TSAb. This finding suggests that the pathogenesis is quite distinct from that in Graves disease. The thyrotoxicosis is caused by an inflammation-induced discharge of preformed hormone due to the thyroiditis. The T4/T3 ratio is higher than in typical Graves disease,and thyroid iodine stores are depleted. Since the thyrotoxicosis is due to an inflammatory process, therapy with antithyroid drugs or potassium iodide is usually to no avail, and RAI treatment of course cannot be given when RAIU is suppressed. Propranolol is usually helpful for symptoms. Glucocorticoids may be of help if the process often transient and mild requires some form of therapy. Propylthiouracil and/or ipodate can be used to decrease T4 to T3 conversion and will ameliorate the illness. Repeated episodes may be handled by surgery or by RAI therapy during a remission. Occasionally painless post-partum thyroiditis is followed by typical Graves Disease(27-29.1).

Hyperemisis gravidarum is frequently associated with elevated serum T4 , FTI, and variably elevated T3, and suppressed TSH. The abnormalities in thyroid function are caused by high levels of hCG. This molecule, or a closely related form, share enough homology with TSH so that it has about 1/1000 the thyroid stimulating activity of TSH, and can produce thyroid stimulation or thyrotoxicosis(29.12-29.14). It is typically self limited without specific treatment, disappears with termination of pregnancy, but may occasionally require anti-thyroid treatment temporarily or throughout pregnancy(29.3). Patients with minimal signs and symptoms, small or no goiter, and elevation of FTI up to 50 % above normal probably do not require treatment. Rarely those with goiter, moderate or severe clinical evidence of thyrotoxicosis, highly elevated T4 and T3 and suppressed TSH are best treated with antithyroid drugs. If antibodies are positive or eye signs are present, the picture is usually interpreted as a form of Graves disease. Familial severe hyperemesis gravidarum with fetal loss has been reported with an activating germline mutation in the TSH-R, which made it specifically more sensitive to activation by hCG(.29.2,29.3). Hyperthyroidism can be induced by hyperplacentosis, which is characterized by increased placental weight and circulating hCG levels higher than those in normal pregnancy(29.4). After hysterotomy, hCG levels declined in the one case reported and hyperthyroidism was corrected.

Congenital hyperthyroidism caused by a germ-line activating mutation in the TSH-R has recently been recognized . The mutations are usually single aminoacid transitions in the extracellular loops or transmembrane segments of the receptor trans-membrane domain. The diagnosis may be difficult to recognize in the absence of a family history. However the patients lack eye signs, and have negative assays for antibodies(29.2, 29.3)

Hydatidiform moles, choriocarcinomas, and rarely seminomas secrete vast amounts of hCG. hCG, with an alpha subunit identical to TSH , and beta subunit related to TSH , that binds to and activates the thyroid TSH receptor with about 1/1,000th the efficiency of TSH itself (Fig.-3)(30-33). Current evidence indicates that very elevated levels of native hCG or perhaps desialated hCG, cause the thyroid stimulation. Many patients have goiter or elevated thyroid hormone levels or both, but little evidence of thyrotoxicosis, whereas others are clearly thyrotoxic. Diagnosis rests on recognizing the tumor (typically during or after pregnancy) and measurement of hCG. Therapy is directed at the tumor.

Hyperthyroidism also is seen as one manifestation of autoimmune thyroid disease induced by interferon-alpha treatment of chronic hepatitis C. It can be self limiting, or severe enough to require cessation of IFN, or in some cases continue on after INF is stopped(33.1).

Hyperthyroidism also occurs during immune reconstitution seen after effective anti-viral therapy of patients with HIV(33.2), has occurred during recovery of low lymphocyte levels induced by therapy with CAMPATH in patients with Multiple sclerosis, has occurred after cessation of immune-suppressive treatment in patients with T1DM.

It should be remembered that thyrotoxicosis is today not only a clinical but also a laboratory diagnosis. Consistent elevation of the fT4 , and the T3 level, and suppressed TSH, or only suppression of TSH, can indicate that thyrotoxicosis is present even in the absence of clear-cut signs or symptoms These elevations themselves are a sufficient indication for therapy, especially in elderly patients with coincident cardiac disease(33a,b). Antithyroid drug treatment of patients with subclinical hyperthyroidism was found to result in a decrease in heart rate, decrease in number of atrial and ventricular premature beats, a reduction of the left ventricular mass index, and left ventricular posterior wall thickness, as well as a reduction in diastolic peak flow velocity. These changes are considered an argument for early treatment of subclinical hyperthyroidism. Subclinical hyperthyroidism may disappear or evolve into Graves hyperthyroidism, or when caused by MNG, persist for long periods unchanged. Individuals of any age with consistent suppression of TSH should be fully evaluated to determine if evidence of hyperthyroidism is present, or there is coincident disease that might be aggrevated by hyperthyroidism. SCH with TSH of 0.2-0.3.5 may not need treatment. Individuals with TSH at or below 0.1uU/ml most likely will require treatment by one of the methods described below.

Apathetic hyperthyroidism designates a thyrotoxic condition characterized by fatigue, apathy, listlessness, dull eyes, extreme weakness, often congestive heart failure, and low-grade fever.[ 34, 35] Often such patients have small goiters, modest tachycardia, occasionally cool and even dry skin, and few eye signs. The syndrome may, in some patients, represent an extreme degree of fatigue induced by long-standing thyrotoxicosis. Once the diagnosis is considered, standard laboratory tests should confirm or deny the presence of thyrotoxicosis even in the absence of classical symptoms and signs.

