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The Present Status of the Treatment of Hyperthyroidism
THE PRESENT STATUS OF THE TREATMENT OF HYPERTHYROIDISM
R. S. DINSMORE, M.D., F.A.C.S., AND R. W. SCHNEIDER, M.D. The present day lack of agreement regarding the best form of treatment for hyperthyroidism is due to the fact that each of the various effective methods available have significant disadvantages. The ideal approach to the problem at this time must include a knowledge of the limitations of these methods so that one may apply one or more of them to each individual case to the greatest advantage. The introduction of antithyroid drugs and radioactive iodine into the field of thyroid study has introduced a changing picture into the management of hyperthyroidism which cannot receive final evaluation for many years. It is the purpose of this paper to review the present treatment of hyperthyroidism in the light of current knowledge without prejudice to the ultimate place of medical and surgical management of this disease. SURGICAL MEASURES
The surgical treatment of hyperthyroidism, whether associated with a diffuse goiter of Graves' disease or an adenomatous goiter, has for many years revolved about one principle, the surgical removal of a sufficient mass of thyroid tissue to bring the total force of thyroid activity into normal range. In adenomatous goiter this approach produces an effect which in most cases may be considered a cure. Recurrences following this procedure in adenomatous goiter are rare. In Graves' disease the fundamental nature of the condition is of course unknown, and hyperthyroidism is only one part of the syndrome. The hyperthyroidism in itself is usually controlled by removing the major portion of thyroid tissue. Standardization of the surgical technic in the management of hyperthyroidism, and the preoperative use of large doses of iodine in thyroid surgery have led to universally good clinical results, with low mortality and morbidity rates. In appraising the surgical treatment of hyperthyroidism, it must be realized that this form of therapy requires hospitalization, that there is a 2 per cent recurrence rate, some morbidity including such conditions as injury to recurrent laryngeal nerves and occasional transient or chronic tetany, that there is some transient hypothyroidism and even true myxedema, and that as with any other major surgery an operative mortality rate can be expected. It must be re-emphasized, however, that the mortality from competently performed thyroid surgery is now extremely low, thanks in no small part to the fact that elderly patients, From the Cleveland Clinio and the Frank E. Bunts Eduoational Institute, Cleveland, Ohio.
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those who are recognized as being bad operative risks and those with recurrent hyperthyroidism, can now be handled satisfactorily by other nonsurgical means. ANTITHYROID DRUGS
Thiouracil.- The introduction of antithyroid drugs into the management of hyperthyroidism has created a changing picture from both medical and operative viewpoints. Thiouracil was the first of a number of antithyroid drugs to be used extensively in the treatment of hyperthyroidism. Before it was placed on the open market thiouracil had been used in the treatment of more than 5000 patients, and had been abundantly proved to be an effective means of controlling any type of hyperthyroidism with the possible exception of thyroid crisis in which its action was shown to be too slow and in the hypermetabolism of acromegaly, where it appears also to be less effective. The rate of response to thiouracil is not easily predicted. A fall in basal metabolic rate of 1 per cent per day is seldom exceeded. At the opposite extreme some patients fail to show any response of consequence for four or five months, but later are well controlled. In general, hyperthyroidism associated with small diffuse goiters responds more quickly, and that associated with large nodular goiters more slowly. The prolonged use of large doses of iodine preceding thiouracil therapy is frequently a barrier to prompt response. At present, its use in the treatment of hyperthyroidism has been abandoned largely because it has been shown to possess no advantages over other less toxic antithyroid drugs. The main disadvantage of thiouracil is its toxic effects, such as fever, rash, or nausea, occurring in 10 to 15 per cent of all patients. These reactions usually preclude its continued use. Much more serious is the agranulocytosis which has been seen in 2 to 3 per cent. Death from this occurs in 0.5 to 1 per cent. Although the effectiveness of this drug is high, the mortality rate from thiouracil is comparable to that of thyroidectomy and therefore did not replace thyroidectomy in the routine management of hyperthyroidism. Thiobarbital, which is a much more potent antithyroid drug, ';vas also shown to be too toxic. Astwood and Vander Laan 1 refer to patients who had previously exhibited intolerance to thiouracil and to thiobarbital. Five patients were given propyl thiouracil after they had experienced severe febrile reactions to one or the other of these two drugs. In none of these were untoward reactions observed from propyl thiouracil. This experience compares favorably with our own. Williams 2 reported a remission rate of 50 per cent in 100 cases of hyperthyroidism treated with thiouracil. It is possible that the general tendency toward early withdrawal of the drug because of the risk of toxic effects may have reduced the number of permanent recurrences in this group. One of the chief advantages of thiouracil was the production of com-
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plete control of the hyperthyroidism without loss of time from work. The complications of hyperthyroidism behaved similarly to their behavior following thyroidectomy. Since thiouracil was no safer than surgery in uncomplicated moderate hyperthyroidism, and did not induce remissions as often as thyroidectomy, its greatest benefit was in the reduction of surgical risks in bad risk patients. When used (1) in severely toxic patients, (2) those with cardiac failure, (3) those who were weak from long-standing disease, or (4) in those of advanced age, many became good operative risks. In those who remained poor risks, continued therapy was recommended. By so limiting the use of thiouracil the mortality attending thyroid surgery was reduced almost to the vanishing point, but the mortality rate of the drug itself remained unchanged. It was evident from experience with thiouracil that a safer drug was needed, and a number of other derivatives of thiouracil have supplied this need. The first clinical trials were made with ethylthiouracil. Fourteen patients received doses from 20 to 100 mg. daily. This limited trial revealed a high degree of activity, but its further use was abandoned because it proved to be a rather difficult substance to synthesize, and animal tests revealed the propyl derivative to be somewhat superior in terms of antithyroid potency and prolongation of action from a single dose. Isopropylthiouracil was tried for a limited time as well, but had properties similar to the ethyl derivative. Little need be said concerning para-aminobenzoic acid which is a weak antithyroid drug possessing distinct toxic propensities. Propylthiouraci1.-Subsequent clinical trial with 6-N -propylthiouracil and methylthiouracil have shown these two derivatives of thiouracil to be potent antithyroid drugs with decidedly less toxic effects than observed from thiouracil, and have largely supplanted it. Astwood l in the first 100 cases treated with the propyl derivative reported, found four instances of transient pruritis, two of transient headache and one of transient arthralgia. One of his patients died during therapy. This man, with advanced cirrhosis of the liver, was thought to have hyperthyroidism as well, and during the course of propylthiouracil administration showed progressive hepatic failure. The introduction of propylthiouracil therapy did not seem to modify the condition and he died in hepatic coma three months later. Astwood felt that his death was unrelated to the use of this drug. Among the first 218 patients treated by McCullagh, Hibbs and Schneider 3 manifestations which they attributed to the toxicity or sensitivity to propylthiouracil were seen in 7 patients. Three had mild symptoms and the drug could be continued. More severe toxic effects appeared in four, consisting of dermatitis, in one, numbness in another, urticaria in a third and granulocytopenia in the fourth. The incidence of toxic reactions in this series was 3.2 per cent, but serious reactions occurred in only 1 per cent. Up to the present time we have not seen any increased incidence of toxic reactions to the use of propylthiouracil.
