Hyperthyroidism

Hyperthyroz'dism M O N T E A. GREER M A R T H A W. McDONALD

TABLE ETIOLOGY

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OF CONTENTS

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E Y E SIGNS AND EXOPIITIIAL1MOS .

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CLINICAL DIAGNOSIS .

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Thyroid Gland

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Integument

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N e r v o u s System .

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M u s c u l a r System

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R e s p i r a t o r y System .

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Skeletal System

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Cardiovascular System .

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H e m a t o p o i e t i c System .

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R e t i c u l o e n d o t h e l i a l System .

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G a s t r o i n t e s t i n a l System Urinary Tract

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R e p r o d u c t i v e System A d r e n a l Cortex

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13

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LABORATORY DIAGNOSTIC AIDS .

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Thyroidal Radioactive Iodine Uptake Test

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Labeled Triiodothyronine Resin Uptake Test TREAT~tENT

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15

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16 18

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Antithyroid Drugs

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Radioiodine

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Surgery .

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SPECIAL TIIERAPEUTIC PROBLEMS

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T h y r o t o x i c o s i s in P r e g n a n c y

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T h y r o t o x i c o s i s in I n f a n t s a n d C h i l d r e n " H o t " Nodules

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Severe T h y r o t o x i c o s i s a n d T h y r o i d Storm . . . . . . .

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is Professor of Medicine and Head of the Division of Endocrinology at the University of Oregon Medical School. t i e received his M.D. from Stanford University and served his internship at the San Francisco General Hospital. Dr. Greer was trained in Endocrinology at tile New England Medical Center and is the recipient of a Research Career Award from the National Institutes of Health. His primary research interests are in normal and abnormal thyroid pbysiology and neuroendocrinology.

is a graduate of Woman's Medical College of Pennsylvania. She served her internship and residency in Internal Medicine at the Medical College of Virginia. At the time this article was written, she held a Public Health Service Clinical Fellowship in Endocrinology under Dr. Greet at the University of Oregon. Now in private practice in Chattanooga, Tennessee, Dr. McDonald devotes part of her time as director of the training program in Internal Medicine at Baroness Erlanger Hospital.

H Y P E R T H Y R O I D I S M is a condition in which there is an excessive amount of circulating thyroid hormone, resulting in a hypermetabolic state. First described in 1825 by Parry, it is also known by the eponyms "Graves' " and "Basedow's" disease, as well as thyrotoxicosis, toxic goiter and exophthalmic goiter. These designations sometimes lead to confusion. For this discussion some clarification of terms is in order. Hyperthyroidism and thyrotoxicosis are synonyms for the hypermetabolic picture and are general terms. "Toxic goiter" implies a hyperactive, enlarged thyroid. It can be divided into two categories-nodular and diffuse. NOTE: Some o[ the work reported in this article was supported by grants from the National Institutes of Health, U.S. Public Health Service.

Our discussion will center primarily on diffusely enlarged, toxic goiters. Among patients with this disease, there are some who also have exophthalmos. Since Graves described the disease with the ocular complication, "Graves' disease" usually denotes the complex of hyperthyroidism, diffuse goiter and exophthalmos. ("Basedow's disease" connotes the same thing, although this term is not as popular in English-speaking countries as in central Europe, for obvious reasons.) However, the eye signs can exist in the absence of the hypermetabolic state. This is usually called "euthyroid Graves' disease." Conversely, diffuse, toxic goiter without eye signs is also often called Graves' disease.

Etiology Most thyroidologists now agree that Graves' disease bears some pathogenetic relationship to a peculiar substance called long-acting thyroid stimulator, popularly abbreviated LATS. A brief account of the fascinating development of the intense current interest in this material seems in order. Just 11 years ago, Adams (1) reported an interesting observation made while attempting to measure the T S H content of blood from patients with Graves' disease. His assay was performed by injecting the test material into guinea pigs whose thyroids had been prelabeled with 13xI and whose endogenous T S H secretion had been suppressed by exogenous thyroxine. T S H caused secretion of labeled thyroid hormone from the gland and a resultant rise in blood radioactivity to a maximum at 2 hours, with a subsequent significant fall by 8-12 hours. However, when sera from thyrotoxic individuals were assayed, the peak response did not occur until 8-10 hours later. The original guinea pig assay was modified for more convenient use in mice by McKenzie (2), who similarly observed the much later peak response when sera from thyrotoxic patients were assayed. The late peak response has been shown to be due to the long half-life of LATS in the blood (7.5 hours) compared with a half-life of a few minutes for TSH. At an international conference in 1960, investigators working in the field decided to name the material "long-

acting thyroid stimulator" to differentiate it from tile shortacting pituitary thyrotropin and to indicate the uncertainty of its origin. That LATS and T S H are not merely different forms of the same shbstance has been shown in several ways. LATS reacts with antihuman gamma-globulin but not with antihtunan TSH, LATS is less stable to heat than TSH, and qualitative differences have been shown by various sophisticated technics such as starch-gel electrophoresis. It would indeed be tempting to accept the hypothesis that LATS is of pituitary or of hypothalamic origin. However, this appears to be untrue. The thyrotoxic state and the ocular signs of Graves' disease can persist or worsen after hypophysectomy (3). Indeed, patients undergoing hypophysectomy or stalk section for unrelated other reasons (such as metastatic breast carcinoma), and those with hypopituitarism from such conditions as postpartum necrosis have been noted to develop thyrotoxicosis after pituitary ablation (4). It is not likely that the action of LATS is on the pituitary gland, for sera containing LATS evoke the same prolonged response in hypophysectomized and intact mice. This implies a direct action of LATS on the thyroid gland itself. LATS has been identified as a 7S gamma-globulln (G or IgG or immunoglobulin) by chemical reduction, enzymatic digestion and neutralization by antibodies to euthyroid human gamma-globulin (5). It has been shown that LATS is an inherent part of the gamma-globulin molecule, not merely attached to it. If LATS is an immunoglobulin, it follows that its antibody action should be demonstrable. Accordingly, it has been shown that LATS is an antibody reacting with the antigen in the thyroid microsomal fraction (6). Further evidence suggesting antibody activity lies in the decrease in LATS titers upon administration of steroids, discussed later under "Treatment." If LATS is an antibody it should be possible to elicit its production with appropriate antigen. This has been accomplished in rabbits by injecting human thyroid microsomes and subsequently obtaining significant amounts of LATS which remained only as long as immunization continued (7).

No sudl response was elicited using liver microsomes in place of thyroid tissue. Whether the LATS obtained by this method is identical to human LATS is not known at this writing. Its prolonged activity is consistent with this idea. However, thyroid hyperfunction was not observed in the immunized rabbits. An interesting hypothesis set forth by Kriss and co-workers (8) is that the inciting event in the thyroid antigen-LATS antibody system is thyroid tissue disease or injury. They proposed that LATS is a result rather than a cause. They supported this by the observation that in 3 out of 9 LATSnegative thyrotoxic patients, LATS was found in the serum several months after irradiation of the gland with x31I. Bauer and Catz (9) have published reports also suggesting that thyroid tissue damage is the culprit and that by giving enormous amounts of radioactive iodine to completely ablate the tissue, LATS titers have disappeared or have been significantly lowered. One might also draw from the latter report that unusually large doses of radioactive iodine eradicated all antibody-forming tissue, but Catz and Perzik (10) have reported similar results with total thyroidectomy. However, these observations have not yet been confirmed by other investigators. If the site of the antibody-forming tissue were known, the treatment of thyrotoxicosis would probably change drastically. This question is still unsettled. Lymphoid tissue has been suggested, and the thymus has been strongly implicated by Gunn and co-workers (11). McKenzie and Gordon (12) studled synthesis of 7S gamma-globulin by cultured leukocytes from patients with detectable LATS in their sera, the results being suggestive but not conclusive. Mention should be made of thyroid auto-antibodies in general. The existence of antibodies in chronic thyroiditis has been recognized for some time. These are antibodies to thyroglobulin and are usually detected by tanned red-cell agglutination. They are also seen in thyrotoxic individuals, particularly following thyroid irradiation or surgery. There also exists another type of thyroid auto-antibody known as "cytotoxic antibody," detected by complement fixation. It is not identified with any particular disease state, but is found more commonly in sera of patients with hyperplastic thyroid

glands. LATS is still another auto-antibody. Its presence is determined immunologically by complement fixation. Thus, the term "thyroid auto-antibodies" is a general one, leading only to confusion unless it is more specifically defined. If LATS is the cause of Graves' disease, we would like to find it in the blood of all persons suffering from the disease. It is not demonstrable in every case, perhaps because our methods of detecting it are yet too insensitive. It is possible that the severity of the disease is not related to the level of circulating LATS, but only to its presence. T h e following correlations with clinical status have been observed: 1. L A T S is more consistently present when there is exophthalmos and pretibial myxedema. 2. Although LATS is detected most frequently in thyrotoxic patients, it has been found in some normal individuals and in some patients who are hypothyroid after treatment for thyrotoxicosis. 8. LATS-negative thyrotoxic patients have been known to develop detectable titers after treatment with radioactive iodine. When present before treatment, the levels become higher after irradiation than after surgery. 4. In patients with pretibial myxedema, high LATS levels have been demonstrated in homogenates from biopsy material of the lesions as well as in the blood. It has not been demonstrated in extracts of retro-orbital, liver or thyroid tissue of patients who have LATS in their serum.

