Hyperthyroidism. Causes, etiology of Graves’ disease, clinical features, general aspects of treatment

Phannac. Ther. C. Vol. I. pp. 401-422. 1976. Pergamon Press.

Printed in Great Britain

Specialist Subject Editors: J. M. HERSHMAN and G. A. BRAY

HYPERTHYROIDISM. CAUSES, ETIOLOGY OF ORA VES' DISEASE, CLINICAL FEATURES, GENERAL ASPECTS OF TREATMENT DAVID LEWIS GEFFNER and JEROME M. HERSHMAN Endocrine Research Laboratory, Medical and Research Services, Veterans Administration Wadsworth Hospital, Department of Endocrinology, Ross-Loos Medical Center and

Department of Medicine, University of California, Los Angeles, California. U.S.A.

CLASSIFICATION AND CAUSES OF HYPERTHYROIDISM Hyperthyroidism is a syndrome of metabolic and pathologic findings resulting from the action of excessive concentrations of circulating thyroid hormone on peripheral tissues. Although the clinical symptoms of hyperthyroidism have been known since antiquity, they were not related to overacitivity of the thyroid gland until the late 19th century (Greenfield, 1893). The causes of hyperthyroidism are listed in Table I. TABLE I. Classification of hyperthyroidism I. Toxic diffuse goiter (Graves', Basedow's, or Parry's disease: exophthalmic goiter) II. Toxic nodular goiter (Plummer's disease) A. Toxic uninodular goiter B. Toxic multinodular goiter III. Toxic goiter with functioning nodules and parenchyma (Marine-Lenhart syndrome) IV. Toxic goiter with chronic thyroiditis (Hashitoxicosis) V. Subacute thyroiditis VI. Malignant goiter VII. Struma ovarii VIII. Paraneoplastic syndromes A. Pituitary tumors B. Trophoblastic tumors C. Miscellaneous tumors IX. Exogenous thyroid administration (thyrotoxicosis factitia and medicamentosa) X. Iodine-induced hyperthyroidism (Coindet's disease, Jod-Basedow) XI. Neonatal thyrotoxicosis

DIFFUSE GOITER OF GRAVES' DISEASE In the United States and Great Britain, the most common form of hyperthyroidism is due to Graves' disease. Graves' disease is characterized by a diffusely hyperplastic goiter often associated with characteristic eye signs, and sometimes associated with pretibial dermopathy and other extrathyroidal manifestations. Fifty to eighty per cent of patients with Graves' disease have a circulating marker called the long-acting thyroid stimulator (LATS) (Carniero et al., 1966; Solomon and Chopra, 1972). The term Graves' disease also includes patients showing the extrathyroidal manifestations without hyperthyroidism. Under prolonged observation, some of these patients develop hyperthyroidism. Other eponyms include: Basedow's disease, Parry's disease, Flajani's disease. Histological examination shows the typical picture of hyperplastic thyroid' follicles with a variable amount of parenchymal lymphocytic infiltration. The infiltrative dermopathy seen over the shins and the exophthalmos is unique to Graves' disease. Typically, the increased thyroid hormone production is associated with depressed

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serum concentration of pituitary thyroid stimulating hormone (TSH) which fails to rise following thyrotropin releasing hormone (TRH) stimulation. This may not be due entirely to the elevated serum concentrations of T 3 and T 4 , as some patients with euthyroid Graves' disease also fail to respond to TRH despite presumably normal thyroid hormone production rates (Franco and Hershman, 1973; Ormston et al., 1973). Recently, hyperthyroid patients with the typical features of Graves' disease have been described with elevated basal concentrations of TSH that show no response (Emerson and Utiger, 1972) or exaggerated response (Chopra et al., 1973) to TRH stimulation. In the former case a primary hypersecretion of TRH by the hypothalamus has been suggested. Hashimoto's thyroiditis is related to Graves' disease in many ways (Buchanan et al., 1961; Doniach et al., 1963; Wyse et at., 1968). Depending on histological or serological criteria, they have been found to co-exist in the same population (Furszyfer et al., 1970), family, and even the same individual (Doniach, 1959; Zellerman and Sedgwick, 1%6). Patients have been described with clear-cut hyperthyroidism, histological and/or serological evidence of Hashimoto's thyroiditis with or without the extrathyroidal manifestations of Graves' disease (Gurkan, 1945; Greene, 1950; £1 Kabir et al., 1963; Fatourechi et al., 1971). Whether or not the two clinical entities are merely different manifestations of the same disorder or represent different stages of the same disease is as yet unknown (Hamilton and Maloof, 1973). The significance of these findings will be discussed more fully in the section on the etiology of Graves' disease. NODULAR GOITER WITH HYPERTHYROIDISM

Plummer (1912) distinguished nodular goiter with hyperthyroidism from the diffusely hypertrophic and hyperplastic goiter associated with exophthalmos (Graves' disease). Hyperthyroidism may be superimposed on previously existing adenomata or simple goiter. Pathological examination of the gland reveals an irregularly enlarged goiter that may contain cellular, colloid, hyperplastic or cystic nodules. The typical extrathyroidal manifestations of Graves' disease do not occur. In this type of hyperthyroidism, a single, well-defined adenoma can cause hyperthyroidism. Histologically the nodule shows hyperplastic acini while the rest of the gland is in the resting state. Radioiodine is concentrated in the hyperfunctioning nodule (Dobyns et al., 1949). Failure of suppression of radioactive iodine uptake following administration of thyroid hormone shows that the nodule is autonomous (Sheline and McCormack, 1960). Nodules that demonstrate a greater uptake of radioiodine on scan of the thyroid are often called 'hot' nodules. As the functional activity of the adenoma increases, that of the rest of the gland decreases (Cope et al., 1947). Not all hot nodules produce the clinical picture of hyperthyroidism. The present concept is that of a spectrum of autonomousfunction in adenomata beginning with small nodules less than one centimeter in size, incapable of producing enough hormone to suppress the remaining thyroid tissue, and ending with larger nodules that not only suppress function of the surrounding tissue, but give rise to clinical hyperthyroidism (Hamburger, 1972). Progression within this spectrum has been observed in several patients (Silverstein et al., 1967; McCormack and Sheline, 1967). Difficulty in the diagnosis of Graves' vs Plummer's disease occurs when diffuse hyperplasia is engrafted on a nodular goiter. There are also patients with the eye signs and pretibial dermopathy of Graves' disease in whom a few nodules exist in 'an otherwise diffuse goiter. Several of these patients had Hashimoto's thyroiditis (Fatourechi et al., 1971). Graves' disease with coexistent functioning nodules has also been described (Charles, 1972). However the etiology of the hyperthyroidism cannot be assigned with certainty to one or the other disease in most of these cases. Genetic studies have given an additional basis for separation of these conditions. Martin and Fisher (1945; 1951) found that the distribution of affected relatives was very similar in patients with nodular goiters whether or not hyperthyroidism was present; this differed greatly from the distribution of affected relatives in patients, with Graves' disease. Furthermore, the inheritance of the ability to taste phenylthiourea is different in the two groups (Kitchin et al., 1959). Clinically confusion still exists. In one large retrospective study, over 20 per cent of

