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The Investigation and Treatment of Hyperthyroidism
The Investigation and Treatment of Hyperthyroidism MARVIN S. WOOL, M.D.
Although the clinical syndrome of hyperthyroidism has been well known and described since the nineteenth century, its major modes of therapy are relatively new. Less than half a century ago the reintroduction of iodine therapy made subtotal thyroidectomy a useful treatment, while it has been only a quarter of a century since the introduction of prolonged antithyroid medical treatment and radioactive iodine therapy. Each of these forms of therapy has become firmly established, but nowhere in medicine is controversy more heated than in the choice of the most efficacious of the three. Such controversy attests only to the fact that none provides the ideal form of therapy. To evaluate the place of each in any given clinical circumstance, it is necessary to have a thorough background of both normal thyroid gland physiology as well as of the pathogenesis of the overactive thyroid gland.
NORMAL THYROID HORMONE PRODUCTION Normal endogenous production of thyroid hormone in man is a four-step process. The first of these, trapping, involves the concentration of ingested iodide into the thyroid gland. This requires a high-energy reaction inasmuch as the intrathyroidal concentration of iodide is many hundredfold that existing in the plasma. This first step is regulated to a major extent by the circulating concentration of thyroid-stimulating hormone (TSH). The second step involves the intrathyroidal oxidation of iodide to iodine and the subsequent organification of iodine to the amino acid tyrosine in a 1 to 1 concentration to produce monoiodotyrosine and in a 2 to 1 relationship to produce diiodotyrosine. Monoiodotyrosine and diiodotyrosine are bound to a unique globulin present only in the thyroid gland called thyroglobulin. The third step of thyroid hormone production involves the coupling of monoiodotyrosine and diiodotyrosine to form triiodothyronine (T3 ) and the combination of two molecules of diiodotyrosine to form thyroxine (T4 ). Each of these is likewise bound to thyroglobulin. The final step of hormone production involves the uncoupling of T 3 and T 4 from thyroglobulin and their release into the circulation. Surgical Clinics of North America- Vol. 50, No. 3, June, 1970
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This step is also primarily regulated by the concentration of TSH in the plasma. T 4 and T 3 are the only known metabolically active thyroid hormones. The former circulates for the most part bound to large proteins in the blood, primarily thyroxine-binding globulin and to a lesser extent thyroxine-binding prealbumin. Only 0.05 per cent of the total serum T 4 exists in the free, or unbound, form. T 3 circulates in the plasma at much lower concentrations than those of thyroxine. It is poorly bound to serum proteins, however, with a much larger percentage existing in the free form. In addition, it possesses about three times the metabolic activity of T 4 , and it therefore plays about an equal metabolic role with T 4 • Most importantly, it is the actual circulating levels of free T 4 and T 3 that govern the pituitary secretory rate of TSH. Low levels of circulating thyroid hormones increase the output and circulating levels of TSH and its effect on the first and fourth steps of thyroid hormone synthesis. Conversely, high circulating levels of T 4 and T 3 will suppress TSH secretion in normal persons. Such a servomechanism has been shown to exist for both the adrenal glands and gonads as well.
PATHOGENESIS OF HYPERTHYROIDISM The pathogenesis of hyperthyroidism may logically be considered to involve the circumvention of this servomechanism of the thyroid and pituitary glands. Hyperthyroidism exists in three distinct forms. The most common, Graves' disease, is associated with diffuse enlargement of the thyroid gland and is the only form associated with ophthalmopathy and dermopathy. It occurs in any age group and in either sex, but most frequently in young women. Hyperthyroidism may also originate with the presence of a multinodular goiter. This syndrome usually occurs in an older patient who has a history of a long-standing, previously nontoxic goiter. It is thought by some to be simply a variant of Graves' disease, but significantly, it is never associated with either dermopathy or ophthalmopathy. The least common type of hyperthyroidism is that which occurs with a solitary hyperfunctioning nodule of the thyroid that depresses the function of the remainder of the gland. This report will be limited to the hyperthyroidism associated with Graves' disease. It was not until the start of this century that hyperthyroidism was definitely associated with the thyroid gland. By the 1930's the theory evolved that the primary disorder did not exist in the thyroid gland but rather at a distant site, the pituitary gland. In fact, a majority believed until the 1950's that Graves' disease represented a hypersecretion of TSH. This theory was gradually refuted by a number of findings, however. First, bioassay and later radioimmunoassay procedures for TSH failed to reveal elevated circulating levels of TSH in hyperthyroidism, and in fact, the highest levels of TSH were found in patients with hypothyroidism. Second, Graves' disease began to be described in patients who had spontaneously occurring hypopituitarism and later in patients who had had complete hypopituitarism produced by therapeutic surgical
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techniques. Third and most damaging, injection of TSH into laboratory animals could produce an experimental model of the hypermetabolism of Graves' disease but could not induce either ophthalmopathy or dermopathy. Despite these obvious shortcomings, the theory of TSH-causation persisted with the uneasy explanation that victims of Graves' disease had somehow an increased sensitivity not only of the thyroid gland but also of the target organs of eyes and skin to normal concentrations ofTSH. No new light was shed until 1956 when Adams and Purves' fortuitously discovered long-acting thyroid stimulator (LATS) while bioassaying the plasma of patients with Graves' disease. This substance had the same characteristics of TSH in rodents, namely, it effected the release of radioactively tagged thyroid hormone from the thyroid gland into the plasma, the only difference being that the action of LATS was delayed and of longer duration. Intensive search for LATS in the plasma of humans has indicated that it never exists in significant concentration in the plasma of patients without thyroid disease. Furthermore, a moderate to high concentration of LATS in the serum is pathognomonic of Graves' disease. Much work has been performed to characterize the nature of LATS. 16 It has clearly been established that it is an immunoglobulin of the lgG class. It was originally thought that as such it represented nothing more than the complexing of TSH to a circulating globulin. However, attempts to split this complex molecule into TSH and the globulin by standard proteolytic techniques have been uniformly unsuccessful. The realization that LATS was in essence an antibody prompted numerous attempts at its neutralization by appropriate concentrations of its presumed antigen, TSH, but all such attempts failed to produce neutralization of the biological effects of LATS. More recent studies have attempted to delineate the "antigen" that stimulates LATS production. Some workers have found that a microsomal fraction of thyroid gland does provide such a stimulus, and it is now generally believed that the thyroid gland itself is the site of the antigenic stimulation for the production of LATS in lymphoid tissue. Still unresolved, however, is the major question of what stimulus provokes the thyroid gland into releasing such an antigen or alternatively triggers the antibody production against a previously benignly existing antigen. Another approach used to assess the role of LATS in the pathogenesis of Graves' disease has been the determination of the prevalence of LATS in various conditions and serial assays of the concentration of LATS during both the natural and altered courses of Graves' disease. The most extensive clinical survey using this approach was carried out by Lipman et al.,t 5 who measured LATS in 325 patients with Graves' disease, in 43 with other diseases of the thyroid, and in 71 patients without thyroid disease. In only one of this last group were they able to find even a low concentration of LATS. In addition, in only 10 per cent of the thyroid patients without Graves' disease were results of LATS determinations positive, three fourths of those in low titers. On the other hand, results of LATS titers were positive in more than 50 per cent of the
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patients with active Graves' disease while they were positive in only 15 per cent of those with inactive Graves' disease. Interestingly, none of the major facets of Graves' disease (hyperthyroidism, ophthalmopathy, and dermopathy) was most significantly related to incidence of LATS. Rather, the number of systems involved by the disease was significant. Less than 50 per cent of the patients with only one organ involved had LATS, nearly two thirds of those with two involved organs showed significant titers, and a remarkable 89 per cent of those with all three systems involved had positive LATS titers. Their serial studies further indicated that (1) highest LATS titers were usually found early in the course of active disease, (2) improvement of ophthalmopathy was usually, but not always, associated with fall in LATS titers and glucocorticoid therapy usually produced a fall in LATS titers together with evidence of clinical improvement, and (3) improvement of hyperthyroidism per se usually did not correlate well with the fall in level of LATS. These conclusions have been confirmed by other studies with the exception that others, while finding a fall in LATS concentration with steroids, have not always found this to parallel clinical improvement in the ophthalmopathy. Last and most interesting, LATS has been demonstrated in the plasma of neonates of mothers with Graves' disease. These infants have manifested both hyperthyroidism and ophthalmopathy, with the symptoms subsiding spontaneously within weeks as the maternally transmitted LATS disappeared. To summarize, the circumstantial evidence is strong that LATS is involved in the pathogenesis of Graves' disease, although proof is lacking that it plays a direct etiologic role. Such a role cannot yet be ascribed to LATS because of the many documented instances in which levels of LATS do not correlate well with the activity or progress of one or all of the manifestations of the disease. At this point, we can conclude only that LATS has been shown distinctly to produce only one of the facets of Graves' disease in adults, namely, hyperthyroidism. Hopefully, such a role can be delineated in the ophthalmopathy, too, inasmuch as the malignant variety of this condition, although quite rare, is the most refractive to therapy.