Eye Signs and Exophthalmos There are two separate ocular manifestations in thyrotoxicosis-noninfiltrative and infiltrative ophthalmopathy. T h e noninfiltrative type is relatively benign and results from sympathetic overactivity, causing spasm of the superior palpebral muscle and retraction of the upper lid. This gives the patient a staring expression. T h e bulb appears to be protruding from the socket, but this is due solely to the retraction of the upper lid. T h e contraction of the palpebral muscles accotmts for the lid lag and infrequent blinking. These eye signs usually disappear with the conventional forms of treatment for the underlying thyrotoxic state.

The infiltrative variety is entirely different in its pathology. Large quantities of mucopolysaccharide and fat are deposited in the orbital tissues. T h e extraocular muscles become markedly enlarged, lose their striations, and loci of degeneration appear along with infiltration of lymphocytes. The same process is thought to occur in pretibial myxedema, eye changes being more destructive because the bony orbit is not able to expand and accommodate the increased bulk. The effect of this seemingly relentless process is manifested in inability to converge or to rotate the eyeballs fully. Diplopia and blurred vision result from poor convergence and accommodation. Swelling of the orbital contents forces the bulb forward (proptosis), depriving the cornea of the physiologic protection of the lids and lacrimal fluid. Corneal ulcerations may occur, and the lacrimal glands enlarge, become inflamed and are sometimes destroyed. The ocular conjunctivae become edematous (chemosis). The increased intraorbital and intraocular pressure can lead to optic nerve damage and blindness. This type of ophthalmopathy may affect one or both eyes and can occur in a clinically euthyroid individual. It can precede the thyrotoxie state, or appear long after the clinical hyperthyroidism has been cured. It appears to be a self-limited, though rarely completely reversible, process. Its arrest is not necessarily correlated with remission of the clinical thyrotoxic state. The etiology of infiltrative exophthalmos is unknown, but may be related to LATS, which is usually present in the serum in this condition. Another factor, exophthalmos-producing substance (EPS), has for some years been implicated as a causative agent (13). This substance is variably present in the serum of patients with malignant exophthalmos and produces exophthalmos in the Atlantic minnow. To date, its relationship to T S H and LATS and to exophthalmos in the human is still controversial.

Clinlcal Diagnosis Classically, the thyrotoxic patient who presents with nervousness, goiter and eye signs can be diagnosed by a junior 8

medical student without difficulty. When eye signs are not present and tile gland is not visibly enlarged, a higher index of suspicion is needed. And when the case is even more "atypical," it presents a challenge to diagnostic acumen, particularly in elderly individuals whose cardiovascular or gastrointestinal involvement may overshadow the other manifestations. The signs and symptoms of the hyperthyroid individual can perhaps best be set forth by considering the organs and systems involved individually.

TItYROID GLAND Though not always visible, the hyperactive gland is usually palpable. Both inspection and palpation are facilitated by having the patient take a sip of water and hold it in his mouth with his neck slightly extended until the examiner tells him to swallow. The gland should rise in swallowing; if it does not, the mass in question is either not the thyroid gland or it is thyroid tissue affixed to underlying structures by malignancy or fibrosis. The estimated size of the gland is of some importance in arriving at the calculated dose of lslI, if that is the form of treatment to be used, and in following the clinical course of the goiter. The normal gland, usually impalpable, weighs about 20-30 Gm. Thus, a gland judged to be twice normal would weigh about 40-60 Gin. However, for the inexperienced examiner, it is difficult to judge what is twice as large as something he normally cannot feel. At best, this is a crude measurement, but worth using in clinical evaluation. Scintlscans are helpful in revealing the size of the gland and its substernal extension, but it is not practical to repeat these at each visit. T h e diffusely enlarged gland is usually soft-rubbery with well-defined borders. A bruit may be heard over the gland. It is of no diagnostic significance other than that it indicates the extreme vascularity of the hyperactive organ.

INTEGUMENT

The palms are typically warm and moist and excessive perspiration is present. Blushing occurs easily. It is suggested that these are manifestations of heat dissipation. Plummer's nails (onycholysis), more common in Graves' disease than other forms of hyperthyroidism, usually appear first on the ring finger. This phenomenon occurs toward the distal end of the nail, the nail leaving the nail bed prematurely and irregularly. The hair is quite fine and resistant to curling. Peripheral edema is common and not necessarily related to pretibial myxedema. The latter is a localized form of thickening over the tibial aspect of the leg just above the ankle. It is nonpitting and, if several loci are present, they often become confluent, affecting the entire leg below the knee. This phenomenon is rare and is usually seen only when exophthalmos is present. In both, there is an infiltration of mucopolysaccharides in the connective tissue. Gynecomastia is seen in about 10~o of the male patients with Graves' disease. It usually disappears after a euthyroid state is achieved. NERVOUS SYSTEM Hyperactivity, hyperirritability and heat intolerance are hallmarks of the disease. Emotional lability is evidenced by women who complain of crying spells for no known reason. Increased energy is surpassed only by increased fatigue. Reflexes are brisk, with shortened reaction time. In our clinic we have not found the photomotogram (a method of objectively recording the speed ot the Achilles reflex) to be a particularly reliable index of thyroid hyperfunction, although others have reported a different experience. 1~'[USCULAR SYSTEI~I

Almost all thyrotoxic patients will have some impairment of muscular function, varying from mild asthenia to profound weakness and even atrophy. A recent study of 54 patients revealed that 50% complained of weakness, and 81% had weak10

ness on clinical examination (14). Ninety-three per cent had abnormal electromyograms of the proximal muscles, whereas only 43% showed such abnormalities in the distal muscles. Elderly patients may present with thyrotoxic myopathy before any other signs or symptoms of the disease are manifest. Muscle weakness may be demonstrated by asking the patient to step up on the seat of a chair, to hold the legs outstretched in extension or to hold the arms upraised.

SKELETAL SYSTEM Osteoporosis may be seen to a mild degree. Whether or not this is related to the mild hypercalcemia sometimes seen in hyperthyroidism is a subject for many papers and few conclusions. Another involvement of bone is called "thyroid acropachy"--a clubbing of the fingers associated with osteoarthropathy. This is said to differ from pulmonary osteoarthropathy, in that tile lesion occurs predominantly at the distal portion of the bones and is not attended by the painful, warm, erythematous reaction seen over the phalanges in pulmonary disorders.

RESPIRATORY SYSTEM Dyspnea on exertion, a common complaint in cardiac and pulmonary disorders, occurs without evidence of either of these. For instance, we recently saw a young, hyperthyroid man who operated a chain saw to fell trees. He complained of inability to carry on his work, not because of weakness in operating the heavy saw, but because he became too dyspneic while carrying the saw from tree to tree. Abnormalities in pulmonary function to explain such dyspnea include reduced vital capacity, weakness of the respiratory muscles, decreased pulmonary compliance and increased respiratory dead space ventilation.

CARDIOVASGULAR SYSTEM Palpitations were described as one of the most prominent symptoms of thyrotoxicosis by yon Basedow, and the years 11

since have borne this out. Tachycardia is nearly ahvays present, but the occurrence of paroxysmal atrial tachycardia in hyperthyroidism is overemphasized, according to a recent study of 200 cases in which not a single such occurrence was 6bserved (15). However, atrial fibrillation is not uncommon (est. about 12%), particularly in the older age groups and in patients with pre-existing cardiac abnormalities. Heart failure is a known complication of severe hyperthyroidism, with or without pre-existing cardiac disease. Physical examination of the heart will almost invariably reveal a forceful apex beat and bounding precordium. A systolic murmur is frequently heard at the base and sometimes over the entire precordium. Occasionally, a "Means' crunch" is heard. This resembles a pericardial friction rub, but is heard at the end of expiration and is located in the second left interspace. This is possibly related to a dilated pulmonary conus in these patients. The changes in hemodynamics in hyperthyroidism include an increased pulse pressure, red cell mass, blood volume, blood velocity and blood flow to the skin, muscle and kidneys. The blood flow to the cerebral and splanchnic circulations is normal, but the AV difference in the splanchnic circulation is increased, implying that there is some determinant of blood flow other than oxygen demand. The necessity to dissipate heat may be the other determinant, since the skin and lungs have increased blood flow. The splanchnic bed, having normal blood flow, meets its oxygen requirements by increased oxygen extraction. The increased pulse pressure is explained by the combination of increased cardiac output with decreased peripheral resistance. HEMATOPOIETIG SYSTEM

A slight to moderate leukopenia and relative lymphocytosis are frequently seen in untreated thyrotoxicosis. This can give rise to alarm in physicians unaware of this association when they detect such changes in the leukocytes in hyperthyroid patients being treated with antithyroid drugs. Appropriate 12

therapy is frequently unnecessarily withdrawn because o[ the panic created. Although the red cells are usually normally maintained, occasionally a severe (usually hypochxomic, normocytic) anemi~ occurs which is unresponsive to iron or other hematinics. This anemia is abolished within a few weeks of the restoration of a euthyroid state. RETICULOENDOTHELIAL SYSTEM

Lymphadenopathy may be generalized, especially in children, and the thymus may be enlarged. Splenomegaly occurs rarely. GASTROINTESTINAL SYSTEM A cardinal complaint is weight loss despite increased appetite. This is expected in view of increased metabolic and catabolic processes, but an occasional patient will give a history of anorexia. Increased frequency of bowel movements, as compared to the prethyrotoxic state, is usually elicited in the history and is thought to be due to increased peristalic activity. Only rarely is there frank diarrhea. The glucose tolerance curve shows a rapid rise and fall because of the faster rate of absorption from the gut. This can give rise to glycosuria. URINARY TRACT Occasionally, polyuria occurs, the increased blood flow and glomerular filtration rate being somewhat increased.

