- Email: [email protected]
Hyperthyroidism
Symposium on Therapeutic Problems
Hyperthyroidism Henry E. Zellmann, MD.
It is not surprising that the various forms of hyperthyroidism fascinate many physicians, for herein lies something for almost everyone. For the scientist, there is the challenge that more than a half century of medical progress has added little to our knowledge of the etiology of the hyperthyroid states. For the clinician, there is almost always a colorful, even dazzling array of signs and symptoms or its counterpart, an obscure subtle illness which tests his diagnostic skill. For the clinical pathologist, there is a surfeit of laboratory tests, and for the therapist, a dilemma of three powerful modalities, with the problem of when and how and on whom to use them. Since it is with therapy that we are chiefly concerned in this volume, it is fortunate that these diseases are not so rare as to have given us little opportunity for their management. Instead, experience has been extensive with all modes of therapy. The fact that probably no more controversial area exists in medicine emphasizes that the ideal method has yet to be discovered. A rigid, unitarian program, however skillfully executed, will surely be a disservice to at least some patients. What we propose is a balanced approach fitting the treatment to the patient rather than the reverse.
GRAVES' DISEASE Although treatment is most effective when directed toward etiology, no such plan is available in Graves' disease. This condition is best viewed as a familial immunologic disorder.G Lymphocytes and plasma cells, in response to an antigen as yet unidentified but presumably of thyroid origin, produce a variety of antibodies directed against one or several target tissues. The thyroid gland responds by secreting an excess of its hormones, thyroxine and triiodothyronine (T-4 and T-3). Thyroid-stimulating hormone (TSH) is not detectable in the serum because the thyroid-pituitary feedback mechanism is intact. TSH will reappear if therapeutic myxedema ensues. Orbital tissues react with the usual picture of thyroid ophthalmopathy, and the skin of the legs, feet, and rarely of the hands shows the changes of infiltration known as "pretibial myxedema." Medical Clinics of North America - Vo!. 56, No. 3, May 1972
717
718
HENRY E. ZELLMANN
The thyroid-stimulating antibody has been identified and termed long-acting thyroid stimulator (LATS). It is a 7-S globulin of the IgG class that, in the mouse bioassay model, induces secretion of radioiodinated thyroxine later than does TSH.H The immunologic identity of the dermal or ocular factors, if indeed they are antibodies, remains elusive. Medical Treatment Our most potent weapons are directed against the hypermetabolic component of this illness. We have much less to offer patients with dermopathy and ophthalmopathy. The rationale of medical therapy alone is based on the premise that the thyroid stimulator, which originates outside the thyroid and outside the pituitary gland, will eventually cease to be produced and TSH will resume its physiologic role. Whatever substance acts on the eyes and skin tends to run a more or less self-limiting course of 1 to 5 or more years and then remits. LATS apparently behaves in a similar manner. The goal, then, is to curtail T-3 and T-4 synthesis with antithyroid drugs and wait until the various stimulators no longer act. Ideally, we would like to be able to select candidates who would enter a remission in 1 or 2 years and subject only them to the discipline required for prolonged medical therapy. Thus, we would reduce by perhaps one half to three quarters the number of patients at risk, however small, from surgical and radioiodine treatment. Alexander and associates 1 have outlined a technique that shows great promise. A 20 minute intravenous uptake of 132 1, which assesses only the trapping mechanism, since it is a short-lived isotope, may be used while the patient is taking both thyroid and antithyroid drugs. Suppression of 132 1 uptake after an interval of 6 months of medical therapy is a favorable prognostic sign. Lack of suppression indicates that a remission is unlikely. Prospects for long-term therapy are children and young adults with small goiters who can be persuaded to follow the program. Frequently, they lack motivation. Anyone familiar with the vicissitudes of inducing young persons to do anything can envision pitfalls in this plan. It is not difficult to judge favorable progress. Clinical improvement, maintenance of normal weight, ability to function in life, school, and work, supplemented when necessary by laboratory confirmation with serum protein-bound iodine (PBI) or T-4, indicate the metabolic trend. Shrinkage of the goiter is an encouraging prognostic sign. A single drug is sufficient in most instances. Added thyroid substance makes metabolic balance easier in unstable hyperthyroidism. Education of the patient and family is perhaps emphasized less than in chronic diseases such as rheumatoid arthritis and diabetes but is just as important. We ask that any indication of infection, localized or generalized, be reported. This is the first line of defense against the complications of agranulocytosis. The choice of drugs is simple enough. Propylthiouracil and methimazole appear to have equal incidence of agranulocytosis, 1 in 300 to 500 patients. The latter is more likely to produce minor reactions involving the skin and joints. All that need be said regarding dosage is to be certain to give enough. Often doubling or tripling the customary amount is suf-
HYPERTHYROIDISM
719
ficient for control of what seems to be intractable hyperthyroidism. We must be certain that the patient takes the appropriate drug faithfully, and our lines of communication must be open. We should be realistic and flexible enough to admit medical failure and to move on to an alternate method. Young, poorly motivated persons with inadequately controlled hyperthyroidism easily lose scholastic momentum and may fall behind a year or two. A career may be jeopardized. From the physical standpoint, inordinate growth in height can be distressing, particularly among girls. Paradoxically, some of these youths become obese during this period of hypermetabolism.