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patients with hyperthyroidism originally though due to autonomously functioning thyroid adenomata were found to have been diagnosed erroneously (Borner, 1971). This correlates well with the study of iodine-induced hyperthyroidism in Tasmania where one or more discrete autonomous nodules were found in 17 per cent of patients, one of whom had detectable LA TS (Vidor et 01., 1973). Other LATS-positive patients with toxic nodular goiter have been described (Lamberg et 01., 1969a). Although there appears to be a reasonable epidemiological, histological and genetic foundation for separating Graves' disease from Plummer's disease, there is a significant overlap between the two diseases. UNUSUAL CAUSES OF HYPERTHYROIDISM

Subacute Thyroiditis Subacute thyroiditis may cause symptoms of hyperthyroidism, but they are often overshadowed by fever and tenderness of the thyroid. Serum T 4 is elevated; radioactive iodine uptake is low; thyroid antibodies are usually absent (Bastenie, 1972). This hyperthyroid phase usually lasts a few days to a few weeks, followed by transient hypothyroidism, then recovery.

Thyroid Carcinoma There is no substantial association between Graves' disease and thyroid carcinoma (Crile, 1936). Hyperfunctioning nodules producing hyperthyroidism are only rarely malignant (Johnson et 01., 1955). Differentiated thyroid carcinomas may cause hyperthyroidism when there is a large functional mass of metastatic tissue (Hunt et 01., 1960; Federman, 1964). Hyperthyroidism truly attributable to hyperfunctioning of the primary carcinoma itself has been reported (Sussman et 01., 1968; Ghose et 01.,1971).

Struma Ouarii Benign cystic teratomas in ovarian dermoid cysts may he composed of any combination of well differentiated ectodermal, mesodermal and endodermal elements. When the majority of tissue consists of thyroidal elements, the term struma ovarii is used. In two large series (Smith, 1946; Kempers et 01., 1970), between 10 and 25 per cent of patients with these tumors may present with hyperthyroidism which is due to hyperfunctioning adenomatous tissue. Nodular cervical goiter is commonly found in many of these patients. It may require scanning of thyroid and pelvis to determine whether the cervical or ovarian struma is responsible for the hyperthyroidism (Brown, 1973). The typical picture of diffuse goiter with exophthalmos may be seen in patients with struma ovarii as well (Judd and Buie, 1962).

Pituitary Tumors Hyperthyroidism has been described in patients with chromophobe adenomas with or without the .associated clinical findings of acromegaly (Werner and Stuart, 1958; Hamwi et al., 1960). These patients are distinct from the usual acromegalic whose hypermetabolism is due to the effects of growth hormone; several had elevated circulating levels of TSH on bioassay (Jailer and Holub, 1%0; Lamberg et al., 1969b). The stimulator secreted by the pituitary tumors is immunologically identical to normal human TSH (Hamilton et al., 1970; Faglia et al., 1972). Some of these patients have had exophthalmos resembling that seen in Graves disease. In addition, Kumahara, and his co-workers (1965) have described a thyroid stimulating substance in the pituitary of patients with typical Graves' disease without pituitary tumors which is distinct from TSH.

Trophoblastic Tumors Increased thyroid function without clinical hyperthyroidism has been reported in thirty seven patients with trophoblastic tumors (Odell et 01., 1963; Galton et 01., 1971).

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Clinical hyperthyroidism has been reported in eight patients with hydatidiform mole and in five with choriocarcinoma (Hershman, 1972). The serum of these patients contained high levels of a thyroid stimulator. Characterization of this stimulator, 'molar' thyrotropin, showed that it had a longer duration of action than pituitary TSH but shorter action than LA TS. The thyrotropin extracted from the molar tissue differed immunologically from human pituitary TSH and from a smaller chorionic TSH extracted from normal placentas (Hershman et al., 1970). Recent studies show that the molar thyrotropin is identical to human chorionic gonadotropin (Kenimer and Hershman, 1974). Secretion of large amounts of this material by hydatidiform moles may cause severe hyperthyroidism (Hershman and Higgins, 1971). Removal of the mole or effective chemotherapy of the choriocarcinoma rapidly reverses the hyperthyroidism.

Miscellaneous Tumors Hyperthyroidism has been found in patients with coexisting cancers (DeGennes et al., 1962; Liechty et al., 1963). The mortality from leukemia in patients with hyperthyroidism is 50 per cent higher than that for the general United States population (Saenger et al., 1968). There is little convincing evidence, however, that there is a causal relationship between hyperthyroidism and non-trophoblastic tumors.

Exogenous Thyroid Administration Administration of excessive doses of thyroid hormone, either prescribed by physicians (thyrotoxicosis medicamentosa) or taken surreptitiously by patients (thyrotoxicosis factilia), may result in all of the signs and symptoms of hyperthyroidism. The factitious illness is part of an underlying psychiatric disturbance; confession of self medication is often unobtainable (Gorman et al., 1969). Despite elevated BMR, radioactive iodine uptake is suppressed. Patients taking medication containing T 4 have elevated levels, and those taking T J have very low levels of T 4 (Rose et al., 1969). Individual tolerance is variable. Nothaft (1912) reported one man who over a few weeks took 1000 5 grain tablets of desiccated thyroid. He developed goiter, exophthalmos, tremor, sweating, wasting and glycosuria, all of which took 10 months to clear. Usually the hyperthyroidism disappears when the medication is discontinued. Many patients have been reported who have developed the typical features of hyperthyroid. ism which have not remitted when thyroid was stopped (Bruun, 1945; Lous, 1945). Ingestion of sausage made from thyroid glands has also been reported responsible for a subsequent epidemic of Graves' disease (quoted by Dyrnling and Becker, 1967). The mechanism whereby ingestion of thyroid may result in lasting hyperthyroidism long after blood concentrations of thyroid hormone should have returned to normal is unknown.