LABORATORY STUDIES Thyroid function tests can be divided into three categories. The first includes those tests that measure the nonspecific effects of increased circulating levels of thyroid hormone. Into this group fall the venerable basal metabolism test and the more recently developed Achilles tendon reflex test, which measures with a photoelectric cell the time of the relaxation phase of the reflex. Prolongation of the relaxation phase is a reasonably useful guide to the diagnosis of hypothyroidism in the absence of other causes of neuropathy. The converse finding, however, of a rapid relaxation phase is not as accurate an indicator of hyperthyroidism. A second category of function tests measures the first step in thyroid hormone synthesis, the trapping of iodide. The commonest such test
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in use is the 24-hour uptake by the thyroid gland of radioactive iodine ( 131 I), with normal uptakes usually considered to be in the range of 15 to 45 per cent. False high determinations of this test are rare. Besides hyperthyroidism, the only common situations leading to high uptakes are iodide deficiency and recent withdrawal from antithyroid drugs, the former being a rare occurrence in this country and the latter being easily delineated by the clinical history. The uptake of orally administered 131 I may also be measured at 2 and 4 hours, in which instances the normal values are approximately one third and two thirds respectively of those at 24 hours. By 6 hours the uptake of 131 I by the thyroid is usually complete and equal to that at 24 hours, except in rare instances of severe hyperthyroidism, in which the uptake is actually higher at 6 hours than at 24, although the latter uptake will still be in the hyperthyroid range. The 24-hour uptake in normal patients can be entirely suppressed by the administration of full replacement doses of thyroid hormone, this situation occurring, of course, because the normal TSH stimulation to iodine uptake by the thyroid is suppressed by the exogenous hormone. In 1955, Greer and Smith9 theorized that such a suppressive mechanism would not be operative in patients with Graves' disease and demonstrated that such patients had no perceptible change in the 24-hour radioactive iodine uptake after a full week's course of thyroid hormone. This work has formed the basis of the so-called Cytomel (liothyronine) suppression test, which is a useful diagnostic tool in patients with borderline function tests. After administration of 100 micrograms of Cytomel daily for 8 days, normal patients will show suppression of 24-hour uptakes to less th/an 50 per cent of the baseline value, whereas patients with Graves' disease will show little suppression and indeed will take up iodine at rates far greater than 50 per cent of their own control levels. Although the 24-hour, or "late," uptake of radioactive iodine is a valuable tool in the initial diagnosis of hyperthyroidism, it has a major shortcoming in the evaluation of the progress of the treated disease. Specifically, the late uptake is invariably decreased by the administration of the antithyroid compounds of the thiouracil family. Because of this problem, recent interest has been focused on the "early," 20-minute uptake of intravenously administered 131 I or the shorter-lived 132 1.2 Normal values for these are in the range of 2 to 8 per cent of the administered dose, while patients with hyperthyroidism usually have distinctly higher values. The advantage of this tool is that it provides a function test that can be studied while antithyroid drugs are being continued. A minor shortcoming is the added logistic problem of administering an isotope intravenously and the handling of 132 I, which has a short halflife of 2 1/2 hours. Nevertheless, this function test has found a place in the modern management of hyperthyroidism which will be delineated more fully later. Radioactive scanning of the thyroid, usually 24 hours after oral administration of 131 I, provides valuable qualitative differentiation among the diffuse symmetrical uptake of Graves' disease, the patchy uptake of toxic multinodular goiter, and the localized uptake in the rarer autonomous nodule.
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The final and probably most commonly employed category of thyroid function tests involves the measurement of circulating thyroid hormones, usually by an indirect technique. Still the most widely used of these tests is the protein-bound iodine (PBI) determination. This is a chemical test requiring meticulous technique and an isolated laboratory area scrupulously free of even minute traces of iodine. The PBI measures the total amount of iodine in plasma that is bound to protein, with normal levels being 3.5 to 8.0 micrograms per 100 ml. Elevation may be found not only in hyperthyroidism but also when the patient has ingested iodine in the form of medication or x-ray contrast media, as well as in situations in which the circulating levels of thyroxine-binding globulin are increased, such as in pregnancy and with the use of estrogen-containing oral contraceptives. The butanol-extractable iodine determination (normal, 3 to 7 micrograms per 100 ml.) can detect contamination with iodide ion but not contamination with organic iodine or a rise in thyroxine-binding globulin. In 1957, Hamolsky et alP developed a technique called the red blood cell uptake of T 3 • This test measured in vitro the relative capacity of the patient's plasma to bind added labeled T 3 as compared with a suspension of the patient's red blood cells. A resin sponge has subsequently been substituted for the red blood cells and it has become a popular test of thyroid function. It is useful when the patient has received exogenous iodides, since they do not affect the determination. Normal values are between 25 and 35 per cent of uptake by the resin sponge, with hyperthyroid patients usually having distinctly higher uptakes. However, much overlap between hypothyroid and normal patients occurs with this test. Spurious determinations occur in patients with abnormalities of serum thyroxine-binding globulin, again most frequently in those taking oral contraceptives. The findings in such patients, however, usually reveal a low resin T 3 uptake and a high PBI level. Clark and Horn, 6 taking cognizance of this relationship, devised the so-called free thyroxine index as a test of thyroid function, it representing the product of the PBI and the resin T 3 uptake, the latter being expressed as a percentage of normal. By this formulation it will be noted that not only normal persons but also patients with high levels of thyroxine-binding globulin (high PBI and low resin T 3 ) as well as patients with low levels of thyroxine-binding globulin (low PBI and high resin T 3 uptake) will all have normal free thyroxine indexes (that is, 2.2 to 7.1 micrograms). More recently, Murphy and Patee 17 have devised a technique for determination of the total serum thyroxine. This test compares the capacity of a patient's plasma sample to bind added labeled T 4 with that of standard solutions of unlabeled T 4 • This test has the advantages of measuring directly the total thyroxine level, being uninfluenced by exogenous iodides, and of being useful in the diagnosis of both hypothyroidism and hyperthyroidism. Normal values range between 6 and 14 micrograms per 100 ml. This test is achieving increasing and deserved popularity and will likely become the single diagnostic test of choice in the near future. The ideal thyroid function test would be the determination of the
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free levels of circulating thyroid hormones, since it is these levels that account for the metabolic status as well as for the control of the thyroidpituitary servomechanism. Such a technique is available for measuring free thyroxine, which accounts for only about 1/2000 of the total circulating thyroxine or about 2 millimicrograms per ml. This technique is still a research laboratory tool, however.
TREATMENT With the array of thyroid function tests now available, the diagnosis of hyperthyroidism can usually be well substantiated by judicious choice of appropriate tests. The selection of the most appropriate therapy is not as easy, however. No form of treatment has achieved universal acceptance for the simple reason that none attacks the disease at its etiologic base. Long-term antithyroid medical treatment simply arrests the overproduction of thyroid hormone for a period sufficient for the disease to undergo a "spontaneous" remission. The so-called definitive modes of therapy, subtotal thyroidectomy and radioactive iodine, simply attempt to ablate a portion of the target thyroid gland, hopefully leaving an appropriate-sized piece of tissue that, although still pathologically stressed, is unable to produce abnormal amounts of thyroid hormone. Therefore, starting with the premise that no present form of therapy is ideal, I will attempt to discuss each and evolve a rational course of selecting the most efficacious therapy for each patient.