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Only 58 per cent show a complete response to 150 mg. or less per day, and only 87.4 per cent to doses of 200 mg. or less per day. Although some patients respond to smaller doses, a dose of 300 mg. or more per day has been effective in 96 per cent of the total. We have customarily used 300 mg. as the initial routine dose, since this is not more toxic than less effective dose levels. Patients with hyperthyroidism associated with small diffuse goiters previously untreated with iodine, react the most rapidly to propylthiouracil. This type of case is among those which are likely to respond with a permanent medical cure. In some instances, however, the thyroid continues to enlarge during treatment, accompanied by rising basal metabolic rate, thus requiring a larger dosage of the drug. In such cases there is not much hope for a permanent medical cure. Hyperthyroidism of longer standing has been more resistant to therapy in our hands. Here the goiter is frequently larger and the total mass of reacting tissue may be a factor limiting this group to less favorable responses to medical cure. In some instances large adenomatous goiters respond much more slowly. However, if larger groups of cases are compared, there is only a small average difference. Concomitant Use of Iodine or Thyroid.-A word might be inserted here concerning the concomitant use of either iodine or thyroid with propylthiouracil. Early in the use of thiouracil, we observed failure to eliminate the thrill and bruit over the thyroid by giving desiccated thyroid in doses of 2 grains per day in three patients. Iodine in doses of 10 mg. per day did so in less than one week. Such small doses of iodine did not interfere with the antithyroid effect obtained from propylthiouracil. There was no significant difference in the rate of fall in basal metabolic rates in one group of patients receiving from 10 to 30 mg. of iodine per day, concurrently with propylthiouracil, as compared to a group receiving propylthiouracil alone. Up to the present time there has been insufficient experience with the use of large doses of iodine given in conjunction with antithyroid drugs. Large doses might slow the desired antithyroid effects. Thus iodine is to be used to prevent or abolish the thrill and bruit which appears in many of these glands, the dosage employed for the present ought to be small. Astwood, however, warns that the use of small doses of iodine concurrently may lessen the number of lasting remissions following the use of antithyroid drugs. One of us has recently seen two patients managed with propylthiouracil without iodine who had no evidence of hyperthyroidism eighteen months after cessation of the drug. There is still no general agreement as to the most desirable procedure to follow once the hyperthyroidism has been initially controlled with propylthiouracil. It seems likely that inadequate dosage with only partial control of the hyperthyroidism would lead to poor ultimate results. In addition, it is well not to reduce the dose too soon, but the maximum tolerated dose should be maintained as long as is possible, rather than reduced as quickly as possible. It has been our practice
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to maintain the initial dose and to administer thyroid when signs of hypothyroidism or myxedema appear, hoping thereby to increase the number of lasting remissions. Methylthiouracil.-Methylthiouracil has also proved to be highly effective in the control of hyperthyroidism. Many accounts of its use have been published in Denmark, Sweden, England, Australia and the United States. The studies of Meulengracht and his associates,4.5 Magnusson and Sorensen,6 and Frish7 include the largest series of cases studied in the earlier period. At first, the drug was considered to have a higher degree of toxicity than propylthiouracil, but the amounts used were in excess of 600 mg. per day. This amount was soon found to be excessive. The Danish indicated that the drug retained its high efficiency at a dosage comparable to propylthiouracil. Actually, it was suggested that a dose of methylthiouracil might be found which would be similar to the effective dose of propylthiouracil and at the same time be more rapid in controlling hyperthyroidism. Kjerulf-Jensen and Meulengracht 8 conclude that methylthiouracil is somewhat more effective than propylthiouracil in controlling hyperthyroidism, and when used in comparable doses shows no greater toxicity. McCullagh and Sirridge 9 treated 100 patients with hyperthyroidism for from one to sixteen months, using 200 to 400 mg. per day. In cases of diffuse goiter, the mean fall in basal metabolic rate in percentage per week, using 200 mg. of methylthiouracil per day, was 4.5, as compared to 4.1 in comparable doses of propylthiouracil. Using 300 mg. per day the mean fall of basal metabolic rate in percentage per week was 6.1, as compared to 3.6 in propylthiouracil treated cases. They pointed out that the difference is not great, however, and that a wide variation in response is present. Toxic effects were recognized in only five patients in this series; four of these were mild, and did not require interruption in treatment. One patient with a history of purpura developed a recurrence of purpura while taking methylthiouracil, but the relationship of the purpura to the drug was not clear. Astwood * regards methylthiouracil to be more effective than propylthiouracil in comparable range of dose. He considers 300 mg. of propylthiouracil to be effective in controlling hyperthyroidism in 96 per cent of cases, whereas methylthiouracil is almost 100 per cent effective in a similar dosage. Meulengracht and Kjerulf-Jensen8 reported follow-up observations in 111 patients treated for one year. The doses employed were 250 mg. three times daily for the first two to three months, 250 mg. once or twice daily during the succeeding few months, with a maintenance dose of 125 mg. during the remainder of treatment. At this range of dosage, toxic reactions were encountered in 7.8 per cent of cases, in comparison to 1 per cent in the smaller dose ranges employed by other investigators. Nine per cent of the individuals treated showed genuine
* Personal communication.