Iodine Induced Hyperthyroidism In 1821, Coindet described symptoms of hyperthyroidism occurring during administration of iodine to goitrous patients (Greer, 1973). Iodine-induced hyperthyroidism appears. almost exclusively in patients with some underlying thyroid abnormality usually manifest by goiter (Vagenakis et al., 1972). There is no relationship to the amount of iodine ingested (Crotti, 1938). Symptoms usually occur 2-3 weeks after the start of medication and grow worse as long as it is continued. Before the advent of effective treatment of hyperthyroidism, it would take months or years for complete regression of symptoms (Sattler, 1952). Exophthalmos, LATS titers and diffuse hyperplasia of the thyroid have been described only rarely; the clinical picture is more consistent with Plummer's disease than with Graves' disease (Vidor et al., 1973). In the absence of feedback control by the hypothalamicpituitary vaxis, iodine concentration may be the major determinant of thyroidal activity in euthyroid patients with nodular goiters containing autonomous thyroid tissue. Provision of more substrate

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for formation of thyroid hormone may be the mechanism whereby hyperthyroidism occurs with iodine ingestion. Neonatal Hyperthyroidism

Most cases of thyrotoxicosis in the newborns of hyperthyroid women are thought to be caused by the transplacental transfer of LATS (Rosenberg et al., 1963). ETIOLOGY OF GRAVES' DISEASE GENERAL

The cause of Graves' disease is unknown. Few epidemiological studies have attempted to survey the incidence of Graves' disease and associated demographic features in the general population (Meulengracht, 1947; Maruchi et al., 1969; Furszyfer et al., 1970). A number of factors have been investigated in selected clinic populations. Because of bias in the selection of patients, it is unclear whether these factors playa causal role or only make the disease clinically manifest. These factors include heredity, sex, psychologic stress, an infectious agent, and immune mechanisms (Hershman, 1967). HEREDITY

There is evidence that Graves' disease is an inherited abnormality. There are numerous families who have two or more members with the disease (Bartels, 1941; Martin and Fisher, 1945) or markers of its presence (Wall et al., 1969). SEX

Graves' disease is two to eight times more common in women (JolI, 1951). The greatest sex difference occurs between the ages of puberty and menopause (Werner, 1973), suggesting that other endocrine glands may influence the expression of Graves' disease. However, there is still a four-fold increase in the incidence of the disease in female children aged 5-15 (Helmholz, 1926). STRESS

Psychological stress as a cause of hyperthyroidism was suggested by Charcot and Trousseau, who believed the disorder to be a neurosis of the vegetative nervous system (quoted by Sattler, 1952). The number of individuals reporting psychic trauma with subsequent development of hyperthyroidism varies with the diligence of the questioner. It is probable that the majority of patients with Graves' disease report no such episodes. Intercurrent psychological stress may exacerbate the hyperthyroidism and possibly the ophthalmopathy of Graves' disease. Relief of anxiety may permit remission but does not cure the disorder. Stress in the predisposed host probably uncovers and exacerbates the disease but does not cause it. Since stress may acutely raise circulating concentrations of adrenal steroids, their subsequent suppressive effects on the immune surveillance system may be the mechanism whereby psychological stress may promote the clinical expression of Graves' disease. Graves' disease has been found coincidentally in patients with Cushing's syndrome (Lamberg, 1964) and during the prolonged administration of steroids (Brown and Lowmann, 1%4). INFECTION

The onset of Graves' disease may follow an acute infection of almost any variety (Alexander et al., 1%8). Typhoid fever, rheumatic fever, streptococcal' infections, influenza, tuberculosis, syphilis, and aspergillosis have all been reported in patients who subsequently developed Graves' disease. In the days before antibiotics, postmortem

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examination often revealed the organisms in the thyroid along with the typical histological changes of hyperthyroidism. Intercurrent infection often precipitates an alarming increase in the severity of symptoms of hyperthyroidism. Sudden increases in the number of patients with Graves' disease have been described (Iverson, 1948; Mculengracht, 1949; Clements, 1954). Although variou s reasons for these 'cpidemics' were offered, the possible involvement of an infectious agent cannot be ruled out (Greenwald, 1966). PITUITARY FACTORS

The discovery of a thyroid stimulator in the pituitary (TSH) provided a potential explanation for the development of Graves' disease. TSH can cause hyperthyroidism when given chronically. However, with development of sensitive radioirnmunoassays for TSH, the vast majority of patients with Graves' disease were found to have undetectable serum levels (Odell et al., 1967). Also, the pituitary thyrotropes appear suppressed histologically (Murray and Ezrin, 1966). Furthermore, Graves' disease has been reported in patients with well documented panhypopituitarism (Fajans, 1958; Werner et al., 1959). However, Kumahara and his coworkers (1965) have reported the isolation of a thyroid stimulator from the pituitary glands of four patients dying with hyperthyroidism that appeared to be distinct from TSH or LATS. INTRINSIC FACTORS

It has been suggested that Graves' disease represents some intrinsic defect of thyroid autoregulation (Chopra et al., 1970; Ingbar, 1972). To date, however, there is no definitive evidence to support this concept. There is no quantitative difference between thyroid cells from patients with Graves' disease and normal cells in their cytoplasmic binding of TSH or the response of the second messenger cyclic-AMP adenyl cyclase system (Orgiazzi et al., 1974). AUTOIMMUNITY

There is increasing evidence that Graves' disease, like Hashimoto's thyroiditis, is an autoimmune disorder. Lymphocytic infiltration of the hyperactive thyroid gland, generalized lymphadenopathy,lymphocytosis, and splenic and thymic hyperplasia have long been recognized in Graves' disease (Sattler, 1952). The finding of circulating immunoglobulins such as LATS (Adams and Kennedy, 1971), and human thyroid stimulator (Onaya et al., 1973) in the serum, and the presence of immunoglobulins, E, M, and G and complement in the thyroid follicular basement membranes (Werner et al., 1972) of patients with diffuse hyperplasia are further evidence of immune mechanisms in the pathogenesis of Graves' disease. LA TS and Other Humoral Factors

LATS, a 7S gamma globulin of IgG class, stimulates .rno use, rat , guinea pig, rabbit, and bovine thyroids (McKenzie, 1972). Indirect evidence that it has a similar effect on the hum an thyroid was demonstrated by infusing plasma from patients with Graves' disease into normal volunteers (Arnaud et al., 1965). Transfer of LATS across the placenta may induce neonatal 'Gra ves' disease (Rosenberg et al., 1963). Serum titers of LA TS ultimately tend to fall following surgery or radioablation of the thyroid gland (Bayliss, 1971). Although LATS is a thyroid stimulator, it can be found in only 50-80 per cent of active cases of Graves' disease (Carniero et al., 1966; Solomon and Chopra, 1972). Conversely, it may be present in high titers in the sera of Graves' patients in the absence of hyperthyroidism (Liddle et al., 1965; Chopra and Solomon, 1970), and in the sera of euthyroid relatives of patients with Graves ' dis ease (Wall et 01., 1%9). Thus, although some feel that its production is the cause of Graves' disease (McKenzie, 1972), others believe it is an epiphenomenon (Hetzel, 1970; Solomon and Chopra, 1972; Volpe et al., 1972).