Antithyroid Treatment Long-term medical therapy of hyperthyroidism has been in use since Astwood's studies with thiouracil starting in :t_943. 3 Since then, less toxic analogues of thiouracil have been employed, namely, propylthiouracil and methimazole (Tapazole) in this country and carbimazole (Neomercazole) in Europe. Long-term medical therapy has been limited for the most part to patients under 40 years of age. It involves initially the administration of from 300 to 750 mg. daily of propylthiouracil or the equivalent of methimazole or carbimazole in three or four divided doses. As clinical euthyroidism is achieved, usually within 2 to 4 months, the dosage of propylthiouracil is reduced to the range of 300 mg. per day and 2 to 3 grains of desiccated thyroid or its equivalent in synthetic hormone is added to the program to obviate any hypothyroidism that might develop from the prolonged use of antithyroid medication alone. This combined therapy program is continued for a minimum of 12 months, at the end of which time the antithyroid preparation is gradually tapered and discontinued over a further 3 to 6 months. If the patient remains euthyroid, thyroid preparation alone is usually continued for an additional 3 months, at the end of which time a 24-hour radioactive iodine uptake test is performed. If such uptake is less than 20 per cent, normal thyroid suppressibility is considered to have returned, and the prospect for permanent remission is excellent. If uptake remains greater than 20 per cent, clinical relapse will usually ensue. Great fortitude is
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required by both patient and physician to carry out such a prolonged program. Minor side effects of antithyroid medication occur in less than 5 per cent of patients. These include a variety of skin reactions, some gastrointestinal symptoms, and less frequently, arthralgias and a cholestatic type of hepatitis. Each of these is easily treatable by lowering the dose of antithyroid medication or by prescribing an alternate preparation. The most serious complication of medical therapy is agranulocytosis, which is to be distinguished from the "physiologic" leukopenia and relative lymphocytosis that occur both in untreated Graves' disease and with the use of antithyroid compounds. Fortunately, this complication is rare, occurring in less than 1 per cent of patients receiving these drugs, is usually graphically heralded by the onset of a sore throat or fever, and spontaneously remits with prompt withdrawal of the offending drug. After the prolonged and often tedious course of combined medical therapy, yield of permanent remissions is disappointingly low-in the range of 50 per cent in most published series. Such a yield, however, could be increased if it could be reasonably predicted at the outset, or early in the course of treatment, in which patients a permanent remission could be expected. Many clinical criteria have been applied in attempts to make such predictions with accuracy.t 4 Unfortunately, none of these has proved to be universally useful. Sex, severity of symptoms, age at onset of disease, and type of goiter (diffuse versus nodular) have all failed to correlate with predictability of response to therapy. Somewhat more useful is the duration of illness before the onset of treatment. Patients whose conditions have been symptomatic for less than 12 months will experience reinission with far greater frequency than those with a longer history of untreated symptoms. Perhaps the best clinical predictor of response is diminution of the size of the goiter during antithyroid therapy. This usually occurs when the goiter is small initially (less than 50 gm.) and signals reversal of the pathologic process. However, often this does not occur until well into the course of therapy. On the other hand, some patients whose goiters do not shrink will nevertheless undergo reinission. The latest most promising attempt at prediction of ultimate medical remission early in the course of treatment has been described by Alexander et al. 2 Their technique involves (1) the pretreatment determination of the early, 20-minute uptake of radioactive iodine while the patient is taking full doses of thyroid, (2) treatment with combined thyroid and antithyroid medication, and (3) periodic repetition of the early uptake test with combined therapy. In their reported group of 26 patients, 17 showed development of suppressibility within 6 months. Relapse occurred in none of these patients during follow-up periods of 3 to 12 months after discontinuance of therapy. On the other hand, seven of the nine patients in whom suppressibility did not develop experienced relapse within 5 months after discontinuing a 1-year course of combined therapy. A second group11 has also reported relapses in only 1 of 26 patients whose early radioactive iodine uptake fell early in the course of therapy. They reported, on the other hand, that 13 of 26 patients who
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showed no fall in uptake level and no suppressibility suffered a relapse shortly after discontinuance of treatment. An intermediate group with no fall in baseline early uptake level but suppressibility of that uptake showed an intermediate relapse rate of about 25 per cent. Although these reports remain fragmentary and the follow-up periods relatively short, such a prognostic test holds great potential import.
Subtotal Thyroidectomy The reintroduction of iodide therapy by Plummer in 1923 made subtotal thyroidectomy a feasible mode of therapy. Iodide is an adequate antithyroid compound, having two major effects. The first, the so-called Wolff-Chaikoff effect, interferes with the organification of iodide to iodotyrosines and thence to formed thyroid hormones. The second inhibits the release of formed thyroid hormones from the thyroid into the plasma. In a number of instances, however, these inhibitory actions fail or "escape." Iodine is therefore not useful for prolonged primary antithyroid therapy. Currently, preparation for subtotal thyroidectomy is accomplished by a 2-month to 4-month course of a thiouracil preparation with the addition of iodides during the final 2 to 3 weeks, the latter having the useful effect of diminishing the vascularity of the hyperplastic gland. Reported series indicate uniformly good results from subtotal thyroidectomy for Graves' disease. 5 • s Most indicate that 80 to 90 per 'Cent of patients achieve permanent remission after a single operation, three fourths of these within 1 year. Recurrent hyperthyroidism persists or develops in 5 to 15 per cent of patients and they require treatment with antithyroid medication or radioactive iodine. Hypothyroidism can be expected to develop in about 10 per cent of patients. Green and Wilsons emphasize that the incidence of this result increases with time and may often go undetected because of lack of recognition of this delayed development. Complications of subtotal thyroidectomy in reported series appear to be comfortingly low. Modern preoperative medical treatment has made operative thyroid storm an obsolescent syndrome. Because of this, mortality from this operation is almost nonexistent and many series of several hundred patients have been reported without a single fatality. Early postoperative complications include local wound swelling from collections of blood or serous fluid, often requiring local evacuation and less frequently re-exploration of the wound. Most series do not report incidences of wound edema, but Green and Wilsons acknowledge that it occurred in 40 of 200 patients. Another early postoperative complication is that of vocal cord paresis. Such a complication only rarely becomes permanent. Finally, the most significant complication of thyroid operation is hypoparathyroidism. Transient tetany is not infrequent within 1 week after operation, but the incidence of permanent hypoparathyroidism fortunately remains at or below 1 per cent in reported series. However, it must be emphasized that the 1 patient in 100 with this unfortunate complication faces a lifetime of difficult medical management and the constant threat of the symptoms of acute hypo-
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calcemia, peripheral and cardiac muscular irritability, tetany, and convulsions. Chronic hypocalcemia also poses the threat of ectopic calcification. On balance, however, the impressively high remission rate from operation together with the equally striking negligible complication rate appears to make operation an attractive therapeutic approach. These statistics, however, are deceivingly bright. It must be remembered that they are compiled from large reported series accumulated by surgeons with extensive experience in thyroid surgery. They are by no means representative of the results that can be achieved by surgeons without such experience. Here as nowhere else in the realm of "general" surgery is familiarity of such essence. As pointed out in an editorial in the Lancet in 1967/8 "There is no place ... for the occasional thyroidectomist." Radioactive Iodine It was with such a background that the advent of radioactive iodine treatment, the "bloodless thyroidectomy," was hailed a quarter of a century ago. Most of the early concerns about this form of therapy have been dispelled. Bone marrow toxicity in the form of leukemia has been linked with massive doses of radioactive iodine employed in some patients with carcinoma of the thyroid, but the much smaller doses employed for hyperthyroidism have convincingly been shown not to lead to a higher percentage of leukemia than seen in the general population. The carcinogenic effect of radioactive iodine on the thyroid gland itself was also an early concern. Such an effect was demonstrated in children treated with radioactive iodine early in the experience, and now most therapists do not use this treatment in patients under the age of 20 years. A carcinogenic effect has not been demonstrated in many thousands of treated adults, however. The only major unanswered question about long-range effects of radioactive iodine is that of the genetic effect on subsequent generations. A significant number of women have already been treated with the modest doses required for hyperthyroidism as well as with the larger doses required in the treatment of carcinoma of the thyroid and have then produced offspring without any increased incidence of observable congenital abnormalities. However, it must be emphasized that only one generation has been studied in this regard and further investigation is necessary. How do the results of radioactive iodine treatment of hyperthyroidism compare with those of the other modalities? Initial enthusiasm was great. Three fourths to four fifths of patients became euthyroid after a single dose of radioactive iodine. Of the remaining 20 to 25 per cent, the vast majority achieved euthyroidism after a second treatment, with only a rare handful requiring three or more treatments. The delay in response of this 20 to 25 per cent proved to be an annoyance, but one easily managed with antithyroid medications. Subsequently, however, it became apparent that increasing numbers of the "euthyroid" patients were becoming hypothyroid with the passage of time. Indeed, the statistics of Dunn and Chapman7 seemed to be representative. In their large series, they found that 20 per cent of the treated patients became hypothyroid within 2 years after treatment and that each year thereafter
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an additional 2 per cent became hypothyroid, producing an ultimate incidence of 40 per cent by 10 years after treatment. Conceivably, all patients who receive such treatment will become myxedematous if they live long enough. What then can be done to decrease the startling prevalence of hypothyroidism? The dosage of radioactive iodine is usually calculated from a formula that relates the dosage directly to the estimated size of the gland and inversely to the percentage of a tracer dose of radioactive iodine taken up by the gland. Such formulas are defective in several ways. The difficulties of clinically estimating thyroid gland size are well known. There is also no way of assuring that the percentage uptake of a tracer dose is equivalent to the percentage uptake of the full therapeutic dose and even whether there is any relation between the percentage uptake and how long the therapeutic dose remains in the thyroid gland to achieve its effect. Most importantly, however, the most crucial factor involved does not appear in any formula for calculating radioactive iodine dosage- that is, the biologic variability of different glands and the unpredictable sensitivity of these glands to even a carefully standardized dose of radiation. With these shortcomings in view, attempts have been made to reduce the incidence of hypothyroidism after radioactive iodine therapy. Most of these efforts have centered around reducing the total dose of iodine administered. Early results from such studies10 have showed a lowered incidence of myxedema but have demonstrated a proportionately greater lag time before the development of euthyroidism in the majority of patients. So the concern about the incidence of hypothyroidism after treatment with radioactive iodine has nevertheless continued. To many, however, this has not proved to be a major problem. These therapists argue convincingly that, if the incidence of this complication is so well delineated, it becomes a simple matter of forewarning the patient of this development and instituting prompt thyroid replacement as soon as euthyroidism has been achieved, even before the development of frank hypothyroidism. The lifetime continuation of thyroid hormone replacement in physiologic doses presents no danger of untoward metabolic or allergic effects and certainly no economic burden. Balanced against the single side effect of hypothyroidism is the remarkable absence of other complications of radioactive iodine therapy. There is no untoward effect on any structure in the region of the thyroid gland-no threat to the laryngeal nerves and no threat to the parathyroid glands. Extremely rare instances of brief exacerbations of hyperthyroidism after treatment have been reported. Such can be avoided in patients at risk, mainly those with cardiovascular complications, by a brief course of antithyroid medication before and after treatment with radioactive iodine.
