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

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 OFORAVES' DISEASE, CLINICAL FEATURES,

GENERAL ASPECTS OF TREATMENT

DAVID LEWIS GEFFNER and JEROME M. HERSHMANEndocrine 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 fromthe action of excessive concentrations of circulating thyroid hormone on peripheraltissues. Although the clinical symptoms of hyperthyroidism have been known sinceantiquity, they were not related to overacitivity of the thyroid gland until the late 19thcentury (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'sdisease: exophthalmic goiter)

II. Toxic nodular goiter (Plummer's disease)A. Toxic uninodular goiterB. 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 goiterVII. Struma ovarii

VIII. Paraneoplastic syndromesA. Pituitary tumorsB. Trophoblastic tumorsC. 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 isdue to Graves' disease. Graves' disease is characterized by a diffusely hyperplasticgoiter often associated with characteristic eye signs, and sometimes associated withpretibial dermopathy and other extrathyroidal manifestations. Fifty to eighty per centof patients with Graves' disease have a circulating marker called the long-acting thyroidstimulator (LATS) (Carniero et al., 1966; Solomon and Chopra, 1972). The term Graves'disease also includes patients showing the extrathyroidal manifestations withouthyperthyroidism. Under prolonged observation, some of these patients develophyperthyroidism.

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 infiltrativedermopathy seen over the shins and the exophthalmos is unique to Graves' disease.Typically, the increased thyroid hormone production is associated with depressed

402 DAVID LEWIS GEFFNER and JEROME M. HERSHMAN

serum concentration of pituitary thyroid stimulating hormone (TSH) which fails to risefollowing thyrotropin releasing hormone (TRH) stimulation. This may not be dueentirely to the elevated serum concentrations of T3 and T4 , as some patients witheuthyroid Graves' disease also fail to respond to TRH despite presumably normalthyroid hormone production rates (Franco and Hershman, 1973; Ormston et al., 1973).

Recently, hyperthyroid patients with the typical features of Graves' disease havebeen described with elevated basal concentrations of TSH that show no response(Emerson and Utiger, 1972) or exaggerated response (Chopra et al., 1973) to TRHstimulation. In the former case a primary hypersecretion of TRH by the hypothalamushas 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 serologicalcriteria, 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/orserological evidence of Hashimoto's thyroiditis with or without the extrathyroidalmanifestations 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 differentmanifestations of the same disorder or represent different stages of the same disease isas yet unknown (Hamilton and Maloof, 1973). The significance of these findings will bediscussed more fully in the section on the etiology of Graves' disease.

NODULAR GOITER WITH HYPERTHYROIDISM

Plummer (1912) distinguished nodular goiter with hyperthyroidism from the diffuselyhypertrophic and hyperplastic goiter associated with exophthalmos (Graves' disease).Hyperthyroidism may be superimposed on previously existing adenomata or simplegoiter. Pathological examination of the gland reveals an irregularly enlarged goiter thatmay contain cellular, colloid, hyperplastic or cystic nodules. The typical extrathyroidalmanifestations of Graves' disease do not occur. In this type of hyperthyroidism, asingle, well-defined adenoma can cause hyperthyroidism. Histologically the noduleshows hyperplastic acini while the rest of the gland is in the resting state. Radioiodine isconcentrated in the hyperfunctioning nodule (Dobyns et al., 1949). Failure ofsuppression of radioactive iodine uptake following administration of thyroid hormoneshows that the nodule is autonomous (Sheline and McCormack, 1960). Nodules thatdemonstrate 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 thegland decreases (Cope et al., 1947). Not all hot nodules produce the clinical picture ofhyperthyroidism. The present concept is that of a spectrum of autonomousfunction inadenomata beginning with small nodules less than one centimeter in size, incapable ofproducing enough hormone to suppress the remaining thyroid tissue, and ending withlarger nodules that not only suppress function of the surrounding tissue, but give rise toclinical hyperthyroidism (Hamburger, 1972). Progression within this spectrum has beenobserved in several patients (Silverstein et al., 1967; McCormack and Sheline, 1967).