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Selective absorption in the manner of an antibody-antigen complex and biological inactivation of LATS (but not TSH), by homogenates and microsomal fractions of human thyroid tissue, has been shown (BealI and Solomon, 1966; Dorrington et al., 1966; Benhamou-Glynn et al., 1969). Thyroid stimulation by LATS is not necessarily accompanied by inactivation of LA TS nor is its inactivation in vitro due to the same binding which precedes thyroid stimulation (Shishiba et al., 1972). LATScan be eluted from thyroid homogenates by acid treatment under conditions known to dissociate immune complexes (Benharnou-Glynn et al., 1969). It has been postulated that lymphocytes make LATS in response to some antigen related to the plasma membrane of the human thyroid (BealI et al., 1971). Stimulation of the lymphocytes of patients with Graves' disease by phytohemagglutinin resulted in LA TS activity in the media and incorporation of "Cvamino acids into the IgG fraction (McKenzie, 1965; Miyai, 1967). Because of this finding of a circulating thyroid stimulating gamma globulin folIowing phytohemagglutinin-induced blast transformation of cultured lymphocytes from patients with Graves' disease, an attempt was made to find a more specific stimulus for LA TS production in vivo. Immunization of animals with crude thyroid extracts or purified thyroglobulin has resulted in the experimental production of autoimmune thyroiditis in the dog, rabbit, and guinea pig (Terplan et al., 1960). Human thyroid extracts have produced thyroiditis in monkeys (Andrada et al., 1968) and in baboons (BealI et al., 1969). Circulating immunoglobulins with thyroid stimulating activity have been produced by immunization of rabbits with thyroid extracts or microsomal fractions of thyroid from humans or rabbits (Pinchera et al., 1966; BealI and Solomon, 1968; McKenzie, 1968). Immunization of guinea pigs has resulted in the development of thyroidal autonomy as measured by suppression of TSH response of TRH (Geffner, 1974).

Cell Mediated Immunity Graves' disease may represent a defect in celI mediated immune response, the appearance of humoral factors, such as LATS being a secondary phenomenon. Thymic enlargement with hyperplasia of the thymic germinal centers has been well recognized (Michie et al., 1967). Halstead (1914) carried out thymectomy for the treatment of thyrotoxicosis with a 30 per cent success rate. Remission of myasthenia gravis and hyperthyroidism has been described folIowing thymectomy in one patient (DeGroot et al., 1967) but not in another (Van Herle and Chopra, 1971). Attempts to directly transform lymphocytes by exposing them to thyroid tissue extracts have given inconsistent results. DeGroot and Jaksina (1969) were unable to demonstrate blast transformation by incubation of peripheral blood lymphocytes from patients with Graves' disease and Hashimoto's thyroiditis with thyroid gland microsomal fraction or supernatant. Ehrenfeld et al. (1971) showed specific in vitro stimulation of peripheral lymphocytes in his patients with Hashimoto's thyroiditis using human thyroglobulin and thyroid gland extracts. Volpe and his co-workers (Edmonds et al., 1970), incubating lymphocytes of hyperthyroid patients in an isolated bovine thyroid cell culture bioassay, were able to demonstrate stimulation of the system which could be suppressed in the presence of anti-human IgG. Phytohemagglutinin did not increase this effect. Patients with untreated Graves' disease and Hashimoto's thyroiditis have a significant increase in thymic-dependent lymphocytes but not in the B -cell lymphocytes associated with humoral immunity as measured by rosette formation (Farid et al., 1~73). Leukocytes from patients with Graves' disease and Hashimoto's thyroiditis also contain lymphocytes which apparently produce migration inhibition factor (MIF), a low molecular weight glycoprotein. In the presence of thyroid antigen, MIF inhibits the migration of leukocytes from patients with Graves' disease (Lamki et al., 1972; Mahieu and Winand, 1972). The mechanism whereby cell mediated immunity is involved in the pathogenesis of Graves' disease is purely speculative. It has been suggested that the disease is inherited as a genetic defect in immune surveillance (Volpe et al., 1972; Werner et al., 1972). A predisposed individual would be unable to dispose of a specific lymphocyte produced

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by mutation which could then give rise to a 'forbidden clone' of celIs. This could directly stimulate the thyroid or stimulate B -cells to produce and release LATS within the thyroid with varying spill-over into the circulation. Environmental factors may be fitted into the framework of this theory. Thus, feeding of thyroid to predisposed individuals might provide the antigenic stimulus which could give rise to a 'forbidden clone'. Epidemics of Graves' disease may be explained if One assumes that an infectious agent might cause an acquired depression of the immune surveillance mechanism in a patient who otherwise has not inherited the defect. The appearance of Graves' disease during immunosuppressive therapy with steroids (Brown and Lowmann, 1967) and cyclophosphamide (McDougalI et al., 1971) may be explained by the same mechanism. THE NATURAL HISTORY OF HYPERTHYROIDISM The course of hyperthyroidism is variable. In addition to the usual symptoms of hyperthyroidism such as weakness, tachycardia, tremor, sweating, nervousness, goiter, and ocular manifestations, carefui questioning often brings out more subtle findings which existed for some time before the onset of these symptoms. At times, the initial symptoms are those of cardiac failure, psychic disturbance or muscular disorder which entirely overshadow the other symptoms. With present therapy, knowledge of the natural history of the disease has been limited by the control of some features at an early stage. In the older literature, it is often impossible to differentiate the type of hyperthyroidism that is being discussed because of confusion in etiology and nomenclature (Plummer, 1913; Barker, 1924; Dunhill, 1926; Fitz, 1926; Eason, 1927; JolI, 1940; Sattler, 1952). The disease may run a natural course so that, if the patient does not die of the hypermetabolism or its complications, there wiII be a tendency to resolution without treatment. Sattler (1952) estimated that 8-12 per cent of patients died of hyperthyroidism before the routine use of surgery in the twentieth century. Graves' disease may result in myxedema spontaneously. Woods et at. (1973) have recently reported that decreased thyroid reserve and frank hypothyroidism may occur as long as 25 years following treatment with antithyroid drugs alone. If the disease remains uncontrolled, a sudden severe exacerbation may develop with or without an intercurrent precipitating cause (McArthur et al., 1947). Before the introduction of iodine and antithyroid drugs, operation on the thyroid led to classic thyroid crisis or storm and was usualIy the cause of death in hyperthyroidism. In typical Graves' disease, there tended to be three main methods of progression: acute or fulminating (thyroid storm), subacute with remission and relapse, and chronic hyperthyroidism. The disease might begin acutely and present with severe symptoms approaching storm. Usually some precipitating event such as infection could be identified. If the patient survived, the remission might be equally dramatic with complete resolution of symptoms. About 25 per cent of milder cases might have a self-limited course with remission occurring in months to years (Sattler, 1952). More commonly the onset is insidious and the disorder is characterized by remission and relapse with variable intensity of symptoms. The severity is variable from case to case. In a few patients, after an insidious onset, the disease appears to continue with comparatively low activity without remission or exacerbation for a number of years. After a variable amount of time, one symptom might overshadow the others. Ophthalrnopathic, cardiac and psychotic variations have been described. CLINICAL FEATURES GENERAL

Many of the clinical findings in hyperthyroidism arc related to the metabolic effects of the excessive circulating levels of thyroid hormones. The signs and symptoms of

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hyperthyroidism must be carefully differentiated from the associated ocular and cutaneous findings of Graves' disease which may be present without any evidence of hyperthyroidism. THE THYROID GLAND