Surgery It goes without saying that thyroidectomy in the hands of skilled surgeons has an impressive record. 4 It is decisive, morbidity is minimal, the complications of hypoparathyroidism and vocal cord paralysis are uncommon, recurrence is rarely seen, and mortality is virtually zero. It is the treatment of choice if the patient lives in an area remote from medical attention. Thyroidectomy should be performed on children and young adults with goiters of moderate to large size or those with unstable hyperthyroidism. Adolescence itself is challenge enough without the burden of a quickly curable metabolic disease that, if unchecked, can seriously interfere with psychologic and physical function. Surprisingly perhaps, a person with a large goiter and significant heart disease is often best managed by thyroidectomy. It is a precise, rapidly executed treatment. These recommendations are contingent on the availability of an expert thyroid surgeon and a well prepared euthyroid patient. Thyroid storm, associated with thyroidectomy, should remain an historical entity. In the absence of the optimal conditions mentioned, alternative approaches of radioiodine and drugs are safer.
Radioiodine Radioiodine therapy was greeted with enthusiasm in 1941. It circumvented the shortcomings of long-term medical treatment and avoided the admittedly few complications of thyroid surgery. It was simple, painless, bloodless, and not at all expensive. Initial fears of leukemogenesis, carcinogenesis, and genetic mutations were not borne out. Sustained enthusiasm, however, is never easy, and here there was no exception. Its power was unquestioned; precision is what it lacked. Failure to respond could be traced almost always to an inadequate dose or to compromise of thyroid uptake by exogenous iodine. The more elaborate formulas proved no better than rather crude empiric choices when it came to selecting the proper dosage. A mood of disillusionment with radioactive iodine therapy began in the early 1960's.5 Myxedema was too often the outcome when conventional amounts of radioactive iodine were used. Halving the customary dose and supplementing the program with stable iodine or an antithyroid drug for a few years does, it is true, reduce the incidence of myxedema, but in many persons it just as surely postpones a final resolution of the problem. Myxedema is not such a dreadful disease either to treat or to have.
720
HENRY
E.
ZELLMANN
Much less is made, it seems, of hundreds of thousands of patients whose adrenal glands have been rendered atrophic by corticosteroid therapy than of the few thousand made myxedematous by radioactive iodine. A plan that includes a little radioiodine and a little antithyroid drug or iodine and a long, long time appears to differ little from prolonged medical treatment, except that it is more complicated and adds the uncertainty of radiation. No one can say that a small dose of radioactive iodine plus adjuvant therapy, which will achieve a euthyroid state in 5 or 10 years, will not induce myxedema in 15, 20, or more years. We, at the Lahey Clinic Foundation, tend to be almost as decisive in using radioiodine as surgery, and we depend on the supervision and education of the patient to avoid the complications of myxedema. Pregnancy The proper management of a hyperthyroid patient when she is pregnant is no less controversial than when she is not, except no one recommends radioiodine. Proponents of medical therapy stress combined treatment using the smallest possible dose of antithyroid drugs supplemented by thyroid substance. 7 Their aim is to prevent even a brief period of hypothyroidism in the fetus whose nervous system requires thyroid hormones for maximal protein synthesis, growth, and maturation. The central problem is the ease with which antithyroid drugs traverse the placenta to the fetal circulation and the relative impermeability of the placenta to maternal thyroxine and triiodothyronine, whether endogenous or exogenous. In other words, the fetus depends on its own T-3 or T-4 for neural development. Comparable results in terms of fetal mortality, that is, living infants, can be achieved by either medical or surgical means. The crucial question, which the medical therapist finds difficult to answer, was asked by Werner: 13 how will we ever know if the infant, who now has an IQ of 105, was destined for 160 before he experienced "mild" hypothyroidism in utero? We believe that this problem is, at present, unsolved, and we recommend thyroidectomy for most patients in the first or second trimester of pregnancy. There is a singular advantage to this plan-the fetus in the current pregnancy, and those in all subsequent pregnancies, is protected from the potential central nervous system effects of hypothyroidism. Less troublesome complications during pregnancy are neonatal goiter with respiratory obstruction and goiter, and exophthalmos resulting from transplacental passage of maternal LATS.