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relapse, making the remission rate three months after the discontinuance of the drug approximately 91 per cEmt. At the present time it is not possible to conclude the ultimate remission rate in the management of hyperthyroidism by antithyroid drugs because there has not been sufficient time in follow-up. It has been suggested that the ultimate remission rate may well depend upon the care exercised in the control of the hyperthyroidism during treatment, and Astwood feels that in better controlled cases this may reach as high as 90 per cent. We have not been this fortunate despite continued effort to control the hyperthyroidism completely or in those in whom hypothyroidism was maintained for many months. Our remission rate in cases treated for one year approximates 50 per cent. Changes in Thyroid Following Antithyroid Drugs.-The changes in the thyroid following the use of ,antithyroid drugs' in Graves' disease have been studied extensively. Rawsonaiid his associates lO demonstrated an increasing hyperplasia of the thyroid with loss .of colloid and increase in vascularity in all cases, comparable to the changes observed in the thyroid of rats treated with thiourea. DeRobertisll showed that these goitrogens worked by interference with enzyme systems within the thyroid involved in the synthesis of organic thyroid fraction from stored inorganic iodine. Under antithyroid agents there is a marked decrease in organic iodine within the gland owing to suppression of the hormone containing organic iodine. Iodine is absorbed but not utilized. The interruption in thyroxine synthesis is believed to stimulate thyrotropic activity in the pituitary, which in turn causes further hyperplasia of the thyroid. This induced hyperplasia can be prevented in the experimental animal by hypophysectomy. The hypertrophy and hyperplasia of the gland at times is very appreciable indeed. Rarely, however, does it lead to sufficient compression of the trachea to be an indication for thyroidectomy. The enlargement usually persists during the period of this treatment. At times this enlargement is of sufficient cosmetic importance to the patient to make thyroidectomy the choice. Once treatment has been discontinued the thyroid may return to its pretreatment size. Meulengracht and KjerulfJensen 8 stated that 50 per cent of their patients had no goiter at the end of treatment; 30 per cent of these had never shown enlargement during therapy; 20 per cent had lost whatever enlargement had appeared during treatment. Among the 50 per cent showing an enlargement of the thyroid at the end of treatment, there had been a reduction in size in 25 per cent, and no change in the remainder. In general, it has been our experience that enlarging glands during treatment persist when the drug is discontinued. We have not seen impressive remissions in this group of cases and feel' for this reason that glands showing tendency to enlarge during therapy are not likely to be cured by antithyroid drugs. Significant Problems Relating to Use of Antithyroid Drugs.-A number of highly significant problems relating to the employment of antithyroid drugs in the management of hyperthyroidism remain to be C
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settled. Thyroidectomy, after proper control of hyperthyroidism, results in permanent and complete return to health in about 90 per cent of cases, and tends to shorten the time of this recovery. In contrast, prolonged drug therapy is at times difficult, due to poor cooperation of the patient; when improvement appears treatment may be allowed to lapse. Some will sooner or later prefer to have their problem settled by thyroidectomy. Unless antithyroid drugs can duplicate surgical results, they will not replace surgery in the management of the uncomplicated hyperthyroidism of Graves' disease. At the present time, hope for this is distinctly less than a few years ago. In the management of recurrent hyperthyroidism, however, where an increased risk to the recurrent laryngeal nerves, or the parathyroids is significant, their use seems more clearly indicated. Complete control of the disease with propyl or methyl thiouracil is usually advised in all patients with severe hyperthyroidism, in all those over 45 years of age, as well as in those with complicating factors, such as poor cardiac status. Once the disease is completely controlled Lugol's solution is given prior to operation, and the antithyroid drug is discontinued. It has been our impression that Lugol's solution must be given for from four to six weeks in order to re9uce the vascularity and the friability of the gland to a minimum at the time of operation. The patient may be ready for surgery sooner but the "gland is not." In patients whose hyperthyroidism is complicated by extreme old age, by cardiac or other disorders which will prevent them ever from becoming good surgical risks-even after the elimination of hyperthyroidism-propylthiouracil or methylthiouracil may have to be continued indefinitely. There remains another group of unsettled questions in relationship to the use of antithyroid drugs in the management of hyperthyroidism. Whether significant histopathologic change will follow the prolonged use of antithyroid drugs is still not established. Bartels12 reviewed 1200 goiters to show' malignant change. Three of them were in adenomatous goiters and four in diffuse goiters He pointed out that this incidence must be compared with that before using antithyroid drugs, before its true significance can be determined. Other questions to be settled concerning the medical management of diffuse goiter relate to the frequency with which the remission rate can be increased by the type of associated therapy in conjunction with the antithyroid drug employed. If the remission rate can be shown to be greater when iodine is withheld, this fact will outweigh the importance of eliminating the thrill and bruit induced during therapy. Similarly, if more lasting remissions can be produced in patients by inducing hypothyroidism (and requiring thyroid extract) this procedure would be preferable to dosages only large enough to produce euthyroidism. RADIOACTIVE IODINE
Radioactive iodine is the latest therapeutic tool introduced for the treatment of hyperthyroidism. Like surgery and antithyroid drugs,
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radioactive iodine also has advantages and disadvantages. Its ultimate place in the treatment of goiter cannot be accurately established for many years. It is now seven years since Hamilton and Lawrence l3 and Hertz and Roberts l4 reported on the treatment of hyperthyroidism with radioactive iodine. The experiences of a great many investigators, including Soley/5 Hertz and Roberts,16 Chapman and Evans, 17 Haines et aU 8 and Crile et aU9 have established the effectiveness of radioactive iodine in the immediate control of hyperthyroidism. All subsequent studies have continued to confirm this and some patients now have been in remission for several years. In the earlier years a mixture of about 90 per cent P30 and about 10 per cent p3l was employed. Since the release of p3l by the Atomic Energy Commission two years ago this isotope has received extensive consideration in the management of hyperthyroidism. A number of properties of p3l make it an attractive isotope for clinical use. It differs from many radioactive substances in that its half life is only eight days. This property is considered to minimize the later ill effects due to retention of a long-lived radioactive substance within the body. Furthermore, its safety is increased bec~use of the fact that its radiation is largely in the form of beta rays which do not penetrate tissues for more than 1 or 2 mm. Since it is concentrated in the thyroid, it does not cause demonstrable damage to tissues immediately outside of the thyroid. Gorbman,2° however, has given young mice massive doses of p3l and produced complete destruction of the thyroid, loss of the parathyroids, lesions in the tracheal epithelium, and in the recurrent laryngeal nerve. Up to now no comparable changes have been demonstrated in patients and damage has not been reported to the kidneys, bone marrow, testes or other organs. Furthermore, the chemical and physiologic behavior of radioactive iodine is identical to that of ordinary iodine and the thyroid handles it in the same way that it does stable iodine. In hyperthyroidism the uptake and concentration of p3l within the thyroid is much greater than in the normal thyroid. Hamilton21 estimates a concentration in the thyroid in an amount 10,000 times greater than in the blood or in any other organ. The isotope is stored within the thyroid until it has lost the major part of its radioactivity, after which most of it is excreted by the kidneys as ordinary iodine. For these reasons the amount of irradiation received by the thyroid after an average dose of radioactive iodine is much greater than the amount of irradiation which can be delivered by roentgen therapy without damage to the skin. The average dose of 4mc. by Oak Ridge standard, given to a patient with Graves' disease and a goiter weighing 50 gm. which takes up 50 per cent of the administered dose, delivers the equivalent of 4000 r to the thyroid. p3l is in the form of sodium iodide and is dissolved in water. It is colorless and tasteless. The amount contained in the average therapeutic dose is equivalent to the iodine in 1/50,000 of a drop of Lugol's solution. Radiation sickness and irritation of the thyroid area are not observed