Difficulty in the diagnosis of Graves' vs Plummer's disease occurs when diffusehyperplasia is engrafted on a nodular goiter. There are also patients with the eye signsand pretibial dermopathy of Graves' disease in whom a few nodules exist in 'anotherwise diffuse goiter. Several of these patients had Hashimoto's thyroiditis(Fatourechi et al., 1971). Graves' disease with coexistent functioning nodules has alsobeen described (Charles, 1972). However the etiology of the hyperthyroidism cannot beassigned 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 verysimilar 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 differentin the two groups (Kitchin et al., 1959).

Clinically confusion still exists. In one large retrospective study, over 20 per cent of

Hyperthyroidism. 403

patients with hyperthyroidism originally though due to autonomously functioningthyroid adenomata were found to have been diagnosed erroneously (Borner, 1971). Thiscorrelates well with the study of iodine-induced hyperthyroidism in Tasmania whereone or more discrete autonomous nodules were found in 17 per cent of patients, one ofwhom had detectable LA TS (Vidor et 01., 1973). Other LATS-positive patients withtoxic nodular goiter have been described (Lamberg et 01., 1969a). Although thereappears to be a reasonable epidemiological, histological and genetic foundation forseparating Graves' disease from Plummer's disease, there is a significant overlapbetween the two diseases.

UNUSUAL CAUSES OF HYPERTHYROIDISM

Subacute Thyroiditis

Subacute thyroiditis may cause symptoms of hyperthyroidism, but they are oftenovershadowed by fever and tenderness of the thyroid. Serum T4 is elevated; radioactiveiodine uptake is low; thyroid antibodies are usually absent (Bastenie, 1972). Thishyperthyroid phase usually lasts a few days to a few weeks, followed by transienthypothyroidism, then recovery.

Thyroid Carcinoma

There is no substantial association between Graves' disease and thyroid carcinoma(Crile, 1936). Hyperfunctioning nodules producing hyperthyroidism are only rarelymalignant (Johnson et 01., 1955). Differentiated thyroid carcinomas may causehyperthyroidism when there is a large functional mass of metastatic tissue (Hunt et 01.,1960; Federman, 1964). Hyperthyroidism truly attributable to hyperfunctioning of theprimary 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 anycombination of well differentiated ectodermal, mesodermal and endodermal elements.When the majority of tissue consists of thyroidal elements, the term struma ovarii isused. In two large series (Smith, 1946; Kempers et 01., 1970), between 10 and 25 per centof patients with these tumors may present with hyperthyroidism which is due tohyperfunctioning adenomatous tissue. Nodular cervical goiter is commonly found inmany of these patients. It may require scanning of thyroid and pelvis to determinewhether the cervical or ovarian struma is responsible for the hyperthyroidism (Brown,1973). The typical picture of diffuse goiter with exophthalmos may be seen in patientswith struma ovarii as well (Judd and Buie, 1962).

Pituitary Tumors

Hyperthyroidism has been described in patients with chromophobe adenomas withor without the .associated clinical findings of acromegaly (Werner and Stuart, 1958;Hamwi et al., 1960). These patients are distinct from the usual acromegalic whosehypermetabolism is due to the effects of growth hormone; several had elevatedcirculating 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 normalhuman TSH (Hamilton et al., 1970; Faglia et al., 1972). Some of these patients have hadexophthalmos resembling that seen in Graves disease. In addition, Kumahara, and hisco-workers (1965) have described a thyroid stimulating substance in the pituitary ofpatients with typical Graves' disease without pituitary tumors which is distinct fromTSH.

Trophoblastic Tumors

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


Clinical hyperthyroidism has been reported in eight patients with hydatidiform moleand in five with choriocarcinoma (Hershman, 1972). The serum of these patientscontained high levels of a thyroid stimulator. Characterization of this stimulator,'molar' thyrotropin, showed that it had a longer duration of action than pituitary TSHbut shorter action than LATS.