TOXIC NODULAR GOITER Far less is known about the cause of this disease than diffuse toxic goiter. In all likelihood, it is a stage in the evolution of nodular goiter. Miller and Block9 outlined several levels of development from a localized area of concentration of radioactivity on scintiscan suppressible by exogenous thyroid hormone through an autonomous stage of nonsuppressibility yet with normal serum tests of thyroid function and no symptoms, to overt hyperthyroidism, namely, an increase in T-3 and T-4 in the serum
721
H YPER THYROIDISM
as well as an appropriate clinical picture. LATS, dermopathy, and ophthalmopathy are uniformly absent. Remission does not occur except in a rare instance when the nodule becomes infarcted. Although pure Plummer's disease with a single hyperfunctional nodule and toxic multinodular goiter may seem superficially different, they are probably the same entity. In the former, paranodular tissue is completely suppressed; in the latter, an irregular pattern of radioactivity with one or occasionally more than one dominant nodule is present. The pathologist can help us little. His diagnosis is usually adenomatous goiter, at times showing hyperplasia but more often not. T -3 THYROTOXICOSIS
Clinicians noted soon after protein-bound iodine (PBI) determinations were introduced 20 years ago that now and then a patient with goiter and convincing clinical evidence of thyrotoxicosis had completely normal serum levels of thyroid hormone. Intuitively, they treated these persons as if they had hyperthyroidism and were gratified when they showed appropriate response. The concept of hypermetabolism caused by excess secretion of triiodothyronine not measured in routine serum test (PBI and the later T4I, T4D, and RT3) slowly emerged. The characteristic features of this disease are the clinical picture of hyperthyroidism in the presence of goiter, usually nodular, with uptake of radioactive iodine not suppressible below 50 per cent of its baseline value by 1 week of triiodo thyronine therapy, 100 micro grams a day. Sterling and associatesl l described a technique for measuring serum levels of T-3, which are elevated in this syndrome, termed T-3 thyrotoxicosis. Radioimmunoassay of T -3 will soon be widely available. Therapy Antithyroid drugs alone will relieve the symptoms of hyperthyroidism even though response is slower than in diffuse toxic goiter presumably because a good deal of hormone is stored in the nodular gland. Since relapse is the rule after discontinuing therapy, definitive control should be sought unless life expectancy is short. Radioiodine is feasible and effective, although we do not believe it to be ideal. Because the 24-hour uptake of radioactive iodine is either normal or not strikingly elevated, the dose is large, from 10 to 20 millicuries, for single hyperfunctioning nodules (compared with 4 to 10 millicuries for diffuse toxic goiter) to as much as 40 to 50 millicuries for multinodular goiter. Single nodules shrink slowly in size. Many can no longer be felt in 1 to 2 years. The size of multinodular goiter remains virtually unchanged. Myxedema is an unusual outcome because the resting paranodular tissue is spared radiation and easily responds when necessary to endogenous TSH. Since these patients are usually older than 50 years, pregnancy does not influence our decision. For the same reason, carcinogenesis is unlikely. Surgery We urge all patients with multinodular toxic goiter and most of those with single hyperfunctioning nodules to accept thyroidectomy. It guaran-
722
HENRY E. ZELLMANN
tees complete, rapid control of hypermetabolism Patients tolerate the operation remarkably well. Perhaps the illness itself is more or less a stress test, so that when euthyroid, the patients find surgery a lesser stress than their initial symptoms. Since the extent of dissection in the neck is less for a multinodular goiter than for diffuse goiter and still less for single nodules, the already small risk to local structures, laryngeal nerves and parathyroids, is further reduced. Persistent and recurrent hyperthyroidism should not occur.
Ancillary Drugs and Procedures Antithyroid drugs act on the thyroid follicular cell within 30 minutes after ingestion. Yet, clinical improvement is delayed for a week or more until pathologic amounts of free and bound thyroid hormones approach physiologic levels. As a rule, no hardship is incurred, and the patient is content to wait. When more rapid action is essential, the beta-adrenergic blocking agent, propranolol hydrochloride,12 is important in controlling distressing peripheral manifestations, such as tachycardia, sweating, and tension signs and symptoms. Its chief place, however, is in managing thyroid storm or crisis. Although experience with the technique is limited, plasmapheresis 2 or exchange transfusion offers promise of the most rapid reduction of plasma levels of thyroid hormones in life-threatening storm. On a less heroic note, the course of therapy in hyperthyroidism is smoother in patients who have adequate amounts of rest, relative freedom from stress, and who avoid or sharply restrict their use of coffee, tea, tobacco, and alcoholic beverages. An all but forgotten, simple, safe, inexpensive drug for control of mild hyperthyroidism with a small diffuse goiter is iodide. Both synthesis and secretion ofT-3 and T-4 are inhibited. Remission may be long-lasting or permanent. Iodides, of course, are contraindicated as the sole agent in more severe degrees of hyperthyroidism.
IATROGENIC AND FACTITIOUS HYPERTHYROIDISM It is not widely known that classic Graves' disease may follow the unnecessary although well intended use of thyroid hormones in euthyroid persons. IQ Although uncommon, it is probably more frequent than the rare case reports would suggest. The mechanism is unknown. These individuals are believed to be genetically vulnerable, and the clinical illness comes to the surface when the thyropituitary axis is disturbed. Diagnosis and treatment of hyperthyroidism can be difficult enough without the added handicap of surreptitious thyroid administration. This is usually a manifestation of severe psychosis, neurosis, or situational reaction. Often the psychodynamic structure is an elaborate one. A good deal must be gained by the illness, that is, coping with life in a euthyroid state must be so threatening that escape by way of the inconvenience of hypermetabolism is an acceptable alternative. The diagnosis is not always obvious, for these patients are often crafty and resourceful. Fea-
723
HYPERTHYROIDISM
tures of the syndrome include clinical evidence of hyperthyroidism without goiter, ophthalmopathy, or dermopathy, with the hallmark being elevated serum tests and zero uptake of radioactive iodine. If triiodothyronine is the drug used, both the serum levels of thyroid hormone and the uptake of radioactive iodine will be low in the presence of hypermetabolism.