Other diagnostic problems Two common diagnostic problems involve (1) the question of hyperthyroidism in patients with goiter of another cause, and (2) mild neuroses such as anxiety, fatigue states, and neurasthenia. Most patients with goiter receive a battery of examinations to survey their thyroid function at some time. Usually these tests are done more for routine assessment than because there is serious concern over the possibility of thyrotoxicosis. In the absence of significant symptoms or signs of hyperthyroidism and ophthalmologic problems, a normal FTI or TSH determination is sufficiently reassuring to the physician and the patient. Of course, the most satisfactory conclusion of such a study is the identification of an alternate cause for enlargement of the thyroid. Some patients complain of fatigue and palpitations, weight loss, nervousness, irritability, and insomnia. These patients may demonstrate brisk reflex activity, tachycardia (especially during examinations), perspiration, and tremulousness. In the abscence of thyrotoxicosis, the hands are more often cool and damp rather than warm and erythematous. Serum TSH assay should be diagnostic.

Mild and temporary elevation of the FTI may occur if there is a transient depression of TBG production for example, when estrogen administration is omitted. This problem is occasionally seen in hospital practice, usually involving a middle-aged woman receiving estrogen medication that is discontinued when the patient is hospitalized. Estrogen withdrawal leads to decreased TBG levels and a transiently elevated FTI. After two to three weeks, both the T4 level and the FTI return to normal ( Table -3). In the differential diagnosis of heart disease, the possibility of thyrotoxicosis must always be considered. Some cases of thyrotoxicosis are missed because the symptoms are so conspicuously cardiac that the thyroid background is not perceived. This is especially true in patients with atrial fibrillation. Many disorders may on occasion show some of the features of hyperthyroidism or Graves disease. In malignant disease, especially lymphoma, weight loss, low grade fever, and weakness are often present. Parkinsonism in its milder forms may initially suggest thyroid disease. So also do the flushed countenance, bounding pulse, thyroid hypertrophy, and dyspnea of pregnancy. Patients with chronic pulmonary disease may have prominent eyes, tremor, tachycardia, weakness, and even goiter from therapeutic use of iodine. One should remember the weakness, fatigue, and jaundice of hepatitis and the puffy eyes of trichinosis and nephritis. Cirrhotic patients frequently have prominent eyes and lid lag, and the alcoholic patient with tremor, prominent eyes, and flushed face may be initially suspected of having thyrotoxicosis. Distinguishing between Graves disease with extreme myopathy and myopathies of other origin can be clinically difficult. The term chronic thyrotoxic myopathy is used to designate a condition characterized by weakness, fatigability, muscular atrophy, and weight loss usually associated with severe thyrotoxicosis. Occasionally fasciculations are seen. The electromyogram result may be abnormal. If the condition is truly of hyperthyroid origin, the thyroid function tests are abnormal and the muscular disorder is reversed when the thyrotoxicosis is relieved. Usually a consideration of the total clinical picture and assessment of TSH and FTI are sufficient to distinguish thyrotoxicosis from polymyositis, myasthenia gravis, or progressive muscular atrophy. True myasthenia gravis may coexist with Graves disease, in which case the myasthenia responds to neostigmine therapy. (The muscle weakness of hyperthyroidism may be slightly improved by neostigmine, but never relieved.) Occasionally electromyograms, muscle biopsy, neostigmine tests, and ACH-receptor antibody assays must be used to settle the problem.

No treatment is ideal and thus indicated in all patients ( 35.1).Three forms of primary therapy for Graves disease are in common use today: (1) destruction of the thyroid by 131-I; (2) blocking of hormone synthesis by antithyroid drugs; and (3) partial or total surgical ablation of the thyroid. Iodine alone as a form of treatment was widely used in the past, but is not used today because its benefits may be transient or incomplete and because more dependable methods became available. Iodine is primarily used now in conjunction with antithyroid drugs to prepare patients for surgical thyroidectomy when that plan of therapy has been chosen. There is, however, some revival of interest in use of iodine treatment as described subsequently. Roentgen irradiation was also used in the past, but is not currently [36]. Suppression of the autoimmune response is being attempted, and currently new treatments blocking the action of Thyroid Stimulating Immunoglobulins are being investigated.

Selection of therapy depends on a multiplicity of considerations [36.1]. Availability of a competent surgeon, for example, undue emotional concern about the hazards of 131-I irradiation, or the probability of adherence to a strict medical regimen might govern ones decision regarding one program of treatment as opposed to another. More than 90% of patients are satistactorly treated cumulating the effects of these treatment.(36.2) Fig. 2

Antithyroid drug therapy offers the opportunity to avoid induced damage to the thyroid (and parathyroids or recurrent nerves), as well as exposure to radiation and operation. In recent studies patients with thyroids under 40 gm weight, with low TRAb levels, and age over 40, were most likely to enter remission (in up to 80%) (36.3, 36.31). The difficulties are the requirement of adhering to a medical schedule for many months or years, frequent visits to the physician, occasional adverse reactions, and, most importantly, a disappointingly low permanent remission rate. Therapy with antithyroid drugs is used as the initial modality in most patients under age 18, in many adults through age 40, and in most pregnant women(36.31). Remission is most likely in young patients, with small thyroids, and mild disease. ATDs may be preferred in elderly patients, those with serious co-morbidities and who have been previously operated upon.