REPRODUCTIVE SYSTEM The oligomenorrhea usually seen in hyperthyroid patients has not been satisfactorily explained. In view of the fact that T S H secretion is suppressed in thyrotoxic patients, one can postulate that other functions of the pituitary-hypothalamic system might be depressed to some degree. However, it is known that A C T H secretion in thyrotoxicosis is increased rather than depressed. 13

ADRENAL CORTEX The reason for an augmented A C T H secretion lies in the accelerated metabolism and excretion of adrenal steroids, thus requiring a greater production to maintain an adequate concentration in the blood. Since the adrenal cortex is under greater than normal stimulation, the glands often become hyperpla,~t c and may have decreased reserve. As mentioned above, the classic case of thyrotoxicosis poses no problem. The differentiation of the hyperthyroid patient from the nervous one proves more interesting. The study conducted by Wayne in 1954 (16) revealed that some signs and symptoms carry greater diagnostic weight than others, and his table of results is still of value to all proponents of physical diagnosis (see accompanying table). The unusual case of "masked" or "apathetic hyperthyroidism" should not go unmentioned. Almost 40 years ago, Lahey described a type of hyperthyroidism characterized by apathy rather than hyperactivity. Other reports have followed, describing patients who presented with complaints often unrelated to thyrotoxicosis but who had in common the placid facies and apathetic personality (17). Close questioning and examination of these patients revealed symptoms and signs which were undisturbing to them but which almost in retrospect suggested the diagnosis. This indifference on the part of the patient may serve to mask the clinical picture; in at least one reported instance, the diagnosis of hypothyroidism was entertained. These patients are usually in the elderly age group, present with cardiovascular or gastrointestinal problems, occassionally in coma, and may have either no palpable thyroid or a small nodular goiter. None of the class!c signs and symptoms are seen with consistency, ahhough tachycardia is usually present. Other forms of "masked thyrotoxicosis" are those in which the findings are truly atypical, but are disguised by their association with prominent signs of other concomitant disease and "monosymptomatic" cases in which all the complaints center on one system, suggesting primary disease in that system. 14

INCIDENCE OF SIGNS AND SYMPTOMS IN TIIYROTOXIC

SYMPTOMS

(T.),

NONTOXIC (N.T,), AND CONTROL (C.) C~SF.S T. N.T. C. SICNS T. N.T. C.

%

%

%

Dyspneaon exertion 81 Palpitation 75 Tiredness 80 Preference for cold 73 Excessive sweating 68 "Nervousness" 59 Appetite: Increased 32 Diminished 13 Weight: Loss 52 Gain 4 Bowels: Diarrhea 8 Constipation 15 Menses: Excessive 3 Scant)' 18

61 75 68 53 54 54

40 26 31 41 31 21

I 14

2 3

27 7

2 16

2 20

0 21

12 9

%

%

Goiter Dilluse enlargement

87 49

Nodular Single adenoma Exophthalmos Lid lag Hyperkinetic Finger tremor }lands: Sweating Hot Auricular fibrillation Regular pulse rate over 90/thin.

32 4 34 62 39 66

56 l l 37 11 (slight) 14 0 5 0 11 2 24 16 22 9 54 26

72 76 19

54 40 8

22 44 0

68

47

19

100

85

78

6 Average pulse rate. 3 Beats/rain.

%

Thyrotoxic: Patients referred to the thyroid clinic and shown after full investigation to be indisputably thyrotoxic (90 patients); Nontoxic: Patients referred to the thyroiu clinic as possible cases of hyperthyroidism but finally shown to be nontoxic (72 patients). Control: Normal individuals drawn as far as possible from the same social class and with the same age and sex distribution as the thyrotoxic cases. None was receiving medical attention (90 patients). From Wayne, E. J.: Brit. M. J. 1:411, 1954.

Laboratory Diagnostic Aids V e r i f i c a t i o n of t h e c l i n i c a l i m p r e s s i o n t h r o u g h s t a n d a r d l a b o r a t o r y tests is v a l u a b l e d i a g n o s t i c a l l y ; o n l y t h e f o u r most c o m m o n l y p e r f o r m e d p r o c e d u r e s ( p r o t e i n - b o u n d i o d i n e , triiodothyronine resin uptake, thyroidal radioiodine uptake and T S H s u p p r e s s i o n test) w i l l be discussed here. T h e b a s a l metab o l i c r a t e w i l l n o t be i n c l u d e d in t h e discussion since it is g e n e r a l l y a g r e e d t h a t its a c c u r a c y in r e f l e c t i n g t h e t h y r o i d state is at b e s t c r u d e . N o o n e single test c a n b e c o n s i d e r e d d i a g n o s t i c of t h y r o i d f u n c t i o n since t h e r e is c o n s i d e r a b l e overl a p b e t w e e n w h a t we t e r m n o r m a l v a l u e s a n d those og overa c t i v e a n d u n d e r a c t i v e t h y r o i d states. M o r e o v e r , t h e v a r i o u s tests m u s t b e i n t e r p r e t e d i n t h e l i g h t of t h e p h y s i c a l state of 15

the patient, his serum level of protein and any medications which may influence the results of the estimations. T h e protein-bound iodine determination measures the amount of circulating iodine precipitated with protein. It is generally regarded as an accurate index of the amount of circulating thyroid hormone. However, some of its value as a single diagnostic test is lost unless one is aware of the multifarious uses of iodine and iodide in cough syrups, medications for chronic lung disease, x-ray contrast media, and as carriers in a widely used antihistamine preparation (Ornade) and an anticholinergic preparation (Darbid), skin preps, iodine-containing douches, vaginal suppositories, iodoform gauze used in surgery, and even in bread containing added iodate as preservatives. These will all falsely elevate the PBI by contamination. A number of drugs or clinical conditions will alter the concentration of thyroxine-binding protein and thus elevate or lower the PBI without there being a concomitant change in thyroid status or in the free thyroxine level in the blood. Certain drugs interfere with the chemical methods used for iodine determination. A comprehensive review of this subject can be found in an article by Davis (18). TItYROIDAL RADIOACTIVE IODINE UPTAKE TEST T h e measurement of the thyroidal accumulation of a tracer dose of radioiodine is one of the most commonly uscd methods for assessing thyroid function. Contrary to a commonly held belief, the quantity of iodine contained in carrier-free radioiodine is so small as to be chemically undetectable in the blood even when therapeutic doses of 10-100 me. are used. T h e rate of accumulation of radioiodine will be inversely proportional to the size of the exchangeable body iodide pool. Thus, thyroid uptake will be rapid in iodinedeficiency states and low when iodides are given chronically, even though a euthyroid status exists under both conditions. Thc uptake is usually measured 24 hours after oral x~lI administration. W i t h a normal dietary intake of iodine, the 24hour uptake averages 15-50~o in euthyroid individuals. T h e 16

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HYPERTHYROIDISM 80

:~

HYPERTHYROIDISM WITH RAPID TURNOVER

6o

~ 4o

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NORMAL

f

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20

/

HYPOTHYROIDISM

/ /

l~

0

/-"

!

v

t

!

6

12

24

48

HOURS

Representative patterns of radioiodine uptake. values are generally below this in hypothyroidism and above this in thyrotoxicosis. In some thyrotoxic patients with a very rapid turnover of iodine in their gland, there may be considerable discharge of 131I by 24 hours. Thus, measurement of uptake at earlier intervals, such as 2 or 4 hours after 131I administration, may be more useful than the usual 24-hour uptake in screening for thyrotoxicosis. However, this often is impractical as a 17

routine procedure. T h e illustration on page 17 demonstrates the various types of uptakes discussed above. Scintiscans are useful in assessing the shape and relative activity of various parts of the thyroid. They are particularly useful in determining whether "hot" or "cold" nodules are present. For studies in patients with diffuse goiter, however, they are redundant. A simple radioiodine uptake is adequate. T h e TSH suppression test (sometimes called thyroid or triiodothyronine suppression test) has proved to be particularly helpful in identifying hyperthyroid patients with normal thyroidal uptakes, as well as euthyroid patients with high uptakes (19, 20). This test makes use of the normal negative feedback relationship in the hypothalamo-pituitary-thyroid axis of euthyroid persons and the nonsuppressibility of thyroid activity in hyperthyroidism. After an initial radioactive iodine uptake, the patient is given 200 mg. desiccated thyroid or its equivalent (e.g., 0.3 mg. sodium L-thyroxine, 75 vg. L-triiodothyronine) for I week. These are physiologic doses which will markedly suppress T S H secretion by the pituitary and thereby thyroid iodine metabolism. T h e thyroid aall uptake is then determined again. In both goitrous and nongoitrous euthyroid patients, the uptake is almost always suppressed to less than 20% of the administered 13~I by this dose of thyroid hormone. However, the thyrotoxic individual's TSH secretion is already maximally suppressed because of the high levels of circulating thyroid hormone produced by LATS stimulation of the thyroid or by autonomous, non-TSH-dependent hyperactivity of the thyroid (hot nodules). Nonsuppressibility of the radioiodine uptake by physiologic doses of thyroid hormone is also frequently, but not always, seen in patients with euthyroid Graves' disease. In using this test in euthyroid patients with nodular goiter, larger doses of thyroid are sometimes required to suppress the thyroidal uptake. In this case, autonomously functioning areas of the thyroid may be beginning to develop. LABELED TRIIODOTHYRONINE RESIN UPTAKE TEST