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from the ordinary dose, but irradiation sickness has occurred when large doses are used, such as in the treatment of cancer of the thyroid. Among the disadvantages, one of the most immediate relates to technical difficulties in distribution and handling. A more important consideration in the use of radioactive iodine is its possible ultimate carcinogenic properties. Although there is little experimental or clinical evidence to suggest that intensive irradiation of this nature will be carcinogenic, this possibility demands careful consideration. Whether the incidence of carcinoma of the thyroid will be significantly altered by its use remains to be demonstrated, but most authorities feel that it is not likely to increase its incidence. None the less, radioactive iodine is largely being reserved for use in older patients with hyperthyroidism, or for patients with short life expectancies. It is also being used where serious heart disease, or other complications, might add considerably to the risk of surgical treatment, and for patients with recurrent hyperthyH>idism, in whom one or more previous resections of the thyroid have been performed, where unilateral paralysis of the vocal cords, or extremely small amounts of thyroid remain from previous operative procedures. The matter of dosage to be employed is one of the major problems confronting investigators in this field. Up to the present time there have not been any uniformly satisfactory methods of estimating the amount of radioactive iodine to be given in one dose to effect a cure. Clinical estimates of the size of the gland are no consistent criterion to dosage partly because of the inaccuracy of proper estimates, but more particularly because of the great variability in the response of different thyroid glands to the same dosage. We have attempted to adopt the policy that for the treatment of Graves' disease the initial dose should be one-half to two-thirds of the average dose required to effect a cure. When 4 mc. are given, about one-half of the patients are well after a single treatment, and only 10 per cent develop transient hypothyroidism. The size of the second dose has been gauged on the response of the hyperthyroidism to the first. If the basal metabolic rate is unchanged after two months, the second dose may be doubled. If the basal metabolic rate has fallen half-way to normal, the first dose may be repeated. If the basal metabolic rate has dropped two-thirds of the way to normal, one-half of the original dose is usually given. If there is only slight residual hyperthyroidism, or if the basal metabolic rate is at the upper limit of normal, no further treatment is given, because maximum effects of a single dose sometimes are not apparent for three or four months. In Graves' disease, our average initial dose has been 4 mc., unless the thyroid is unusually large and the hyperthyroidism severe, in which case 6 or even 8 mc. have been given. Our experience has indicated that the dose required to control hyperthyroidism of Graves' disease is dependent more upon severity than upon the size of the gland, although individual variability must be recognized. Crile and his associates19 have demonstrated that in nodular goiter with hyperthyroidism the
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average initial dose should be distinctly increased over that of diffuse goiter. In these 8 to 15 mc., depending upon the size of the gland, have been employed. In general the results from treatment in Graves' disease are highly satisfactory. Approximately 65 per cent are well controlled on one dose at the end of three months. The thyroid gland invariably reduces in size, and in Graves' disease is usually no longer palpable. Nodular goiters usually shrink but do not disappear. Auricular fibrillation tends to revert to normal sinus rhythm just as after thyroidectomy. Recently Kelsey, Haines and Keating 22 have published a review of the present status of radioactive iodine in the treatment of thyroid disease. The addition of the series reported by Crile's group to the series reviewed by these authors brings the total cases to 446. Undoubtedly many others have not been included in this study. However, 54 per cent of the 446 cases were euthyroid after one dose of P3r, while hypothyroidism occurred in only 4.2 per cent. Some of these were transient. Williams and his co-workers23 mention the occasional accentuation of hyperthyroidism after the first dose. We have recently seen several instances of this type. Exophthalmos behaves in general in the same way that it does following thyroidectomy or antithyroid drugs. Soley and Miller24 mention an increase in exophthalmos in six out of twentysix so studied. Collected observations show a uniform fall in basal metabolic rate, a fall in protein bound iodine, and a rise in blood lipids. Transient fever, rise in sedimentation rate, and tenderness of the thyroid area have also been observed. Transient leukopenia was seen in one instance, but agranulocytosis has not been observed. There have been no recurrences seen in those cases in whom euthyroidism has occurred. lt is to be predicted that radioactive iodine will reduce many of the present indications for propylthiouracil and methylthiouracil. lt is likely that it is the treatment of choice when hyperthyroidism is present in the bad risk patient, or attended by complications such as recurrent hyperthyroidism, or vocal cord paralysis, because it is likely to produce a more lasting remission than antithyroid agents have been shown to do. lt is likely that it will never be the routine treatment for nodular goiter with hyperthyroidism because surgery usually cures the disease permanently and tentative observations show a less satisfactory response to 1131. Many years of observation will be required to determine whether or not it will be the ultimate method of treatment for young patients with Graves' disease. Since apparently no complications, apart from hypothyroidism, attend the use of radioactive iodine, it is probably the most promising treatment of hyperthyroidism of the future. REFERENCES 1. Astwood, E. B., and Vander Laan, W. P.: Treatment of Hyperthyroidism with propylthiouracil. Ann. Int. Med. 25: 813, 1946. 2. Williams, R. H.: Thiouracil Treatment of Thyrotoxicosis; Results of Prolonged Treatment. J. Clin. Endocrinol. 6: 1, 1946.
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3. McCullagh, E. P., Hibbs, R. E. and Schneider, R. W.: Propylthiouracil in Treatment of Hyperthyroidism. Am. J. M. Sc. 214: 545,1947. 4. Meulengracht, E. and Schmith, K.: Treatment of Thyrotoxicosis with Methylthiouracil. Acta med. Scandinav. 122: 294, 1945. 5. Meulengracht, E., Kjerulf-Jensen, K. and Schmith, K.: Cited by Barfred, A., Nord. med. 32: 2800, 1946. 6. Magnusson, P. and Soerensen, G.: Treatment of Hyperthyroidism with Methylthiouracil. Acta med. Scandinav. 125: 263, 1946. 7. Frish, R. A.: Cited by Barfred, A." 8. Meulengracht, E. and Kjerulf-Jensen, K.: Prolonged Methylthiouracil Treatment in Thyrotoxicosis; Results after Cessation of Treatment. J. Clin. Endocrinol. 8: 1060, 1948. 9. McCullagh, E. P. and Sirridge, W. A.: Methylthiouracil in Treatment of Hyperthyroidism. J. Clin. Endocrinol. 8: 1051, 1948. 10. Rawson, R. W. et al.: Action of Thiouracil upon Thyroid Gland in Graves' Disease. J. Clin. Endocrinol. 4: 1, 1944. 11. DeRobertis, E.: Proteolytic Activity in Physiology, Pathology and Therapeutics of Thyroid Gland. Presented at Ann. Meet. Am. A. Study Goiter, April 3-5, 1947. 12. Bartels, E. C.: Appraisal of Goitrogens; Results of Treatment with Thiouracil, Propylthiouracil and Related Antithyroid Drugs. J. Clin. Endocrinol. 8: 766, 1948. 13. Hamilton, J. G. and Lawrence, J. H.: Recent Clinical Developments in Therapeutic Application of Radio-phosphorus and Radio-iodine. J. Clin. Investigation 21: 624, 1942. 14. Hertz, S. and Roberts, A.: Application of Radioactive Iodine in Therapy of Graves' Disease. J. Clin. Investigation 21: 624,1942. 15. Hamilton, J. G. and Soley, M. H.: Studies in Iodine Metabolism of Thyroid Gland in situ by Use of Radio-iodine in Normal Subjects and in Patients with Various Types of Goiter. Am. J. Physiol. 131: 135, 1940. 16. Hertz, S. and Roberts, A.: Radioactive Iodine in Study of Thyroid Physiology. J.A.M.A. 131: 86, 1946. 17. Chapman, E. M. and Evans, R. D.: Treatment of Hyperthyroidism with Radioactive Iodine. J.A.M.A. 131: 86, 1946. 18. Haines, S. F. et a!.: Use of Radioiodine in Treatment of Exophthalmic Goiter. J. Clin. Endocrinoi. 8: 813,1948. 19. Crile, G., Jr., McCullagh, E. P. and Glasser, 0.: Radioactive Iodine in Treatment of Hyperthyroidism. Cleveland Clin. Quart. 16: 1, 1949. 20. Gorbman, A.: Effects of Radiotoxic Dosages of 1'31 upon Thyroid and Contiguous Tissues in mice. Proc. Soc. Exper. BioI. & Med. 66: 212, 1947. 21. Hamilton, J. G.: Use of Radioactive Tracers in Biology and Medicine. Radiology 39: 541,1942. 22. Kelsey, M. P. et a!.: Radioiodine in Study and Treatment of Thyroid Disease; a Review. J. Clin. Endocrinoi. 9: 171, 1949. 23. Williams, R. H. et al.: Reciprocal Relationships of Radioiodotherapeusis and Thyroid Function. J. Clin. Investigation 27: 562, 1948. 24. Soley, M. H., and Miller, E. R: Treatment of Graves' Disease with Radioactive iodine. M. Clin. North America 32: 3, 1948.