Iodine-131 therapy is quick, easy, moderatly expensive, avoids surgery, and is without significant risk in adults and probably teenagers. The larger doses required to give prompt and certain control generally induce hypothyroidism, and low doses are associated with a frequent requirement for retreatment or ancillary medical management over one to two years. 131-I is used as the primary therapy in most persons over age 40 and in most adults above age 21 if antithyroid drugs fail to control the disease. Treatment of children with 131-I is less common, as discussed later. It can be used in the elderly and those with co-morbidities with precautions.

Surgery, which was the main therapy until 1950, has been to a large extent replaced by 131-I treatment. As the high frequency of 131-I induced hypothyroidism became apparent, some revival of interest in thyroidectomy occurred. The major advantage of surgery is that definitive management is often obtained over an 8- to 12-week period, including preoperative medical control, and many patients are euthyroid after operation. Its well-known disadvantages include expense, surgery itself, and the risks of recurrent nerve and parathyroid damage, hypothyroidism, and recurrence. Nevertheless, if a skillful surgeon is available, surgical management may be used as the primary or secondary therapy in many young adults, as the secondary therapy in children poorly controlled on antithyroid drugs, in pregnant women requiring excessive doses of antithyroid drugs, in patients with significant exophthalmos, and in patients with coincident suspicious thyroid nodules. Early total thyroidectomy has been recommended for treating older, chronically ill patients with thyrotoxic storm if high-dose thionamide treatment, iopanoic acid, and glucocorticoids fail to improve the patients condition within 12 24 hours (36.4).

Two recent surveys reporting trends in therapeutic choices made by thyroidologists have been published [37]. In Europe, most physicians tended to treat children and adults first with antithyroid drugs, and adults secondarily with 131-I or less frequently surgery. Surgery was selected as primary therapy for patients with large goiters. 131-I was selected as the primary treatment in older patients. Most therapists attempted to restore euthyroidism by use of 131-I or surgery. In the United States, 131-I is the initial modality of therapy selected by members of the American Thyroid Association for management of uncomplicated Graves disease in an adult woman [38]. Two-thirds of these clinicians attempt to give 131-I in a dosage calculated to produce euthyroidism, and one-third plan for thyroid ablation.

Introduction-In many thyroid clinics 131-I therapy is now used for most patients with Graves disease who are beyond the adolescent years. It is used in most patients who have had prior thyroid surgery, because the incidence of complications, such as hypoparathyroidism and recurrent nerve palsy, is especially high in this group if a second thyroidectomy is performed. Likewise, it is the therapy of choice for any patient who is a poor risk for surgery because of complicating disease. Surgery may be preferred in patients with significant ophthalmopathy, often combined with prednisone prophylaxis.

Treatment of children-The question of an age limit below which RAI should not be used frequently arises. With lengthening experience these limits have been lowered. Several studies with average follow-up periods of 12 15 years attest to the safety of 131-I therapy in adults [ 39- 41]. In two excellent studies treated persons showed no tendency to develop thyroid cancer, leukemia, or reproductive abnormalities, and their children had no increase in congenital defects or evidence of thyroid damage [ 42- 44]. Franklyn and co workers recently reported on a population based study of 7417 patients treated with 131-I for thyrotoxicosis in England [44.1]. They found an overall decrease in incidence of cancer mortality, but a specific increase in mortality from cancer of the small bowel (7 fold) and of the thyroid (3.25) fold. The absolute risk remains very low, and it is not possible to determine whether the association is related to the basic disease, or to radioiodine treatment. Although there is much less data on long term results in children, there is a increased use of this treatment in teenagers age 15-18, as discussed below. The epidemic of thyroid cancer apparently induced by radioactive iodine isotopes in infants and children living around Chernobyl suggests caution in use of 131-I in younger children. Since the possibility of a general induction of cancer by 131-I is of central concern, it is interesting to calculate the risk in children using the data presented by Rivkees et al (44.2) who are proponents of use of RAI for therapy in young children..The risk of death from any cancer due specifically to radiation exposure is noted by these authors to be 0.16%/rem for children, and the whole body radiation exposure from RAI treatment at age 10 to be 1.45 rem/mCi administered. Rivkees et al advise treatment with doses of RAI greater then 160 uCi/gram thyroid, to achieve a thyroidal radiation dose of at least 150Gy (about 15000 rads). Assuming a reasonable RAIU of 50% and gland size of 40 gm, the administered dose would thus be 40(gm) x 160uCi/gm x 2 (to account for 50% uptake) =12.8 mCi. Thus the long term cancer death risk would be 12.8 (mCi) x 1.45 rem (per mCi) x 0.16% (per rem) = 3%. For a dose of 15mCi the theoretical incremental risk of a later radiation-induced cancer mortality would be 4% at age 5, 2% at age 10, and 1% at age 15. Whether or not accepting a specific 2-4% risk of death from any cancer because of this treatment is of course a matter of judgment by the physician and family. However, this would seem to many persons to constitute a significant risk that might be avoided. We note that this is a thoretical risk, based on known effects of ioniing radiation to induce malignancies, but not so far proven in this setting.

