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Clinical Use of Thiouracil
CLINICAL USE OF THIOURACIL'" SAMUEL F. HAINES AND F. RAYMOND MATING,
JR.
SINCE H. S. Plummer introduced strong solution of iodine (Lugol's solution) in the treatment of exophthalmic goiter in 1922, the administration of iodine followed by subtotal thyroidectomy has become the method of choice for dealing with this disease. The recent advent of goitrogenic drugs, of which thiouracil has had the most extensive trial, represents a distinct advance in knowledge of the physiology of the thyroid and a radical innovation in therapeutic methods. In the past three years widespread use has produced a considerable volume of information regarding the use and limitations of thiouracil in the treatment of hyperthyroidism. Insufficient time has elapsed, however, for conclusive evaluation of its usefulness in relation to administration of iodine or to surgical treatment of hyperthyroidism. There has not been time, for example, for adequate appraisal of the permanence of remissions of exophthalmic goiter induced by thiouracil alone, or of the effects its use may have on the morbidity and mortality rates following subtotal thyroidectomy for this condition. Nevertheless, regardless of whether thiouracil continues to be the antithyroid drug of choice, or whether, as may be, it is eventually replaced by one or another of the hundreds of similar compounds being studied, it is apparent that a new and important tool in the management of hyperthyroidism has appeared on the scene. PHYSIOLOGIC OBSERVATIONS
MacKenzie and MacKenzie, Astwood and others,2 Richter and Clisby and Kennedy observed that certain chemical substances, when given to rats, induce rapid and striking thyroid hyperplasia associated with lowered metabolic rates and other evidences of thyroid deficiency. One group of such substances is related to the aniline dyes and contains several of the commonly used sulfonamide compounds~ The other group consists of substances related to thiourea. From the latter group Astwood selected thiouracil for clinical trial because it is relatively more goitrogenic and relatively less toxic than the other compounds studied. " We wish to thank Dr. Stanton M. Hardy of Lederle Laboratories, Incorporated, for supplying us with the thiouracil used in our studies.
845
846
SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
In contrast to the actions of other goitrogens, such as cabbage, acetonitrile and soy bean meal, these new goitrogens produce thyroid hyperplasia even when iodine is given, although thyroxine or desiccated thyroid abolishes their effect. The intense thyroid hyperplasia which they produce can also be prevented by hypophysectomy. Rawson, Tannheimerand Peacock16 and Larson and others,12 using radioactive iodine, found that thiouracil greatly reduces but does not abolish the capacity of the thyroid to collect iodine. This effect is maximal within an hour after the administration of thiouracil, whereas histologic changes in the thyroid are not apparent until twenty-four hours have passed. In vivo and in vitro studies by Franklin, Lerner and Chaikoff showed that thiouracil prevents the elaboration of diiodotyrosine or of thyroxine by the thyroid. It appeared that the failure of synthesis of diiodotyrosine and thyroxine accounts for the impaired capacity of the thyroid treated with thiouracil to collect injected iodine. The small proportion of iodine which always enters the thyroid despite the presence of thiouracil remains in the form of inorganic iodide. On the basis of such studies, it has been postulated that thiouracil and analogous compounds exert their action by interfering with the production of thyroid hormone by the thyroid gland, that the resulting deficiency of thyroid hormone directly or indirectly stimulates the anterior lobe of the pituitary and that the increased secretion of thyroid stimulating hormone by the anterior lobe induces thyroid hyperplasia. Rawson and his associates 17 have shown that the effect of thiouracil on the human thyroid in cases of exophthalmic goiter is in nearly all respects identical with that observed in animals. The capacity of the human thyroid to collect iodine is promptly and markedly retarded by. thiouracil. Comparison of specimens obtained from toxic thyroids before and after thiouracil therapy showed, despite the favorable clinical course induced by the drug, a measurable increase in the degree of thyroid hypertrophy which was present. The addition of iodine to thiouracil was followed by ·a reduction of the degree of hypertrophy which was present, despite the fact that administration of iodine under these circumstances was not followed by any increase of the iodine content of the thyroid. '* Williams and his associates 22 have investigated the· absorption,
.. These and other observations by Rawson and his associates 18 at the Massachusetts General Hospital have led them to suggest that iodine exerts two actions on the thyroid gland in cases of exophthalmic goiter: an iodinating action and an involuting action; and that these two actions can be separated one from another by means of thiouracil.