R. S. DINSMORE, M.D., F.A.C.S., AND R. W. SCHNEIDER, M.D. The present day lack of agreement regarding the best form of treatment for hyperthyroidism is due to the fact that each of the various effective methods available have significant disadvantages. The ideal approach to the problem at this time must include a knowledge of the limitations of these methods so that one may apply one or more of them to each individual case to the greatest advantage. The introduction of antithyroid drugs and radioactive iodine into the field of thyroid study has introduced a changing picture into the management of hyperthyroidism which cannot receive final evaluation for many years. It is the purpose of this paper to review the present treatment of hyperthyroidism in the light of current knowledge without prejudice to the ultimate place of medical and surgical management of this disease. SURGICAL MEASURES
The surgical treatment of hyperthyroidism, whether associated with a diffuse goiter of Graves' disease or an adenomatous goiter, has for many years revolved about one principle, the surgical removal of a sufficient mass of thyroid tissue to bring the total force of thyroid activity into normal range. In adenomatous goiter this approach produces an effect which in most cases may be considered a cure. Recurrences following this procedure in adenomatous goiter are rare. In Graves' disease the fundamental nature of the condition is of course unknown, and hyperthyroidism is only one part of the syndrome. The hyperthyroidism in itself is usually controlled by removing the major portion of thyroid tissue. Standardization of the surgical technic in the management of hyperthyroidism, and the preoperative use of large doses of iodine in thyroid surgery have led to universally good clinical results, with low mortality and morbidity rates. In appraising the surgical treatment of hyperthyroidism, it must be realized that this form of therapy requires hospitalization, that there is a 2 per cent recurrence rate, some morbidity including such conditions as injury to recurrent laryngeal nerves and occasional transient or chronic tetany, that there is some transient hypothyroidism and even true myxedema, and that as with any other major surgery an operative mortality rate can be expected. It must be re-emphasized, however, that the mortality from competently performed thyroid surgery is now extremely low, thanks in no small part to the fact that elderly patients, From the Cleveland Clinio and the Frank E. Bunts Eduoational Institute, Cleveland, Ohio.
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those who are recognized as being bad operative risks and those with recurrent hyperthyroidism, can now be handled satisfactorily by other nonsurgical means. ANTITHYROID DRUGS
Thiouracil.- The introduction of antithyroid drugs into the management of hyperthyroidism has created a changing picture from both medical and operative viewpoints. Thiouracil was the first of a number of antithyroid drugs to be used extensively in the treatment of hyperthyroidism. Before it was placed on the open market thiouracil had been used in the treatment of more than 5000 patients, and had been abundantly proved to be an effective means of controlling any type of hyperthyroidism with the possible exception of thyroid crisis in which its action was shown to be too slow and in the hypermetabolism of acromegaly, where it appears also to be less effective. The rate of response to thiouracil is not easily predicted. A fall in basal metabolic rate of 1 per cent per day is seldom exceeded. At the opposite extreme some patients fail to show any response of consequence for four or five months, but later are well controlled. In general, hyperthyroidism associated with small diffuse goiters responds more quickly, and that associated with large nodular goiters more slowly. The prolonged use of large doses of iodine preceding thiouracil therapy is frequently a barrier to prompt response. At present, its use in the treatment of hyperthyroidism has been abandoned largely because it has been shown to possess no advantages over other less toxic antithyroid drugs. The main disadvantage of thiouracil is its toxic effects, such as fever, rash, or nausea, occurring in 10 to 15 per cent of all patients. These reactions usually preclude its continued use. Much more serious is the agranulocytosis which has been seen in 2 to 3 per cent. Death from this occurs in 0.5 to 1 per cent. Although the effectiveness of this drug is high, the mortality rate from thiouracil is comparable to that of thyroidectomy and therefore did not replace thyroidectomy in the routine management of hyperthyroidism. Thiobarbital, which is a much more potent antithyroid drug, ';vas also shown to be too toxic. Astwood and Vander Laan 1 refer to patients who had previously exhibited intolerance to thiouracil and to thiobarbital. Five patients were given propyl thiouracil after they had experienced severe febrile reactions to one or the other of these two drugs. In none of these were untoward reactions observed from propyl thiouracil. This experience compares favorably with our own. Williams 2 reported a remission rate of 50 per cent in 100 cases of hyperthyroidism treated with thiouracil. It is possible that the general tendency toward early withdrawal of the drug because of the risk of toxic effects may have reduced the number of permanent recurrences in this group. One of the chief advantages of thiouracil was the production of com-
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plete control of the hyperthyroidism without loss of time from work. The complications of hyperthyroidism behaved similarly to their behavior following thyroidectomy. Since thiouracil was no safer than surgery in uncomplicated moderate hyperthyroidism, and did not induce remissions as often as thyroidectomy, its greatest benefit was in the reduction of surgical risks in bad risk patients. When used (1) in severely toxic patients, (2) those with cardiac failure, (3) those who were weak from long-standing disease, or (4) in those of advanced age, many became good operative risks. In those who remained poor risks, continued therapy was recommended. By so limiting the use of thiouracil the mortality attending thyroid surgery was reduced almost to the vanishing point, but the mortality rate of the drug itself remained unchanged. It was evident from experience with thiouracil that a safer drug was needed, and a number of other derivatives of thiouracil have supplied this need. The first clinical trials were made with ethylthiouracil. Fourteen patients received doses from 20 to 100 mg. daily. This limited trial revealed a high degree of activity, but its further use was abandoned because it proved to be a rather difficult substance to synthesize, and animal tests revealed the propyl derivative to be somewhat superior in terms of antithyroid potency and prolongation of action from a single dose. Isopropylthiouracil was tried for a limited time as well, but had properties similar to the ethyl derivative. Little need be said concerning para-aminobenzoic acid which is a weak antithyroid drug possessing distinct toxic propensities. Propylthiouraci1.-Subsequent clinical trial with 6-N -propylthiouracil and methylthiouracil have shown these two derivatives of thiouracil to be potent antithyroid drugs with decidedly less toxic effects than observed from thiouracil, and have largely supplanted it. Astwood l in the first 100 cases treated with the propyl derivative reported, found four instances of transient pruritis, two of transient headache and one of transient arthralgia. One of his patients died during therapy. This man, with advanced cirrhosis of the liver, was thought to have hyperthyroidism as well, and during the course of propylthiouracil administration showed progressive hepatic failure. The introduction of propylthiouracil therapy did not seem to modify the condition and he died in hepatic coma three months later. Astwood felt that his death was unrelated to the use of this drug. Among the first 218 patients treated by McCullagh, Hibbs and Schneider 3 manifestations which they attributed to the toxicity or sensitivity to propylthiouracil were seen in 7 patients. Three had mild symptoms and the drug could be continued. More severe toxic effects appeared in four, consisting of dermatitis, in one, numbness in another, urticaria in a third and granulocytopenia in the fourth. The incidence of toxic reactions in this series was 3.2 per cent, but serious reactions occurred in only 1 per cent. Up to the present time we have not seen any increased incidence of toxic reactions to the use of propylthiouracil.