Low 131-I uptake-Certain other findings may dictate the choice of therapy. Occasionally, the 131-I uptake is significantly blocked by prior iodine administration. The effect of iodide dissipates in a few days after stopping exposure, but it may take 3-12 weeks for the effect of amiodarone or IV contrast dyes to be lost. One may either wait for a few days to weeks until another 131-I tracer indicates that the uptake is in a treatable range or use an alternative therapeutic approach such as antithyroid drugs. Coincident nodule(s)-Sometimes a patient with thyrotoxicosis harbors a thyroid gland with a configuration suggesting the presence of a malignant neoplasm. These patients probably should have surgical exploration. While FNA may exclude malignancy, the safety of leaving a highly irradiated nodule in place for many years is not established. Currently few patients who will have RAI therapy are subjected to ultrasonagraphy or scintiscaning. However Stocker et al. found that 12% of Graves patients had cold defects on scan, and among these half were referred for surgery. Six of 22, representing 2% of all Graves patients, 15% of patients with cold nodules, 25% of patients with palpable nodules, and 27% of those going to surgery, had papillary cancer in the location corresponding to the cold defect. Of these patients, one had metastasis to bone and two required multiple treatments with radioiodine. They argue for evaluating patients with a thyroid scintigram and further diagnostic evaluation of cold defects(44.3). Certainly any patient with GD in whom a thyroid nodule is detected, deserves consideration for surgical treatment

Ophthalmopathy-131-I therapy causes an increase in titers of TSH-R Abs, and anti-TG or TPO antibodies, which reflects an activation of autoimmunity. It probably is due to release of thyroid antigens by cell damage, and possibly destruction of intrathyroidal T cells. Many thyroidologists are convinced that 131-I therapy can lead to exacerbation of infiltrative ophthalmopathy, perhaps because of this immunologic response. Tallstedt and associates published data indicating that 131-I therapy causes exacerbation of ophthalmopathy in nearly 25% of patients, while surgery is followed by this response in about half as many.The same group conducted a second randomized trial (44.3) with a follow-up of 4 yr. Patients with a recent diagnosis of Graves hyperthyroidism were randomized to treatment with iodine-131 (163 patients) or 18 months of medical treatment (150 patients). Early substitution with L-T4 was given in both groups.: Worsening or development of eye problems was significantly more common in the iodine-131 treatment group (63 patients; 38.7%) compared with the medical treatment group (32 patients; 21.3%) (P < 0.001). This adverse effect of RAI therapy has since been confirmed in multiple meta-analyses of randomized studies (44.4-44.7) Thus, as described below, patients with significant ophthalmopathy may receive corticosteroids along with131-I, or may be selected for surgical management. The indications and contraindications for 131-I therapy are given in Table 5.

There are two basically different goals in 131-I dose selection. The traditional approach has been to attempt to give the thyroid 1) sufficient radiation to return the patient to euthyroidism, but not induce hypothyroidism. An alternative approach is to intend to 2) induce hypothyroidism, or euthyroidism and avoid any possible return of hyperthyroidism.

BackgroundThe dosage initially was worked out by a trial-and-error method and by successive approximations. By 1950, the standard dose was 160 uCi 131-I per gram of estimated thyroid weight. Of course, estimating the weight of the thyroid gland by examination of the neck is an inexact procedure, but can now be made more accurate by use of ultrasound. Also, marked variation in radiation sensitivity no doubt exists and cannot be estimated at all. It was gratifying that in practice this dosage scheme worked well enough. In the early 1960s, it was recognized that a complication of RAI therapy was a high incidence of hypothyroidism. This reached 20 40% in the first year after therapy and increased about 2.5% per year, so that by 10 years 50 80% of patients had low function [45,46]. In an effort to reduce the incidence of late hypothyroidism, Hagen and colleagues reduced the quantity of 131-I to 0.08 mCi per gram of estimated gland weight [48]. No increase was reported in the number of patients requiring retreatment, and there was a substantial reduction in the incidence of hypothyroidism. Most of these patients were maintained on potassium iodide for several months after therapy, in order to ameliorate the thyrotoxicosis while the radioiodine had its effect [ 49, 50]. Patients previously treated with 131-I are sensitive to and generally easily controlled by KI. However KI often precipitates hypothyroidism in these patients, which may revert to hyperthyroidism when the KI is discontinued.

Over the years some effort was made to refine the calculation. Account was taken of uptake, half-life of the radioisotope in the thyroid, concentration per gram, and so on, but it is evident that the result in a given instance depends on factors that cannot be estimated precisely [47,]. One factor must be the tendency of the thyroid to return to normal if a dose of radiation is given that is large enough to make the gland approach, for a time, a normal functional state. In many patients, cure is associated with partial or total thyroid ablation. Although we, and many endocrinologists, attempt to scale the dose to the particular patient, some therapists believe it is futile, advocate giving up this attempt, and provide a standard dose giving up to 10000 rads to the thyroid(47.1). Leslie et al reported a comparison of fixed dose treatment and treatment adjusted for 24 hour RAIU, using low or high doses, and found no difference in outcome in either rate of control or induction of hypothyroidism on comparison of the methods. They favor the use of a fixed dose treatment with a single high or low dose (47.2).

Many attempts have been made to improve the therapeutic program by giving the RAI in smaller doses. Reinwein et al [51]. studied 334 patients several years after they had been treated with serial doses of less than 50 uCi 131-I per gram of estimated thyroid weight. One-third of these patients had increased levels of TSH, although they were clinically euthyroid. Only 3% were reported to be clinically hypothyroid.