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distribution and excretion of thiouracil. They found it to be rapidly absorbed from the gastro-intestinal tract and readily excreted in the urine. Larger concentrations were observed in cells than in extracellular fluid, particularly large amounts occurring in white blood cells. Bone marrow, ovaries, thyroid and pituitary also contained large amounts. Rapid destruction of thiouracil appeared to occur in the stomach and bowel. Bielschowsky found that giving thiouracil and 2-acetaminofluorine (a potent carcinogen) to rats produced adenomatous and anaplastic, invasive tumors of the thyroid, whereas either substance alone would not do so. Broders and Parkhill have called attention to the numerous mitoses and the extreme hyperplasia seen in thyroids of persons who had exophthalmic goiter which had been treated with thiouracil. These observations led Hinton and Lord to suggest that, in some instances, thiouracil might prove capable of increasing the incidence of malignant lesions in the thyroid. On this basis these authors advised against its use in all cases of nodular goiter. This conClusion is based entirely on theoretical considerations and, it must be emphasized, has not thus far found any support in reported clinical observations. CLINICAL CONSIDERATIONS
Since Astwood's reportl in May, 1943, of control of hyperthyroidism by thiouracil in three cases, many reports on its clinical use have appeared. The effectiveness of the drug in controlling hyperthyroidism in practically all cases is now unquestioned, and Van Winkle and others reported therapeutic failure regardless of dose in only 4.3 per cent of cases when one excludes those failures dependent on toxic reactions. Early in its use dosages of thiouracil of 0.2 gm. three times a day, or more, were frequently employed. It soon became apparent that smaller doses of the drug were effective. At present, in most instances 0.2 gm. is given twice daily, usually at 8 A.M. and at 8 P.M. Because of the rapidity with which the drug is excreted from the body it has been found more effective to give the drug in divided doses at approximately equal intervals. After the signs and symptoms of hyperthyroidism have been completely controlled, smaller doses will frequently maintain a normal metabolic rate. The effective maintenance dose varies and must be determined for each patient. The time before the response to thiouracil becomes apparent has varied considerably. Some observers report an apparent improvement in the patient's clinical condition after a few days of treatment but in most instances one or two weeks of treatment have
848
SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
elapsed before benefit is noted. Pretreatment with iodine delays the response to thiouracil and patients who have large nodular goiters respond more slowly than those who have small diffuse goiters. Many observers expect the basal metabolic rate to have become normal after about siX or eight weeks of treatment. However, failure to achieve this does not indicate failure of the drug, for several patients have reached normal metabolic levels only after months of treatment. In our personal experience the time of treatment needed to control hyperthyroidism has been longer than in many of the reported cases. It is probable that the longer time needed by patients having large nodular goiters or by those patients who have recently received iodine is due to the longer time needed to allow the exhaustion of large amounts of colloid and thyroid hormone present in the thyroid gland. Various changes have been found to occur in the thyroid gland during treatment with thiouracil, as noted previously. The gland has been reported by some observers to increase in size, while others have not noted any change in size. Most observers agree that the gland becomes softer and the development of bruits over the gland is frequent. The signs and symptoms of hyperthyroidism subside gradually and continuously. Simultaneously the basal metabolic rate falls and the blood cholesterol increases. In patients who have auricular fibrillation the cardiac rhythm may become normal; in some, however, auricular fibrillation remains as a permanent result of hyperthyroidism. The appearance of the eyes usually improves. This improvement is, we believe, due chiefly to lessening of lid lag and of contraction of facial muscles, and possibly to other unrecognized factors. That it is not due to lessening of protrusion of the eyeballs has been confirmed by Barr and Shorr, who found by actual measurements of the position of the globes that many patients taking thiouracil showed an increasing prominence of the eyes. In their cases 2 mm. of protrusion was occasionally reached and in one instance 4 mm. occurred. Williams and Bissell21 reported one instance of serious exophthalmos developing during treatment with thiouracil. Dobyns and Haines found a measurable increase in protrusion of the eyes in all of eleven patients treated with thiouracil. In one instance severe exophthalmos developed. In this case the progress of the protrusion of the eyes stopped when administration of thiouracil was discontinued. If administration is continued in sufficient dosage, thiouracil occasionally leads to the development of myxedema. Reduction of the dose of thiouracil as soon as the signs of hyperthyroidism disappear usually, but not always, prevents such an occurrence. Barr and
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Shorr stated that the clinical signs of myxedema and an elevation of the concentration of cholesterol in the blood may occur before the basal metabolic rate falls below normal levels. Our experience corroborates this observation. Thiouracil has not been used long enough to know what incidence of recurrence may follow when it is used as the total treatment of hyperthyroidism. Barr and Shorr reported that after treatment for two to seven months, eleven relapses occurred in fortyseven cases in which the drug had been withdrawn for from one to sixteen and a half months. Van Winkle and others reported relapses in 33.7 per cent of 1,236 cases in which satisfactory remission had been induced by thiouracil. The duration of treatment in these cases was not recorded. Many factors may determine whether a remission induced by thiouracil is permanent, as is also true when exophthalmic goiter is treated surgically. It seems probable that the intensity and persistence of the cause of exophthalmic goiter are relatively greater in some than in other cases. In a small series of our patients who had exophthalmic goiter which recurred following surgical resection of most of the thyroid glimd, recurrences have also taken place after control of hyperthyroidism by thiouracil. This has also been observed by Barr and Shorr. A much longer time will . be needed before any definite knowledge can be obtained of the incidence of recurrence or relapse after thiouracil therapy. Many workers with this drug hav~ not tried to use it as a total treatment of hyperthyroidism, but have preferred to use it as a method of preoperative preparation. Early in the course of such programs it became apparent that the surgical difficulties of operating on patients prepared with thiouracil were greater than after preparation with iodine. In the former case the thyroid gland was vascular and friable and the control of hemorrhage was occasionally difficult. Although postoperative reactions were generally mild, in a few instances severe postoperative reactions occurred. This raises the question whether preparation with thiouracil will necessarily prevent a postoperative crisis. Although that question cannot be definitely answered, it seems safer to administer iodine after thiouracil has controlled hyperthyroidism and before surgical treatment is undertaken. The work of Rawson and others noted previously confirms the rationale of this procedure by demonstrating involution of the thyroid as the result of administration of iodine even though thiouracil is being given. Administration of iodine also overcomes the increased bleeding and friability which cause surgical djfficulties. Iodine may be given for a week or two before operation, during which time administration of thiouracil may be either stopped or continued. In either case the thyroid gland becomes
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SAMUEL F. HAINES, F. RAYMOND KEATING, JR