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Only 58 per cent show a complete response to 150 mg. or less per day, and only 87.4 per cent to doses of 200 mg. or less per day. Although some patients respond to smaller doses, a dose of 300 mg. or more per day has been effective in 96 per cent of the total. We have customarily used 300 mg. as the initial routine dose, since this is not more toxic than less effective dose levels. Patients with hyperthyroidism associated with small diffuse goiters previously untreated with iodine, react the most rapidly to propylthiouracil. This type of case is among those which are likely to respond with a permanent medical cure. In some instances, however, the thyroid continues to enlarge during treatment, accompanied by rising basal metabolic rate, thus requiring a larger dosage of the drug. In such cases there is not much hope for a permanent medical cure. Hyperthyroidism of longer standing has been more resistant to therapy in our hands. Here the goiter is frequently larger and the total mass of reacting tissue may be a factor limiting this group to less favorable responses to medical cure. In some instances large adenomatous goiters respond much more slowly. However, if larger groups of cases are compared, there is only a small average difference. Concomitant Use of Iodine or Thyroid.-A word might be inserted here concerning the concomitant use of either iodine or thyroid with propylthiouracil. Early in the use of thiouracil, we observed failure to eliminate the thrill and bruit over the thyroid by giving desiccated thyroid in doses of 2 grains per day in three patients. Iodine in doses of 10 mg. per day did so in less than one week. Such small doses of iodine did not interfere with the antithyroid effect obtained from propylthiouracil. There was no significant difference in the rate of fall in basal metabolic rates in one group of patients receiving from 10 to 30 mg. of iodine per day, concurrently with propylthiouracil, as compared to a group receiving propylthiouracil alone. Up to the present time there has been insufficient experience with the use of large doses of iodine given in conjunction with antithyroid drugs. Large doses might slow the desired antithyroid effects. Thus iodine is to be used to prevent or abolish the thrill and bruit which appears in many of these glands, the dosage employed for the present ought to be small. Astwood, however, warns that the use of small doses of iodine concurrently may lessen the number of lasting remissions following the use of antithyroid drugs. One of us has recently seen two patients managed with propylthiouracil without iodine who had no evidence of hyperthyroidism eighteen months after cessation of the drug. There is still no general agreement as to the most desirable procedure to follow once the hyperthyroidism has been initially controlled with propylthiouracil. It seems likely that inadequate dosage with only partial control of the hyperthyroidism would lead to poor ultimate results. In addition, it is well not to reduce the dose too soon, but the maximum tolerated dose should be maintained as long as is possible, rather than reduced as quickly as possible. It has been our practice
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to maintain the initial dose and to administer thyroid when signs of hypothyroidism or myxedema appear, hoping thereby to increase the number of lasting remissions. Methylthiouracil.-Methylthiouracil has also proved to be highly effective in the control of hyperthyroidism. Many accounts of its use have been published in Denmark, Sweden, England, Australia and the United States. The studies of Meulengracht and his associates,4.5 Magnusson and Sorensen,6 and Frish7 include the largest series of cases studied in the earlier period. At first, the drug was considered to have a higher degree of toxicity than propylthiouracil, but the amounts used were in excess of 600 mg. per day. This amount was soon found to be excessive. The Danish indicated that the drug retained its high efficiency at a dosage comparable to propylthiouracil. Actually, it was suggested that a dose of methylthiouracil might be found which would be similar to the effective dose of propylthiouracil and at the same time be more rapid in controlling hyperthyroidism. Kjerulf-Jensen and Meulengracht 8 conclude that methylthiouracil is somewhat more effective than propylthiouracil in controlling hyperthyroidism, and when used in comparable doses shows no greater toxicity. McCullagh and Sirridge 9 treated 100 patients with hyperthyroidism for from one to sixteen months, using 200 to 400 mg. per day. In cases of diffuse goiter, the mean fall in basal metabolic rate in percentage per week, using 200 mg. of methylthiouracil per day, was 4.5, as compared to 4.1 in comparable doses of propylthiouracil. Using 300 mg. per day the mean fall of basal metabolic rate in percentage per week was 6.1, as compared to 3.6 in propylthiouracil treated cases. They pointed out that the difference is not great, however, and that a wide variation in response is present. Toxic effects were recognized in only five patients in this series; four of these were mild, and did not require interruption in treatment. One patient with a history of purpura developed a recurrence of purpura while taking methylthiouracil, but the relationship of the purpura to the drug was not clear. Astwood * regards methylthiouracil to be more effective than propylthiouracil in comparable range of dose. He considers 300 mg. of propylthiouracil to be effective in controlling hyperthyroidism in 96 per cent of cases, whereas methylthiouracil is almost 100 per cent effective in a similar dosage. Meulengracht and Kjerulf-Jensen8 reported follow-up observations in 111 patients treated for one year. The doses employed were 250 mg. three times daily for the first two to three months, 250 mg. once or twice daily during the succeeding few months, with a maintenance dose of 125 mg. during the remainder of treatment. At this range of dosage, toxic reactions were encountered in 7.8 per cent of cases, in comparison to 1 per cent in the smaller dose ranges employed by other investigators. Nine per cent of the individuals treated showed genuine
* Personal communication.
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relapse, making the remission rate three months after the discontinuance of the drug approximately 91 per cEmt. At the present time it is not possible to conclude the ultimate remission rate in the management of hyperthyroidism by antithyroid drugs because there has not been sufficient time in follow-up. It has been suggested that the ultimate remission rate may well depend upon the care exercised in the control of the hyperthyroidism during treatment, and Astwood feels that in better controlled cases this may reach as high as 90 per cent. We have not been this fortunate despite continued effort to control the hyperthyroidism completely or in those in whom hypothyroidism was maintained for many months. Our remission rate in cases treated for one year approximates 50 per cent. Changes in Thyroid Following Antithyroid Drugs.-The changes in the thyroid following the use of ,antithyroid drugs' in Graves' disease have been studied extensively. Rawsonaiid his associates lO demonstrated an increasing hyperplasia of the thyroid with loss .of colloid and increase in vascularity in all cases, comparable to the changes observed in the thyroid of rats treated with thiourea. DeRobertisll showed that these goitrogens worked by interference with enzyme systems within the thyroid involved in the synthesis of organic thyroid fraction from stored inorganic iodine. Under antithyroid agents there is a marked decrease in organic iodine within the gland owing to suppression of the hormone containing organic iodine. Iodine is absorbed but not utilized. The interruption in thyroxine synthesis is believed to stimulate thyrotropic activity in the pituitary, which in turn causes further hyperplasia of the thyroid. This induced hyperplasia can be prevented in the experimental animal by hypophysectomy. The hypertrophy and hyperplasia of the gland at times is very appreciable indeed. Rarely, however, does it lead to sufficient compression of the trachea to be an indication for thyroidectomy. The enlargement usually persists during the period of this treatment. At times this enlargement is of sufficient cosmetic importance to the patient to make thyroidectomy the choice. Once treatment has been discontinued the thyroid may return to its pretreatment size. Meulengracht and KjerulfJensen 8 stated that 50 per cent of their patients had no goiter at the end of treatment; 30 per cent of these had never shown enlargement during therapy; 20 per cent had lost whatever enlargement had appeared during treatment. Among the 50 per cent showing an enlargement of the thyroid at the end of treatment, there had been a reduction in size in 25 per cent, and no change in the remainder. In general, it has been our experience that enlarging glands during treatment persist when the drug is discontinued. We have not seen impressive remissions in this group of cases and feel' for this reason that glands showing tendency to enlarge during therapy are not likely to be cured by antithyroid drugs. Significant Problems Relating to Use of Antithyroid Drugs.-A number of highly significant problems relating to the employment of antithyroid drugs in the management of hyperthyroidism remain to be C