ASSOCIATED PSYCHOSIS AND NEUROSIS Hyperthyroidism may be associated with troublesome symptoms of psychosis or neurosis. It is metabolic stress which causes the breakdown. Past and subsequent history will often reveal decompensation following stress of other sorts, loss of esteem, job, or loved one. It is important to recognize that if disabling nervous symptoms persist, when from a clinical and laboratory standpoint a euthyroid state is reached, additional antithyroid measures are futile and must be supplemented by psychologic ones, either drugs or formal psychiatric assistance or both. At times, nervous symptoms overshadow those of hypermetabolism and interfere with successful resolution of the underlying thyroid problem.
SUMMARY Until more logical avenues open before us, our options in dealing with hyperthyroidism remain limited by our ignorance of its etiology. For toxic multinodular goiter, thyroidectomy offers an immediate curative solution. The large dose of radioactive iodine required, the delayed response, and the residual goiter make radioiodine less than an ideal choice. A single hyperfunctioning nodule may be excised easily and quickly; radioiodine here is usually just as effective, but its action is slower. Except as a temporizing measure where life expectancy is short, prolonged medical therapy should not be offered to these patients. Subtotal thyroidectomy has and deserves its enduring reputation as excellent treatment for diffuse toxic goiter from childhood through youth to middle age. When performed during the first two trimesters of pregnancy, subtotal thyroidectomy should protect against fetal hypothyroidism. When thyroid enlargement is minimal and the patient is cooperative, preferably in fact a bit compulsive, a trial of medical therapy is justified. Radioiodine is easily the simplest permanent way to deal with diffuse toxic goiter after the age of 40. We avoid using it during pregnancy and in fact do not recommend it enthusiastically for women in their childbearing years. Fear of leukemia and thyroid cancer ha:;; not, so far, materialized. Radioiodine is, however, an imprecise tool, tending to induce myxedema if it is relied upon as the sole agent. A multifaceted plan, including a small dose of radioiodine, antithyroid drugs, or iodine, and the passage of a long, long time, may delay the end point interminably and still carry the
724
HENRY
E.
ZELLMANN
risk of ultimate myxedema. For this reason, we plan to give enough radioiodine to control the hyperthyroid process with one dose, supple-, mented when necessary by a few weeks or months of antithyroid therapy. As to the future, little improvement can be expected in the management of toxic nodular goiter lest it be in the area of prevention. Hopefully, Graves' disease may someday yield to an immunologic attack. A limited trial of immunosuppressive drugs has thus far been disappointing. The ultimate weapon against hyperthyroidism remains to be discovered.
REFERENCES 1. Alexander, W. D., Harden, R. M., Shimmins, J., et al.: Treatment of thyrotoxicosis based on thyroidal suppressibility. Lancet 2:681-684 (Sept. 30) 1967. 2. Ashkar, F. C., Katims, R. B., Smoak, W. M., 3d, et al.: Thyroid storm treatment with blood exchange and plasmapheresis. J.A.M.A. 214:1275-1279 (Nov. 16) 1970. 3. Bell, G. 0., and Hall, J.: Hyperthyroidism and pregnancy. MED. CLIN. N. AMER. 44:363-367 (March) 1960. 4. Colcock, B. P., and King, M. L.: The mortality and morbidity of thyroid surgery. Surg. Gynec. Obstet. 114: 131-136 (Feb.) 1962. 5. Dunn, J. T., and Chapman, K M.: Rising incidence of hypothyroidism after radioactiveiodine therapy in thyrotoxicosis. New Eng. J. Med. 271 :1037-1042 (Nov. 12) 1964. 6. Hall, R.: Hyperthyroidism - pathogenesis and diagnosis. Brit. Med. J. 1 : 743-745 (March 21) 1970. 7. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med. 273:627-633 (Sept. 16) 1965. 8. McKenzie, J. M.: The long-acting thyroid stimulator: its role in Graves' disease. Recent Progr. Harm. Res. 23:1-46, 1967. 9. Miller, J. M., and Block, M. A.: Functional autonomy in multinodular goiter. J.A.M.A. 214:535-539 (Oct. 19) 1970. 10. Paz, A. T., Zellmann, H. K, and Bell, G. 0.: Graves' disease following thyroid therapy. Lahey Clin. Found. Bull. 18:11-16 (Jan.-March) 1969. 11. Sterling, K., Refetoff, S., and Selenkow, H. A.: T-3 thyrotoxicosis. Thyrotoxicosis due to elevated serum triiodothyronine levels. J.A.M.A. 213:571-575 (July 7) 1970. 12. Vinik, A. 1., Pimstone, B. L., and Hoffenberg, R.: Sympathetic nervous system blocking in hyperthyroidism. J. Clin. Endocrinol. 28:725-727 (May) 1968. 13. Werner, S. C.: Moderator: panel discussions on hyperthyroidism. 1. Hyperthyroidism in the pregnant woman and the neonate. n, Etiology and treatment of hyperthyroidism in the adult. J. Clin. Endocrinol. 27:1637-1654 and 1763-1777 (Nov.) 1967. 605 Commonwealth Avenue Boston, Massachusetts 02215
Hyperthyroidism Henry E. Zellmann, MD.