Dosage adjustmentsmade to induce euthyroidism usually include a factor inc reassing with gland size, a standard dose in microCuries per gram, and a correction to account for 131-I uptake [52]. ALow Dose Protocol was designed to compensate for the apparent radiosensitivity of small glands and resistance of larger glands [53]. Using this approach, after one year, 10% of patients were hypothyroid, 60% are euthyroid, and 30% remained intrinsically toxic [53], although euthyroid by virtue of antithyroid drug treatment. At ten year follow-up, 40% were euthyroid and 60% hypothyroid. A problem with low-dose therapy is that about 25% of patients require a second treatment and 5% require a third. Although this approach reduces early hypothyroidism, it does so at a cost in time, money and patient convenience (Fig. 2). To answer these problems, patients can be re-treated, if need be, within six months, and propranolol and antithyroid drugs can be given between 131-I doses if needed. Unfortunately, experience shows that even low-dose 131-Itherapy is followed by a progressive development of hypothyroidism in up to 40 50% of patients ten years after therapy[ 54- 57].

Thyroid rads, avg.

Impressed by the need to retreat nearly a third of patients, a Moderate Dose Protocol was developed Table -6). This is a fairly conventional program with a mean dose of about 9 mCi. The 131-I dosage is related to gland weight and RAIU, and is increased as gland weight increases. The calculation used is as follows:

uCi given = (estimated thyroid weight in grams) X (uCi/g for appropriate weight from Table 6) / (fractional RAIU at 24 hours) (For readers who may find difficult the conversion of older units in Curies, rads, and rems to newer units of measurement, see Table -7.)

Thyroid rads, avg.

Probably it is wise to do uptakes and treatment using either capsules or liquid isotope for both events. Rini et al have reported that RAIU done with isotope in a capsule appears to give significantly lower values (25 30% lower) than when the isotope is administered in liquid form, and this can significantly influence the determination of the dosage given for therapy(57.1). Berg et al report using a relatively similar protocol (absorbed doses of 100-120 Gy) and that 93% of their patients required replacement therapy after 1-5 years [57.2]. Many studies have presented methods for more accurately delivering a specific radiation dose to the thyroid, and report curing up to 90% of patients, with low incidence of recurrence or hypothyroidism(57.3, 57.4). Franklyn and co-workers analyzed their data on treatment of 813 hyperthyroid patients with radioactive iodide and corroborate many of the previously recognized factors involved in response. Lower dose (in this case 5 mCi), male gender, goiters of medium or large size and severe hyperthyroidism were factors that were associated with failure to cure after one treatment. They suggest using higher fixed initial doses of radioiodine for treating such patients (58.2), as do Leslie et al(58.4). Santos et al (58.4) compared fixed doses of 10 and 15mCi and found no difference in outcome at 12 months post treatment. These authors suggest a standard 10mCi dose, with the larger dose reserved for larger glands.

Planned thyroid partial or complete ablation-All attempts to induce euthyroidism by a calculated moderate dose protocol end up with some patients hypothyroid, and others with persistent hyperthyroidism requiring further treatment. At this time many physicians giving 131-I therapy make no attempt to achieve euthyroidism, and instead use a dose sufficient to largely destroy the thyroid, followed by L- T4 replacement therapy [58]. For example, a dose is given that will result in 7-20 mCi retained at 24 hrs, which is intended to induce hypothyroidism, accepting that in some (or many) patients this will ablate the thyroid completely. A dose of 30 Mci was found to offer a slightly higher cure rate, not surprisingly, at one year than 15 Mci (95 vs 74% (58.1), They argue that this is realistic and preferable since it offers 1) near certainty of prompt control, 2) avoids any chance of persistent or recurrent disease, 3)there is no benefit in having residual thyroid tissue, and 4) hypothyroidism is inevitable in most patients given RAI. Probably many patients given this treatment do in fact have some residual thyroid tissue that is either heavily damaged or reduced in amount so that it can not produce normal amounts of hormone. So far there is no evidence, in adults, that this residual radiated tissue will develop malignant change. There is no certainty at this time that one approach is better than the other. It may be worth remembering that over 50% of patients given calculated moderate dose therapy remain euthyroid after ten years and can easily be surveyed at yearly intervals for hypothyroidism. When giving large doses of 131-I it is prudent to calculate the rads delivered to the gland (as above), which can reach 40-50,000rads. Such large doses of radiation can cause clinically significant radiation thyroiditis, and occasionally damage surrounding structures. And lastly, a speculation. Practitioners comment that the incidence of serious ophthalmopathy seems to be less that in former decades. Prompt diagnosis and therapy might contribute to such a change. Another factor could be the more common ablation of the thyroid during therapy for Graves disease, since this should over time reduce exposure of patients immune system to thyroid antigens.

Lithium with RAI therapy- Although rarely used, RAI combined with lithium is safe and more effective than RAI alone in the cure of hyperthyroidism due to Graves disease, probably because it it causes greater retention of RAI within the thyroid gland.. Bogazzi et al (58.5)reported a study combining lithium with RAI therapy. MMI treatment was withdrawn 5 days prior to treatment, Two hundred ninety-eight patients were treated with RAI plus lithium (900 mg/d for 12 d starting 5 days prior to 131-I treatment) and 353 with RAI alone. RAI dosage was 260mCi/g estimated thyroid weight, corrected for RAIU (done on lithium).. All patients receive prednisone 0.5mg/kg/day, beginning on day 7 after RAI, tapering over 2 months. Patients treated with RAI plus lithium had a higher cure rate (91.0%) than those treated with RAI alone (85.0%, P = 0.030). In addition, patients treated with RAI plus lithium were cured more rapidly (median 60 d) than those treated with RAI alone (median 90 d, P = 0.000). Treatment with lithium inhibited the serum FT4 increase seen after methimazole withdrawal and RAI therapy.