T h e dilemma of assessing thyroid function by thyroidal radioiodine uptake or PBI determinations in the face of 18

exogenous iodine contamination has been eased by the fact that the 131I triiodothyronine resin uptake test is not affected by nonhormonal organic or inorganic iodine in the serum. Interpretation of the test requires some understanding of its basis. This test measures the in vitro partition of lslI-labeled triiodothyronine (T3) between tile patient's plasma and a specially treated resin. Unsaturated thyroxine-binding protein (TBP) in the plasma competes with the resin for radioactive Ts. If there is a large excess of unsaturated TBP, the resin takes up less T3. The binding of the labeled hormone to the resin is thus inversely proportional to the unsaturated thyroxine-binding capacity of the plasma. Glinical situations in which there is a relative decrease in the unsaturated TBP, such as thyrotoxicosls, will have an increased T3 resin uptake. A relative increase in the unsaturated TBP, sudl as in hypothyroidism, will give a low T3 resin uptake. Because of the indirect and empirical nature of the T3 test and the incomplete state of our knowledge of thyroid hormone-plasma protein equilibria, this test is primarily valuable in situations in which the radioiodine uptake and PBI are not reliable. The Ta test is not affected by contamination of the blood with various organic iodine compounds or by inorganic iodide, even though exogenous iodine will affect the other more commonly used studies. This test may be particularly helpful in evaluation of possible hyperthyroidism in pregnancy. In this situation, the PBI is usually high because of an increased TBP appearing toward the end of the first trimester, and caused by increased estrogen secretion. Thyroid radioiodine uptake studies are usually not done in pregnant individuals because of potential damage to the fetal thyroid. If the patient is merely pregnant and not also thyrotoxic, a T3 resin uptake would be expected to be low because of the increase in the TBP caused by pregnancy and its relative unsaturation. However, if the pregnant patient is at the same time thyrotoxic, the thyroxinebinding capacity of her serum proteins would be relatively saturated and there would be a high T3 resin uptake. 19

Treatment

The choices available for therapy of hyperthyroidism have not changed dramatically over the past quarter of a century. However, we have accumulated considerably more information about the long-term results and possible complications of the various forms of therapy. Some of the initial fears concerning treatment with new therapeutic modalities have proved to be unwarranted; on the other hand, unexpected complications have become apparent. A choice usually has to be made among the three main types of treatment-antithyroid drugs, radioiodine or surgery. Frequently, combinations of these three are employed. ANTITHYROID DRUGS There are various types of chemical substances which interfere with the formation of thyroid hormone. These are popularly lumped together as "antithyroid drugs," even though widely ditfering classes of pharmacologic agents are included under this generic heading. For the purposes of this discussion, we can arbitrarily divide them into two groups. The first consists of agents which depress formation of thyroid hormone by inhibiting the organic binding and synthesis into thyroid hormone of that iodine which enters the thyroid gland as inorganic iodide. This group includes a number of separate subgroups, but the only compounds of this type commonly employed in the treatment of hyperthyroidism are the thionamides. This group includes materials related to thiouracil. In the United States, the most frequently prescribed drugs of this class are propylthiouracil and methimazole (Tapazole), although outside North America other agents such as methylthiouracil and neomercazole are frequently used. The second class of antithyroid agents comprises monovalent anions which inhibit the iodide-concentrating capacity of the thyroid gland. These substances decrease thyroid hormone formation by markedly reducing the amount of inorganic iodide which can enter the thyroid. In therapeutically tolerated doses, these drugs do not significantly interfere with organic binding and subsequent synthesis into thyroid hor20

mone of that iodide which does enter tile gland. Therefore, they are effective in the treatment of hyperthyroidism only when additional iodine is not given simultaneously. In the presence of a greatly expanded body iodide pool, as can be produced by simuhaneous treatment with Lugol's solution, the monovalent anions, such as thiocyanate and perchlorate, are not effective inlfibitors of thyroid hormone formation. Enough iodide can enter the thyroid under these conditions by simple diffusion to ensure an undiminished production of thyroid hormone. TnIor~aMiDEs.--As mentioned above, propylthiouracil and methimazole are the commonly used members of this group in the treatment of hyperthyroidism in the United States. Standard therapy is to give I00 mg. of propylthiouracil or 10-15 mg. of methimazole every 8 hours, and to continue this treatment for a period of about 1 year. Although such doses are effective in about 90~o of thyrotoxic patients, larger quantities will be required by some patients. A permanent remission can be expected in approximately 50~o of the patients treated for this length of time. Some improvement of signs and symptoms usually begins within the first 2-4: weeks of treatment, and a complete remission is usually achieved within 3 months. There is considerable individual variation in tile length of time required to produce a remission, however. One must remember that these drugs do not inhibit the secretion of preformed thyroid hormone in the gland, but only depress formation of new hormone. The time required to achieve a remission thus depends both upon the store of preformed hormone in the thyroid gland and its rate of secretion. In patients with small glands and with a very rapid turnover of iodine in the gland, remission should be achieved relatively rapidly. On the other hand, patients with large glands and with a correspondingly relatively vast store of preformed hormone will require much longer to become euthyroid in response to treatment. In some patients (approximately 10~o), hypothyroidism will develop. This is manifested by a sudden increase in the size of the thyroid gland, cold intolerance, fatigue, delayed Achilles tendon reflexes and other evidence of subnormal thy21

roid function. The increase in the size of the goiter is probably the most crucial clue. The current explanation of this phenomenon is that the thyroid gland in hyperthyroidism is overactive because of stimulation by LATS or because of autonomous hyperactivity. In both cases, the secretion of TSH from the pituitary is markedly suppressed while the patient is hyperthyroid, because of the negative feedback on pituitary TSH secretion from high levels of circulating thyroid hormone. When the thyroid hormone levels are decreased in tile blood to a point below that found in the euthyroid state, TSH secretion from the pituitary will resume. Thus, TSH secretion and the resultant increase in goiter size can be kept in check either by reducing tile dose of antithyroid drugs so that a less effective block of thyroid hormone synthesis is achieved, or by continuing tile same dose of antithyroid drugs and supplying thyroid hormone exogenously. Obviously, if the patient becomes hypothyroid, this is an effectivedose of the drug. If the dose of antithyroid substance is reduced, it may be decreased too far. The patient no longer will have an effective dose and some recurrence of hyperthyroidism may appear. It is for this reason that we prefer to continue with a known effectual dose of drug and merely titrate back to a euthyroid state with additional thyroid hormone, usually 3 gr. of desiccated thyroid or its equivalent daily. With both propyhhiouracil and methimazole, the incidence of toxic reactions is quite slight. Less than 5% of the patients will have some drug rash or itching as a manifestation of sensitivity to the drug. Usually, this disappears if the patient is changed to another antithyroid compound, but sometimes the patient appears to be sensitive to all of them. In our experience, such reactions occur most frequently in patients with a previous allergic history. Occasionally, if the reactions are not too severe, temporary benefit can be achieved from antihistamines and the drug continued. In a few patients, the rash and itching will gradually disappear and will not recur after antihistamines have been discontinued. Most often, however, such toxic reactions require the choice of another modality of treatment. This is usually radioiodine, since the 29

drug reactions most frequently appear within tile first 2-4 weeks of therapy with antithyroid drugs, and the patients are not yet sufficiently into a remission to permit a surgical approach. T h e ' d e v e l o p m e n t of agranulocytosis is frequently brought up as a serious potential hazard in the use of these drugs. Although this was a problem with the earlier antithyroid compounds, such as thiouracil, it is a rare occurrence with either methimazole or propylthiouracil. Physicians frequently become concerned because they find some leukopenia and a relative lymphocytosis in treated patients; the drug is with. drawn because it is felt that agranulocytosis is developing. However, as mentioned above, a relative lymphocytosis and leukopenia is commonly seen in untreated thyrotoxicosis. We do not feel that weekly leukocyte counts and differential smears are of any practical value in following patients treated with antithyroid drugs. If agranulocytosis is to develop, it usually does so within a few hours. A normal count in the morning does not preclude the development of agranulocytosis by that evening. Therefore, routine white blood counts are of no prognostic or warning value. We feel it is much more reasonable to warn the patient of possible symptoms of a depressed white blood count, such as malaise, fever, sore throat, etc. If these develop, he is instructed to contact us immediately and appropriate diagnostic studies can be obtained at that time. Some commonly voiced complaints against the use of antithyroid drugs are that proper use of the pills is difficult to achieve, frequent visits to the physician are required, and that the expense and bother of such treatment are so annoying to the patients that they usually will not maintain the correct regimen for the required length of time. There is some truth to such objections, but usually the frequency of visits to the physician's office is n o greater than would be required for following the patient after treatment with radioiodine or in preparation and follow-up for surgery. After the diagnosis is established and therapy with antithyroid drugs is instituted, we usually see the patient at 4-6 week intervals thereafter until the required 1 year of treatment has been concluded. 23

Satisfactory evaluation of the patient's progress usually can be achieved by simple clinical maneuvers. These include weight, pulse rate, eye findings (including measurement of the proptosis with a Luede exophthalmometer and examination for ophthalmoplegia), presence of tremor, degree of moisture and temperature of the skin, forcefulness of the cardiac impulse, size of the thyroid gland (estimated in grams) and presence or absence of thrill and bruit, and speed of the Achilles tendon reflex. In addition, any appropriate subjective changes in temperature tolerance, nervousness, bowel hab9its, vision, energy, appetite, etc., are recorded. T h e entire office visit rarely takes more than 10-15 minutes. Although it is usually measured, we have not found it of value to check the blood pressure at each visit. Although the widened pulse pressure in untreated thyrotoxicosis gradually returns to normal as a remission is achieved, the development of remission can be detected more easily and more reliably by the other criteria noted. We do not feel it is usually necessary to obtain routine laboratory studies at each visit. T h e only test worth following is the PBI, which will return to normal as a euthyroid state is achieved or become depressed below normal if myxedema is produced. Although this test is helpful and we usually obtain it, it rarely gives us reason to change our evaluation of the progress of the disease from our purely clinical findings. At the end of the year of therapy, the drug is stopped abruptly and not tapered off. If thyroid hormone had been given because of the development of hypothyroidism, this, too, is stopped abruptly. T h e patient is then seen 1 month later. If a relapse will occur promptly, this is usually clinically obvious by the end of 1 month. T h e choice can then be made whether to resume treatment with antithyroid drugs or to choose some other form of therapy. Our personal preference is that if the patient promptly relapses after a satisfactory course of treatment, the chance of his relapsing again after another course of antithyroid drugs is so high that we prefer treatment with radioiodine. If the patient has stayed in remission at the end of the first month, we see him again 2 months later, then in another 24