A RATIONAL APPROACH TO THE TREATMENT OF HYPERTHYROIDISM Two "definitive" modes of therapy exist for the hyperthyroidism of Graves' disease-radioactive iodine and subtotal thyroidectomy. Treat-
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ment with radioactive iodine must remain the treatment of choice in patients more than 40 years of age or past the reasonable expectation of childbearing. It is simple, requires no hospitalization, and is remarkably free of morbidity. Its single, well-publicized shortcoming of frequently producing hypothyroidism can easily be obviated by awareness of this complication and the prompt utilization of thyroid replacement therapy as soon as the euthyroid state is achieved. Radioactive iodine also remains the treatment of choice for patients who have had persistence or relapse of hyperthyroidism after subtotal thyroidectomy. It is also valuable for any patient, regardless of age, in whom operation is precluded by a severe coexistent illness. In fact, at many centers it is the treatment of choice for all patients with Graves' disease over the age of 25, although most physicians prefer to await more substantial evidence on long-range genetic effects before routinely employing this therapy in the 25-year-old to 40-year-old group. The only absolute contraindication to radioactive iodine therapy remains pregnancy. Subtotal thyroidectomy, in skilled and experienced surgical hands, provides an effective, mortality-free form of therapy for the young adult with the hyperthyroidism of Graves' disease. Postoperative disability is short-lived, and early and late morbidity is infrequent. What then is the role of "nondefinitive" treatment with prolonged antithyroid medical therapy? Is there a place for "nondefinitive" treatment for a disease that often, perhaps in 50 per cent of patients, will enter into a permanent remission after a reasonable period? The obvious answer is yes. The equally obvious problem is that of prognosticating those patients with a favorable outlook relatively early, so that they may be spared submission to any definitive form of therapy, no matter how benign. Of equal importance is determining with speed and accuracy those patients who cannot be expected to respond permanently to conservative treatment so that they may promptly be offered definitive treatment. The efforts toward such prognosis in our group and in many others have been directed at young adults with Graves' disease, a group that would provide eventual candidates for subtotal thyroidectomy. The choice of this emphasis rests on two major considerations. First, these are the patients in whom there would be the greatest incentive to spare any definitive procedure. Second, subtotal thyroidectomy invariably requires a period of 2 to 4 months of preparation with antithyroid medication that provides additional time for evaluating the patient as well as a head start in any proposed long-range course of medical therapy. Our approach to this problem has been flexible. All young adults with Graves' disease receive antithyroid medical therapy. In those patients whose duration of illness is long, whose goiters are large (more than 50 gm.), whose reliability is poor, or whose response to the initial stages of therapy is slow, the aim is prompt achievement of the euthyroid state and progression to subtotal thyroidectomy. In the remaining patients with a short duration of illness, a moderate to small goiter, and prompt response to initial therapy, the attempt at long-range combined medical therapy is extended. In the past, unfortunately, little prognostic information could be gathered in this lengthy 12-month to 18-month trial with the
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exception of change in goiter size. Shrinkage of the goiter in response to combined thyroid-antithyroid medication provides much optimism about the outcome but no guarantee of success. Not until the end of the trial, after antithyroid medication is discontinued and the suppression test is carried out, is there a real indication of the likely outcome. The introduction by Alexander et al. 2 of the early uptake test has added a new dimension to the management of Graves' disease, however. It provides a prognostic indication that can be applied early in the course of combined medical therapy without interrupting that therapy. If longer follow-up studies do indeed substantiate the accuracy of this prognostic index, it will become a valuable tool. Even at present, there is a place for it in patients under the age of 40 with Graves' disease. Enthusiasts suggest that even older patients who are candidates for eventual treatment with radioactive iodine should be given the benefit of a several-month course of antithyroid treatment, during which the response and suppressibility of the early uptake can be determined. If results are favorable, eventual treatment with radioactive iodine can be avoided in favor of medical therapy. An important caution is that no studies have yet suggested that permanent remission will be maintained with anything less than a full year's course of medical therapy, even in patients with a promising early uptake response. Special mention needs to be made of the treatment of Graves' disease during pregnancy. Early in the experience with antithyroid drugs, the medical treatment of hyperthyroidism in pregnancy presented great difficulty. The well-documented fact that the thiouracil derivatives easily crossed the placenta accounted for a high incidence of goitrous neonates produced, even in the event that the pregnancy proceeded to term. More recently it has been well demonstrated13 that full-term antithyroid therapy when combined with thyroid hormone supplementation is an effective mode of treatment. The success of this newer form of medical therapy hinges upon the carefully tapered doses of antithyroid compounds employed plus the probability that enough of the full replacement dose of thyroid hormone given the mother crosses the placenta to obviate the development of hypothyroidism in the fetus. During recent years also, it has been well documented4 that a patient with Graves' disease carefully prepared with antithyroid medication during the first and early second trimester, submitted to subtotal thyroidectomy in the second trimester, and given full replacement doses of thyroid for the duration of the pregnancy will have an equally favorable outlook for a successful pregnancy and delivery. Therefore, it has been our policy to treat pregnant patients with Graves' disease in much the same manner as those who are not pregnant, with the exception that minimal doses of antithyroid drugs and full replacement doses of thyroid preparations are utilized in those undergoing long-term medical treatment.
FUTURE TREATMENT OF GRAVES' DISEASE The development of accurate prognostic tests will certainly be of advantage in utilizing most effectively the three modes of therapy now
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available to us. It must be kept in mind that none of these yet provides the ideal solution, for the cogent reason that none attacks the etiologic basis of the disease. If, however, LATS, well characterized as an antibody, can be implicated as the etiologic agent in the pathogenesis of Graves' disease in adults, as it has been implicated in neonatal Graves' disease, then new horizons will be opened. Graves' disease may then indeed be classified as an autoimmune disease and patients may become candidates for the employment of immunosuppressive therapy. Thus far, only scant experience has been accumulated,' 9 primarily because present immunosuppressive treatments entail greater morbidity than the classic forms of treatment of Graves' disease. Nevertheless, the exploration of the role of LATS provides the most exciting frontier in thyroidology today.
REFERENCES 1. Adams, D. D., and Purves, H. D., quoted by Lipman, L. M., eta!." 2. Alexander, W. D., Harden, R. M., Shimmins, J., eta!.: Treatment of thyrotoxicosis based on thyroidal suppressibility. Lancet, 2:681-684, 1967. 3. Astwood, E. B.: Treatment of hyperthyroidism with thiourea and thiouracil. J.A.M.A., 122:78-81, 1943. 4. Bell, G. 0., and Hall, J.: Hyperthyroidism in pregnancy. Med. Clin. N. Amer., 44:363-367, 1960. 5. Caswell, H. T., Robbins, R. R., and Rosemond, G. P.: Definitive treatment of 536 cases of hyperthyroidism with I-131 or surgery. Ann. Surg., 164:593-599, 1966. 6. Clark, F., and Horn, D. B.: Assessment of thyroid function by the combined use of the serum protein-bound iodine and resin uptake of 131 1-triiodothyronine. J. Clin. Endocr., 25:39-45, 1965. 7. Dunn, J. T., and Chapman, E. M.: Rising incidence of hypothyroidism after radioactiveiodine therapy in thyrotoxicosis. New Eng. J. Med., 271:1037-1042, 1964. 8. Green, M., and Wilson, G. M.: Thyrotoxicosis treated by surgery or iodine-131. With special reference to development of hypothyroidism. Brit. Med. J., 1:1005-1010, 1964. 9. Greer, M. A., and Smith, G. E.: Method for increasing accuracy of radioiodine uptake as test for thyroid function by use of desiccated thyroid. J. Clin. Endocr., 14:1374-1384, 1954. 10. Hagen, G. A., Ouellette, R. P., and Chapman, E. M.: Comparison of high and low dosage levels of ' 31 1 in the treatment of thyrotoxicosis. New Eng. J. Med., 277:559-562, 1967. 11. Hales, I., Spiel, J., Reeve, T., et al.: Prediction of the long-term results of antithyroid drug therapy for thyrotoxicosis. J. Clin. Endocr., 29:998-1001, 1969. 12. Hamolsky, M. W., Stein, M., and Freedberg, A. S.: The thyroid hormone-plasma protein complex in man. II. A new in vitro method for study of "uptake" of labelled hormonal components by human erythrocytes. J. Clin. Endocr., 17:33-44, 1957. 13. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med., 273:627-633, 1965. 14. Hershman, J. M., Givens, J. R., Cassidy, C. E., eta!.: Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocr., 26:803-807, 1966. 15. Lipman, L. M., Green, D. E., Snyder, N. J., et a!.: Relationship of long-acting thyroid stimulator to the clinical features and course of Graves' disease. Amer. J. Med., 43:486498, 1967. 16. McKenzie, J. M.: The long-acting thyroid stimulator: its role in Graves' disease. Recent Progr. Hormone Res., 23:1-46, 1967. 17. Murphy, B. E., and Patee, C. J.: Determination of thyroxine utilizing the property of protein-binding. J. Clin. Endocr., 24:187-196, 1964. 18. Treatment of hyperthyroidism. Lancet, 2:406-407, 1967. 19. Werner, S. C., and Platman, S. R.: Remission of hyperthyroidism (Graves' disease) and altered pattern of serum-thyroxine binding induced by prednisone. Lancet, 2:751-755, 1965.