noticeably firmer during the course of treatment with iodine. In some such instances the bruits do not disappear. We agree with Bartels and others who feel that iodine should always be given after thiouracil preparation of patients who have hyperthyroidism. The most serious obstacle to the use of thiouracil is the occurrence of toxic reactions. Of these, agranulocytosis is the one of greatest seriousness. In several cases this condition has been reported to have developed and a few deaths have been recorded. Evidence presented by Moore and also by Van Winkle and his associates indicates that the occurrence of agranulocytosis is not influenced by the size of the dose of thiouracil. Moore in a study of 1,091 patients treated by twelve groups of observers found an incidence of agranulocytosis of 1.8 per cent with a death rate of 26 per cent among patients who had agranulocytosis. Van Winkle and associates reviewed 5,745 patients treated by 328 clinical investigators and found that granulocytopenia occurred in 2.5 per cent of cases, and that 14 per cent of patients who had granulocytopenia died, thus giving a total mortality rate for all the patients treated with thiouracil of 0.4 per cent. Milder degrees of leukopenia occur frequently. They are often very transient and do not necessarily indicate interruption of treatment. When leukopenia of any degree occurs it is important that· frequent leukocyte counts be made in order that treatment may be stopped before agranulocytosis occurs. Even moderate reductions of the total leukocyte count should arouse enough suspicion to call for differential leukocyte counts. Our patient who had agranulocytosis following thiouracil therapy had an absence of granulocytes in the blood smear at a time when the total leukocyte count was 4,200 in each cubic millimeter of blood. Van Winkle and his associates did not find evidence that the administration of pyridoxine, pantothenic acid, folic acid or vitamins during the time of treatment with thiouracil would prevent leukopenia and agranulocytosis. When agranulocytosis occurs during the course of thiouracil treatment, administration of the drug should be discontinued and not started again for that patient. It has seemed a wise precaution to administer penicillin in massive doses in order· to prevent, if possible, the progress or development of infections. It is beyond the scope of this paper to discuss the relative merits of different types of treatment of agranulocytosis. Probably related to agranulocytosis as a complication is thrombocytopenia, one case of which was reported by Evans and Flink and one by Barr and Shorr. The former authors also reported two cases in which increased bleeding tendency with positive cuff test developed during treatment with thiouracil. Van Winkle stated that
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purpura was reported by six of the investigators who contributed to his study. Fever is probably the commonest manifestation of toxic reaction to thiouracil. In some instances it may be so severe as to indicate withdrawal of the drug, but occasionally if the febrile reaction is not severe, administration of the drug can be stopped temporarily and reinstituted in smaller dosage without recurrence of the fever. McArthur, Rawson and Means expressed the belief that the febrile reaction is a manifestation of true drug idiosyncrasy. Cutaneous reactions are also seen occasionally. If the rash is proved to be due to thiouracil, administration of the drug probably should be permanently discontinued. Jaundice, nausea and vomiting, muscular pains, general malaise and many other reactions have been attributed to thiouracil in rare cases. Their infrequence or their mildness make th{:)m of much less importance than agranulocytosis. The incidence of toxic reactions and the severity of some of them make caution during the period of administration of thiouracil imperative. The patient should be under frequent observations, temperature recordings should be made frequently and leukocyte counts should be made at short intervals. Even slight reduction of leukocyte counts should be taken seriously and followed closely with differential blood counts. Since agranulocytosis may appear very abruptly, serial total leukocyte counts do not constitute adequate protection. The patient must be instructed to consult the physician at the first sign of sore throat or other evidence of infection. The dose of the drug should be reduced as soon as the evidences of hyperthyroidism have been controlled. Moore found that reactions necessitating cessation of the drug occurred in approximately 8 to 10 per cent of the patients treated. The mortality rate in his study attributable directly to the drug was 0.5 per cent. Van Winkle and associates found that in approximately 13 per cent of cases there was some untoward reaction to thiouracil therapy. The mortality rate attributable to thiouracil in this series was 0.4 per cent, all of the deaths being due to granulocytopenia. In view of the definite, though slight, risk involved in treating hyperthyroid patients with thiouracil, consideration must be given in each instance to the relative risk for that patient of the various mathods of treatment available. Thiouracil has been used for too short a time for one to know definitely how frequently patients who have mild or moderately severe exophthalmic goiter may have the disease brought permanently and completely under control with the drug alone. Proper evaluation of the ultimate role that thiouracil
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SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
is to play as a total treabnent of hyperthyroidism will depend on accurate comparison between the risk of toxic reactions to thiouracil and relapses following its use on the one hand, and the surgical mortality rate of subtotal thyroidectomy, the risk of parathyroid insufficiency, injuries to the recurrent nerve, and so forth, and the incidence of recurrence or persistence of hyperthyroidism following surgical treatment on the other hand. Occasionally, patients who have hyperthyroidism are seen with complicating conditions Which in themselves add materially to the risk of surgical treatment. In such cases thiouracil may be used as total treatment of the hyperthyroidism with strikingly good results. Actually in some instances in which such a program has been begun, the patient's condition has improved so greatly that operation on the thyroid has been performed later without excessive risk. Notable among such instances are patients having l;lyperthyroidism and severe angina pectoris in whom the cardiac condition may show great improvement after a period of control of hyperthyroidism. The risk of partial thyroidectomy after preparation with iodine in cases of mildly or moderately severe exophthalmic goiter without complications approximates closely the risk of thyroidectomy for adenomatous goiter without hyperthyroidism. Therefore there seems, at present, to be no indication for the use of thiouracil as preoperative treabnent in such cases, for the risk of administration of the drug would be added to the minimal risk of this operation. When, however, the risk of thyroidectomy is greatly increased by the intensity of hyperthyroidism, administration of thiouracil as a preoperative measure should be considered. Included in this group are, for example, patients who have extreme degrees of hyperthyroidism and large friable thyroid glands in whom anticipated technical difficulties superimposed on the severe hyperthyroidism may indicate the performance of two partial lobectomies at different times. In such cases complete control of hyperthyroidism by thiouracil may bring the patient into such condition that a double resection of the thyroid may safely be done at a single operation. In our experience such cases constitute only a small percentage of cases of exophthalmic goiter. Patients having severe hyperthyroidism associated with adenomatous goiter may show little or no improvement after administration of iodine. In such cases preparation with thiouracil, even though much time may be needed for it, can be of great help in reducing surgical risk. It is our feeling at the present time that the most important indications for the use of thiouracil are (1) as a total treabnent for hyperthyroidism in those cases in which complications prohibit surgical treabnent of the disease, (2) as a preoperative treabnent
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in those caSes in which the severity of hyperthyroidism is responsible for an anticipated high surgical risk or (3) as a preoperative treatment in those cases in which complications increase the surgical risk, especially if temporary relief of hyperthyroidism will bring about some amelioration of the complicating condition. It is not our practice to use the drug as a preoperative treatment of patients who have mild or moderately severe exophthalmic goiter, for the time involved is long and, in our opinion, the ultimate risk to the patient will not be lessened. Also, we have not used thiouracil as total treatment for hyperthyroidism in cases of mild or moderately severe exophthalmic goiter, for we felt that the drug could not be administered without constant careful observation. We feel that the risk of administration of the drug in such cases is as great as, or greater than, the risk of partial thyroidectomy in similar cases.