Pretreatment with antithyroid drugsPatients are often treated directly after diagnosis, without prior therapy with antithyroid drugs. This is safe and common in patients with mild hyperthyroidsm and especially those without eye problems. However often physicians give antithyroid drugs before 131-I treatment in order to deplete the gland of stored hormone and to restore the FTI to normal before 131-I therapy. This offers several benefits. The possibility of 131-I induced exacerbation of thyrotoxicosis is reduced, the patient recovers toward normal health, and there is time to reflect on the desired therapy and review any concerns about the use of radioisotope for therapy. If the patient has been on antithyroid drug, it is discontinued two days before RAIU and therapy. Patients can be treated while on antithyroid drug, but this reduces the dose retained, reduces the post-therapy increment in hormone levels, and reduces the cure rate, so seems illogical(58.6) . When antithyroid drugs are discontinued the patients disease may exacerbate, and this must be carefully followed. Beta blockers can be given in this interim, but there is no reason for a prolonged interval between stopping antithyroid drug, and 131-I therapy, unless there is uncertainty about the need for the treatment. Pretreatment with antithyroid drug does not appear in most studies to reduce the efficacy of 131-I treatment. [59] but the debate about the effect of antithyroid drug pretreatment on the efficacy of radioactive iodine therapy continues. In recent studies in which patients were on or off antithyroid therapy, which was discontinued four days, or 1-2 days before treatment, there was no effect on the efficacy of treatment at a one year endpoint (59.1,59.2, 59,3). In another study Bonnema et al found that PTU pretreatment , stopped 4 days prior to 131-I, reduced the efficacy of 131-I(59.6).

Pretreatment is usually optional but is logical in patients with large glands and severe hyperthyroidism. Antithyroid drug therapy does reduce the pretreatment levels of hormone and reduces the rise in thyroid hormone level that may occur after radioactive iodide treatment. This certainly could have a protective effect in individuals who have coincident serious illness such as coronary artery disease, or perhaps individuals who have very large thyroid glands (59.3). It is indicated in two circumstances. In patients with severe heart disease, an 131-I- induced exacerbation of thyrotoxicosis could be serious or fatal. Pretreatment may reduce exacerbation of eye disease (see below), and it does reduce the post-RAI increase in antibody titers(59.1,59.31). The treatment dose of 131-I is best given as soon as possible after the diagnostic RAIU in order to reduce the period in which thyrotoxicosis may exacerbate without treatment, and since any intake of iodine (from diet or medicines or tests) would alter uptake of the treatment dose (59.4), and 2 days seems sufficient.

Post 131-I treatment managementMany patients remain on beta-blockers but require no other treatment after 131-I therapy. Antithyroid drugs can be reinstituted after 5 ( or preferably 7 ) days, with minimal effect on retention of the treatment dose of 131-I.

Alternatively, one may prescribe antithyroid drug (typically 10 mg methimazole q8h) beginning one day after administration of 131-I and add KI (2 drops q8h) after the second dose of methimazole. KI is continued for two weeks, and antithyroid drug as needed. This promotes a rapid return to euthyroidism, but by preventing recirculation of 131-I it can lower the effectiveness of the treatment. This method has been employed in a large number of patients, and is especially useful in patients requiring rapid control- for example, with CHF. A typical response is shown in Fig -3. It also has provided the largest proportion of patients remaining euthyroid at 10 years after therapy, in comparison to other treatment protocols. Glinoer and Verelst also report successful use of this strategy [59.1]. As noted, antithyroid drugs may be given starting 7-10 days after RAI without significantly lowering the radiation dose delivered to the gland.

Treatment using 125-I was tried as an alternative to 131-I, because it might offer certain advantages [60]. 125-I is primarily a gamma ray emitter, but secondary low-energy electrons are produced that penetrate only a few microns, in contrast to the high-energy beta rays of 131-I. Thus, it might theoretically be possible to treat the cytoplasm of the thyroid cell with relatively little damage to the nucleus. Appropriate calculations indicated that the radiation dose to the nucleus could be perhaps one-third that to the cytoplasm, whereas this difference would not exist for 131-I. Extensive therapeutic trials have nonetheless failed to disclose any advantage thus far for 125I. Larger doses 10-20 mCi are required, increasing whole body radiation considerably [ 61, 62].

Doses of 131-I up to 33 mCi can be given to an outpatient basis, and this level is rarely exceeded in treatment of Graves disease. However patients must be given advice (written if possible) on precautions to be followed to prevent unneccessary or excessive exposure of other individuals by radiaactivity administered to the patient. For maximum safety, patients who have received 20 mCi should avoid extended time in public places for 1 day, maximize distance (6 feet) from children and pregnant women for 2 days, may return to work after 1 day, sleep in a separate (6-feet separation) bed from adults for 8 days, sleep in a separate bed from pregnant partners, infant, or child for 20 days, and avoid contact with body fluids (saliva, urine) for at least one week. Lower therapeutic doses require proportionally more moderate precautions. The basic NRC rule is that patients may be released from hospital when (1) the 131I measured dose rate is 7mrem/hr at 1m, or (2) when the expected total dose another person would receive is unlikely to exceed 500mrem (5mSv). Written precaution instructions are required If 100mrem (1mSv) may be exceeded in any person. This topic is well covered in articles by Sisson et al (http://www.ncbi.nlm.nih.gov/pubmed/21417738) andLiu et al (62.1).