3 months, and then at 6-month intervals for the first 2 years. Following that, if the patient remains well, we have him return at yearly intervals. The best clue that a lasting remission will b e achieved by treatment with antithyroid drugs is the marked reduction in goiter size that is sometimes seen as the patient becomes euthyroid. In our experience, the goiters rarely disappear completely, but frequently become much smaller. Presumably, this reduction in goiter size indicates that the initiating factor (LATS?) has decreased or disappeared through some unknown mechanism. Wily the goiters rarely disappear completely, even when a lasting remission is achieved, is not clear, but it may be related to the fact that thyroid enlargement, which has been present for a considerable period, regardless of the initiating cause (iodine deficiency, goitrogen, etc.), does not allow a return of the thyroid gland to a normal size. This may be because the hyperplasia of follicular cells which occurs during the process of thyroid enlargement disappears very slowly. It is known that the turnover of thyroid cells is much slower than that of many other tissues. The necessity for taking pills every 8 hours, as is usually recommended, makes some patients unwilling or unable to maintain a prescribed regimen of antithyroid d r u g therapy. Frequent administration of th~ drug has long been recommended, presumably because of rapid metabolism and/or excretion of the commonly employed antithyroid compounds, necessitating replenishment of their availability to the thyroid every few hours. However, this concept of rapid dissipation of the effectiveness of the drug has never been established experimentally. We have found that in almost all patients, administration of the required daily dose of the drug as a single dose, given at one time, is just as effective as giving the dose in divided quantities throughout the day (21). Thus, instead of 100 mg. of propylthiouracll every 8 hours, 300 mg. can be given once a day. Such a program is more readily accepted by the patient. School children, particularly, are more easily treated by this plan. There are a few patients in whom divided administration of the drug may achieve better results than 25

if it is given once a day. Therefore, in any severely thyrotoxic patient it is probably safer to start therapy with divided doses until a remission is achieved and then switch to the same total daily dose given only once daily. We have now had several years' experience with this form of treatment and are quite convinced that administration of a single daily dose is effective in almost all patients and is significantly better tolerated as a regimen than divided doses. RADIOIODINE

Radioiodine has become increasingly popular as a choice of treatment in hyperthyroidism because of several inherent advantages. Most cases respond to a single dose, thereby obviating long-term administration of drugs or the complications of surgery. In terms, of over-all cost, it is probably the cheapest form of therapy. Except in rare instances, its use does not require hospitalization and no time is lost from work, as is necessary with thyroid surgery. Patients who are not good surgical risks, or who are not sufficiently cooperative to embark upon a course of long-term antithyroid drug therapy, can receive radioiodine without difficulty. However, there are some disadvantages. The most serious problem, and one which ha's received increasing attention in the past few years, is a progressive increase in the development of hypothyroidism in patients who have been treated with radioiodine (22). Although within the first year the portion of patients treated either with subtotal thyroidectomy or radioiodine who develop myxedema is approximately the same, namely, 10-15~o, subsequently the incidence of myxedema in the radioiodine-treated patients increases arithmetically, whereas (at least from the statistics currently available) the incidence of hypothyroidism in surgically treated patients does not show nearly so marked a rate of development. From the results of several large series which have been studied, it appears that the development of hypothyroidism in patients treated with radioiodine may be as high as 50~o by the twentieth post-therapy year. At that time, the rate of increase is still linear, indicating that by 40 years after treatment 26

with radioiodine almost all patients could be expected to have developed myxedema. Although hypothyroidism is easily controlled by adequate doses of thyroid hormone, it is a complication to be avoided, if possible, since many patients, even thougll they know they have the disease and are being adequately treated, stop taking thyroid hormone because they feel they are well enough to do without it. They insidiously drop into profound hypothyroidism, which may seriously incapacitate them before the diagnosis is again re-established and treatment is once more started. Other complications which have been feared in the past, such as the development of leukemia, cancer of the thyroid or other sequelae of radiation injury, have not yet been seen. It has now been 20 years since large-scale administration of radioiodine therapeutically was begun. If these complications were to present any serious problem, reports probably would have become available by now. There also has been concern that radioiodine treatment of individuals in the childbearing age is potentially dangerous because of genetic abnormalities which might be produced. However, it can be calculated that the radiation which would reach the gonads would be quite small and probably not of serious concern. As yet, no increased incidence of genetic malformations has been reported, although too short a time has elapsed for any such data to be of value. Another potential danger is that radioiodine therapy will precipitate thyroid storm in a patient with fulminant thyrotoxicosis who has a large gland filled with thyroid hormone. In such instances, radiation damage is assumed to cause a rapid release of hormone from the gland and to tip the balance in a precarious situation in the wrong direction. Such instances are quite rare and usually can be avoided by pretreatment of the patient with antithyroid drugs until significant improvement in the clinical state has been produced. At this time, the drugs are withdrawn for a few days to allow them to be metabolized and excreted so that the uptake of radioiodine by the thyroid will not be depressed. A therapeutic dose of radioiodine can then be given. Many formulae have been devised for calculating the prop27

er therapeutic dose to give a patient. Since the greatest variation is with the biologic response of the patient's thyroid gland, such calculations are crude, at best, b u t are useful in that they maintain a pseudoscientific relationship to treatment. In our own practice, we use a commonly applied formula of administering a dose of ~31I calculated to deliver 100 /~c. per Gm. of thyroid tissue. This requires an estimate of the size of the thyroid gland obtained by palpation, which is a rather crude approximation. T h e required quantity of ~31I in mc. is calculated by dividing the estimated weight of the thyroid gland by the percent accumulation of a previous tracer dose of radioiodine by the thyroid gland at 24 hours and an appropriate correction factor. An example is: Estimated weight of thyroid : 75 Gm. 24-hour 131I uptake -- 80%. Therapeutic 131I = 75/80 X 10 = 9.4 mc. It usually takes about the same length of time to observe the first clinical change in a thyrotoxic patient following treatment with radioiodine as it does after institution of antithyroid drugs. As with drugs, it also requires about 3 months for the m a x i m u m therapeutic effect to occur and for a euthyroid state to develop. It is unwise to retreat a patient who maintains some degree of hyperthyroidism before 3 months have elapsed following 13xI therapy, because of the progressive damage from radiation. At the end of 3 months, if hyperthyroidism still persists, treatment with a further dose of radioiodine should not be given if the radioiodine uptake at that time is quite low (below 20%). Hyperthyroidism existing in the presence of such a low uptake at 3 months posttherapy usually indicates that the gland has been quite severely damaged by radiation. A remission has not yet been achieved because some preformed thyroid hormone is still being lost from the irradiated gland. A euthyroid state almost always follows within a m o n t h or two under such circumstances, and may progress on to hypothyroidism. If, however, the patient is still hyperthyroid and has a high radioiodine uptake and PBI at 3 months after 13xI 28

therapy, a second therapeutic dose is indicated. This can be estimated on the same basis as the first dose, correction being made for any change in uptake or thyroid weight that may have been produced in the meantime. Sometimes, to minimize the sub'sequent development of myxedema, a smaller dose per gram of thyroid is used with second or subsequent x~:l therapy that may be necessary. Some clinicians prefer to use smaller doses than we employ; these smaller doses are repeated, as necessary, every 1-3 months, or combined with antithyroid drug therapy. In this way, they feel that their incidence of late-developing myxedema is reduced. In patients who are severely thyrotoxic but in whom a31I therapy is deemed the treatment of choice, antithyroid drugs are sometimes used beginning 2-3 days after the therapeutic dose of radioiodine, at a time when all of it has been accumulated within the thyroid gland. T h e patients are then followed just as they would be if they were being treated with antithyroid drugs alone. At the end of 3 months, assuming that a remission has been achieved, the antithyroid drugs are stopped. If a relapse occurs within 1 m o n t h following discontinuation of the antithyroid drugs, it is assumed that the remission was produced by the antithyroid drugs rather than by the radioactive iodine, and a second dose of radioiodine is given at that time. If the remission is maintained, it is assumed that this was produced by the radioiodine, since a 3-month period of therapy with antithyroid drugs usually will not achieve lasting remission. In such a case, the antithyroid drugs can then be omitted permanently. T h e question of whether only patients over a certain age limit should be treated with a3q has not yet been answered satisfactorily. However, since there is no evidence as yet that any serious complication other than myxedema follows radioiodine therapy, we have come to the conclusion that it is reasonable not to use radioiodine in any situation in which antithyroid drugs are not acceptable. We feel that the dangers from a3Xl are considerably less than those from surgery in the younger age group. However, we do not recommend its use in women who are pregnant at the time therapy for hyperthyroidism is required, because of the danger to the fetus, nor 29

would we use it within the first 2-3 years of life because of the apparent risk of subsequent cancer of the thyroid in infants irradiated over the thyroid region. Because of the high incidence of post-131I-therapy myxedema, which may occur at any time in the subsequent course of the patient's life, for the past 2 years we have felt that it is best to institute therapy with physiologic maintenance doses of thyroid hormone immediately after the patient treated with radioiodine has become euthyroid. We emphasize to the patient that, although such therapy may not be indicated at the time it is initiated, the chance of requiring thyroid replacement at some subsequent period is very great, and if the patient lives long enough, will approach 1007o according to current statistics. Should a recurrence of hyperthyroidism develop subsequently, it is very simple to detect it. The radioiodine uptake will not be suppressed by exogenous thyroid hormone if hyperthyroidism is produced by hyperfunction of the patient's own thyroid gland. SURGERY