REFERENCES 1. Astwood, E. B.: Treatment of hyperthyroidism with thiourea and thiouracil. J.A.M.A. 122:78--81 (May 8) 1943. 2. Astwood, E. B., Sullivan, J., Bissell, Adele and Tyslowitz, R.: Action of certain sulfonamides and of thiourea on the function of the thyroid gland of the rat. Endocrinology. 32:210--225 (Feb.) 1943. 3. Barr, D. P. and Shorr, Ephraim: Observations in the treatment of Graves' disease with thiouracil. Ann. Int. Med. 23:754-778 (Nov.) 1945. 4. Bartels, E. C.: Thiouracil; its use in the preoperative management of severe hyperthyroidism; preliminary report. J .A.M.A. 125:24-26 (May 6) 1944. 5. Bielschowsky, F.: Distant tumours produced by 2-amino- and 2-acetylamino-fluorine. Brit. J. Exper. Path. 25:1-4 (Feb.) 1944. 6. Broders, A. C. and Parkhill, E. M.: Symposium on surgical lesions of thyroid; diffuse and adenomatous goiter and goiter induced by various agents. Surgery. 16:633-646 (Nov.) 1944. 7. Dobyns, B. M. and Haines, S. F.: Unpublished data. 8. Evans, G. T. and Flink, E. B.: Thio-uracil therapy in hyperthyroidism. Minnesota Med. 27:1002-1010 (Dec.) 1944. 9. Franklin, A. L., Lemer, S. R. and Chaikoff, I. L.: The effect of thiouracil on the formation of thyroxine and diiodotyrosine by the thyroid gland of the rat with radioactive iodine as indicator. Endocrinology. 34:265-268 (Apr.) 1944. 10. Hinton, J. W. and Lord, J. W., Jr.: Is surgery indicated in all cases of nodular goiter, toxic and nontoxic? J .A.M.A. 129:605-606 (Oct. 27) 1945. 11. Kennedy, T. H.: Thio-ureas as goitrogenic substances. Nature, London. 150: 233-234 (Aug. 22) 1942. 12. Larson, R. A., Keating, F. R., Jr., Peacock, Wendell and Rawson, R. W.: . Comparison of effect of thiouracil and of injected thyrotropic hormone on collection of radioactive iodine and the anatomic changes induced in thyroid of the chick. Endocrinology. 36:149-159 (Feb.) 1945. 13. McArthur, Janet W., Rawson, R. W. and Means, J. H.: Idiosyncratic febrile reactions to thiouracil: clinical characteristics and possible pharmacologic significance. Ann. Int. Med. 23:915-923 (Dec.) 1945.
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14. MacKenzie, C. G. and MacKenzie, Julia B.: Effect of sulfonamides and thioureas on the thyroid gland and basal metabolism. Endocrinology. 32:185-209 (Feb.) 1943. 15. Moore, F. D.: Toxic manifestations of thiouracil therapy. J.A.M.A. 130: 315-319 (Feb. 9) 1946. 16. Rawson, R W., Tannheimer, J. F. and Peacock, Wendell: The uptake of radioactive iodine by the thyroids of rats made goiterous by potassium thiocyanate and by thiouracil. Endocrinology. 34:245-253 (Apr.) 1944. 17. Rawson, R. W., Evans, R. D., Means, J. H., Peacock, W. c., Lerman, J. and Cortell, R E.: Action of thiouracil upon thyroid gland in Graves' disease. J. Clin. Endocrinol. 4:1-11 (Jan.) 1944. 18. Rawson R. W., Moore, F. D., Peacock, Wendell, Means, J. H., Cope, . Oliver and RiddeIl, Charlotte B.: Effect of iodine on the thyroid gland in Graves' disease when given in conjunction with thiouracil-a twoaction theory of iodine. J. Clin. Investigation. 24:869-877 (Nov.) 1945. 19. Richter, C. P. and Clisby, K. H.: Toxic effects of bitter-tasting phenylthiocarbamide. Arch. Path. 38:46-57 (Jan.) 1942. 20. Van Winkle, Walton, Jr., Hardy, S. M., Hazel, G. R, Hines, D. c., Newcomer, H. S., Sharp, E. A. and Sisk, W. N.: The clinical toxicity of thiouracil; a survey of 5,745 cases. J.A.M.A. 180:343-347 (Feb. 9) 1946. 21. Williams, R. H. and BisseIl, G. W.: Thiouracil in treatment of thyrotoxicosis. New England J. Med. 229:97-108 (July 15) 1943. 22. Williams, R. H., Kay, Gloria A. and Jandorf, B. J.: Thiouracil. Its absorption, distribution, and excretion. J. Clin. Investigation. 23:613-627 (Sept.) 1944.