--
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settled. Thyroidectomy, after proper control of hyperthyroidism, results in permanent and complete return to health in about 90 per cent of cases, and tends to shorten the time of this recovery. In contrast, prolonged drug therapy is at times difficult, due to poor cooperation of the patient; when improvement appears treatment may be allowed to lapse. Some will sooner or later prefer to have their problem settled by thyroidectomy. Unless antithyroid drugs can duplicate surgical results, they will not replace surgery in the management of the uncomplicated hyperthyroidism of Graves' disease. At the present time, hope for this is distinctly less than a few years ago. In the management of recurrent hyperthyroidism, however, where an increased risk to the recurrent laryngeal nerves, or the parathyroids is significant, their use seems more clearly indicated. Complete control of the disease with propyl or methyl thiouracil is usually advised in all patients with severe hyperthyroidism, in all those over 45 years of age, as well as in those with complicating factors, such as poor cardiac status. Once the disease is completely controlled Lugol's solution is given prior to operation, and the antithyroid drug is discontinued. It has been our impression that Lugol's solution must be given for from four to six weeks in order to re9uce the vascularity and the friability of the gland to a minimum at the time of operation. The patient may be ready for surgery sooner but the "gland is not." In patients whose hyperthyroidism is complicated by extreme old age, by cardiac or other disorders which will prevent them ever from becoming good surgical risks-even after the elimination of hyperthyroidism-propylthiouracil or methylthiouracil may have to be continued indefinitely. There remains another group of unsettled questions in relationship to the use of antithyroid drugs in the management of hyperthyroidism. Whether significant histopathologic change will follow the prolonged use of antithyroid drugs is still not established. Bartels12 reviewed 1200 goiters to show' malignant change. Three of them were in adenomatous goiters and four in diffuse goiters He pointed out that this incidence must be compared with that before using antithyroid drugs, before its true significance can be determined. Other questions to be settled concerning the medical management of diffuse goiter relate to the frequency with which the remission rate can be increased by the type of associated therapy in conjunction with the antithyroid drug employed. If the remission rate can be shown to be greater when iodine is withheld, this fact will outweigh the importance of eliminating the thrill and bruit induced during therapy. Similarly, if more lasting remissions can be produced in patients by inducing hypothyroidism (and requiring thyroid extract) this procedure would be preferable to dosages only large enough to produce euthyroidism. RADIOACTIVE IODINE
Radioactive iodine is the latest therapeutic tool introduced for the treatment of hyperthyroidism. Like surgery and antithyroid drugs,
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radioactive iodine also has advantages and disadvantages. Its ultimate place in the treatment of goiter cannot be accurately established for many years. It is now seven years since Hamilton and Lawrence l3 and Hertz and Roberts l4 reported on the treatment of hyperthyroidism with radioactive iodine. The experiences of a great many investigators, including Soley/5 Hertz and Roberts,16 Chapman and Evans, 17 Haines et aU 8 and Crile et aU9 have established the effectiveness of radioactive iodine in the immediate control of hyperthyroidism. All subsequent studies have continued to confirm this and some patients now have been in remission for several years. In the earlier years a mixture of about 90 per cent P30 and about 10 per cent p3l was employed. Since the release of p3l by the Atomic Energy Commission two years ago this isotope has received extensive consideration in the management of hyperthyroidism. A number of properties of p3l make it an attractive isotope for clinical use. It differs from many radioactive substances in that its half life is only eight days. This property is considered to minimize the later ill effects due to retention of a long-lived radioactive substance within the body. Furthermore, its safety is increased bec~use of the fact that its radiation is largely in the form of beta rays which do not penetrate tissues for more than 1 or 2 mm. Since it is concentrated in the thyroid, it does not cause demonstrable damage to tissues immediately outside of the thyroid. Gorbman,2° however, has given young mice massive doses of p3l and produced complete destruction of the thyroid, loss of the parathyroids, lesions in the tracheal epithelium, and in the recurrent laryngeal nerve. Up to now no comparable changes have been demonstrated in patients and damage has not been reported to the kidneys, bone marrow, testes or other organs. Furthermore, the chemical and physiologic behavior of radioactive iodine is identical to that of ordinary iodine and the thyroid handles it in the same way that it does stable iodine. In hyperthyroidism the uptake and concentration of p3l within the thyroid is much greater than in the normal thyroid. Hamilton21 estimates a concentration in the thyroid in an amount 10,000 times greater than in the blood or in any other organ. The isotope is stored within the thyroid until it has lost the major part of its radioactivity, after which most of it is excreted by the kidneys as ordinary iodine. For these reasons the amount of irradiation received by the thyroid after an average dose of radioactive iodine is much greater than the amount of irradiation which can be delivered by roentgen therapy without damage to the skin. The average dose of 4mc. by Oak Ridge standard, given to a patient with Graves' disease and a goiter weighing 50 gm. which takes up 50 per cent of the administered dose, delivers the equivalent of 4000 r to the thyroid. p3l is in the form of sodium iodide and is dissolved in water. It is colorless and tasteless. The amount contained in the average therapeutic dose is equivalent to the iodine in 1/50,000 of a drop of Lugol's solution. Radiation sickness and irritation of the thyroid area are not observed