It is not surprising that the various forms of hyperthyroidism fascinate many physicians, for herein lies something for almost everyone. For the scientist, there is the challenge that more than a half century of medical progress has added little to our knowledge of the etiology of the hyperthyroid states. For the clinician, there is almost always a colorful, even dazzling array of signs and symptoms or its counterpart, an obscure subtle illness which tests his diagnostic skill. For the clinical pathologist, there is a surfeit of laboratory tests, and for the therapist, a dilemma of three powerful modalities, with the problem of when and how and on whom to use them. Since it is with therapy that we are chiefly concerned in this volume, it is fortunate that these diseases are not so rare as to have given us little opportunity for their management. Instead, experience has been extensive with all modes of therapy. The fact that probably no more controversial area exists in medicine emphasizes that the ideal method has yet to be discovered. A rigid, unitarian program, however skillfully executed, will surely be a disservice to at least some patients. What we propose is a balanced approach fitting the treatment to the patient rather than the reverse.
GRAVES' DISEASE Although treatment is most effective when directed toward etiology, no such plan is available in Graves' disease. This condition is best viewed as a familial immunologic disorder.G Lymphocytes and plasma cells, in response to an antigen as yet unidentified but presumably of thyroid origin, produce a variety of antibodies directed against one or several target tissues. The thyroid gland responds by secreting an excess of its hormones, thyroxine and triiodothyronine (T-4 and T-3). Thyroid-stimulating hormone (TSH) is not detectable in the serum because the thyroid-pituitary feedback mechanism is intact. TSH will reappear if therapeutic myxedema ensues. Orbital tissues react with the usual picture of thyroid ophthalmopathy, and the skin of the legs, feet, and rarely of the hands shows the changes of infiltration known as "pretibial myxedema." Medical Clinics of North America - Vo!. 56, No. 3, May 1972
717
718
HENRY E. ZELLMANN
The thyroid-stimulating antibody has been identified and termed long-acting thyroid stimulator (LATS). It is a 7-S globulin of the IgG class that, in the mouse bioassay model, induces secretion of radioiodinated thyroxine later than does TSH.H The immunologic identity of the dermal or ocular factors, if indeed they are antibodies, remains elusive. Medical Treatment Our most potent weapons are directed against the hypermetabolic component of this illness. We have much less to offer patients with dermopathy and ophthalmopathy. The rationale of medical therapy alone is based on the premise that the thyroid stimulator, which originates outside the thyroid and outside the pituitary gland, will eventually cease to be produced and TSH will resume its physiologic role. Whatever substance acts on the eyes and skin tends to run a more or less self-limiting course of 1 to 5 or more years and then remits. LATS apparently behaves in a similar manner. The goal, then, is to curtail T-3 and T-4 synthesis with antithyroid drugs and wait until the various stimulators no longer act. Ideally, we would like to be able to select candidates who would enter a remission in 1 or 2 years and subject only them to the discipline required for prolonged medical therapy. Thus, we would reduce by perhaps one half to three quarters the number of patients at risk, however small, from surgical and radioiodine treatment. Alexander and associates 1 have outlined a technique that shows great promise. A 20 minute intravenous uptake of 132 1, which assesses only the trapping mechanism, since it is a short-lived isotope, may be used while the patient is taking both thyroid and antithyroid drugs. Suppression of 132 1 uptake after an interval of 6 months of medical therapy is a favorable prognostic sign. Lack of suppression indicates that a remission is unlikely. Prospects for long-term therapy are children and young adults with small goiters who can be persuaded to follow the program. Frequently, they lack motivation. Anyone familiar with the vicissitudes of inducing young persons to do anything can envision pitfalls in this plan. It is not difficult to judge favorable progress. Clinical improvement, maintenance of normal weight, ability to function in life, school, and work, supplemented when necessary by laboratory confirmation with serum protein-bound iodine (PBI) or T-4, indicate the metabolic trend. Shrinkage of the goiter is an encouraging prognostic sign. A single drug is sufficient in most instances. Added thyroid substance makes metabolic balance easier in unstable hyperthyroidism. Education of the patient and family is perhaps emphasized less than in chronic diseases such as rheumatoid arthritis and diabetes but is just as important. We ask that any indication of infection, localized or generalized, be reported. This is the first line of defense against the complications of agranulocytosis. The choice of drugs is simple enough. Propylthiouracil and methimazole appear to have equal incidence of agranulocytosis, 1 in 300 to 500 patients. The latter is more likely to produce minor reactions involving the skin and joints. All that need be said regarding dosage is to be certain to give enough. Often doubling or tripling the customary amount is suf-
HYPERTHYROIDISM
719
ficient for control of what seems to be intractable hyperthyroidism. We must be certain that the patient takes the appropriate drug faithfully, and our lines of communication must be open. We should be realistic and flexible enough to admit medical failure and to move on to an alternate method. Young, poorly motivated persons with inadequately controlled hyperthyroidism easily lose scholastic momentum and may fall behind a year or two. A career may be jeopardized. From the physical standpoint, inordinate growth in height can be distressing, particularly among girls. Paradoxically, some of these youths become obese during this period of hypermetabolism.