The thyrotropin extracted from the molar tissue differed immunologically fromhuman pituitary TSH and from a smaller chorionic TSH extracted from normalplacentas (Hershman et al., 1970). Recent studies show that the molar thyrotropin isidentical to human chorionic gonadotropin (Kenimer and Hershman, 1974). Secretionof large amounts of this material by hydatidiform moles may cause severehyperthyroidism (Hershman and Higgins, 1971). Removal of the mole or effectivechemotherapy of the choriocarcinoma rapidly reverses the hyperthyroidism.

Miscellaneous Tumors

Hyperthyroidism has been found in patients with coexisting cancers (DeGennes etal., 1962; Liechty et al., 1963). The mortality from leukemia in patients withhyperthyroidism 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 causalrelationship between hyperthyroidism and non-trophoblastic tumors.

Exogenous Thyroid Administration

Administration of excessive doses of thyroid hormone, either prescribed byphysicians (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; confessionof self medication is often unobtainable (Gorman et al., 1969).

Despite elevated BMR, radioactive iodine uptake is suppressed. Patients takingmedication containing T4 have elevated levels, and those taking T J have very low levelsof T4 (Rose et al., 1969). Individual tolerance is variable. Nothaft (1912) reported oneman who over a few weeks took 1000 5 grain tablets of desiccated thyroid. Hedeveloped goiter, exophthalmos, tremor, sweating, wasting and glycosuria, all of whichtook 10 months to clear.

Usually the hyperthyroidism disappears when the medication is discontinued. Manypatients 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 asubsequent epidemic of Graves' disease (quoted by Dyrnling and Becker, 1967). Themechanism whereby ingestion of thyroid may result in lasting hyperthyroidism longafter blood concentrations of thyroid hormone should have returned to normal isunknown.

Iodine Induced Hyperthyroidism

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

Hyperthyroidism 405

for formation of thyroid hormone may be the mechanism whereby hyperthyroidismoccurs with iodine ingestion.

Neonatal Hyperthyroidism

Most cases of thyrotoxicosis in the newborns of hyperthyroid women are thought tobe 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 haveattempted to survey the incidence of Graves' disease and associated demographicfeatures in the general population (Meulengracht, 1947; Maruchi et al., 1969; Furszyferet 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 playacausal 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 arenumerous 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). Thegreatest 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 infemale children aged 5-15 (Helmholz, 1926).

STRESS

Psychological stress as a cause of hyperthyroidism was suggested by Charcot andTrousseau, who believed the disorder to be a neurosis of the vegetative nervous system(quoted by Sattler, 1952). The number of individuals reporting psychic trauma withsubsequent development of hyperthyroidism varies with the diligence of thequestioner. It is probable that the majority of patients with Graves' disease report nosuch episodes. Intercurrent psychological stress may exacerbate the hyperthyroidismand possibly the ophthalmopathy of Graves' disease. Relief of anxiety may permitremission but does not cure the disorder. Stress in the predisposed host probablyuncovers and exacerbates the disease but does not cause it.

Since stress may acutely raise circulating concentrations of adrenal steroids, theirsubsequent suppressive effects on the immune surveillance system may be themechanism whereby psychological stress may promote the clinical expression ofGraves' disease. Graves' disease has been found coincidentally in patients withCushing's syndrome (Lamberg, 1964) and during the prolonged administration ofsteroids (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 whosubsequently developed Graves' disease. In the days before antibiotics, postmortem