Ablative thyroid surgery was once the only available form of therapy for hyperthyroidism, and it still holds an important place in our armamentarium. Preoperative preparation with antithyroid drugs and iodine has greatly reduced the mortality previously attendant upon this procedure, but the morbidity and mortality are still considerably higher than with the nonoperative forms of treatment. The complication rate varies inversely with the surgical ability and experience of the operator, as one would expect. Nevertheless, postoperative hypoparathyroidism, recurrent laryngeal nerve paralysis, wound infection, anesthetic accidents, etc., are hazards which, although rare, nevertheless, occur even in the large medical centers. Acute postoperative hypoparathyroidism may occur even though the parathyroid glands have not been removed. It sometimes persists as long as 6 months, the serum calcium thereafter returning to normal levels without specific treatment. Perhaps injury to the remaining thyroid tissue may 30

precipitate the release of thyrocalcitonin, a hormone which lowers serum calcium. However, if this were true, one would expect a similar situation to arise in patients undergoing destruction of the thyroid gland with irradiation. So far, this ha~ not been reported. Probably there is transient damage to the parathyroid glands because of interruption of the blood supply during surgery. A mild form of parathyroid insufficiency has been reported to occur in 28% of patients who have undergone subtotal thyroidectomy without removal of the parathyroid glands or ligation of the inferior thyroid arteries (29). Patients to be operated upon should be prepared with antithyroid drugs until they become euthyroid, then given stable iodine in the form of Lugol's solution or saturated solution of potassium iodide (5-10 drops per day) in addition, for the last 10-14 days before surgery. The stable iodine reduces the vascularity and secretion of hormone from the gland by some unknown mechanism. In some medical centers, antithyroid drugs are not used, preparation being made only with the administration of stable iodine. However, since a certain proportion of thyrotoxic patients do not respond well to iodine, initial treatment with antithyroid drugs is much safer. There is experimental evidence that as little as 6 rag. of iodine per day (the amount contained in one drop of Lugors solution) is adequate to produce a remission in most patients with hypothyroidism. However, since toxic manifestations of iodine are rarely, if ever, seen with the employment of 5-10 drops of saturated iodine solutions 3 times daily, it seems preferable to use the treatment schedule indicated above. Since iodine can enter the thyroid gland, where it exerts its effect only as inorganic iodide, the use of a saturated potassium iodide solution seems preferable to the employment of Lugol's solution, since the bitter taste and objectionable brown color are thereby avoided. Because of the greater hazards necessarily associated with thyroidectomy, we feel that it has only limited usefulness in the treatment of hyperthyroidism. Any condition in which it would be of value can almost ahvays be treated equally 31

well and with less attendant risk with radioiodine. One possible advantage of surgery is that the late occurrence of myxedema is probably less with surgery than with radioiodine therapy, although this has not been adequately established ,-as yet. Opinion is not uniform in the evaluation of surgery, however. At many medical centers where there is a long experience with various forms of treatment for thyrotoxicosis, subtotal thyroidectomy is still the preferred form of treatment. However, at most medical centers, as at our own, the surgical treatment of thyrotoxicosis is employed with progressively decreasing frequency. TREATMENT OF EXOPHTIIALMOs.--Since the cause of the eye changes in Graves' disease, as of hyperthyroidism itself, is still unknown, treatment is still largely empirical. Fortunately, in the majority of patients with Graves' disease the eye manifestations are mild enough that no special treatment is required. Usually, as a euthyroid state is achieved, the noninfiltrative ophthalmopathy improves, often to the point of complete remission. Occasionally, a complete regression of the proptosis is also achieved, but this is rare. More commonly, there will be a very gradual partial regression of the exophthalmos, requiring many months, but some residual proptosis remains indefinitely. If severe paresis of the extraocular muscles occurs during the course of the disease, it usually does not regress completely and may require corrective surgery. This should be done only after a stable condition has been present for several months, since surgical intervention, when progressive changes are occurring, will require additional surgery later on. Treatment of noninfiltrative exophthalmos has been accomplished successfully with beta adrenergic-blocking drugs. Sneddon and T u r n e r (25) have reported abolishment of lid retraction and lid lag by instillation of 10% guanethidine eye drops. Other studies have reported similar success with oral or intramuscular reserpine. Since this is usually a cos. metically disturbing but non-life-threatening manifestation of the disease, treatment directed toward this problem is not often necessary. If chemosis, burning or corneal irritation is a problem because of lagophthalmos, 10% methyl cellulose 32

eye drops, dark glasses, elevation of the head of the bed at night, and occasionally tarsorrhaphy are useful. Infiltrative exophthalmos is a more serious problem, but again is usually self-limited. Strangely enough, this type of ophthalmopathy often seems to bear no direct relation to the course of the hyperthyroidism. It sometimes appears before thyrotoxicosls can be demonstrated. Occasionally, it will appear or become much worse after a euthyroid state is achieved. The course of the exophthalmos does not seem to bear any direct relationship to the type of therapy used in treating the thyrotoxicosis. Various measures have been advocated f o r treating the infiltrative exophthalmos, including hypophysectomy, orbital decompression, pituitary or retrobulbar irradiation and conjunctival mobilization to protect the cornea. There is no convincing evidence that any of these measures are useful or that the treatment may not be worse than the disease in some instances. Although the cause of infiltrative exophthalmos is not known, current evidence indicates it may have something to do with LATS. Certainly, the use of large doses of glucocorticoids produces striking benefit in many instances. Assuming that LATS represents some sort of autoimmune disturbance, glucocorticoids might have a twofold action, both to reduce the formation of LATS and to decrease the inflammatory reaction in the orbit. Snyder et al. (24) have found that the LATS titer decreases with large doses of adrenal steroids, and Werner and Platman (25) have reported that not only do the eye signs improve but that in some instances there also is remission of the thyrotoxicosis itself when high doses of steroids are employed, even though no specific treatment is directed toward the thyrotoxicosis. The decision to institute glucocorticoid therapy is made on evidence of progressive ophthalmopathy, such as increasingly severe chemosis, blurring of vision, papilledema, diplopia, corneal ulceration, etc. High doses must be used initially, with subsequent doses tapered to a level just sumcient to maintain control of the progression. Werner has suggested that there is a critical level of steroids which must be exceeded to gain control (26). This critical level varies from 33

patient to patient, and sometimes necessitates doses as high as 140 rag. prednisone or its equivalent daily. We generally start with an initial dose of 60 rag. prednisone daily for a period of 2-3 weeks, by which time there is usually considerable improvement in the eyes. A very gradual tapering of the dose can be begun at that time. At the first sign of recurrence or progression, steroids must be temporarily increased until a stable state is reached. The ancillary measures mentioned above for noninfihrative exophthalmos are also employed, and sometimes diuretics are also used in an attempt to decrease retrobulbar fluid accumulation. Our results with treating infiltrative ophthalmopathy with steroids have usually, though not invariably, been quite rewarding and in consonance with the experience of others (26,27).

Special Therapeutic Problems THYROTOXICOSIS IN PREGNANCY

Since both Graves' disease and fecundity are common in young women, the problem of hyperthyroidism in pregnancy is not particularly unusual. The incidence of abortion is relatively high in such individuals if the thyrotoxicosis is not treated. Although there is no disagreement that the disease needs therapy in these circumstances, there is considerable dispute as to how it can best be accomplished. It should be emphasized that making a correct diagnosis of hyperthyroidism in pregnancy presents certain difficulties. An increased metabolic rate, heat intolerance, and an elevated PBI are commonly found in normal pregnancies. A small nontoxic goiter is also not unusual in such patients. Since 131I is not usually employed for diagnostic tests in the pregnant individual because of fear of damage to the fetal thyroid, evaluation of the problem may be difficult. It is in this particular situation that the lsII-T3-resin uptake is most useful. The PBI rises in pregnancy because of an increase in thyroxine-binding protein in the serum. However, production of thyroid hormone is normal during pregnancy and the relative saturation of the increased thyroxine-binding protein is there34

fore low. Consequently, in normal pregnancy the T : r e s i n uptake will be quite low. If both the PBI and T : r e s i n uptake are elevated, this is strong confirmatory evidence that thyrotoxicosis does actually exist. Radioiodine therapy is obviously contraindicated in the pregnant patient. Therefore, the debate centers on whether surgery or antithyroid drugs are preferable. From available published statistics, the end-results of these two forms of treatment in pregnancy seem to be roughly comparable. However, because of the reasons given previously, we prefer antithyroid drugs to surgery in this as in other conditions. Antithyroid drugs are a special problem in the pregnant patient in that they cross the placental barrier and will affect the fetal thyroid as well as that of the mother. Hence, it is important to keep the dose at the minimal level required to achieve a remission in the mother, and to particularly avoid a dose which will produce hypothyroidism. It is probably best to even permit a mild degree of thyrotoxicosis if one must compromise on one side or the other. Neither thyroxine nor triiodothyronine pass the placental barrier well. Therefore, giving supplemental exogenous thyroid hormone to the mother will not necessarily prevent hypothyroidism in the fetus if large doses of antithyroid drugs are given. Our group has had a collective experience of treating over 100 pregnant women with antithyroid drugs. There have been no instances of hypothyroidism produced in the newborn infant. One infant was born with a small goiter, but this regressed within a few days of birth and the child had a subsequently normal development. It is important to remember that the PBI is usually elevated in pregnancy, so that one should not attempt to bring the PBI to a nonpregnant, euthyroid level with antithyroid drugs, but should maintain a slightly elevated level. Following tile clinical manifestations is probably of greatest value in evaluation of the response to therapy. Antithyroid drugs are excreted in the milk. T h e mother should, consequently, not nurse the baby post partum to avoid a possible effect on the infant. 35