JR.
SINCE H. S. Plummer introduced strong solution of iodine (Lugol's solution) in the treatment of exophthalmic goiter in 1922, the administration of iodine followed by subtotal thyroidectomy has become the method of choice for dealing with this disease. The recent advent of goitrogenic drugs, of which thiouracil has had the most extensive trial, represents a distinct advance in knowledge of the physiology of the thyroid and a radical innovation in therapeutic methods. In the past three years widespread use has produced a considerable volume of information regarding the use and limitations of thiouracil in the treatment of hyperthyroidism. Insufficient time has elapsed, however, for conclusive evaluation of its usefulness in relation to administration of iodine or to surgical treatment of hyperthyroidism. There has not been time, for example, for adequate appraisal of the permanence of remissions of exophthalmic goiter induced by thiouracil alone, or of the effects its use may have on the morbidity and mortality rates following subtotal thyroidectomy for this condition. Nevertheless, regardless of whether thiouracil continues to be the antithyroid drug of choice, or whether, as may be, it is eventually replaced by one or another of the hundreds of similar compounds being studied, it is apparent that a new and important tool in the management of hyperthyroidism has appeared on the scene. PHYSIOLOGIC OBSERVATIONS
MacKenzie and MacKenzie, Astwood and others,2 Richter and Clisby and Kennedy observed that certain chemical substances, when given to rats, induce rapid and striking thyroid hyperplasia associated with lowered metabolic rates and other evidences of thyroid deficiency. One group of such substances is related to the aniline dyes and contains several of the commonly used sulfonamide compounds~ The other group consists of substances related to thiourea. From the latter group Astwood selected thiouracil for clinical trial because it is relatively more goitrogenic and relatively less toxic than the other compounds studied. " We wish to thank Dr. Stanton M. Hardy of Lederle Laboratories, Incorporated, for supplying us with the thiouracil used in our studies.
845
846
SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
In contrast to the actions of other goitrogens, such as cabbage, acetonitrile and soy bean meal, these new goitrogens produce thyroid hyperplasia even when iodine is given, although thyroxine or desiccated thyroid abolishes their effect. The intense thyroid hyperplasia which they produce can also be prevented by hypophysectomy. Rawson, Tannheimerand Peacock16 and Larson and others,12 using radioactive iodine, found that thiouracil greatly reduces but does not abolish the capacity of the thyroid to collect iodine. This effect is maximal within an hour after the administration of thiouracil, whereas histologic changes in the thyroid are not apparent until twenty-four hours have passed. In vivo and in vitro studies by Franklin, Lerner and Chaikoff showed that thiouracil prevents the elaboration of diiodotyrosine or of thyroxine by the thyroid. It appeared that the failure of synthesis of diiodotyrosine and thyroxine accounts for the impaired capacity of the thyroid treated with thiouracil to collect injected iodine. The small proportion of iodine which always enters the thyroid despite the presence of thiouracil remains in the form of inorganic iodide. On the basis of such studies, it has been postulated that thiouracil and analogous compounds exert their action by interfering with the production of thyroid hormone by the thyroid gland, that the resulting deficiency of thyroid hormone directly or indirectly stimulates the anterior lobe of the pituitary and that the increased secretion of thyroid stimulating hormone by the anterior lobe induces thyroid hyperplasia. Rawson and his associates 17 have shown that the effect of thiouracil on the human thyroid in cases of exophthalmic goiter is in nearly all respects identical with that observed in animals. The capacity of the human thyroid to collect iodine is promptly and markedly retarded by. thiouracil. Comparison of specimens obtained from toxic thyroids before and after thiouracil therapy showed, despite the favorable clinical course induced by the drug, a measurable increase in the degree of thyroid hypertrophy which was present. The addition of iodine to thiouracil was followed by ·a reduction of the degree of hypertrophy which was present, despite the fact that administration of iodine under these circumstances was not followed by any increase of the iodine content of the thyroid. '* Williams and his associates 22 have investigated the· absorption,
.. These and other observations by Rawson and his associates 18 at the Massachusetts General Hospital have led them to suggest that iodine exerts two actions on the thyroid gland in cases of exophthalmic goiter: an iodinating action and an involuting action; and that these two actions can be separated one from another by means of thiouracil.