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from the ordinary dose, but irradiation sickness has occurred when large doses are used, such as in the treatment of cancer of the thyroid. Among the disadvantages, one of the most immediate relates to technical difficulties in distribution and handling. A more important consideration in the use of radioactive iodine is its possible ultimate carcinogenic properties. Although there is little experimental or clinical evidence to suggest that intensive irradiation of this nature will be carcinogenic, this possibility demands careful consideration. Whether the incidence of carcinoma of the thyroid will be significantly altered by its use remains to be demonstrated, but most authorities feel that it is not likely to increase its incidence. None the less, radioactive iodine is largely being reserved for use in older patients with hyperthyroidism, or for patients with short life expectancies. It is also being used where serious heart disease, or other complications, might add considerably to the risk of surgical treatment, and for patients with recurrent hyperthyH>idism, in whom one or more previous resections of the thyroid have been performed, where unilateral paralysis of the vocal cords, or extremely small amounts of thyroid remain from previous operative procedures. The matter of dosage to be employed is one of the major problems confronting investigators in this field. Up to the present time there have not been any uniformly satisfactory methods of estimating the amount of radioactive iodine to be given in one dose to effect a cure. Clinical estimates of the size of the gland are no consistent criterion to dosage partly because of the inaccuracy of proper estimates, but more particularly because of the great variability in the response of different thyroid glands to the same dosage. We have attempted to adopt the policy that for the treatment of Graves' disease the initial dose should be one-half to two-thirds of the average dose required to effect a cure. When 4 mc. are given, about one-half of the patients are well after a single treatment, and only 10 per cent develop transient hypothyroidism. The size of the second dose has been gauged on the response of the hyperthyroidism to the first. If the basal metabolic rate is unchanged after two months, the second dose may be doubled. If the basal metabolic rate has fallen half-way to normal, the first dose may be repeated. If the basal metabolic rate has dropped two-thirds of the way to normal, one-half of the original dose is usually given. If there is only slight residual hyperthyroidism, or if the basal metabolic rate is at the upper limit of normal, no further treatment is given, because maximum effects of a single dose sometimes are not apparent for three or four months. In Graves' disease, our average initial dose has been 4 mc., unless the thyroid is unusually large and the hyperthyroidism severe, in which case 6 or even 8 mc. have been given. Our experience has indicated that the dose required to control hyperthyroidism of Graves' disease is dependent more upon severity than upon the size of the gland, although individual variability must be recognized. Crile and his associates19 have demonstrated that in nodular goiter with hyperthyroidism the
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R. S. DINSMORE, R. W. SCHNEIDER
average initial dose should be distinctly increased over that of diffuse goiter. In these 8 to 15 mc., depending upon the size of the gland, have been employed. In general the results from treatment in Graves' disease are highly satisfactory. Approximately 65 per cent are well controlled on one dose at the end of three months. The thyroid gland invariably reduces in size, and in Graves' disease is usually no longer palpable. Nodular goiters usually shrink but do not disappear. Auricular fibrillation tends to revert to normal sinus rhythm just as after thyroidectomy. Recently Kelsey, Haines and Keating 22 have published a review of the present status of radioactive iodine in the treatment of thyroid disease. The addition of the series reported by Crile's group to the series reviewed by these authors brings the total cases to 446. Undoubtedly many others have not been included in this study. However, 54 per cent of the 446 cases were euthyroid after one dose of P3r, while hypothyroidism occurred in only 4.2 per cent. Some of these were transient. Williams and his co-workers23 mention the occasional accentuation of hyperthyroidism after the first dose. We have recently seen several instances of this type. Exophthalmos behaves in general in the same way that it does following thyroidectomy or antithyroid drugs. Soley and Miller24 mention an increase in exophthalmos in six out of twentysix so studied. Collected observations show a uniform fall in basal metabolic rate, a fall in protein bound iodine, and a rise in blood lipids. Transient fever, rise in sedimentation rate, and tenderness of the thyroid area have also been observed. Transient leukopenia was seen in one instance, but agranulocytosis has not been observed. There have been no recurrences seen in those cases in whom euthyroidism has occurred. lt is to be predicted that radioactive iodine will reduce many of the present indications for propylthiouracil and methylthiouracil. lt is likely that it is the treatment of choice when hyperthyroidism is present in the bad risk patient, or attended by complications such as recurrent hyperthyroidism, or vocal cord paralysis, because it is likely to produce a more lasting remission than antithyroid agents have been shown to do. lt is likely that it will never be the routine treatment for nodular goiter with hyperthyroidism because surgery usually cures the disease permanently and tentative observations show a less satisfactory response to 1131. Many years of observation will be required to determine whether or not it will be the ultimate method of treatment for young patients with Graves' disease. Since apparently no complications, apart from hypothyroidism, attend the use of radioactive iodine, it is probably the most promising treatment of hyperthyroidism of the future. REFERENCES 1. Astwood, E. B., and Vander Laan, W. P.: Treatment of Hyperthyroidism with propylthiouracil. Ann. Int. Med. 25: 813, 1946. 2. Williams, R. H.: Thiouracil Treatment of Thyrotoxicosis; Results of Prolonged Treatment. J. Clin. Endocrinol. 6: 1, 1946.
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3. McCullagh, E. P., Hibbs, R. E. and Schneider, R. W.: Propylthiouracil in Treatment of Hyperthyroidism. Am. J. M. Sc. 214: 545,1947. 4. Meulengracht, E. and Schmith, K.: Treatment of Thyrotoxicosis with Methylthiouracil. Acta med. Scandinav. 122: 294, 1945. 5. Meulengracht, E., Kjerulf-Jensen, K. and Schmith, K.: Cited by Barfred, A., Nord. med. 32: 2800, 1946. 6. Magnusson, P. and Soerensen, G.: Treatment of Hyperthyroidism with Methylthiouracil. Acta med. Scandinav. 125: 263, 1946. 7. Frish, R. A.: Cited by Barfred, A." 8. Meulengracht, E. and Kjerulf-Jensen, K.: Prolonged Methylthiouracil Treatment in Thyrotoxicosis; Results after Cessation of Treatment. J. Clin. Endocrinol. 8: 1060, 1948. 9. McCullagh, E. P. and Sirridge, W. A.: Methylthiouracil in Treatment of Hyperthyroidism. J. Clin. Endocrinol. 8: 1051, 1948. 10. Rawson, R. W. et al.: Action of Thiouracil upon Thyroid Gland in Graves' Disease. J. Clin. Endocrinol. 4: 1, 1944. 11. DeRobertis, E.: Proteolytic Activity in Physiology, Pathology and Therapeutics of Thyroid Gland. Presented at Ann. Meet. Am. A. Study Goiter, April 3-5, 1947. 12. Bartels, E. C.: Appraisal of Goitrogens; Results of Treatment with Thiouracil, Propylthiouracil and Related Antithyroid Drugs. J. Clin. Endocrinol. 8: 766, 1948. 13. Hamilton, J. G. and Lawrence, J. H.: Recent Clinical Developments in Therapeutic Application of Radio-phosphorus and Radio-iodine. J. Clin. Investigation 21: 624, 1942. 14. Hertz, S. and Roberts, A.: Application of Radioactive Iodine in Therapy of Graves' Disease. J. Clin. Investigation 21: 624,1942. 15. Hamilton, J. G. and Soley, M. H.: Studies in Iodine Metabolism of Thyroid Gland in situ by Use of Radio-iodine in Normal Subjects and in Patients with Various Types of Goiter. Am. J. Physiol. 131: 135, 1940. 16. Hertz, S. and Roberts, A.: Radioactive Iodine in Study of Thyroid Physiology. J.A.M.A. 131: 86, 1946. 17. Chapman, E. M. and Evans, R. D.: Treatment of Hyperthyroidism with Radioactive Iodine. J.A.M.A. 131: 86, 1946. 18. Haines, S. F. et a!.: Use of Radioiodine in Treatment of Exophthalmic Goiter. J. Clin. Endocrinoi. 8: 813,1948. 19. Crile, G., Jr., McCullagh, E. P. and Glasser, 0.: Radioactive Iodine in Treatment of Hyperthyroidism. Cleveland Clin. Quart. 16: 1, 1949. 20. Gorbman, A.: Effects of Radiotoxic Dosages of 1'31 upon Thyroid and Contiguous Tissues in mice. Proc. Soc. Exper. BioI. & Med. 66: 212, 1947. 21. Hamilton, J. G.: Use of Radioactive Tracers in Biology and Medicine. Radiology 39: 541,1942. 22. Kelsey, M. P. et a!.: Radioiodine in Study and Treatment of Thyroid Disease; a Review. J. Clin. Endocrinoi. 9: 171, 1949. 23. Williams, R. H. et al.: Reciprocal Relationships of Radioiodotherapeusis and Thyroid Function. J. Clin. Investigation 27: 562, 1948. 24. Soley, M. H., and Miller, E. R: Treatment of Graves' Disease with Radioactive iodine. M. Clin. North America 32: 3, 1948.