Although the clinical syndrome of hyperthyroidism has been well known and described since the nineteenth century, its major modes of therapy are relatively new. Less than half a century ago the reintroduction of iodine therapy made subtotal thyroidectomy a useful treatment, while it has been only a quarter of a century since the introduction of prolonged antithyroid medical treatment and radioactive iodine therapy. Each of these forms of therapy has become firmly established, but nowhere in medicine is controversy more heated than in the choice of the most efficacious of the three. Such controversy attests only to the fact that none provides the ideal form of therapy. To evaluate the place of each in any given clinical circumstance, it is necessary to have a thorough background of both normal thyroid gland physiology as well as of the pathogenesis of the overactive thyroid gland.
NORMAL THYROID HORMONE PRODUCTION Normal endogenous production of thyroid hormone in man is a four-step process. The first of these, trapping, involves the concentration of ingested iodide into the thyroid gland. This requires a high-energy reaction inasmuch as the intrathyroidal concentration of iodide is many hundredfold that existing in the plasma. This first step is regulated to a major extent by the circulating concentration of thyroid-stimulating hormone (TSH). The second step involves the intrathyroidal oxidation of iodide to iodine and the subsequent organification of iodine to the amino acid tyrosine in a 1 to 1 concentration to produce monoiodotyrosine and in a 2 to 1 relationship to produce diiodotyrosine. Monoiodotyrosine and diiodotyrosine are bound to a unique globulin present only in the thyroid gland called thyroglobulin. The third step of thyroid hormone production involves the coupling of monoiodotyrosine and diiodotyrosine to form triiodothyronine (T3 ) and the combination of two molecules of diiodotyrosine to form thyroxine (T4 ). Each of these is likewise bound to thyroglobulin. The final step of hormone production involves the uncoupling of T 3 and T 4 from thyroglobulin and their release into the circulation. Surgical Clinics of North America- Vol. 50, No. 3, June, 1970
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This step is also primarily regulated by the concentration of TSH in the plasma. T 4 and T 3 are the only known metabolically active thyroid hormones. The former circulates for the most part bound to large proteins in the blood, primarily thyroxine-binding globulin and to a lesser extent thyroxine-binding prealbumin. Only 0.05 per cent of the total serum T 4 exists in the free, or unbound, form. T 3 circulates in the plasma at much lower concentrations than those of thyroxine. It is poorly bound to serum proteins, however, with a much larger percentage existing in the free form. In addition, it possesses about three times the metabolic activity of T 4 , and it therefore plays about an equal metabolic role with T 4 • Most importantly, it is the actual circulating levels of free T 4 and T 3 that govern the pituitary secretory rate of TSH. Low levels of circulating thyroid hormones increase the output and circulating levels of TSH and its effect on the first and fourth steps of thyroid hormone synthesis. Conversely, high circulating levels of T 4 and T 3 will suppress TSH secretion in normal persons. Such a servomechanism has been shown to exist for both the adrenal glands and gonads as well.
PATHOGENESIS OF HYPERTHYROIDISM The pathogenesis of hyperthyroidism may logically be considered to involve the circumvention of this servomechanism of the thyroid and pituitary glands. Hyperthyroidism exists in three distinct forms. The most common, Graves' disease, is associated with diffuse enlargement of the thyroid gland and is the only form associated with ophthalmopathy and dermopathy. It occurs in any age group and in either sex, but most frequently in young women. Hyperthyroidism may also originate with the presence of a multinodular goiter. This syndrome usually occurs in an older patient who has a history of a long-standing, previously nontoxic goiter. It is thought by some to be simply a variant of Graves' disease, but significantly, it is never associated with either dermopathy or ophthalmopathy. The least common type of hyperthyroidism is that which occurs with a solitary hyperfunctioning nodule of the thyroid that depresses the function of the remainder of the gland. This report will be limited to the hyperthyroidism associated with Graves' disease. It was not until the start of this century that hyperthyroidism was definitely associated with the thyroid gland. By the 1930's the theory evolved that the primary disorder did not exist in the thyroid gland but rather at a distant site, the pituitary gland. In fact, a majority believed until the 1950's that Graves' disease represented a hypersecretion of TSH. This theory was gradually refuted by a number of findings, however. First, bioassay and later radioimmunoassay procedures for TSH failed to reveal elevated circulating levels of TSH in hyperthyroidism, and in fact, the highest levels of TSH were found in patients with hypothyroidism. Second, Graves' disease began to be described in patients who had spontaneously occurring hypopituitarism and later in patients who had had complete hypopituitarism produced by therapeutic surgical
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techniques. Third and most damaging, injection of TSH into laboratory animals could produce an experimental model of the hypermetabolism of Graves' disease but could not induce either ophthalmopathy or dermopathy. Despite these obvious shortcomings, the theory of TSH-causation persisted with the uneasy explanation that victims of Graves' disease had somehow an increased sensitivity not only of the thyroid gland but also of the target organs of eyes and skin to normal concentrations ofTSH. No new light was shed until 1956 when Adams and Purves' fortuitously discovered long-acting thyroid stimulator (LATS) while bioassaying the plasma of patients with Graves' disease. This substance had the same characteristics of TSH in rodents, namely, it effected the release of radioactively tagged thyroid hormone from the thyroid gland into the plasma, the only difference being that the action of LATS was delayed and of longer duration. Intensive search for LATS in the plasma of humans has indicated that it never exists in significant concentration in the plasma of patients without thyroid disease. Furthermore, a moderate to high concentration of LATS in the serum is pathognomonic of Graves' disease. Much work has been performed to characterize the nature of LATS. 16 It has clearly been established that it is an immunoglobulin of the lgG class. It was originally thought that as such it represented nothing more than the complexing of TSH to a circulating globulin. However, attempts to split this complex molecule into TSH and the globulin by standard proteolytic techniques have been uniformly unsuccessful. The realization that LATS was in essence an antibody prompted numerous attempts at its neutralization by appropriate concentrations of its presumed antigen, TSH, but all such attempts failed to produce neutralization of the biological effects of LATS. More recent studies have attempted to delineate the "antigen" that stimulates LATS production. Some workers have found that a microsomal fraction of thyroid gland does provide such a stimulus, and it is now generally believed that the thyroid gland itself is the site of the antigenic stimulation for the production of LATS in lymphoid tissue. Still unresolved, however, is the major question of what stimulus provokes the thyroid gland into releasing such an antigen or alternatively triggers the antibody production against a previously benignly existing antigen. Another approach used to assess the role of LATS in the pathogenesis of Graves' disease has been the determination of the prevalence of LATS in various conditions and serial assays of the concentration of LATS during both the natural and altered courses of Graves' disease. The most extensive clinical survey using this approach was carried out by Lipman et al.,t 5 who measured LATS in 325 patients with Graves' disease, in 43 with other diseases of the thyroid, and in 71 patients without thyroid disease. In only one of this last group were they able to find even a low concentration of LATS. In addition, in only 10 per cent of the thyroid patients without Graves' disease were results of LATS determinations positive, three fourths of those in low titers. On the other hand, results of LATS titers were positive in more than 50 per cent of the
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patients with active Graves' disease while they were positive in only 15 per cent of those with inactive Graves' disease. Interestingly, none of the major facets of Graves' disease (hyperthyroidism, ophthalmopathy, and dermopathy) was most significantly related to incidence of LATS. Rather, the number of systems involved by the disease was significant. Less than 50 per cent of the patients with only one organ involved had LATS, nearly two thirds of those with two involved organs showed significant titers, and a remarkable 89 per cent of those with all three systems involved had positive LATS titers. Their serial studies further indicated that (1) highest LATS titers were usually found early in the course of active disease, (2) improvement of ophthalmopathy was usually, but not always, associated with fall in LATS titers and glucocorticoid therapy usually produced a fall in LATS titers together with evidence of clinical improvement, and (3) improvement of hyperthyroidism per se usually did not correlate well with the fall in level of LATS. These conclusions have been confirmed by other studies with the exception that others, while finding a fall in LATS concentration with steroids, have not always found this to parallel clinical improvement in the ophthalmopathy. Last and most interesting, LATS has been demonstrated in the plasma of neonates of mothers with Graves' disease. These infants have manifested both hyperthyroidism and ophthalmopathy, with the symptoms subsiding spontaneously within weeks as the maternally transmitted LATS disappeared. To summarize, the circumstantial evidence is strong that LATS is involved in the pathogenesis of Graves' disease, although proof is lacking that it plays a direct etiologic role. Such a role cannot yet be ascribed to LATS because of the many documented instances in which levels of LATS do not correlate well with the activity or progress of one or all of the manifestations of the disease. At this point, we can conclude only that LATS has been shown distinctly to produce only one of the facets of Graves' disease in adults, namely, hyperthyroidism. Hopefully, such a role can be delineated in the ophthalmopathy, too, inasmuch as the malignant variety of this condition, although quite rare, is the most refractive to therapy.