CLINICAL USE OF THIOURACIL
847
distribution and excretion of thiouracil. They found it to be rapidly absorbed from the gastro-intestinal tract and readily excreted in the urine. Larger concentrations were observed in cells than in extracellular fluid, particularly large amounts occurring in white blood cells. Bone marrow, ovaries, thyroid and pituitary also contained large amounts. Rapid destruction of thiouracil appeared to occur in the stomach and bowel. Bielschowsky found that giving thiouracil and 2-acetaminofluorine (a potent carcinogen) to rats produced adenomatous and anaplastic, invasive tumors of the thyroid, whereas either substance alone would not do so. Broders and Parkhill have called attention to the numerous mitoses and the extreme hyperplasia seen in thyroids of persons who had exophthalmic goiter which had been treated with thiouracil. These observations led Hinton and Lord to suggest that, in some instances, thiouracil might prove capable of increasing the incidence of malignant lesions in the thyroid. On this basis these authors advised against its use in all cases of nodular goiter. This conClusion is based entirely on theoretical considerations and, it must be emphasized, has not thus far found any support in reported clinical observations. CLINICAL CONSIDERATIONS
Since Astwood's reportl in May, 1943, of control of hyperthyroidism by thiouracil in three cases, many reports on its clinical use have appeared. The effectiveness of the drug in controlling hyperthyroidism in practically all cases is now unquestioned, and Van Winkle and others reported therapeutic failure regardless of dose in only 4.3 per cent of cases when one excludes those failures dependent on toxic reactions. Early in its use dosages of thiouracil of 0.2 gm. three times a day, or more, were frequently employed. It soon became apparent that smaller doses of the drug were effective. At present, in most instances 0.2 gm. is given twice daily, usually at 8 A.M. and at 8 P.M. Because of the rapidity with which the drug is excreted from the body it has been found more effective to give the drug in divided doses at approximately equal intervals. After the signs and symptoms of hyperthyroidism have been completely controlled, smaller doses will frequently maintain a normal metabolic rate. The effective maintenance dose varies and must be determined for each patient. The time before the response to thiouracil becomes apparent has varied considerably. Some observers report an apparent improvement in the patient's clinical condition after a few days of treatment but in most instances one or two weeks of treatment have
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SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
elapsed before benefit is noted. Pretreatment with iodine delays the response to thiouracil and patients who have large nodular goiters respond more slowly than those who have small diffuse goiters. Many observers expect the basal metabolic rate to have become normal after about siX or eight weeks of treatment. However, failure to achieve this does not indicate failure of the drug, for several patients have reached normal metabolic levels only after months of treatment. In our personal experience the time of treatment needed to control hyperthyroidism has been longer than in many of the reported cases. It is probable that the longer time needed by patients having large nodular goiters or by those patients who have recently received iodine is due to the longer time needed to allow the exhaustion of large amounts of colloid and thyroid hormone present in the thyroid gland. Various changes have been found to occur in the thyroid gland during treatment with thiouracil, as noted previously. The gland has been reported by some observers to increase in size, while others have not noted any change in size. Most observers agree that the gland becomes softer and the development of bruits over the gland is frequent. The signs and symptoms of hyperthyroidism subside gradually and continuously. Simultaneously the basal metabolic rate falls and the blood cholesterol increases. In patients who have auricular fibrillation the cardiac rhythm may become normal; in some, however, auricular fibrillation remains as a permanent result of hyperthyroidism. The appearance of the eyes usually improves. This improvement is, we believe, due chiefly to lessening of lid lag and of contraction of facial muscles, and possibly to other unrecognized factors. That it is not due to lessening of protrusion of the eyeballs has been confirmed by Barr and Shorr, who found by actual measurements of the position of the globes that many patients taking thiouracil showed an increasing prominence of the eyes. In their cases 2 mm. of protrusion was occasionally reached and in one instance 4 mm. occurred. Williams and Bissell21 reported one instance of serious exophthalmos developing during treatment with thiouracil. Dobyns and Haines found a measurable increase in protrusion of the eyes in all of eleven patients treated with thiouracil. In one instance severe exophthalmos developed. In this case the progress of the protrusion of the eyes stopped when administration of thiouracil was discontinued. If administration is continued in sufficient dosage, thiouracil occasionally leads to the development of myxedema. Reduction of the dose of thiouracil as soon as the signs of hyperthyroidism disappear usually, but not always, prevents such an occurrence. Barr and
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Shorr stated that the clinical signs of myxedema and an elevation of the concentration of cholesterol in the blood may occur before the basal metabolic rate falls below normal levels. Our experience corroborates this observation. Thiouracil has not been used long enough to know what incidence of recurrence may follow when it is used as the total treatment of hyperthyroidism. Barr and Shorr reported that after treatment for two to seven months, eleven relapses occurred in fortyseven cases in which the drug had been withdrawn for from one to sixteen and a half months. Van Winkle and others reported relapses in 33.7 per cent of 1,236 cases in which satisfactory remission had been induced by thiouracil. The duration of treatment in these cases was not recorded. Many factors may determine whether a remission induced by thiouracil is permanent, as is also true when exophthalmic goiter is treated surgically. It seems probable that the intensity and persistence of the cause of exophthalmic goiter are relatively greater in some than in other cases. In a small series of our patients who had exophthalmic goiter which recurred following surgical resection of most of the thyroid glimd, recurrences have also taken place after control of hyperthyroidism by thiouracil. This has also been observed by Barr and Shorr. A much longer time will . be needed before any definite knowledge can be obtained of the incidence of recurrence or relapse after thiouracil therapy. Many workers with this drug hav~ not tried to use it as a total treatment of hyperthyroidism, but have preferred to use it as a method of preoperative preparation. Early in the course of such programs it became apparent that the surgical difficulties of operating on patients prepared with thiouracil were greater than after preparation with iodine. In the former case the thyroid gland was vascular and friable and the control of hemorrhage was occasionally difficult. Although postoperative reactions were generally mild, in a few instances severe postoperative reactions occurred. This raises the question whether preparation with thiouracil will necessarily prevent a postoperative crisis. Although that question cannot be definitely answered, it seems safer to administer iodine after thiouracil has controlled hyperthyroidism and before surgical treatment is undertaken. The work of Rawson and others noted previously confirms the rationale of this procedure by demonstrating involution of the thyroid as the result of administration of iodine even though thiouracil is being given. Administration of iodine also overcomes the increased bleeding and friability which cause surgical djfficulties. Iodine may be given for a week or two before operation, during which time administration of thiouracil may be either stopped or continued. In either case the thyroid gland becomes
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SAMUEL F. HAINES, F. RAYMOND KEATING, JR