The presence of a goiter is a constant finding in hyperthyroidism. Though its absence casts grave doubt upon the diagnosis, it may not be palpably enlarged in 1-3 per cent of patients with the typical picture of Graves' disease with hyperthyroidism (Means et al., 1963). Absence of palpable thyroid tissue in the neck should arouse suspicion of an extra-thyroidal source of thyroid hormone, particularly if the scan shows no accumulation of radioactive material in the neck or substernal region. In most cases of substernal goiter, thyroid tissue will still be palpable in the neck, but occasional instances of hyperfunctional substernal goiter occur, especially after the patient has already undergone thyroidectomy. Substernal goiters are seen as shadows behind the manubrium on X-ray examination. In contrast to other structures which may give rise to comparable shadows in this area, an enlarged thyroid displaces the trachea laterally. In rare cases the thyroid is present in the posterior part of the tongue, and lingual thyroid tissue causing hyperthyroidism has been reported (Snapper and Kahn, 1%7). In patients with an autonomous nodule, the hyperactive nodules are almost always easily palpable in the neck as they are usually greater than 3 em in size when symptoms of hyperthyroidism occur (Kempers et al., 1970). Sometimes, one may find the typical eye signs of Graves' disease with nodular goiter. Mild hyperthyroidism with thyroid tenderness associated with fever and elevated sedimentation rate is strongly suggestive of subacute (granulomatous) thyroiditis. A systolic or continuous bruit heard over the thyroid is indicative of thyroid hyperacitivity, but must be differentiated from transmitted cardiac murmurs and carotid bruits. Venous hums may be extinguished by pressing gently above the thyroid to occlude venous return. Although goiter may increase neck (and collar) size, it is often noticed first by friends and family rather than the patient. Patients may complain of a lump in the throat or dysphagia. Diffuse, soft cervical adenopathy may occur as part of the picture of the generalized reticuloendothelial hyperplasia of Graves' disease. INTEGUMENT

The skin is often smooth, warm and moist. The hyperdynamic vasomotor system causes sweating or flushing (Youmans, 1931). The patient feels warm and prefers a colder environment, often to the distress of the euthyroid spouse. Observation and touching of the warm, sweating, tremulous hand of the patient is a helpful diagnostic maneuver. In general, these cutaneous signs are expressions of increased heat production. Neurasthenic patients with excessive catecholamine secretion whose complaints may mimic those of hyperthyroidism generally have cool moist hands because of peripheral vasoconstriction. Changes in pigmentation may occur (Bartels et al., 1937). Hyperpigmentation may be diffuse or patchy, especially over the face. In contrast to the bronzing seen in Addison's disease, mucous membranes are rarely involved. Vitiligo is often seen in association with Graves' disease, possibly on an associated autoimmune basis (Locke, 1967). Hair tends to be fine, soft and straight. Older women complain that their hair will no longer take a 'permanent wave', and younger women that their hair increasingly frays at the ends. Temporary hair loss is common, often catastrophic, if associated with alopecia areata or autoimmune alopecia totalis in Graves' disease. Onycholysis (Plummer's nails) produces a margin from which the distal 'part of the nail separates making it difficult to clean dirt from under the nails (Bean, 1962). Pretibial myxedema is a finding unique to Graves' disease and occasionally

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Hashimoto's thyroiditis. Like the exophthalmos, it may appear independently of the hyperthyroidism (Beierwaltes, 1954). The lesions begin as reddish-brown papules most commonly on the lateral anterior aspects of the lower shins. They enlarge and converge to form irregular plaques several centimeters in diameter. Histologically they consist of dermal deposits of mucopolysaccharides. Occasionally the ankles and legs may be completely involved with non-pitting, brawny edema which is difficult to distinguish from elephantiasis. The presence of localized myxedema is better correlated with elevated LATS titers than hyperthyroidism and ophthalmopathy (Kriss et al., 1964). NERVOUS, MUSCULAR AND SKELETAL SYSTEMS

Nervousness, irritability, restlessness, insomnia, increased fatiguability, tremor and muscular weakness are common complaints. The hyperactivity is more apparent to the physician than to the patient. It is common for the hyperthyroid patient to feel overly optimistic or even euphoric, but many are irritable, react quickly and inappropriately with excessive laughter or crying spells in response to trivial stimuli. They may appear quite agitated and emotionally unstable. Loss of concentrating ability leads to loquacious conversations which rush along without logical goal. There may be great restlessness with rapidly performed, jerky movements, but unlike chorea they are purposeful and associated with a fine tremor of the hands. Cerebration may be quick. It is frequently difficult to perform simple mental tasks, and the patient may show poor judgement. There may be clear failure of insight into the problem. Frank psychosis can be precipitated in the predisposed individual. Hyperthyroidism has been implicated as a factor in the development of criminal behavior (Davis et al., 1971). Marked irritability, restlessness and insomnia may herald impending thyroid storm. In elderly individuals delirium may occur even with slight hypermetabolic features. After many years irreversible psychosis may occur (Dunlap and Moersch, 1935). Tremor is a fairly constant manifestation of hyperthyroidism. It is usually evident in the outstretched hands and is accentuated by effort. While usually fine and rapid with eight to ten vibrations per second, it may be so coarse as to suggest Parkinson's disease. Occasionally the whole body wi11 shake. The rapidity of contraction and relaxation of muscles in response to deep tendon reflexes is increased. Muscle weakness occurs quite early in the course of hyperthyroidism. Symptoms range from mild to severe weakness and muscular atrophy (Thorn and Eder, 1946). Characteristically it is the proximal girdle muscles that are most affected. Patients complain of weakness particularly when rising from a chair, climbing stairs, or combing their hair. It may be brought out by having the patient step up on a stool. More distal involvement and actual muscle atrophy occur and occasionally must be differentiated from progressive muscular atrophy (Ramsay, 1966). Myasthenia gravis may mimic hyperthyroidism" clinically with muscle weakness progressing throughout the day, bulbar palsy, and falsely positive responses to neostigmine (Weikhardt and Redmond, 1960). However, 3 to 6 per cent of patients with hyperthyroidism also have associated myasthenia gravis (Grob, 1958). There is an association between hyperthyroidism and sporadic hypokalemic periodic paralysis which is particularly evident in Japanese and Chinese (Engel, 1961) and usually found during the course of active hyperthyroidism. The attacks often disappear once the hyperthyroidism is controlled. Subachromial bursitis appears to be more common than in the general population (Skillern, 1952). Onset of muscle cramps and arthralgias during treatment should alert the clinician to the possible development of hypothyroidism as arthralgias are a common and early sign of hypothyroidism and are not associated with hyperthyroidism. Thyrotoxic acropachy with clubbing of the fingers and toes due to periosteal proliferation has been described in Graves' disease (Malkinson, 1963). Increased bone resorption in hyperthyroidism leads to demineralization. The bones of patients with long-standing disease may have decreased density on X-ray (Kranes,

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1971). Hypercalcemia occurs in some hyperthyroid patients, but it is usually mild and asymptomatic. Although the incidence of hypercalcemia was reported to be 20 per cent in one series of seventy-seven patients (Baxter and Bondy, 1966), we could not confirm this high incidence. We found only one patient with hypercalcemia in a group of seventy-one unselected consecutive hyperthyroid patients; the other seventy had normal serum calcium values. Serum calcium, if elevated, returns to normal with therapy of hyperthyroidism. If hypercalcemia persists, another basis for it is likely. THE CARDIOVASCULAR SYSTEM