THYROTOXICOSIS IN INFANTS AND CHILDREN

Thyrotoxicosis in newborn infants is quite rare. When it does occur, the mothers almost always have active Graves' disease or have had it in the past. Since, in those patients studied recently, LATS is almost invariably detectable in serum of both the mother and the infant (28), it is assumed that this neonatal disease is caused by transmission of LATS across the placenta to induce hyperthyroidism in the infant. Usually, no specific therapeutic measures are necessary, since the hyperthyroidism, goiter and exophthalmos (if present) subside spontaneously within a few weeks. Thyrotoxicosis in children beyond the first 2-3 years of life is also much less commonly seen than in the young adult population, but it is considerably more common than neonatal thyrotoxicosis. As with the adult form of the disease, there is continuing debate over whether medical or surgical management is preferable. The choice of therapy depends upon the prejudices of the physician. From the published resuits, a lasting remission can be achieved with more certainty by surgery than by the standard use of antithyroid drugs. However, antithyroid drugs are just as effective in children as in adults in inducing a remission. One must weigh the usual risk of complications with surgery, particularly that of possible cervical keloid formation in young females, against the approximately 50~ o probability that the patients will not maintain a permanent remission after discontinuation of antithyroid drugs. It is generally held that radioiodine should not be used in children because of the greater risk of future development of thyroid carcinoma in individuals with such a long life expectancy ahead of them. However, as mentioned earlier, there is as yet no evidence that this is more than a theoretical peril. Our personal preference is to treat hyperthyroidism in children with antithyroid drugs as the initial step. It must be emphasized that the dose requirements for these agents in children is not dependent upon the size of the child. From our experience, the dose requirements, even in children below the age of 10, are at least as large and sometimes larger 36

than those for adults. Therefore, the full adult dose should always be used initially, and required adjustments in this should be made as outlined above. T h e r a p y of hyperthyroidism in children has been considerably simplified by the finding that in /hOSt patients a single daily dose of antithyroid drug is as efficacious as divided doses. Previously, one of the difficulties in treating childhood thyrotoxicosis with antithyroid drugs was that there was great difficulty in obtaining a regular 8-hour schedule of administration. Children in school or at play frequently forget their afternoon dose. Since they also often sleep more than 8 hours at night, an 8-hour interval between evening and morning doses is also difficult to maintain. We have treated several children with single daily doses of antithyroid drugs and have found it to be much better tolerated by both the patient and his parents than was the divided schedule. It has been advocated by some pediatric endocrinologists that antithyroid drugs should be continued for at least 2 years in children to obtain a better chance of a lasting remission once the drugs are stopped. This has not been our experience. We have found that the persistence of remission after a 1-year course of therapy is about the same in children as in adults. If a relapse does occur after stopping therapy, the problem of the next step to take is more difficult than with adults. Because of the potential danger of future thyroid cancer, we also would prefer not to give radioiodine if a relapse has occurred in children, although this would be our choice in adults. W h a t we have done is to continue the children who relapse with antithyroid drugs until they reach maturity, then to give them the choice of either continuing with antithyroid drugs indefinitely or of taking radioiodine as a form of treatment. In our limited experience with a few patients who continue to relapse once antithyroid drugs have been discontinued, the pattern of repeated relapses has continued as long as we have been able to follow the patients. Nevertheless, most of them have chosen to repeat courses of antithyroid drugs, when necessary, rather than to take radioiodine. T h e pattern for m a n y of these young "relapsers" (as well as for 37

the older ones) is to stay in remission for 1-2 years after each course of antithyroid drugs before another relapse occurs. Thus, they can be free of the necessity of taking any drugs directed at their thyroid for a prolonged period before retreatment is necessary. If they have to take the drugs only once a day, they seem to have no objection to such therapy; it is no different than taking the morning vitamins. It should be emphasized that one is particularly anxious not to allow hypothyroidism to develop in children during therapy. It is known that adequate thyroid hormone is necessary for normal growth, development and maturation. T h e appearance of hypothyroidism is detected in the same way as in adults, and is also treated by adding thyroid hormone to the regimen or by reducing the dose of antithyroid drugs. It is our feeling that, although we are aware of the potential risk of carcinogenesis in children who receive radio. iodine, if the choice must be restricted to surgery versus radioiodine, we prefer radioiodine. We have used radioiodine in a few children below the age of 16. We feel that its theoretical advantages over surgery are at least as compelling as in the adult population. "HOT" NODULES An area of the thyroid gland which is considerably more active than the surrounding tissue in accumulating radioiodine, as determined by scintiscan, is characterized as a "hot" nodule. H o t nodules are almost ahvays autonomously functioning and are not under the control of T S H (or presumably of LATS either). If these autonomous areas become active enough to secrete thyroid hormone in excess of that normally produced by the entire thyroid gland, T S H secretion is suppressed, and the remaining normal thyroid tissue becomes as inactive as would be seen in hypopituitarism. Such a situation may exist without there being clinically overt thyrotoxicosis or even a significant elevation of the PBI. Frequently, however, obvious thyrotoxicosis is produced. A h h o u g h hyperthyroidism caused by hot nodules can be treated as effectively by antithyroid drugs as can other forms 38

of thyrotoxicosis, the disease is produced by autonomous thyroid tissue, and lasting remissions after discontinuation of the drug do not occur. A more definitive treatment is to remove the nodule and thus be rid of the precipitating cause of the hyperthyroidism. Although at first glance, surgery after proper preparation would seem the treatment of choice, this is not necessarily so if one considers the problem more carefully. Since the hot nodules which produce thyrotoxicosis cause almost complete suppression of radioiodine accumulation by the surrounding tissue, radioiodine therapy can be employed very successfully. It will destroy only the hyperactive nodule. Once the oversecretion of thyroid hormone by the nodule has disappeared, T S H secretion by the pituitary is resumed and the normal thyroid tissue can again function to produce physiologic amounts of thyroid hormone. Radioiodine should thus be an even more reasonable form of therapy for this condition than for Graves' disease. T h e risk of subsequent hypothyroidism should be almost nil. T h e decision of what to do about hot nodules which are not associated with frank hyperthyroidism is more difficult. In this situation, one wonders whether it is better to follow the patient along until hyperthyroidism actually develops (if it ever does) or to go ahead and remove the potentially offensive tissue. Our experience with such cases is limited. However, we have seen at least 2 patients in whom clinically overt thyrotoxicosis eventually developed in initially "benign" hot nodules. It is therefore our feeling that such hyperfunctioning nodules probably should be treated when they are first recognized. This can be done safely by pretreating the patient with 0.8 mg. sodium-L-thyroxine (or its equivalent) daily for a week. A pretreatment scan is then made to make sure that the normal thyroid tissue has been adequately suppressed; therapeutic radioiodine is then given. Thyrotoxicosis developing in long-standing multinodular goiter (Plummer's syndrome) is probably a variation of the hot nodule, in which a number of areas in tile thyroid are affected. These patients are usually in the older age group, and radioiodine therapy is quite effective, although larger 39

doses than usual may occasionally be required. Sometimes new areas of nodular hyperactivity develop in patients who have initially undergone a satisfactory remission. Retreatment with radioiodine can then be given. In toxic nodular goiter, some physicians feel that surgery is the treatment of choice because the entire diseased thyroid gland can be removed at one swoop more effectively than with radioiodine. SEVERE THYROTOXICOSIS AND TtlYROID STORM

Occasionally, thyrotoxicosis is so severe as to raise serious concern for the survival of the patient. There may be exaggerated signs of hyperactivity, atrial fibrillation, tachycardia, heart failure, hyperpyrexia and even delirium. T h e most extreme form of this variable complex is called "thyroid storm," and is usually precipitated by some acute traumatic incident or surgery, which was not necessarily directed against the thyroid gland itself. Although thyroid storm was common in the early days of thyroid surgery, it is now quite rare if the patients are adequately prepared and in a euthyroid state before operation is performed. Nevertheless, it does sometimes occur and may even develop in patients with progressively severe thyrotoxicosis in whom no immediate precipitating factor is apparent. W h e n severe hyperthyroidism exists, one wishes to obtain a return to a euthyroid state as rapidly as possible. Since both antithyroid drugs and radioiodine require several weeks to exert their full effect, they are of little use in the treatment of acute or impending emergencies. Surgery is also of no value, since it cannot be performed if the patient is not euthyroid without the danger of precipitating a storm. W h a t is required is some measure which will cause an immediate lowering of the level of circulating thyroid hormone. Even better would be some method of counteracting the peripheral effects of thyroid hormone, but as yet no available agent will meet these requirements. Large doses of stable iodine, as mentioned above, will cause a marked reduction in the secretion of thyroid hormone within 1-2 days in most thyrotoxic patients. Therefore, this drug 40