noticeably firmer during the course of treatment with iodine. In some such instances the bruits do not disappear. We agree with Bartels and others who feel that iodine should always be given after thiouracil preparation of patients who have hyperthyroidism. The most serious obstacle to the use of thiouracil is the occurrence of toxic reactions. Of these, agranulocytosis is the one of greatest seriousness. In several cases this condition has been reported to have developed and a few deaths have been recorded. Evidence presented by Moore and also by Van Winkle and his associates indicates that the occurrence of agranulocytosis is not influenced by the size of the dose of thiouracil. Moore in a study of 1,091 patients treated by twelve groups of observers found an incidence of agranulocytosis of 1.8 per cent with a death rate of 26 per cent among patients who had agranulocytosis. Van Winkle and associates reviewed 5,745 patients treated by 328 clinical investigators and found that granulocytopenia occurred in 2.5 per cent of cases, and that 14 per cent of patients who had granulocytopenia died, thus giving a total mortality rate for all the patients treated with thiouracil of 0.4 per cent. Milder degrees of leukopenia occur frequently. They are often very transient and do not necessarily indicate interruption of treatment. When leukopenia of any degree occurs it is important that· frequent leukocyte counts be made in order that treatment may be stopped before agranulocytosis occurs. Even moderate reductions of the total leukocyte count should arouse enough suspicion to call for differential leukocyte counts. Our patient who had agranulocytosis following thiouracil therapy had an absence of granulocytes in the blood smear at a time when the total leukocyte count was 4,200 in each cubic millimeter of blood. Van Winkle and his associates did not find evidence that the administration of pyridoxine, pantothenic acid, folic acid or vitamins during the time of treatment with thiouracil would prevent leukopenia and agranulocytosis. When agranulocytosis occurs during the course of thiouracil treatment, administration of the drug should be discontinued and not started again for that patient. It has seemed a wise precaution to administer penicillin in massive doses in order· to prevent, if possible, the progress or development of infections. It is beyond the scope of this paper to discuss the relative merits of different types of treatment of agranulocytosis. Probably related to agranulocytosis as a complication is thrombocytopenia, one case of which was reported by Evans and Flink and one by Barr and Shorr. The former authors also reported two cases in which increased bleeding tendency with positive cuff test developed during treatment with thiouracil. Van Winkle stated that
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purpura was reported by six of the investigators who contributed to his study. Fever is probably the commonest manifestation of toxic reaction to thiouracil. In some instances it may be so severe as to indicate withdrawal of the drug, but occasionally if the febrile reaction is not severe, administration of the drug can be stopped temporarily and reinstituted in smaller dosage without recurrence of the fever. McArthur, Rawson and Means expressed the belief that the febrile reaction is a manifestation of true drug idiosyncrasy. Cutaneous reactions are also seen occasionally. If the rash is proved to be due to thiouracil, administration of the drug probably should be permanently discontinued. Jaundice, nausea and vomiting, muscular pains, general malaise and many other reactions have been attributed to thiouracil in rare cases. Their infrequence or their mildness make th{:)m of much less importance than agranulocytosis. The incidence of toxic reactions and the severity of some of them make caution during the period of administration of thiouracil imperative. The patient should be under frequent observations, temperature recordings should be made frequently and leukocyte counts should be made at short intervals. Even slight reduction of leukocyte counts should be taken seriously and followed closely with differential blood counts. Since agranulocytosis may appear very abruptly, serial total leukocyte counts do not constitute adequate protection. The patient must be instructed to consult the physician at the first sign of sore throat or other evidence of infection. The dose of the drug should be reduced as soon as the evidences of hyperthyroidism have been controlled. Moore found that reactions necessitating cessation of the drug occurred in approximately 8 to 10 per cent of the patients treated. The mortality rate in his study attributable directly to the drug was 0.5 per cent. Van Winkle and associates found that in approximately 13 per cent of cases there was some untoward reaction to thiouracil therapy. The mortality rate attributable to thiouracil in this series was 0.4 per cent, all of the deaths being due to granulocytopenia. In view of the definite, though slight, risk involved in treating hyperthyroid patients with thiouracil, consideration must be given in each instance to the relative risk for that patient of the various mathods of treatment available. Thiouracil has been used for too short a time for one to know definitely how frequently patients who have mild or moderately severe exophthalmic goiter may have the disease brought permanently and completely under control with the drug alone. Proper evaluation of the ultimate role that thiouracil
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SAMUEL F. HAINES, F. RAYMOND KEATING, JR.
is to play as a total treabnent of hyperthyroidism will depend on accurate comparison between the risk of toxic reactions to thiouracil and relapses following its use on the one hand, and the surgical mortality rate of subtotal thyroidectomy, the risk of parathyroid insufficiency, injuries to the recurrent nerve, and so forth, and the incidence of recurrence or persistence of hyperthyroidism following surgical treatment on the other hand. Occasionally, patients who have hyperthyroidism are seen with complicating conditions Which in themselves add materially to the risk of surgical treatment. In such cases thiouracil may be used as total treatment of the hyperthyroidism with strikingly good results. Actually in some instances in which such a program has been begun, the patient's condition has improved so greatly that operation on the thyroid has been performed later without excessive risk. Notable among such instances are patients having l;lyperthyroidism and severe angina pectoris in whom the cardiac condition may show great improvement after a period of control of hyperthyroidism. The risk of partial thyroidectomy after preparation with iodine in cases of mildly or moderately severe exophthalmic goiter without complications approximates closely the risk of thyroidectomy for adenomatous goiter without hyperthyroidism. Therefore there seems, at present, to be no indication for the use of thiouracil as preoperative treabnent in such cases, for the risk of administration of the drug would be added to the minimal risk of this operation. When, however, the risk of thyroidectomy is greatly increased by the intensity of hyperthyroidism, administration of thiouracil as a preoperative measure should be considered. Included in this group are, for example, patients who have extreme degrees of hyperthyroidism and large friable thyroid glands in whom anticipated technical difficulties superimposed on the severe hyperthyroidism may indicate the performance of two partial lobectomies at different times. In such cases complete control of hyperthyroidism by thiouracil may bring the patient into such condition that a double resection of the thyroid may safely be done at a single operation. In our experience such cases constitute only a small percentage of cases of exophthalmic goiter. Patients having severe hyperthyroidism associated with adenomatous goiter may show little or no improvement after administration of iodine. In such cases preparation with thiouracil, even though much time may be needed for it, can be of great help in reducing surgical risk. It is our feeling at the present time that the most important indications for the use of thiouracil are (1) as a total treabnent for hyperthyroidism in those cases in which complications prohibit surgical treabnent of the disease, (2) as a preoperative treabnent
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in those caSes in which the severity of hyperthyroidism is responsible for an anticipated high surgical risk or (3) as a preoperative treatment in those cases in which complications increase the surgical risk, especially if temporary relief of hyperthyroidism will bring about some amelioration of the complicating condition. It is not our practice to use the drug as a preoperative treatment of patients who have mild or moderately severe exophthalmic goiter, for the time involved is long and, in our opinion, the ultimate risk to the patient will not be lessened. Also, we have not used thiouracil as total treatment for hyperthyroidism in cases of mild or moderately severe exophthalmic goiter, for we felt that the drug could not be administered without constant careful observation. We feel that the risk of administration of the drug in such cases is as great as, or greater than, the risk of partial thyroidectomy in similar cases.