The pulse rate is rapid due to supraventricular tachycardia. Atrial fibrillation, either paroxysmal or continuous, is frequent in the elderly. The apex beat is forceful with a bounding 'precordium. Cardiomegaly with the eventual development of congestive failure may occur. Cardiac output is usually increased (DeGroot et al., 1960) and circulation time is accelerated. Pulse pressure is increased with rise in systolic blood pressure (Hurxthal, 1931). Loud arterial sounds can be heard with a stethoscope over the uncompressed brachial artery. A pulmonic systolic scratch most audible on full expiration over the sternum in the second left interspace may be mistaken for pericardial rub (Means et al., 1963). The brachial arterial sounds and the pleuropericardial scratch disappear with return to euthyroidism. It is often difficult to tell if there is coexistent heart disease in the thyrotoxic patient with tachycardia, palpitations, systolic hypertension and congestive heart failure. Atrial fibrillation and congestive heart failure usually require larger than normal doses of digitalis for a beneficial response. Occasionally, dependent edema may be encountered unrelated to localized myxedema. Its occurrence does not necessarily indicate the onset of congestive failure (Means et al., 1963). THE RETICULOENDOTHELIAL AND HEMIC SYSTEMS

Relative lymphocytosis is common. Lymphadenopathy associated with thymic hyperplasia and elevated circulating concentrations of T-cell lyrnpholytes occur. The splenic tip may become palpable (Axelrod and Berman, 1951). Chronic normocytic normochromic anemia occurs in long standing hyperthyroidism, possibly because of nutritional deficiencies associated with achlorhydria and malabsorption due to diarrhea. Impaired utilization 'of iron has been found in anemic hyperthyroid patients (Rivlin and Wagner, 1969). GASTROINTESTINAL SYSTEM

Hyperthyroidism is characteristically associated with weight loss due to increased catabolism and increased gut peristalsis which causes diarrhea and occasionally leads to overt malabsorption (Siurala et al., 1966). Patients tend to compensate for this by increased food intake. Van Muller first called attention to the paradox of weight loss despite excellent appetite (quoted by Sattler, 1952). Sometimes compensation is sufficient to prevent weight loss, and especially in- peripubertal thyrotoxicosis, there may be a sudden increase in weight. If anorexia develops, weight loss may be excessive. Epigastric pain with vomiting has been described (Chapmen and Maloof, 1956). Nausea and vomiting usually occur only in severe cases. The resulting caloric deprivation and dehydration may precipitate thyroid storm. Achlorhydria is often present (Brown et al., 1941) and histamine does not stimulate gastric acid production (Dotevall et al., 1967). Production of gastric enzymes is reduced (Siurala and Lamberg, 1959). Numerous abnormalities in hepatic morphology and liver function tests have been described (Lamberg and Gordin, 1954), but clinical evidence of liver dysfunction is rare. Mild hepatomegaly, with or without associated congestive failure, may occur. Frank jaundice is extremely rare without preexisting disorders of bilirubin metabolism or hepatic dysfunction.

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GENITOURINARY SYSTEM

Aside from an increase in renal blood flow and glomerular filtration rate which may lead to mild polyuria, there are no urinary tract symptoms. Changes in menstruation are very common in adult women. Oligomenorrhea is more frequent than menometrorrhagia. The etiology of amenorrhea during hyperthyroidism is unclear. Proliferative endometria suggest a hypothalamic or pituitary disturbance with lack of release of luteinizing hormone (LH) and ovulation (Goldsmith et al., 1952). However, serum LH concentrations are higher than normal in hyperthyroid women (Akande and Hockaday, 1972). Fertility may be decreased and the incidence of miscarriage may be increased in hyperthyroid women, but this has been disputed (Burrow, 1972). Hyperthyroid men tend to be less hirsute than average and have less axillary hair (Williams, 1947). Impotence and decreased libido occur in a significant proportion of hyperthyroid men. Mild degrees of gynecomastia are occasionally seen. This may be due to the increased production of LH and elevated serum concentrations of free estradiol (E;) seen in hyperthyroidism (Chopra and Tulchinsky, 1974), or it may result from increased peripheral conversion of androstenedione to estrogens (Southern et al., 1974). DIAGNOSTIC TESTS Improvement in the methodology of thyroid function tests in the past few years has obviated the need for retrospective diagnosis based on a clinical trial of therapy. Before undertaking therapy which could result in destruction of the thyroid, the diagnosis should be documented by laboratory tests. In addition, the tests serve as a reference to evaluate the effectiveness of therapy. " Measurement of serum thyroxine (serum T 4) by competitive protein binding or .radioimmunoassay is probably the single best test to establish the diagnosis. A measurement of the saturation of the binding globulin such as the resin uptake of triiodothyronine is useful to validate that the elevated serum T 4 is due to hyperthyroidism in which the binding globulin"is relatively saturated. In rare instances serum T 4 is normal and the concentration of triiodothyronine in serum (serum T 3) is elevated because of preferential hypersecretion of T3 , leading to Tj-induced thyrotoxicosis. Therefore, a normal serum T 4 does not exclude the diagnosis of hyperthyroidism with. certainty. Elevation of serum 1'3 is a consistent finding and is probably a more sensitive index of hyperthyroidism. Measurements of thyroid uptake of radioiodine are less useful and should be reserved for special purposes. The thyroid uptake is necessary if the therapeutic dose of radioactive iodine is calculated on the basis of the uptake or biological half-life of the radioiodine. Radioiodine scans of the thyroid are necessary to establish the diagnosis of hyperfunctioning nodules and to locate ectopic or metastatic hyperfunctioning thyroid tissue. TREATMENT OF HYPERTHYROIDISM GENERAL ASPECTS OF TREATMENT

Since the true etiology of Graves' disease is unclear, treatment cannot be directed at the cause of the disorder; instead it is aimed mainly at controlling the excessive secretion of thyroid hormone. There is no preventive therapy except avoidance of high intake of iodine in patients with goiter. Treatment with long-term antithyroid medications temporarily controls the overproduction of thyroid hormone until the disease undergoes spontaneous remission. The other modes of therapy, thyroidectomy and radioactive iodine, simply attempt to remove a portion of the gland and leave enough tissue to produce a normal amount of thyroid hormone. That no therapy is universally acceptable reflects the fact that all have significant risks.