Surgery It goes without saying that thyroidectomy in the hands of skilled surgeons has an impressive record. 4 It is decisive, morbidity is minimal, the complications of hypoparathyroidism and vocal cord paralysis are uncommon, recurrence is rarely seen, and mortality is virtually zero. It is the treatment of choice if the patient lives in an area remote from medical attention. Thyroidectomy should be performed on children and young adults with goiters of moderate to large size or those with unstable hyperthyroidism. Adolescence itself is challenge enough without the burden of a quickly curable metabolic disease that, if unchecked, can seriously interfere with psychologic and physical function. Surprisingly perhaps, a person with a large goiter and significant heart disease is often best managed by thyroidectomy. It is a precise, rapidly executed treatment. These recommendations are contingent on the availability of an expert thyroid surgeon and a well prepared euthyroid patient. Thyroid storm, associated with thyroidectomy, should remain an historical entity. In the absence of the optimal conditions mentioned, alternative approaches of radioiodine and drugs are safer.
Radioiodine Radioiodine therapy was greeted with enthusiasm in 1941. It circumvented the shortcomings of long-term medical treatment and avoided the admittedly few complications of thyroid surgery. It was simple, painless, bloodless, and not at all expensive. Initial fears of leukemogenesis, carcinogenesis, and genetic mutations were not borne out. Sustained enthusiasm, however, is never easy, and here there was no exception. Its power was unquestioned; precision is what it lacked. Failure to respond could be traced almost always to an inadequate dose or to compromise of thyroid uptake by exogenous iodine. The more elaborate formulas proved no better than rather crude empiric choices when it came to selecting the proper dosage. A mood of disillusionment with radioactive iodine therapy began in the early 1960's.5 Myxedema was too often the outcome when conventional amounts of radioactive iodine were used. Halving the customary dose and supplementing the program with stable iodine or an antithyroid drug for a few years does, it is true, reduce the incidence of myxedema, but in many persons it just as surely postpones a final resolution of the problem. Myxedema is not such a dreadful disease either to treat or to have.
720
HENRY
E.
ZELLMANN
Much less is made, it seems, of hundreds of thousands of patients whose adrenal glands have been rendered atrophic by corticosteroid therapy than of the few thousand made myxedematous by radioactive iodine. A plan that includes a little radioiodine and a little antithyroid drug or iodine and a long, long time appears to differ little from prolonged medical treatment, except that it is more complicated and adds the uncertainty of radiation. No one can say that a small dose of radioactive iodine plus adjuvant therapy, which will achieve a euthyroid state in 5 or 10 years, will not induce myxedema in 15, 20, or more years. We, at the Lahey Clinic Foundation, tend to be almost as decisive in using radioiodine as surgery, and we depend on the supervision and education of the patient to avoid the complications of myxedema. Pregnancy The proper management of a hyperthyroid patient when she is pregnant is no less controversial than when she is not, except no one recommends radioiodine. Proponents of medical therapy stress combined treatment using the smallest possible dose of antithyroid drugs supplemented by thyroid substance. 7 Their aim is to prevent even a brief period of hypothyroidism in the fetus whose nervous system requires thyroid hormones for maximal protein synthesis, growth, and maturation. The central problem is the ease with which antithyroid drugs traverse the placenta to the fetal circulation and the relative impermeability of the placenta to maternal thyroxine and triiodothyronine, whether endogenous or exogenous. In other words, the fetus depends on its own T-3 or T-4 for neural development. Comparable results in terms of fetal mortality, that is, living infants, can be achieved by either medical or surgical means. The crucial question, which the medical therapist finds difficult to answer, was asked by Werner: 13 how will we ever know if the infant, who now has an IQ of 105, was destined for 160 before he experienced "mild" hypothyroidism in utero? We believe that this problem is, at present, unsolved, and we recommend thyroidectomy for most patients in the first or second trimester of pregnancy. There is a singular advantage to this plan-the fetus in the current pregnancy, and those in all subsequent pregnancies, is protected from the potential central nervous system effects of hypothyroidism. Less troublesome complications during pregnancy are neonatal goiter with respiratory obstruction and goiter, and exophthalmos resulting from transplacental passage of maternal LATS.