406 DAVID LEWIS GEFFNER and JEROME M. H ERSHMAN

examination often revealed the organisms in the thyroid along with the typicalhistological changes of hyperthyroidism. Intercurrent infection often precipitates analarming increase in the severity of symptoms of hyperthyroidism. Sudden increases inthe number of patients with Graves' disease have been described (Iverson, 1948;Mculengracht, 1949; Clements, 1954). Although various 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 potentialexplanation for the development of Graves' disease. TSH can cause hyperthyroidismwhen given chronically. However, with development of sensitive radioirnmunoassaysfor TSH, the vast majority of patients with Graves' disease were found to haveundetectable serum levels (Odell et al., 1967). Also, the pituitary thyrotropes appearsuppressed histologically (Murray and Ezrin, 1966). Furthermore, Graves' disease hasbeen reported in patients with well documented panhypopituitarism (Fajans, 1958;Werner et al., 1959). However, Kumahara and his coworkers (1965) have reported theisolation of a thyroid stimulator from the pituitary glands of four patients dying withhyperthyroidism that appeared to be distinct from TSH or LATS.

INTRINSIC FACTORS

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

AUTOIMMUNITY

There is increasing evidence that Graves' disease, like Hashimoto's thyroiditis, is anautoimmune disorder. Lymphocytic infiltration of the hyperactive thyroid gland,generalized lymphadenopathy,lymphocytosis, and splenic and thymic hyperplasia havelong been recognized in Graves' disease (Sattler, 1952). The finding of circulatingimmunoglobulins such as LATS (Adams and Kennedy, 1971), and human thyroidstimulator (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 mechanismsin the pathogenesis of Graves' disease.

LATS and Other Humoral Factors

LATS, a 7S gamma globulin of IgG class, stimulates .rnouse, rat , guinea pig, rabbit,and bovine thyroids (McKenzie, 1972). Indirect evidence that it has a similar effect onthe hum an thyroid was demonstrated by infusing plasma from patients with Graves'disease into normal volunteers (Arnaud et al., 1965). Transfer of LATS across theplacenta may induce neonatal 'Gra ves' disease (Rosenberg et al., 1963). Serum titers ofLATS 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 ofactive 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 theabsence of hyperthyroidism (Liddle et al., 1965; Chopra and Solomon, 1970), and in thesera of euthyroid relatives of patients with Graves ' disease (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; Volpeet al., 1972).

Hyperthyroidism 407

Selective absorption in the manner of an antibody-antigen complex and biologicalinactivation of LATS (but not TSH), by homogenates and microsomal fractions ofhuman thyroid tissue, has been shown (BealI and Solomon, 1966; Dorrington et al.,1966; Benhamou-Glynn et al., 1969). Thyroid stimulation by LATS is not necessarilyaccompanied by inactivation of LA TS nor is its inactivation in vitro due to the samebinding which precedes thyroid stimulation (Shishiba et al., 1972). LATScan be elutedfrom thyroid homogenates by acid treatment under conditions known to dissociateimmune complexes (Benharnou-Glynn et al., 1969).

It has been postulated that lymphocytes make LATS in response to some antigenrelated to the plasma membrane of the human thyroid (BealI et al., 1971). Stimulation ofthe lymphocytes of patients with Graves' disease by phytohemagglutinin resulted inLATS activity in the media and incorporation of "Cvamino acids into the IgG fraction(McKenzie, 1965; Miyai, 1967). Because of this finding of a circulating thyroidstimulating gamma globulin folIowing phytohemagglutinin-induced blast transformation of cultured lymphocytes from patients with Graves' disease, an attempt was madeto find a more specific stimulus for LATS production in vivo.

Immunization of animals with crude thyroid extracts or purified thyroglobulin hasresulted in the experimental production of autoimmune thyroiditis in the dog, rabbit,and guinea pig (Terplan et al., 1960). Human thyroid extracts have produced thyroiditisin monkeys (Andrada et al., 1968) and in baboons (BealI et al., 1969). Circulatingimmunoglobulins with thyroid stimulating activity have been produced by immunization of rabbits with thyroid extracts or microsomal fractions of thyroid from humans orrabbits (Pinchera et al., 1966; BealI and Solomon, 1968; McKenzie, 1968). Immunizationof guinea pigs has resulted in the development of thyroidal autonomy as measured bysuppression of TSH response of TRH (Geffner, 1974).