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SURGERY

General Indications The role of surgery in the management of hyperthyroidism has decreased markedly in the past 20 years. Less than 10 per cent of patients with Graves' disease are now treated by subtotal thyroidectomy at one large clinic which specialized in this form of therapy (Sanfelippo et al., 1973). With increasing medical management there is now less opportunity for surgeons to become proficient in thyroid surgery. This may have the effect of diminishing the quality of surgery, increasing its complications, and making medical management even more attractive (Black, 1972). Despite advances in the noninvasive management by drugs and radioactive iodine, surgery remains a safe and effective alternative treatment when carried out by an experienced surgeon (Wool, 1970). The indications for surgery will vary according to the clinical status of the patient and the decision of the patient's physicians. Few generalizations can be made that will not be contradicted by others. There are some clinical situations where surgery should be strongly considered. In the patient with hypersensitivity to antithyroid drugs or a patient in whom a trial of 1-2 years of antithyroid medication has failed to induce a remission, surgery represents a real alternative to radioactive iodine. A thyroidectomy scar is sometimes a reasonable cosmetic improvement for a patient who has had a huge goiter for a long period of time. Surgery may be elected out of fear of radiation. This is particularly true in prepubertal children for whom radiation may be a greater hazard. The older patient with a large multinodular goiter may prefer surgery since radioactive iodine may control the hyperthyroidism without appreciably reducing the size of the thyroid gland. Surgery is the treatment of choice if there are symptoms of compression. There are clinical situations where surgery is contraindicated. In the elderly debilitated patient with significant cardiac, pulmonary, cerebrovascular, hepatic or renal complications, surgery may be extremely hazardous. In patients who earn "their living by using their voices, post-surgical vocal cord paralysis may be catastrophic. Thyroidectomy should be avoided in patients who have had a previous thyroidectomy because the complications are much greater with recurrent surgery. Preoperative Considerations All patients should be rendered euthyroid prior to the surgical procedure by the use of antithyroid drugs, such as propylthiouracil and methimazole, and inorganic iodine. The aims are to decrease circulating concentrations of thyroid hormones and to decrease the vascularity of the gland. Iodine decreases the size and vascularity of the thyroid gland when used in conjunction with the thiocarbamides. This decreases blood loss during surgery and makes the mechanics of the operation easier (Rawson et al., 1945). Preparation for surgery is usually accomplished by a 2-4 month course of antithyroid drug with the addition of iodine during the final 1-2 weeks. Ideally, the catabolism of hyperthyroidism is reversed; the patient should regain his weight and strength, and have no resting tachycardia before surgery. Beta blocking agents have been used alone in the preoperative period (Pimstone et al., 1969; Lee et al., 1973; Michie et al., 1974), but this seems unwise if the patient can wait the several weeks necessary for the salutary effects of the drugs to occur (Riddle and Schwartz, 1970). Addition- of propranolol to the ordinary drug program provides faster relief of symptoms. Methods of Operation Bilateral subtotal resection is the surgical procedure of choice in diffuse hyperplasia. Where a single adenoma is causing hyperthyroidism, it may be removed by enucleation alone. Details of the actual operative procedure have been reviewed in standard surgical texts (Schwartz, 1969; Harrison, 1972). As generally practiced, the posterior portion of the capsule is left along with 2-4 g of thyroid tissue from each lobe (Taylor and Painter, 1962; Plested and Pollock, 1967). It is important to recognize the difference

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between true autonomous adenomata of the thyroid and 'hot' nodules belonging to toxic nodular goiter, since in the latter case subtotal thyroidectomy rather than nodulectomy must be performed. Total thyroidectomy has no place in the treatment of hypermetabolism of thyrotoxicosis (Heimann, 1969). COMPLICATIONS OF THYROIDECTOMY

Mortality Before the advent of the preoperative drug therapy to obtain euthyroidism, the mortality rates for multiple stage and partial or hemithyroidectomies for hyperthyroidism approached 10 per cent. The preoperative use of iodine decreased mortality rates of about 1-3 per cent between 1930 and 1942 (Hurxthal, 1945). With .the addition of antithyroid drugs, mortality for subtotal thyroidectomy has decreased to less than 0.2 per cent in the period 1941 to 1960 (Heimann, 1969).

Early Postoperative Complications Early postoperative complications include local edema and collections of blood which may require local evacuation and occasionally reexploration of the wound. Respiratory obstruction due to hematoma may require a tracheostomy. Wound edema was reported in 20 per cent of patients in one series (Green and Wilson, 1964). Post-operative thyroid crisis is now extremely rare and should not occur if the patient is euthyroid prior to surgery (Hershman, 1966). Wound infection, atelectasis, pneumonia, and pulmonary embolus have to be considered along with the morbidity which is peculiar to thyroid surgery (McDougall and Greig, 1971). Keloid formation or an ugly scar is an important post-operative complication in the young female. Rarely, damage to the cervical sympathetic nerves may result in unilateral ptosis, enophthalmos, and miosis.

Vocal Cord Paralysis Temporary paralysis of one or both vocal cords due to surgical trauma of the recurrent laryngeal nerves, edema and/or ecchymosis in the tissues of the neck is seen in about 10 per cent of patients (Bloomstedt, 1959). Unilateral paresis with hoarseness may be treated by rest and reassurance that a good speaking voice will return in several weeks to months. Bilateral paralysis may 'result in aphonia if the cords do not approximate. If they do, the speaking voice may be satisfactory, but there may be dyspnea and stridor. If permanent injury results in respiratory crowing and air hunger with exertion, tracheostomy should be considered (Hawe and Lothian, 1960). Resuturing of the nerves has not been successful. Figures for objective persistent paralysis vary from 1-15 per cent in large series (Ranke and Hollinger, 1955; Riddell, ]960; Blackburn and Salmon, 196]; Gould et al., ]965; Cassidy, 1962; Roy et al., ]967). However, 30 per cent of patients notice an alteration in voice (Borgstrom, ]956; Painter, 1960).

Hypoparathyroidism Transient hypocalcemic tetany occurs within a few days of operation. Removal of excessive amounts of parathyroid tissue or damage to the end-arteries supplying the glands may result in permanent hypoparathyroidism manifested by numbness and tingling of the hands, feet, lips and sides of the face, anxiety and depression, carpopedal spasm, and Trousseau's and Chvostek's signs. Without treatment there may be progression to laryngeal spasm causing respiratory distress , anoxemia, delirium, generalized convulsions, and death. In many patients the symptoms of tetany disappear after a few days even though the serum calcium concentration remains persistently low. Long-term complications of untreated hypoparathyroidism include impaired intellec-