LABORATORY STUDIES Thyroid function tests can be divided into three categories. The first includes those tests that measure the nonspecific effects of increased circulating levels of thyroid hormone. Into this group fall the venerable basal metabolism test and the more recently developed Achilles tendon reflex test, which measures with a photoelectric cell the time of the relaxation phase of the reflex. Prolongation of the relaxation phase is a reasonably useful guide to the diagnosis of hypothyroidism in the absence of other causes of neuropathy. The converse finding, however, of a rapid relaxation phase is not as accurate an indicator of hyperthyroidism. A second category of function tests measures the first step in thyroid hormone synthesis, the trapping of iodide. The commonest such test
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in use is the 24-hour uptake by the thyroid gland of radioactive iodine ( 131 I), with normal uptakes usually considered to be in the range of 15 to 45 per cent. False high determinations of this test are rare. Besides hyperthyroidism, the only common situations leading to high uptakes are iodide deficiency and recent withdrawal from antithyroid drugs, the former being a rare occurrence in this country and the latter being easily delineated by the clinical history. The uptake of orally administered 131 I may also be measured at 2 and 4 hours, in which instances the normal values are approximately one third and two thirds respectively of those at 24 hours. By 6 hours the uptake of 131 I by the thyroid is usually complete and equal to that at 24 hours, except in rare instances of severe hyperthyroidism, in which the uptake is actually higher at 6 hours than at 24, although the latter uptake will still be in the hyperthyroid range. The 24-hour uptake in normal patients can be entirely suppressed by the administration of full replacement doses of thyroid hormone, this situation occurring, of course, because the normal TSH stimulation to iodine uptake by the thyroid is suppressed by the exogenous hormone. In 1955, Greer and Smith9 theorized that such a suppressive mechanism would not be operative in patients with Graves' disease and demonstrated that such patients had no perceptible change in the 24-hour radioactive iodine uptake after a full week's course of thyroid hormone. This work has formed the basis of the so-called Cytomel (liothyronine) suppression test, which is a useful diagnostic tool in patients with borderline function tests. After administration of 100 micrograms of Cytomel daily for 8 days, normal patients will show suppression of 24-hour uptakes to less th/an 50 per cent of the baseline value, whereas patients with Graves' disease will show little suppression and indeed will take up iodine at rates far greater than 50 per cent of their own control levels. Although the 24-hour, or "late," uptake of radioactive iodine is a valuable tool in the initial diagnosis of hyperthyroidism, it has a major shortcoming in the evaluation of the progress of the treated disease. Specifically, the late uptake is invariably decreased by the administration of the antithyroid compounds of the thiouracil family. Because of this problem, recent interest has been focused on the "early," 20-minute uptake of intravenously administered 131 I or the shorter-lived 132 1.2 Normal values for these are in the range of 2 to 8 per cent of the administered dose, while patients with hyperthyroidism usually have distinctly higher values. The advantage of this tool is that it provides a function test that can be studied while antithyroid drugs are being continued. A minor shortcoming is the added logistic problem of administering an isotope intravenously and the handling of 132 I, which has a short halflife of 2 1/2 hours. Nevertheless, this function test has found a place in the modern management of hyperthyroidism which will be delineated more fully later. Radioactive scanning of the thyroid, usually 24 hours after oral administration of 131 I, provides valuable qualitative differentiation among the diffuse symmetrical uptake of Graves' disease, the patchy uptake of toxic multinodular goiter, and the localized uptake in the rarer autonomous nodule.
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The final and probably most commonly employed category of thyroid function tests involves the measurement of circulating thyroid hormones, usually by an indirect technique. Still the most widely used of these tests is the protein-bound iodine (PBI) determination. This is a chemical test requiring meticulous technique and an isolated laboratory area scrupulously free of even minute traces of iodine. The PBI measures the total amount of iodine in plasma that is bound to protein, with normal levels being 3.5 to 8.0 micrograms per 100 ml. Elevation may be found not only in hyperthyroidism but also when the patient has ingested iodine in the form of medication or x-ray contrast media, as well as in situations in which the circulating levels of thyroxine-binding globulin are increased, such as in pregnancy and with the use of estrogen-containing oral contraceptives. The butanol-extractable iodine determination (normal, 3 to 7 micrograms per 100 ml.) can detect contamination with iodide ion but not contamination with organic iodine or a rise in thyroxine-binding globulin. In 1957, Hamolsky et alP developed a technique called the red blood cell uptake of T 3 • This test measured in vitro the relative capacity of the patient's plasma to bind added labeled T 3 as compared with a suspension of the patient's red blood cells. A resin sponge has subsequently been substituted for the red blood cells and it has become a popular test of thyroid function. It is useful when the patient has received exogenous iodides, since they do not affect the determination. Normal values are between 25 and 35 per cent of uptake by the resin sponge, with hyperthyroid patients usually having distinctly higher uptakes. However, much overlap between hypothyroid and normal patients occurs with this test. Spurious determinations occur in patients with abnormalities of serum thyroxine-binding globulin, again most frequently in those taking oral contraceptives. The findings in such patients, however, usually reveal a low resin T 3 uptake and a high PBI level. Clark and Horn, 6 taking cognizance of this relationship, devised the so-called free thyroxine index as a test of thyroid function, it representing the product of the PBI and the resin T 3 uptake, the latter being expressed as a percentage of normal. By this formulation it will be noted that not only normal persons but also patients with high levels of thyroxine-binding globulin (high PBI and low resin T 3 ) as well as patients with low levels of thyroxine-binding globulin (low PBI and high resin T 3 uptake) will all have normal free thyroxine indexes (that is, 2.2 to 7.1 micrograms). More recently, Murphy and Patee 17 have devised a technique for determination of the total serum thyroxine. This test compares the capacity of a patient's plasma sample to bind added labeled T 4 with that of standard solutions of unlabeled T 4 • This test has the advantages of measuring directly the total thyroxine level, being uninfluenced by exogenous iodides, and of being useful in the diagnosis of both hypothyroidism and hyperthyroidism. Normal values range between 6 and 14 micrograms per 100 ml. This test is achieving increasing and deserved popularity and will likely become the single diagnostic test of choice in the near future. The ideal thyroid function test would be the determination of the
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free levels of circulating thyroid hormones, since it is these levels that account for the metabolic status as well as for the control of the thyroidpituitary servomechanism. Such a technique is available for measuring free thyroxine, which accounts for only about 1/2000 of the total circulating thyroxine or about 2 millimicrograms per ml. This technique is still a research laboratory tool, however.
TREATMENT With the array of thyroid function tests now available, the diagnosis of hyperthyroidism can usually be well substantiated by judicious choice of appropriate tests. The selection of the most appropriate therapy is not as easy, however. No form of treatment has achieved universal acceptance for the simple reason that none attacks the disease at its etiologic base. Long-term antithyroid medical treatment simply arrests the overproduction of thyroid hormone for a period sufficient for the disease to undergo a "spontaneous" remission. The so-called definitive modes of therapy, subtotal thyroidectomy and radioactive iodine, simply attempt to ablate a portion of the target thyroid gland, hopefully leaving an appropriate-sized piece of tissue that, although still pathologically stressed, is unable to produce abnormal amounts of thyroid hormone. Therefore, starting with the premise that no present form of therapy is ideal, I will attempt to discuss each and evolve a rational course of selecting the most efficacious therapy for each patient.
Antithyroid Treatment Long-term medical therapy of hyperthyroidism has been in use since Astwood's studies with thiouracil starting in :t_943. 3 Since then, less toxic analogues of thiouracil have been employed, namely, propylthiouracil and methimazole (Tapazole) in this country and carbimazole (Neomercazole) in Europe. Long-term medical therapy has been limited for the most part to patients under 40 years of age. It involves initially the administration of from 300 to 750 mg. daily of propylthiouracil or the equivalent of methimazole or carbimazole in three or four divided doses. As clinical euthyroidism is achieved, usually within 2 to 4 months, the dosage of propylthiouracil is reduced to the range of 300 mg. per day and 2 to 3 grains of desiccated thyroid or its equivalent in synthetic hormone is added to the program to obviate any hypothyroidism that might develop from the prolonged use of antithyroid medication alone. This combined therapy program is continued for a minimum of 12 months, at the end of which time the antithyroid preparation is gradually tapered and discontinued over a further 3 to 6 months. If the patient remains euthyroid, thyroid preparation alone is usually continued for an additional 3 months, at the end of which time a 24-hour radioactive iodine uptake test is performed. If such uptake is less than 20 per cent, normal thyroid suppressibility is considered to have returned, and the prospect for permanent remission is excellent. If uptake remains greater than 20 per cent, clinical relapse will usually ensue. Great fortitude is
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required by both patient and physician to carry out such a prolonged program. Minor side effects of antithyroid medication occur in less than 5 per cent of patients. These include a variety of skin reactions, some gastrointestinal symptoms, and less frequently, arthralgias and a cholestatic type of hepatitis. Each of these is easily treatable by lowering the dose of antithyroid medication or by prescribing an alternate preparation. The most serious complication of medical therapy is agranulocytosis, which is to be distinguished from the "physiologic" leukopenia and relative lymphocytosis that occur both in untreated Graves' disease and with the use of antithyroid compounds. Fortunately, this complication is rare, occurring in less than 1 per cent of patients receiving these drugs, is usually graphically heralded by the onset of a sore throat or fever, and spontaneously remits with prompt withdrawal of the offending drug. After the prolonged and often tedious course of combined medical therapy, yield of permanent remissions is disappointingly low-in the range of 50 per cent in most published series. Such a yield, however, could be increased if it could be reasonably predicted at the outset, or early in the course of treatment, in which patients a permanent remission could be expected. Many clinical criteria have been applied in attempts to make such predictions with accuracy.t 4 Unfortunately, none of these has proved to be universally useful. Sex, severity of symptoms, age at onset of disease, and type of goiter (diffuse versus nodular) have all failed to correlate with predictability of response to therapy. Somewhat more useful is the duration of illness before the onset of treatment. Patients whose conditions have been symptomatic for less than 12 months will experience reinission with far greater frequency than those with a longer history of untreated symptoms. Perhaps the best clinical predictor of response is diminution of the size of the goiter during antithyroid therapy. This usually occurs when the goiter is small initially (less than 50 gm.) and signals reversal of the pathologic process. However, often this does not occur until well into the course of therapy. On the other hand, some patients whose goiters do not shrink will nevertheless undergo reinission. The latest most promising attempt at prediction of ultimate medical remission early in the course of treatment has been described by Alexander et al. 2 Their technique involves (1) the pretreatment determination of the early, 20-minute uptake of radioactive iodine while the patient is taking full doses of thyroid, (2) treatment with combined thyroid and antithyroid medication, and (3) periodic repetition of the early uptake test with combined therapy. In their reported group of 26 patients, 17 showed development of suppressibility within 6 months. Relapse occurred in none of these patients during follow-up periods of 3 to 12 months after discontinuance of therapy. On the other hand, seven of the nine patients in whom suppressibility did not develop experienced relapse within 5 months after discontinuing a 1-year course of combined therapy. A second group11 has also reported relapses in only 1 of 26 patients whose early radioactive iodine uptake fell early in the course of therapy. They reported, on the other hand, that 13 of 26 patients who
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showed no fall in uptake level and no suppressibility suffered a relapse shortly after discontinuance of treatment. An intermediate group with no fall in baseline early uptake level but suppressibility of that uptake showed an intermediate relapse rate of about 25 per cent. Although these reports remain fragmentary and the follow-up periods relatively short, such a prognostic test holds great potential import.