Cell Mediated Immunity

Graves' disease may represent a defect in celI mediated immune response, theappearance of humoral factors, such as LATS being a secondary phenomenon. Thymicenlargement with hyperplasia of the thymic germinal centers has been well recognized(Michie et al., 1967). Halstead (1914) carried out thymectomy for the treatment ofthyrotoxicosis with a 30 per cent success rate. Remission of myasthenia gravis andhyperthyroidism has been described folIowing thymectomy in one patient (DeGroot etal., 1967) but not in another (Van Herle and Chopra, 1971).

Attempts to directly transform lymphocytes by exposing them to thyroid tissueextracts have given inconsistent results. DeGroot and Jaksina (1969) were unable todemonstrate blast transformation by incubation of peripheral blood lymphocytes frompatients with Graves' disease and Hashimoto's thyroiditis with thyroid glandmicrosomal fraction or supernatant. Ehrenfeld et al. (1971) showed specific in vitrostimulation of peripheral lymphocytes in his patients with Hashimoto's thyroiditis usinghuman thyroglobulin and thyroid gland extracts. Volpe and his co-workers (Edmonds etal., 1970), incubating lymphocytes of hyperthyroid patients in an isolated bovinethyroid cell culture bioassay, were able to demonstrate stimulation of the system whichcould be suppressed in the presence of anti-human IgG. Phytohemagglutinin did notincrease this effect. Patients with untreated Graves' disease and Hashimoto'sthyroiditis have a significant increase in thymic-dependent lymphocytes but not in theB -cell lymphocytes associated with humoral immunity as measured by rosetteformation (Farid et al., 1~73). Leukocytes from patients with Graves' disease andHashimoto's thyroiditis also contain lymphocytes which apparently produce migrationinhibition factor (MIF), a low molecular weight glycoprotein. In the presence of thyroidantigen, 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 ofGraves' disease is purely speculative. It has been suggested that the disease is inheritedas a genetic defect in immune surveillance (Volpe et al., 1972; Werner et al., 1972). Apredisposed individual would be unable to dispose of a specific lymphocyte produced


by mutation which could then give rise to a 'forbidden clone' of celIs. This coulddirectly stimulate the thyroid or stimulate B -cells to produce and release LATS withinthe thyroid with varying spill-over into the circulation.

Environmental factors may be fitted into the framework of this theory. Thus, feedingof thyroid to predisposed individuals might provide the antigenic stimulus which couldgive rise to a 'forbidden clone'. Epidemics of Graves' disease may be explained if Oneassumes that an infectious agent might cause an acquired depression of the immunesurveillance mechanism in a patient who otherwise has not inherited the defect. Theappearance of Graves' disease during immunosuppressive therapy with steroids(Brown and Lowmann, 1967) and cyclophosphamide (McDougalI et al., 1971) may beexplained by the same mechanism.

THE NATURAL HISTORY OF HYPERTHYROIDISM

The course of hyperthyroidism is variable. In addition to the usual symptoms ofhyperthyroidism such as weakness, tachycardia, tremor, sweating, nervousness, goiter,and ocular manifestations, carefui questioning often brings out more subtle findingswhich existed for some time before the onset of these symptoms. At times, the initialsymptoms are those of cardiac failure, psychic disturbance or muscular disorder whichentirely overshadow the other symptoms. With present therapy, knowledge of thenatural history of the disease has been limited by the control of some features at anearly stage. In the older literature, it is often impossible to differentiate the type ofhyperthyroidism that is being discussed because of confusion in etiology andnomenclature (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 thehypermetabolism or its complications, there wiII be a tendency to resolution withouttreatment. Sattler (1952) estimated that 8-12 per cent of patients died ofhyperthyroidism before the routine use of surgery in the twentieth century. Graves'disease may result in myxedema spontaneously. Woods et at. (1973) have recentlyreported that decreased thyroid reserve and frank hypothyroidism may occur as long as25 years following treatment with antithyroid drugs alone. If the disease remainsuncontrolled, a sudden severe exacerbation may develop with or without anintercurrent precipitating cause (McArthur et al., 1947). Before the introduction ofiodine and antithyroid drugs, operation on the thyroid led to classic thyroid crisis orstorm 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 chronichyperthyroidism. The disease might begin acutely and present with severe symptomsapproaching storm. Usually some precipitating event such as infection could beidentified. If the patient survived, the remission might be equally dramatic withcomplete resolution of symptoms. About 25 per cent of milder cases might have aself-limited course with remission occurring in months to years (Sattler, 1952). Morecommonly the onset is insidious and the disorder is characterized by remission andrelapse 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 withcomparatively 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 effectsof the excessive circulating levels of thyroid hormones. The signs and symptoms of