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tual ability, and cataracts (Lachmann, 1941). The frequency of tetany was reported to be between 0.3 and 4 per cent in six series; hypocalcemia occurred in 1-6 per cent of adults (Wade, 1960) and 2-7 per cent of children (Hayles et al., 1959; Bacon and Lowrey, 1965). Permanent hypocalcemia due to hypoparathyroidism occurs in 2-4 per cent of operated patients (Hurxthal, 1945; Cassidy, 1963; Wade, 1965; Heimann, 1%9). The concept of partial parathyroid insufficiency following surgery or radioactive iodine therapy has been debated in the literature (Jones and Fourman, 1963; Michie et al., 1966). Its prevalence and clinical significance are unknown. Its existence is based on the demonstration of delay in recovery from hypocalcemia induced by infusion of EDTA. Presumably damage to the parathyroid glands occurred during surgery leaving sufficient function to maintain a serum calcium in the normal range, but not sufficient reserve to maintain homeostasis during times of stress. This complication occurs in 24 per cent of patients with thyroidectomy (Jones and Fourman, 1963). Its contribution to post-operative anxiety, depression and other non-specific complaints is unclear (Michie et al., 1966; Fourman et al., 1967). Frank tetany must be treated promptly with parenteral calcium. A 10-20% solution of calcium gluconate in a dose of 10-20 ml may be given slowly, or 30-60 ml may be given in 1000 ml of a 5% solution of glucose in water. The dose may be repeated as necessary to maintain the serum calcium in the low normal range, about 8.0-9.0 mg/loo ml. Injectable parathyroid hormone is to be avoided because there is no reliable preparation, daily injections are required, and repeated doses result in allergic reactions. Vitamin D is given for the long-term control of calcium metabolism if . hypoparathyroidism is permanent. The present commercially available preparations of ergocalciferol (Vitamin D2 ) , cholecalciferol (Vitamin D3) and dihydrotachysterol are useless for the immediate treatment of tetany since it takes days to weeks before the response. Once tetany is controlled, chronic therapy should include large amounts of oral calcium (about 1-2 g of calcium/day) together with ergocalciferol, 50,000 units per day or dihydrotachysterol, 0.8-2.4 mg/day. The full effect of a change in the dose of vitamin D may not be seen for a month or so, and acute intoxication with hypercalcemia is difficult to predict. Faster acting derivatives such as 1.25 dihydroxycholecalciferol are not yet commercially' available. After one to two months, if serum calcium is normal, treatment should be stopped and serum calcium followed to see if hypoparathyroidism is permanent. Many patients do not require additional calcium supplementation. The advantage of maintaining calcium concentrations at slightly lower levels to stimulate residual parathyroid tissue or prevent inadvertent vitamin D toxicity must be balanced against the risk of the long term complications. During pregnancy and lactation, serum calcium concentration should be checked more frequently. Recurrence

Recurrence rates in large series range from about 3-8 per cent in adults (Heimann, 1969; Green and Wilson, 1964) to 18 per cent in children (Hayles et al., 1959). Recurrence rates may be related to the size of the thyroid remnant. The striking feature of recurrent hyperthyroidism following surgery is that it may occur over a wide time interval unlike treatment with anti-thyroid drugs where 70 per cent of relapses occur within a year (Hershman et al., 1966; Hausmann, 1972). McLarty (1969) found that half of his ninety cases of recurrent hyperthyroidism occurred more than 5 years after surgery. Recurrent hyperthyroidism should not be treated by a second operation since rate of the complications is much higher than those following the first thyroidectomy. Post -operative Hypothyroidism

Transient hypothyroidism may be seen following surgical treatment of hyperthyroidism. The etiology is unclear. If symptomatic it can be treated, and treatment stopped after 1 year to assess whether or not it is permanent. Hypothyroidism occurring 6 months to 1 year after therapy is permanent with rare exceptions.

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The incidence of hypothyroidism reported in the literature is quite variable. The variation in surgical results partially reflects differences in surgical techniques, but usually depends on the reason for thyroidectomy, the length of follow-up, the type of patients selected for surgical treatment, the number of patients available for follow-up, and whether surgeons or internists have evaluated the patient (Goldman, 1949; McDougall and Greig, 1971). Only a few of the numerous papers published on the subject have dealt adequately with this problem. Where long-term evaluation has been carried out, the incidence of post-operative hypothyroidism has been reported to be 5-43 per cent (Hershman, 1966; Nofal et al., 1966). Other surgical series reveal that with long-term follow-up about 50 per cent of the patients will be receiving thyroid medication even though the incidence of proven hypothyroidism is lower (Beahrs and Sakulsky, 1968; Sawyers et al., 1972). The incidence of hypothyroidism appears to increase slowly with time. It has been stated that the incidence of this complication is less than that seen following radioactive iodine. To a certain extent this may be due to patient selection, as the patients treated surgically tended to be younger and to have more nodular goiters-that is to be relatively more resistant to developing hypothyroidism after whatever form of treatment is elected (Bronsky et al., 1968). Iatrogenic hypothyroidism following treatment for hyperthyroidism is a public health problem of great magnitude. In the United States where the incidence of hyperthyroidism is 20 per 100,000 people, we have calculated that treatment of the disease will result in a pool of about a quarter of a million patients with hypothyroidism in the United States by 1980 (Geffner, 1972). There appears to be an association between the presence of thyroid auto-antibodies (Hjort, 1963; Irvine and Stewart, 1967) or significant lymphoid infiltration of the gland and the subsequent development of hypothyroidism (Green and Wilson, 1964; Beahrs and Sakulsky, 1968). Because of this, it is probably wise to treat such patients with thyroid replacement soon after surgery.

,

IMMUNOSUPPRESSIVE THERAPY

If Graves' disease were due to autoimmunity, therapy with agents that suppress the immune response might result in amelioration of the disease. The efficacious use of homologous serum in hyperthyroidism was reported by Bebe in 1900. Werner and Platrnan (1965) treated five mildly to' moderately hyperthyroid patients with prednisone for 1.5 to 2.5 months. They noted a decrease in goiter and a sustained remission in three of the patients. During treatment there was an increase in nervousness and tachycardia. The acute administration of prednisone is known to increase BMR (Werner, 1950).Side effects included cushingoid features, slight growth of facial hair, euphoria and severe leg weakness. All patients were thought to be euthyroid at the end of therapy, and three patients remained euthyroid for several months. The one patient with elevated LATS had progressive fall in titer. The use of prednisone in combination with radioactive iodine or anti-thyroid drugs has been suggested without much clinical data to prove its worth (Taka and Banos, 1971). The appearance of hyperthyroidism during corticosteroid therapy has been described in euthyroid patients with Hashimoto's thyroiditis (Singer, 1966), and in patients with no known thyroid disease (Brown and Lowman, 1964), as well as in patients given other immunosuppressive drugs (McDougall et al., 1971). It is probably wise to avoid giving corticosteroids except as indicated for control of the ophthalmopathy.

SUMMARY The etiology of Graves' disease remains unknown. The leading current theory considers it to be an hereditary autoimmune disorder of both humoral and cell-mediated immunity with production of abnormal thyroid stimulators. Uncommon causes of hyperthyroidism include autonomous thyroid nodules, administration of iodine to

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patients with nodular goiter, subacute thyroiditis, trophoblastic tumors producing molar thyrctropin.large differentiated thyroid carcinomas, struma ovarii, pituitary tumors producing thyrotropin, and taking excessive amounts of thyroid medication. The clinical features of hyperthyroidism are described. Subtotal thyroidectomy is effective treatment, but has the disadvantage of significant complications which include hypothyroidism, rare mortality, hypoparathyroidism, paralysis of vocal cords and altered voice, recurrence of hyperthyroidism, rare thyroid crisis and morbidity from the wound. ACKNOWLEDG EMENT Supported in part by Veterans Administration Research Grant 3590 and USPHS Grant HD-7181.

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