REFERENCES 1. Astwood, E. B.: Treatment of hyperthyroidism with thiourea and thiouracil. J.A.M.A. 122:78--81 (May 8) 1943. 2. Astwood, E. B., Sullivan, J., Bissell, Adele and Tyslowitz, R.: Action of certain sulfonamides and of thiourea on the function of the thyroid gland of the rat. Endocrinology. 32:210--225 (Feb.) 1943. 3. Barr, D. P. and Shorr, Ephraim: Observations in the treatment of Graves' disease with thiouracil. Ann. Int. Med. 23:754-778 (Nov.) 1945. 4. Bartels, E. C.: Thiouracil; its use in the preoperative management of severe hyperthyroidism; preliminary report. J .A.M.A. 125:24-26 (May 6) 1944. 5. Bielschowsky, F.: Distant tumours produced by 2-amino- and 2-acetylamino-fluorine. Brit. J. Exper. Path. 25:1-4 (Feb.) 1944. 6. Broders, A. C. and Parkhill, E. M.: Symposium on surgical lesions of thyroid; diffuse and adenomatous goiter and goiter induced by various agents. Surgery. 16:633-646 (Nov.) 1944. 7. Dobyns, B. M. and Haines, S. F.: Unpublished data. 8. Evans, G. T. and Flink, E. B.: Thio-uracil therapy in hyperthyroidism. Minnesota Med. 27:1002-1010 (Dec.) 1944. 9. Franklin, A. L., Lemer, S. R. and Chaikoff, I. L.: The effect of thiouracil on the formation of thyroxine and diiodotyrosine by the thyroid gland of the rat with radioactive iodine as indicator. Endocrinology. 34:265-268 (Apr.) 1944. 10. Hinton, J. W. and Lord, J. W., Jr.: Is surgery indicated in all cases of nodular goiter, toxic and nontoxic? J .A.M.A. 129:605-606 (Oct. 27) 1945. 11. Kennedy, T. H.: Thio-ureas as goitrogenic substances. Nature, London. 150: 233-234 (Aug. 22) 1942. 12. Larson, R. A., Keating, F. R., Jr., Peacock, Wendell and Rawson, R. W.: . Comparison of effect of thiouracil and of injected thyrotropic hormone on collection of radioactive iodine and the anatomic changes induced in thyroid of the chick. Endocrinology. 36:149-159 (Feb.) 1945. 13. McArthur, Janet W., Rawson, R. W. and Means, J. H.: Idiosyncratic febrile reactions to thiouracil: clinical characteristics and possible pharmacologic significance. Ann. Int. Med. 23:915-923 (Dec.) 1945.
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14. MacKenzie, C. G. and MacKenzie, Julia B.: Effect of sulfonamides and thioureas on the thyroid gland and basal metabolism. Endocrinology. 32:185-209 (Feb.) 1943. 15. Moore, F. D.: Toxic manifestations of thiouracil therapy. J.A.M.A. 130: 315-319 (Feb. 9) 1946. 16. Rawson, R W., Tannheimer, J. F. and Peacock, Wendell: The uptake of radioactive iodine by the thyroids of rats made goiterous by potassium thiocyanate and by thiouracil. Endocrinology. 34:245-253 (Apr.) 1944. 17. Rawson, R. W., Evans, R. D., Means, J. H., Peacock, W. c., Lerman, J. and Cortell, R E.: Action of thiouracil upon thyroid gland in Graves' disease. J. Clin. Endocrinol. 4:1-11 (Jan.) 1944. 18. Rawson R. W., Moore, F. D., Peacock, Wendell, Means, J. H., Cope, . Oliver and RiddeIl, Charlotte B.: Effect of iodine on the thyroid gland in Graves' disease when given in conjunction with thiouracil-a twoaction theory of iodine. J. Clin. Investigation. 24:869-877 (Nov.) 1945. 19. Richter, C. P. and Clisby, K. H.: Toxic effects of bitter-tasting phenylthiocarbamide. Arch. Path. 38:46-57 (Jan.) 1942. 20. Van Winkle, Walton, Jr., Hardy, S. M., Hazel, G. R, Hines, D. c., Newcomer, H. S., Sharp, E. A. and Sisk, W. N.: The clinical toxicity of thiouracil; a survey of 5,745 cases. J.A.M.A. 180:343-347 (Feb. 9) 1946. 21. Williams, R. H. and BisseIl, G. W.: Thiouracil in treatment of thyrotoxicosis. New England J. Med. 229:97-108 (July 15) 1943. 22. Williams, R. H., Kay, Gloria A. and Jandorf, B. J.: Thiouracil. Its absorption, distribution, and excretion. J. Clin. Investigation. 23:613-627 (Sept.) 1944.