Subtotal Thyroidectomy The reintroduction of iodide therapy by Plummer in 1923 made subtotal thyroidectomy a feasible mode of therapy. Iodide is an adequate antithyroid compound, having two major effects. The first, the so-called Wolff-Chaikoff effect, interferes with the organification of iodide to iodotyrosines and thence to formed thyroid hormones. The second inhibits the release of formed thyroid hormones from the thyroid into the plasma. In a number of instances, however, these inhibitory actions fail or "escape." Iodine is therefore not useful for prolonged primary antithyroid therapy. Currently, preparation for subtotal thyroidectomy is accomplished by a 2-month to 4-month course of a thiouracil preparation with the addition of iodides during the final 2 to 3 weeks, the latter having the useful effect of diminishing the vascularity of the hyperplastic gland. Reported series indicate uniformly good results from subtotal thyroidectomy for Graves' disease. 5 • s Most indicate that 80 to 90 per 'Cent of patients achieve permanent remission after a single operation, three fourths of these within 1 year. Recurrent hyperthyroidism persists or develops in 5 to 15 per cent of patients and they require treatment with antithyroid medication or radioactive iodine. Hypothyroidism can be expected to develop in about 10 per cent of patients. Green and Wilsons emphasize that the incidence of this result increases with time and may often go undetected because of lack of recognition of this delayed development. Complications of subtotal thyroidectomy in reported series appear to be comfortingly low. Modern preoperative medical treatment has made operative thyroid storm an obsolescent syndrome. Because of this, mortality from this operation is almost nonexistent and many series of several hundred patients have been reported without a single fatality. Early postoperative complications include local wound swelling from collections of blood or serous fluid, often requiring local evacuation and less frequently re-exploration of the wound. Most series do not report incidences of wound edema, but Green and Wilsons acknowledge that it occurred in 40 of 200 patients. Another early postoperative complication is that of vocal cord paresis. Such a complication only rarely becomes permanent. Finally, the most significant complication of thyroid operation is hypoparathyroidism. Transient tetany is not infrequent within 1 week after operation, but the incidence of permanent hypoparathyroidism fortunately remains at or below 1 per cent in reported series. However, it must be emphasized that the 1 patient in 100 with this unfortunate complication faces a lifetime of difficult medical management and the constant threat of the symptoms of acute hypo-
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calcemia, peripheral and cardiac muscular irritability, tetany, and convulsions. Chronic hypocalcemia also poses the threat of ectopic calcification. On balance, however, the impressively high remission rate from operation together with the equally striking negligible complication rate appears to make operation an attractive therapeutic approach. These statistics, however, are deceivingly bright. It must be remembered that they are compiled from large reported series accumulated by surgeons with extensive experience in thyroid surgery. They are by no means representative of the results that can be achieved by surgeons without such experience. Here as nowhere else in the realm of "general" surgery is familiarity of such essence. As pointed out in an editorial in the Lancet in 1967/8 "There is no place ... for the occasional thyroidectomist." Radioactive Iodine It was with such a background that the advent of radioactive iodine treatment, the "bloodless thyroidectomy," was hailed a quarter of a century ago. Most of the early concerns about this form of therapy have been dispelled. Bone marrow toxicity in the form of leukemia has been linked with massive doses of radioactive iodine employed in some patients with carcinoma of the thyroid, but the much smaller doses employed for hyperthyroidism have convincingly been shown not to lead to a higher percentage of leukemia than seen in the general population. The carcinogenic effect of radioactive iodine on the thyroid gland itself was also an early concern. Such an effect was demonstrated in children treated with radioactive iodine early in the experience, and now most therapists do not use this treatment in patients under the age of 20 years. A carcinogenic effect has not been demonstrated in many thousands of treated adults, however. The only major unanswered question about long-range effects of radioactive iodine is that of the genetic effect on subsequent generations. A significant number of women have already been treated with the modest doses required for hyperthyroidism as well as with the larger doses required in the treatment of carcinoma of the thyroid and have then produced offspring without any increased incidence of observable congenital abnormalities. However, it must be emphasized that only one generation has been studied in this regard and further investigation is necessary. How do the results of radioactive iodine treatment of hyperthyroidism compare with those of the other modalities? Initial enthusiasm was great. Three fourths to four fifths of patients became euthyroid after a single dose of radioactive iodine. Of the remaining 20 to 25 per cent, the vast majority achieved euthyroidism after a second treatment, with only a rare handful requiring three or more treatments. The delay in response of this 20 to 25 per cent proved to be an annoyance, but one easily managed with antithyroid medications. Subsequently, however, it became apparent that increasing numbers of the "euthyroid" patients were becoming hypothyroid with the passage of time. Indeed, the statistics of Dunn and Chapman7 seemed to be representative. In their large series, they found that 20 per cent of the treated patients became hypothyroid within 2 years after treatment and that each year thereafter
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an additional 2 per cent became hypothyroid, producing an ultimate incidence of 40 per cent by 10 years after treatment. Conceivably, all patients who receive such treatment will become myxedematous if they live long enough. What then can be done to decrease the startling prevalence of hypothyroidism? The dosage of radioactive iodine is usually calculated from a formula that relates the dosage directly to the estimated size of the gland and inversely to the percentage of a tracer dose of radioactive iodine taken up by the gland. Such formulas are defective in several ways. The difficulties of clinically estimating thyroid gland size are well known. There is also no way of assuring that the percentage uptake of a tracer dose is equivalent to the percentage uptake of the full therapeutic dose and even whether there is any relation between the percentage uptake and how long the therapeutic dose remains in the thyroid gland to achieve its effect. Most importantly, however, the most crucial factor involved does not appear in any formula for calculating radioactive iodine dosage- that is, the biologic variability of different glands and the unpredictable sensitivity of these glands to even a carefully standardized dose of radiation. With these shortcomings in view, attempts have been made to reduce the incidence of hypothyroidism after radioactive iodine therapy. Most of these efforts have centered around reducing the total dose of iodine administered. Early results from such studies10 have showed a lowered incidence of myxedema but have demonstrated a proportionately greater lag time before the development of euthyroidism in the majority of patients. So the concern about the incidence of hypothyroidism after treatment with radioactive iodine has nevertheless continued. To many, however, this has not proved to be a major problem. These therapists argue convincingly that, if the incidence of this complication is so well delineated, it becomes a simple matter of forewarning the patient of this development and instituting prompt thyroid replacement as soon as euthyroidism has been achieved, even before the development of frank hypothyroidism. The lifetime continuation of thyroid hormone replacement in physiologic doses presents no danger of untoward metabolic or allergic effects and certainly no economic burden. Balanced against the single side effect of hypothyroidism is the remarkable absence of other complications of radioactive iodine therapy. There is no untoward effect on any structure in the region of the thyroid gland-no threat to the laryngeal nerves and no threat to the parathyroid glands. Extremely rare instances of brief exacerbations of hyperthyroidism after treatment have been reported. Such can be avoided in patients at risk, mainly those with cardiovascular complications, by a brief course of antithyroid medication before and after treatment with radioactive iodine.