TOXIC NODULAR GOITER Far less is known about the cause of this disease than diffuse toxic goiter. In all likelihood, it is a stage in the evolution of nodular goiter. Miller and Block9 outlined several levels of development from a localized area of concentration of radioactivity on scintiscan suppressible by exogenous thyroid hormone through an autonomous stage of nonsuppressibility yet with normal serum tests of thyroid function and no symptoms, to overt hyperthyroidism, namely, an increase in T-3 and T-4 in the serum
721
H YPER THYROIDISM
as well as an appropriate clinical picture. LATS, dermopathy, and ophthalmopathy are uniformly absent. Remission does not occur except in a rare instance when the nodule becomes infarcted. Although pure Plummer's disease with a single hyperfunctional nodule and toxic multinodular goiter may seem superficially different, they are probably the same entity. In the former, paranodular tissue is completely suppressed; in the latter, an irregular pattern of radioactivity with one or occasionally more than one dominant nodule is present. The pathologist can help us little. His diagnosis is usually adenomatous goiter, at times showing hyperplasia but more often not. T -3 THYROTOXICOSIS
Clinicians noted soon after protein-bound iodine (PBI) determinations were introduced 20 years ago that now and then a patient with goiter and convincing clinical evidence of thyrotoxicosis had completely normal serum levels of thyroid hormone. Intuitively, they treated these persons as if they had hyperthyroidism and were gratified when they showed appropriate response. The concept of hypermetabolism caused by excess secretion of triiodothyronine not measured in routine serum test (PBI and the later T4I, T4D, and RT3) slowly emerged. The characteristic features of this disease are the clinical picture of hyperthyroidism in the presence of goiter, usually nodular, with uptake of radioactive iodine not suppressible below 50 per cent of its baseline value by 1 week of triiodo thyronine therapy, 100 micro grams a day. Sterling and associatesl l described a technique for measuring serum levels of T-3, which are elevated in this syndrome, termed T-3 thyrotoxicosis. Radioimmunoassay of T -3 will soon be widely available. Therapy Antithyroid drugs alone will relieve the symptoms of hyperthyroidism even though response is slower than in diffuse toxic goiter presumably because a good deal of hormone is stored in the nodular gland. Since relapse is the rule after discontinuing therapy, definitive control should be sought unless life expectancy is short. Radioiodine is feasible and effective, although we do not believe it to be ideal. Because the 24-hour uptake of radioactive iodine is either normal or not strikingly elevated, the dose is large, from 10 to 20 millicuries, for single hyperfunctioning nodules (compared with 4 to 10 millicuries for diffuse toxic goiter) to as much as 40 to 50 millicuries for multinodular goiter. Single nodules shrink slowly in size. Many can no longer be felt in 1 to 2 years. The size of multinodular goiter remains virtually unchanged. Myxedema is an unusual outcome because the resting paranodular tissue is spared radiation and easily responds when necessary to endogenous TSH. Since these patients are usually older than 50 years, pregnancy does not influence our decision. For the same reason, carcinogenesis is unlikely. Surgery We urge all patients with multinodular toxic goiter and most of those with single hyperfunctioning nodules to accept thyroidectomy. It guaran-
722
HENRY E. ZELLMANN
tees complete, rapid control of hypermetabolism Patients tolerate the operation remarkably well. Perhaps the illness itself is more or less a stress test, so that when euthyroid, the patients find surgery a lesser stress than their initial symptoms. Since the extent of dissection in the neck is less for a multinodular goiter than for diffuse goiter and still less for single nodules, the already small risk to local structures, laryngeal nerves and parathyroids, is further reduced. Persistent and recurrent hyperthyroidism should not occur.
Ancillary Drugs and Procedures Antithyroid drugs act on the thyroid follicular cell within 30 minutes after ingestion. Yet, clinical improvement is delayed for a week or more until pathologic amounts of free and bound thyroid hormones approach physiologic levels. As a rule, no hardship is incurred, and the patient is content to wait. When more rapid action is essential, the beta-adrenergic blocking agent, propranolol hydrochloride,12 is important in controlling distressing peripheral manifestations, such as tachycardia, sweating, and tension signs and symptoms. Its chief place, however, is in managing thyroid storm or crisis. Although experience with the technique is limited, plasmapheresis 2 or exchange transfusion offers promise of the most rapid reduction of plasma levels of thyroid hormones in life-threatening storm. On a less heroic note, the course of therapy in hyperthyroidism is smoother in patients who have adequate amounts of rest, relative freedom from stress, and who avoid or sharply restrict their use of coffee, tea, tobacco, and alcoholic beverages. An all but forgotten, simple, safe, inexpensive drug for control of mild hyperthyroidism with a small diffuse goiter is iodide. Both synthesis and secretion ofT-3 and T-4 are inhibited. Remission may be long-lasting or permanent. Iodides, of course, are contraindicated as the sole agent in more severe degrees of hyperthyroidism.
IATROGENIC AND FACTITIOUS HYPERTHYROIDISM It is not widely known that classic Graves' disease may follow the unnecessary although well intended use of thyroid hormones in euthyroid persons. IQ Although uncommon, it is probably more frequent than the rare case reports would suggest. The mechanism is unknown. These individuals are believed to be genetically vulnerable, and the clinical illness comes to the surface when the thyropituitary axis is disturbed. Diagnosis and treatment of hyperthyroidism can be difficult enough without the added handicap of surreptitious thyroid administration. This is usually a manifestation of severe psychosis, neurosis, or situational reaction. Often the psychodynamic structure is an elaborate one. A good deal must be gained by the illness, that is, coping with life in a euthyroid state must be so threatening that escape by way of the inconvenience of hypermetabolism is an acceptable alternative. The diagnosis is not always obvious, for these patients are often crafty and resourceful. Fea-
723
HYPERTHYROIDISM
tures of the syndrome include clinical evidence of hyperthyroidism without goiter, ophthalmopathy, or dermopathy, with the hallmark being elevated serum tests and zero uptake of radioactive iodine. If triiodothyronine is the drug used, both the serum levels of thyroid hormone and the uptake of radioactive iodine will be low in the presence of hypermetabolism.