If adequate treatment has been given, the T4 level falls progressively, beginning in one to three weeks.. Labeled thyroid hormones, iodotyrosines, and iodoproteins appear in the circulation [63,63.1]. TG is released, starting immediately after therapy. Another iodoprotein, which seems to be an iodinated albumin, is also found in plasma. This compound is similar or identical to a quantitatively insignificant secretion product of the normal gland. It comprises up to 15% or more of the circulating serum 131-I in thyrotoxic patients [64]. It is heavily labeled after 131-I therapy, and its proportional secretion is probably increased by the radiation. Iodotyrosine present in the serum may represent leakage from the thyroid gland, or may be derived from peripheral metabolism of TG or iodoalbumin released from the thyroid.

The return to the euthyroid state usually requires at least two months, and often the declining function of the gland proceeds gradually over six months to a year. For this reason, it is logical to avoid retreating a patient before six months have elapsed unless there is no evidence of control of the disease. While awaiting the response to131-I the symptoms may be controlled by propranolol, antithyroid drugs, or iodide. Hypothyroidism develops transiently in 10 20% of patients, but thyroid function returns to normal in most of these patients in a period ranging from three to six months. These patients rarely become toxic again. Others develop permanent hypothyroidism and require replacement therapy. It is advantageous to give the thyroid adequate time to recover function spontaneously before starting permanent replacement therapy. This can be difficult for the patient unless partial T4 replacement is given. Unfortunately, one of the common side effects of treating hyperthyroidism is weight gain, averaging about 20 lbs through four years after treatment (64.1).

Patients may develop transient increases in FTI and T3 at 2-4 months after treatment [63.1], sometimes associated with enlargement of the thyroid. This may represent an inflammatory or immune response to the irradiationinduced thyroid damage, and the course may change rapidly with a dramatic drop to hypothyroidism in the 4-5th month.

Hypothyroidism may ultimately be inescapable after any amount of radiation that is sufficient to reduce the function of the hyperplastic thyroid to normal [65]. Many apparently euthyroid patients (as many as half) have elevated serum levels of TSH long after 131-I therapy, with normal plasma hormone levels [66]. An elevated TSH level with a low normal T4level is an indicator of changes progressing toward hypothyroidism [67]. The hypothyroidism is doubtless also related to the continued autoimmune attack on thyroid cells. Hypofunction is a common end stage of Graves disease independent of 131-I use; it occurs spontaneously as first noted in 1895(!) [68] and in patients treated only with antithyroid drugs [69]. Just as after surgery, the development of hypothyroidism is correlated positively with the presence of antithyroid antibodies.

During the rapid development of postradiation hypothyroidism, the typical symptoms of depressed metabolism are evident, but two rather unusual features also occur. The patients may have marked aching and stiffness of joints and muscles. They may also develop severe centrally located and persistent headache. The headache responds rapidly to thyroid hormone therapy. Hair loss can also be dramatic at this time.

In patients developing hypothyroidism rapidly, the plasma T4 level and FTI accurately reflect the metabolic state. However, it should be noted that the TSH response may be suppressed for weeks or months by prior thyrotoxicosis; thus, the TSH level may not accurately reflect hypothyroidism in these persons and should not be used in preference to the FTI or FT4.

If permanent hypothyroidism develops, the patient is given replacement hormone therapy and is impressed with the necessity of taking the medication for the remainder of his or her life. Thyroid hormone replacement is not obligatory for those who develop only temporary hypothyroidism, although it is possible that patients in this group should receive replacement hormone, for their glands have been severely damaged and they are likely to develop hypothyroidism at a later date. Perhaps these thyroids, under prolonged TSH stimulation, may tend to develop adenomatous or malignant changes, but this has not been observed. Many middle-aged women gain weight excessively after radioactive iodide treatment of hyperthyroidism. Usually such patients are on what is presumed to be appropriate T4 replacement therapy. Tigas et al note that such weight gain is less common after ablative therapy for thyroid cancer, in which case larger doses of thyroxine are generally prescribed. Thus they question whether the excessive weight gain after radioactive iodide treatment of Graves disease is due to the fact that insufficient thyroid hormone is being provided, even though TSH is within the normal range. They suggest that restoration of serum TSH to the reference range by T4 alone may not constitute adequate hormone replacement [ 69a}. We noted above that the correct reference range for TT4 and FT4, when the patient is on replacement T4, should be 20% higher than normal.

Permanent replacement therapy (regardless of the degree of thyroid destruction) for children who receive 131-I has a better theoretical basis. In these cases, it is advisable to prevent TSH stimulation of the thyroid and so mitigate any possible tendency toward carcinoma formation.

Exacerbation of thyrotoxicosis-During the period immediately after therapy, there may be a transient elevation of the T4 or T3 level [70], but usually the T4 level falls progressively toward normal. Among treated hyperthyroid patients with Graves disease, only rare exacerbations of the disease are seen. These patients may have cardiac problems such as worsening angina pectoris, congestive heart failure, or disturbances of rhythm such as atrial fibrillation or even ventricular tachycardia. Radiation-induced thyroid storm and even death have unfortunately been reported [71- 73]. These untoward events argue for pretreatment of selected patients who have other serious illness, especially cardiac disease, with antithyroid drugs prior to 131-I therapy.