A RATIONAL APPROACH TO THE TREATMENT OF HYPERTHYROIDISM Two "definitive" modes of therapy exist for the hyperthyroidism of Graves' disease-radioactive iodine and subtotal thyroidectomy. Treat-
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ment with radioactive iodine must remain the treatment of choice in patients more than 40 years of age or past the reasonable expectation of childbearing. It is simple, requires no hospitalization, and is remarkably free of morbidity. Its single, well-publicized shortcoming of frequently producing hypothyroidism can easily be obviated by awareness of this complication and the prompt utilization of thyroid replacement therapy as soon as the euthyroid state is achieved. Radioactive iodine also remains the treatment of choice for patients who have had persistence or relapse of hyperthyroidism after subtotal thyroidectomy. It is also valuable for any patient, regardless of age, in whom operation is precluded by a severe coexistent illness. In fact, at many centers it is the treatment of choice for all patients with Graves' disease over the age of 25, although most physicians prefer to await more substantial evidence on long-range genetic effects before routinely employing this therapy in the 25-year-old to 40-year-old group. The only absolute contraindication to radioactive iodine therapy remains pregnancy. Subtotal thyroidectomy, in skilled and experienced surgical hands, provides an effective, mortality-free form of therapy for the young adult with the hyperthyroidism of Graves' disease. Postoperative disability is short-lived, and early and late morbidity is infrequent. What then is the role of "nondefinitive" treatment with prolonged antithyroid medical therapy? Is there a place for "nondefinitive" treatment for a disease that often, perhaps in 50 per cent of patients, will enter into a permanent remission after a reasonable period? The obvious answer is yes. The equally obvious problem is that of prognosticating those patients with a favorable outlook relatively early, so that they may be spared submission to any definitive form of therapy, no matter how benign. Of equal importance is determining with speed and accuracy those patients who cannot be expected to respond permanently to conservative treatment so that they may promptly be offered definitive treatment. The efforts toward such prognosis in our group and in many others have been directed at young adults with Graves' disease, a group that would provide eventual candidates for subtotal thyroidectomy. The choice of this emphasis rests on two major considerations. First, these are the patients in whom there would be the greatest incentive to spare any definitive procedure. Second, subtotal thyroidectomy invariably requires a period of 2 to 4 months of preparation with antithyroid medication that provides additional time for evaluating the patient as well as a head start in any proposed long-range course of medical therapy. Our approach to this problem has been flexible. All young adults with Graves' disease receive antithyroid medical therapy. In those patients whose duration of illness is long, whose goiters are large (more than 50 gm.), whose reliability is poor, or whose response to the initial stages of therapy is slow, the aim is prompt achievement of the euthyroid state and progression to subtotal thyroidectomy. In the remaining patients with a short duration of illness, a moderate to small goiter, and prompt response to initial therapy, the attempt at long-range combined medical therapy is extended. In the past, unfortunately, little prognostic information could be gathered in this lengthy 12-month to 18-month trial with the
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exception of change in goiter size. Shrinkage of the goiter in response to combined thyroid-antithyroid medication provides much optimism about the outcome but no guarantee of success. Not until the end of the trial, after antithyroid medication is discontinued and the suppression test is carried out, is there a real indication of the likely outcome. The introduction by Alexander et al. 2 of the early uptake test has added a new dimension to the management of Graves' disease, however. It provides a prognostic indication that can be applied early in the course of combined medical therapy without interrupting that therapy. If longer follow-up studies do indeed substantiate the accuracy of this prognostic index, it will become a valuable tool. Even at present, there is a place for it in patients under the age of 40 with Graves' disease. Enthusiasts suggest that even older patients who are candidates for eventual treatment with radioactive iodine should be given the benefit of a several-month course of antithyroid treatment, during which the response and suppressibility of the early uptake can be determined. If results are favorable, eventual treatment with radioactive iodine can be avoided in favor of medical therapy. An important caution is that no studies have yet suggested that permanent remission will be maintained with anything less than a full year's course of medical therapy, even in patients with a promising early uptake response. Special mention needs to be made of the treatment of Graves' disease during pregnancy. Early in the experience with antithyroid drugs, the medical treatment of hyperthyroidism in pregnancy presented great difficulty. The well-documented fact that the thiouracil derivatives easily crossed the placenta accounted for a high incidence of goitrous neonates produced, even in the event that the pregnancy proceeded to term. More recently it has been well demonstrated13 that full-term antithyroid therapy when combined with thyroid hormone supplementation is an effective mode of treatment. The success of this newer form of medical therapy hinges upon the carefully tapered doses of antithyroid compounds employed plus the probability that enough of the full replacement dose of thyroid hormone given the mother crosses the placenta to obviate the development of hypothyroidism in the fetus. During recent years also, it has been well documented4 that a patient with Graves' disease carefully prepared with antithyroid medication during the first and early second trimester, submitted to subtotal thyroidectomy in the second trimester, and given full replacement doses of thyroid for the duration of the pregnancy will have an equally favorable outlook for a successful pregnancy and delivery. Therefore, it has been our policy to treat pregnant patients with Graves' disease in much the same manner as those who are not pregnant, with the exception that minimal doses of antithyroid drugs and full replacement doses of thyroid preparations are utilized in those undergoing long-term medical treatment.
FUTURE TREATMENT OF GRAVES' DISEASE The development of accurate prognostic tests will certainly be of advantage in utilizing most effectively the three modes of therapy now
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available to us. It must be kept in mind that none of these yet provides the ideal solution, for the cogent reason that none attacks the etiologic basis of the disease. If, however, LATS, well characterized as an antibody, can be implicated as the etiologic agent in the pathogenesis of Graves' disease in adults, as it has been implicated in neonatal Graves' disease, then new horizons will be opened. Graves' disease may then indeed be classified as an autoimmune disease and patients may become candidates for the employment of immunosuppressive therapy. Thus far, only scant experience has been accumulated,' 9 primarily because present immunosuppressive treatments entail greater morbidity than the classic forms of treatment of Graves' disease. Nevertheless, the exploration of the role of LATS provides the most exciting frontier in thyroidology today.
REFERENCES 1. Adams, D. D., and Purves, H. D., quoted by Lipman, L. M., eta!." 2. Alexander, W. D., Harden, R. M., Shimmins, J., eta!.: Treatment of thyrotoxicosis based on thyroidal suppressibility. Lancet, 2:681-684, 1967. 3. Astwood, E. B.: Treatment of hyperthyroidism with thiourea and thiouracil. J.A.M.A., 122:78-81, 1943. 4. Bell, G. 0., and Hall, J.: Hyperthyroidism in pregnancy. Med. Clin. N. Amer., 44:363-367, 1960. 5. Caswell, H. T., Robbins, R. R., and Rosemond, G. P.: Definitive treatment of 536 cases of hyperthyroidism with I-131 or surgery. Ann. Surg., 164:593-599, 1966. 6. Clark, F., and Horn, D. B.: Assessment of thyroid function by the combined use of the serum protein-bound iodine and resin uptake of 131 1-triiodothyronine. J. Clin. Endocr., 25:39-45, 1965. 7. Dunn, J. T., and Chapman, E. M.: Rising incidence of hypothyroidism after radioactiveiodine therapy in thyrotoxicosis. New Eng. J. Med., 271:1037-1042, 1964. 8. Green, M., and Wilson, G. M.: Thyrotoxicosis treated by surgery or iodine-131. With special reference to development of hypothyroidism. Brit. Med. J., 1:1005-1010, 1964. 9. Greer, M. A., and Smith, G. E.: Method for increasing accuracy of radioiodine uptake as test for thyroid function by use of desiccated thyroid. J. Clin. Endocr., 14:1374-1384, 1954. 10. Hagen, G. A., Ouellette, R. P., and Chapman, E. M.: Comparison of high and low dosage levels of ' 31 1 in the treatment of thyrotoxicosis. New Eng. J. Med., 277:559-562, 1967. 11. Hales, I., Spiel, J., Reeve, T., et al.: Prediction of the long-term results of antithyroid drug therapy for thyrotoxicosis. J. Clin. Endocr., 29:998-1001, 1969. 12. Hamolsky, M. W., Stein, M., and Freedberg, A. S.: The thyroid hormone-plasma protein complex in man. II. A new in vitro method for study of "uptake" of labelled hormonal components by human erythrocytes. J. Clin. Endocr., 17:33-44, 1957. 13. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med., 273:627-633, 1965. 14. Hershman, J. M., Givens, J. R., Cassidy, C. E., eta!.: Long-term outcome of hyperthyroidism treated with antithyroid drugs. J. Clin. Endocr., 26:803-807, 1966. 15. Lipman, L. M., Green, D. E., Snyder, N. J., et a!.: Relationship of long-acting thyroid stimulator to the clinical features and course of Graves' disease. Amer. J. Med., 43:486498, 1967. 16. McKenzie, J. M.: The long-acting thyroid stimulator: its role in Graves' disease. Recent Progr. Hormone Res., 23:1-46, 1967. 17. Murphy, B. E., and Patee, C. J.: Determination of thyroxine utilizing the property of protein-binding. J. Clin. Endocr., 24:187-196, 1964. 18. Treatment of hyperthyroidism. Lancet, 2:406-407, 1967. 19. Werner, S. C., and Platman, S. R.: Remission of hyperthyroidism (Graves' disease) and altered pattern of serum-thyroxine binding induced by prednisone. Lancet, 2:751-755, 1965.