ASSOCIATED PSYCHOSIS AND NEUROSIS Hyperthyroidism may be associated with troublesome symptoms of psychosis or neurosis. It is metabolic stress which causes the breakdown. Past and subsequent history will often reveal decompensation following stress of other sorts, loss of esteem, job, or loved one. It is important to recognize that if disabling nervous symptoms persist, when from a clinical and laboratory standpoint a euthyroid state is reached, additional antithyroid measures are futile and must be supplemented by psychologic ones, either drugs or formal psychiatric assistance or both. At times, nervous symptoms overshadow those of hypermetabolism and interfere with successful resolution of the underlying thyroid problem.
SUMMARY Until more logical avenues open before us, our options in dealing with hyperthyroidism remain limited by our ignorance of its etiology. For toxic multinodular goiter, thyroidectomy offers an immediate curative solution. The large dose of radioactive iodine required, the delayed response, and the residual goiter make radioiodine less than an ideal choice. A single hyperfunctioning nodule may be excised easily and quickly; radioiodine here is usually just as effective, but its action is slower. Except as a temporizing measure where life expectancy is short, prolonged medical therapy should not be offered to these patients. Subtotal thyroidectomy has and deserves its enduring reputation as excellent treatment for diffuse toxic goiter from childhood through youth to middle age. When performed during the first two trimesters of pregnancy, subtotal thyroidectomy should protect against fetal hypothyroidism. When thyroid enlargement is minimal and the patient is cooperative, preferably in fact a bit compulsive, a trial of medical therapy is justified. Radioiodine is easily the simplest permanent way to deal with diffuse toxic goiter after the age of 40. We avoid using it during pregnancy and in fact do not recommend it enthusiastically for women in their childbearing years. Fear of leukemia and thyroid cancer ha:;; not, so far, materialized. Radioiodine is, however, an imprecise tool, tending to induce myxedema if it is relied upon as the sole agent. A multifaceted plan, including a small dose of radioiodine, antithyroid drugs, or iodine, and the passage of a long, long time, may delay the end point interminably and still carry the
724
HENRY
E.
ZELLMANN
risk of ultimate myxedema. For this reason, we plan to give enough radioiodine to control the hyperthyroid process with one dose, supple-, mented when necessary by a few weeks or months of antithyroid therapy. As to the future, little improvement can be expected in the management of toxic nodular goiter lest it be in the area of prevention. Hopefully, Graves' disease may someday yield to an immunologic attack. A limited trial of immunosuppressive drugs has thus far been disappointing. The ultimate weapon against hyperthyroidism remains to be discovered.
REFERENCES 1. Alexander, W. D., Harden, R. M., Shimmins, J., et al.: Treatment of thyrotoxicosis based on thyroidal suppressibility. Lancet 2:681-684 (Sept. 30) 1967. 2. Ashkar, F. C., Katims, R. B., Smoak, W. M., 3d, et al.: Thyroid storm treatment with blood exchange and plasmapheresis. J.A.M.A. 214:1275-1279 (Nov. 16) 1970. 3. Bell, G. 0., and Hall, J.: Hyperthyroidism and pregnancy. MED. CLIN. N. AMER. 44:363-367 (March) 1960. 4. Colcock, B. P., and King, M. L.: The mortality and morbidity of thyroid surgery. Surg. Gynec. Obstet. 114: 131-136 (Feb.) 1962. 5. Dunn, J. T., and Chapman, K M.: Rising incidence of hypothyroidism after radioactiveiodine therapy in thyrotoxicosis. New Eng. J. Med. 271 :1037-1042 (Nov. 12) 1964. 6. Hall, R.: Hyperthyroidism - pathogenesis and diagnosis. Brit. Med. J. 1 : 743-745 (March 21) 1970. 7. Herbst, A. L., and Selenkow, H. A.: Hyperthyroidism during pregnancy. New Eng. J. Med. 273:627-633 (Sept. 16) 1965. 8. McKenzie, J. M.: The long-acting thyroid stimulator: its role in Graves' disease. Recent Progr. Harm. Res. 23:1-46, 1967. 9. Miller, J. M., and Block, M. A.: Functional autonomy in multinodular goiter. J.A.M.A. 214:535-539 (Oct. 19) 1970. 10. Paz, A. T., Zellmann, H. K, and Bell, G. 0.: Graves' disease following thyroid therapy. Lahey Clin. Found. Bull. 18:11-16 (Jan.-March) 1969. 11. Sterling, K., Refetoff, S., and Selenkow, H. A.: T-3 thyrotoxicosis. Thyrotoxicosis due to elevated serum triiodothyronine levels. J.A.M.A. 213:571-575 (July 7) 1970. 12. Vinik, A. 1., Pimstone, B. L., and Hoffenberg, R.: Sympathetic nervous system blocking in hyperthyroidism. J. Clin. Endocrinol. 28:725-727 (May) 1968. 13. Werner, S. C.: Moderator: panel discussions on hyperthyroidism. 1. Hyperthyroidism in the pregnant woman and the neonate. n, Etiology and treatment of hyperthyroidism in the adult. J. Clin. Endocrinol. 27:1637-1654 and 1763-1777 (Nov.) 1967. 605 Commonwealth Avenue Boston, Massachusetts 02215