is of the greatest value in ameliorating the symptoms of hyperthyroidism as rapidly as possible. A theoretical danger in employing iodine alone as a form of treatment is that, since it is given in quantities so greatly in excess of the normal dietary intake, it is possible that an increased store of thyroid hormone will be produced in the gland. If iodine fails to reduce secretion of thyroid hormone (as is the case in some thyrotoxic patients), or if the patient later becomes "iodine fast" and the material no longer has its usual effectiveness in holding thyroid secretion in check, an even more serious situation may exist than before treatment was started. T h e patient may remain or again become severely thyrotoxic, but now have such a large store of hormone in the gland, compared to the previous condition, that treatment with antithyroid drugs may take several months before a remission can be brought about. Radioiodine is dangerous to use under such circumstances because destruction of the gland and the consequent release of massive amounts of thyroid hormone may produce thyroid storm itself. Although rare, we have observed instances of thyroid storm following employment of radioiodine in these circumstances. In 1 case it resuited in death. Therefore, we believe that in severe thyrotoxicosis it is best to first initiate treatment with large doses of an antithyroid compound which can reasonably be expected to produce a complete or near-complete block in the synthesis of thyroid hormone before stable iodine is given. Since the effectiveness of antithyroid drugs is usually manifest within 30-60 minutes after oral ingestion, the administration of iodine can be begun 1 hour after the antithyroid drugs. Because it is more potent than propylthiouracil, we prefer, in this situation, to use methimazole in doses of 80-60 rag. every 8 hours, simultaneously with 5 drops of saturated potassium iodide solution. W i t h such a program, a euthyroid state is usually produced, even in severely thyrotoxic patients, within 2-3 weeks. Once the patient has become euthyroid, the iodine can be discontinued and the antithyroid drugs maintained at the same dosage level for a period of 3-4 weeks until the excess iodide has been excreted. Dosage of methimazole can then be 41

reduced to the standard level or changed to propylthiouracil. At the end of 1 month, antithyroid drugs can be stopped completely, if it is desired to treat the patient with radioiodine. If a surgical approach is felt desirable, operation can be performed within 2-3 weeks after initiating therapy, as soon as the patient becomes euthyroid. One might wonder why, if a remission can be achieved more rapidly with the combined use of large doses of methimazole and stable iodide, this form of treatment is not employed routinely, since it will induce a more rapid remission than any other form of therapy. Our reason for not doing so is that we have found the incidence of toxic reactions to the large dose of methlmazole to be much more frequent than with the usually employed doses. Drug rash, itching or other minor toxic manifestations have occurred in about 25% of the patients so treated, compared to ~ 5 % of patients given the usual dose. Although serious toxicity, such as agranulocytosls, has been seen only rarely, it nevertheless seems reasonable to us to employ this combined therapy only in patients in whom there is serious concern for their continued existence, unless the hyperthyroidism is improved rapidly. In thyroid storm, the patients are often unable to take medication by mouth because of delirium, nausea and vomiting. Thionamides are generally quite insoluble in aqueous solutions and are not available in parenteral form. However, methimazole is considerably more soluble than propylthiouracil and can be given intramuscularly in acute emergencies. T h e treatment of thyroid storm, other than for the specific measures mentioned above, is primarily empirical. Since there may be decreased adrenal reserve in thyrotoxicosls, corticosteroids are often given in doses of 200 rag. of hydrocortisone daily, or its equivalent, during the acute phase. Obvious supportive measures, such as ice packs and alcohol sponges to reduce the high fever, intravenous fluids to maintain or restore hydration, and antibiotics to counteract infections, if present, are employed. Intramuscular reserpine (up to 2.5 mg. every 8 hours) or oral guanethidine (50-150 mg. daily) has been used to reduce the peripheral sym42

pathomimetic effects of thyroid storm. It should be borne in mind that these drugs can cause marked hypotension; this may prove deleterious rather than beneficial if shock occurs or if surgery becomes necessary. When heart failure complicates the picture, digitalis therapy should be instituted; above usual amounts may be necessary to bring about compensation, since thyrotoxic patients are known to be more resistant to cardiac glycosides than euthyroid individuals. With the regimen above, or some variant of it, patients in thyroid storm usually improve within 2-4 days and reach a manageable state in 1 week. Despite heroic treatment, employing all known therapeutic measures, some patients fail to respond and die. No abnormality which can account for the demise has been found at autopsy. REFERENCES 1. Adams, D. D.: Pathogenesis of the hyperthyroidism of Graves' disease, Brit. M. J. 1:1015, 1965. 2. McKenzie, J. M.: Delayed thyroid response to serum from thyrotoxic patients, Endocrinology 62:865, 1958. 3. Furth, E. D., Becker, R. B., and Kane, J. W.: Appearance of unilateral infiltrative exophthalmos of Graves' disease after the successful treatment of the same process in the contralateral eye by apparently total surgical hypophysectomy. J. Clin. Endocrinol. 22:518, 1962. 4. Fajans, S. S.: Hyperthyroidism in a patient with postpartum necrosis of the pituitary: Case report and implications, J, Clin. Endocrinol. 18:271, 1958. 5. Adams, D. D., and Sharard, A.: Neutralization of long-acting thyroid stimulator by antibodies to euthyroid human serum, Australasian Ann. Med. 14:192, 1965. 6. Beall, G. N., and Solomon, D. H.: Inhibition of long-acting thyroid stimulator by thyroid particulate fractions, J. Clin. Invest. 45:552, 1966. 7. Solomon, D. H., and Beall, G. N.: Production of LATS in rabbits by immunization, Clin. Res. 15:127, 1967 (abstract). 8. Kriss, J. P., Pleshakov, V., Rosenblum, A., and Chien, J. R.: Studies on the Formation of Long-acting Thyroid Stimulator Globulin (LATS) and the Alteration of its Biologic Activity by Enzymatic Digestion and Partial Chemical Degradation, in Cassano, C., and Andreoli, M. (eds.): Current Topics in Thyroid Research (New York: Academic Press, Inc., 1965), p. 433. 9. Bauer, F. K., and Catz, B.: Radioactive iodine therapy for pro~essire malignant exophthalmos, Acta endocrinol. 51:15, 1966. 43

10. Catz, B., and Perzik, S. L.: Subtotal vs. Total Surgical Ablation of the Thyroid, Malignant Exophthalmos and its Relation to Remnant Thyroid, in Cassano, C., and Andreoli, M . (eds.): Current Topics in Thyroid Research (New York: Academic Press, Inc., 1965), p. 1183. 11. Gunn, A., Michie, W., and h'vine, W. J.: The thymus in thyroid tissue, Lancet 2:776, 1964. 12. McKenzie, J. M., and Gordon, J.: T h e Origin of the Long-acting Thyroid Stimulator, in Cassano, C., and Andreoli, M. (eds.): Current Topics in Thyroid Research (New York: Academic Press, Inc., 1965) p. 445. 13, Pimstone, B., Hoffenberg, R., and Black, E.: Parallel assays of thyrotrophin, long-acting thyroid stimulator and exophthalmosproducing substance in some endocrine disorders, J. Clin. Endocrinol. 23:336, 1963. 14. Ramsay, I. D.: Electromyography in thyrotoxicosis, Quart. J. Med. 34:255, 1965. 15. Vazifdar, J. P., and Levine, S. A.: Rarity of atrial tachycardia in acute myocardial infarction and in thyrotoxicosis, Arch. Int. Med. 118:41, 1966. 16. Wayne, E. J.: The diagnosis of thyrotoxicosis, Brit. M. J. 1:411, 1954, 17. McGee, R. R., Whittaker, R., and Tullis, L F.: Apathetic thyroidism: Review of the literature and report of 4 cases, Ann. Int. Med. 50: 1418, 1959. 18. Davis, P. J.: Factors affecting the determination of the serum protein-bound iodine, Am. J. Med. 40:918, 1966. 19. Greet, M. A., and Smith, G. E.: Method for increasing the accuracy of the radioiodine uptake as a test for thyroid function by use of desiccated thyroid, J. Clin. Endoerinol. 14:1374, 1954. 20. Werner, S. C., and Spooner, M.: A new and simple test for hyperthyroidism employing L-triiodothyronine and the 24-hour I131 uptake method, B u l l New York Acad. Med. 31:137, 1955. 21. Greer, M. A., Meihoff, W. C., and Studer, H.: Treatment of hyperthyroidism with a single daily dose of propylthiouracil, New England J. Med. 272:888, 1965. 22. Dunn, J. T., and Chapman, E. M.: Rising incidence of hypothyroidism after radioactive iodine therapy in thyrotoxicosis, Ne~t England J. Med. 271:1037, 1964. 23. Sneddon, J. M., and Turner, P.: Adrenergic blockade and the eye signs of thyrotoxicosis, Lancet 2:525, 1966. 24. Snyder, N. J., Green, D. E., and Solomon, D. H.: Glucocorticoidinduced disappearance of the long-acting thyroid stimulator in the ophthalmopathy of Graves' disease, J . Clin. Endocrinol. 24:1129, 1964. 25. Werner, S. C., and Platman, S. R.: Remission of hyperthyroidism (Graves' disease) and altered pattern of sernm-thyroxine binding induced by prednisone, Lancet 2:751, 1965. 44

26. Wemer, S. C.: Prednisone in emergency treatment of malignant e.xophthalmos, Lancet 1:1004, 1966. 27. Brown, J., Cobum, J. W., Wigod, tLA., Hiss, J. M., Jr., and Dowling, J. T.: Adrenal steroid therapy of severe infiltrative ophthalmopathy of Graves' disease, Am. J. Med. 34:786, 1963. 28. McKenzie, J. M.: Neonatal Graves' disease, J. Clin. Endocrinol. 24:660, 1964. 29. Jones, K. H., and Fourman, P.: Prevalence of parathyroid insufficiency after thyroidectomy, Lancet 2:119, 1965. "

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