The immediate side effects of 131-I therapy are typically minimal. As noted above, transient exacerbation of thyrotoxicosis can occur, and apparent thyroid storm has been induced within a day (or days) after 131-I therapy. A few patients develop mild pain and tenderness over the thyroid and, rarely, dysphagia. Some patients develop temporary hair loss, but this condition occurs two to three months after therapy rather than at two to three weeks, as occurs after ordinary radiation epilation. Hair loss also occurs after surgical therapy, so that it is a metabolic rather than a radiation effect. If the loss of hair is due to the change in metabolic status, it generally recovers in a few weeks or months. However hair thinning, patchy alopecia, and total alopecia, are all associated with Graves Disease, probably as another auto-immune processes. In this situation the prognosis for recovery is less certain, and occasionally some other therapy for the hair loss (such as steroids) is indicated. Permanent hypoparathyroidism has been reported very rarely as a complication of RAI therapy for heart disease and thyrotoxicosis[ 74- 76]. Patients treated for hyperthyroidism with 131-I received approximately 39 microGy/MBq administered (about 0.144rad/mCi) of combined beta and gamma radiation to the testes. This is reported to cause no significant changes in FSH. Nevertheless, testosterone declines transiently for several months, but there is no variation in sperm motility or % abnormal forms (76.1). Long term studies of patients after RAI treatment by Franklyn et al (76.2) show a slight increase in mortality which appears to be related to cardiovascular disease, possibly related to periods of hypothyroidism.

Worsening of ophthalmopathy after RAIIn contrast to the experience with antithyroid drugs or surgery, antithyroid antibodies including TSAb levels increase after RAI [ 77, 78]. (Fig. 11-4, above). Coincident with this condition, exophthalmos may be worsened [79].(Fig. 11-5, below). This change is most likely an immunologic reaction to discharged thyroid antigens.The relationship of radiation therapy to exacerbation of exophthalmos has beem questioned], but much recent data indicates that there is a definite correlation[ 79, 80, 80.1, 80.2, 80.3]. Many therapists consider bad eyes to be a relative contraindication to RAI. Induction of hypothyroidism, with elevation of TSH, may contribute to worsening of ophthalmopathy. This offers support for early induction of T4 replacement (80.3). Pretreatment with antithyroid drugs has been used empirically in an attempt to prevent this complication. Its benefit, if any, may be related to an immunosuppressive effect of PTU, described below. Treatment with methimazole before and for three months after I-131 therapy has been shown to help prevent the treatment-induced rise in TSH-R antibodies which is otherwise seen[81].

Prophylaxis with prednisone after 131-I helps prevent exacerbation of exophthalmos, and this approach is now the standard approach in patients who have significant exophthalmos at the time of treatment [ 82, 82.1]. (Fig. 6, below) The recommended dose is 30 mg/day for one month, tapering then over 2-3 months. Of course prednisone or other measures can be instituted at the time of any worsening of ophthalmopathy. In this instance doses of 30-60 mg/day are employed, and usually are required over several months. While treatment with prednisone helps prevent eye problems, it does not appear to reduce the effectiveness of RAI in controlling the hyperthyroidism(82.2). Thyroidectomy, with total removal of the gland, should be considered for patients with serious active eye disease. Operative removal of the thyroid is followed by gradual diminution is TSH-R antibodies.(82.3 ), and as shown by Tallstedt is associated with a lower incidence of worsening eye problems than is initial RAI treatment. Several studies document better outcomes of ophthalmopathy in patients with GD who have total thyroidectomy vs those treated by other means(82.4, 82.5, 82.6).

Failure of 131-I to cure thyrotoxicosis occurs occasionally even after 2 or 3 treatments, and rarely 4 or 5 therapies are given. The reason for this failure is usually not clear. The radiation effect may occur slowly. A large store of hormone in a large gland may be one cause of a slow response. Occasional glands having an extremely rapid turnover of 131-I requiring such high doses of the isotope that surgery is preferable to continued 131-I therapy and its attendant whole body radiation. If a patient fails to respond to one or two doses of 131-I, it is important to consider that rapid turnover may reduce the effective radiation dose. Turnover can easily be estimated by measuring RAIU at 4, 12, 24, and 48 hours, or longer. The usual combined physical and biological half-time of 131-I retention is about 6 days. This may be reduced to 1 or 2 days in some cases, especially in patients who have had prior therapy or subtotal thyroidectomy. If this rapid release of 131-I is found, and 131-I therapy is desired, the total dose given must be increased to compensate for rapid release. A rough guide to this increment is as follows:

Increased dose = usual dose X ( (usual half time of 6 days) / (observed half time of X days) )

Most successfully treated glands return to a normal or cosmetically satisfactory size. Some large glands remain large, and in that sense may constitute a treatment failure. In such a situation secondary thyroidectomy could be done, but it is rarely required in practice.

Long term care- Patients who have been treated with RAI should continue under the care of a physician who is interested in their thyroid problem for the remainder of their lives. The first follow-up visit should be made six to eight weeks after therapy. By this time, it will often be found that the patient has already experienced considerable improvement and has begun to gain weight. The frequency of subsequent visits will depend on the progress of the patient. Symptoms of hypothyroidism, if they develop, are usually not encountered until after two to four months, but one of the unfortunate facts of RAI therapy is that hypothyroidism may occur almost any time after the initial response.

In the early days of RAI treatment for Graves disease, only patients over 45 years of age were selected for treatment because of the fear of ill effects of radiation. This age limit was gradually lowered, and some clinics, after experience extending over nearly 40 years, have now abandoned most age limitation. The major fear has been concern for induction of neoplasia, as well as the possibility that 131-I might induce undesirable mutations in the germ cells that would appear in later generations.

See the original post here:
Thyroid Disease Manager : Diagnosis and Treatment of Graves

Comments are closed.