Hyperthyroidism 409

hyperthyroidism must be carefully differentiated from the associated ocular andcutaneous findings of Graves' disease which may be present without any evidence ofhyperthyroidism.

THE THYROID GLAND

The presence of a goiter is a constant finding in hyperthyroidism. Though its absencecasts grave doubt upon the diagnosis, it may not be palpably enlarged in 1-3 per cent ofpatients 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 anextra-thyroidal source of thyroid hormone, particularly if the scan shows noaccumulation of radioactive material in the neck or substernal region. In most cases ofsubsternal goiter, thyroid tissue will still be palpable in the neck, but occasionalinstances of hyperfunctional substernal goiter occur, especially after the patient hasalready undergone thyroidectomy. Substernal goiters are seen as shadows behind themanubrium on X-ray examination. In contrast to other structures which may give riseto 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 lingualthyroid tissue causing hyperthyroidism has been reported (Snapper and Kahn, 1%7).

In patients with an autonomous nodule, the hyperactive nodules are almost alwayseasily palpable in the neck as they are usually greater than 3 em in size when symptomsof hyperthyroidism occur (Kempers et al., 1970). Sometimes, one may find the typicaleye signs of Graves' disease with nodular goiter. Mild hyperthyroidism with thyroidtenderness associated with fever and elevated sedimentation rate is strongly suggestiveof subacute (granulomatous) thyroiditis.

A systolic or continuous bruit heard over the thyroid is indicative of thyroidhyperacitivity, but must be differentiated from transmitted cardiac murmurs andcarotid bruits. Venous hums may be extinguished by pressing gently above the thyroidto occlude venous return.

Although goiter may increase neck (and collar) size, it is often noticed first by friendsand family rather than the patient. Patients may complain of a lump in the throat ordysphagia.

Diffuse, soft cervical adenopathy may occur as part of the picture of the generalizedreticuloendothelial hyperplasia of Graves' disease.

INTEGUMENT

The skin is often smooth, warm and moist. The hyperdynamic vasomotor systemcauses sweating or flushing (Youmans, 1931). The patient feels warm and prefers acolder environment, often to the distress of the euthyroid spouse. Observation andtouching of the warm, sweating, tremulous hand of the patient is a helpful diagnosticmaneuver. In general, these cutaneous signs are expressions of increased heatproduction. Neurasthenic patients with excessive catecholamine secretion whosecomplaints may mimic those of hyperthyroidism generally have cool moist handsbecause of peripheral vasoconstriction.

Changes in pigmentation may occur (Bartels et al., 1937). Hyperpigmentation may bediffuse or patchy, especially over the face. In contrast to the bronzing seen inAddison's disease, mucous membranes are rarely involved. Vitiligo is often seen inassociation 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 nolonger take a 'permanent wave', and younger women that their hair increasingly frays atthe ends. Temporary hair loss is common, often catastrophic, if associated withalopecia areata or autoimmune alopecia totalis in Graves' disease.

Onycholysis (Plummer's nails) produces a margin from which the distal 'part of thenail separates making it difficult to clean dirt from under the nails (Bean, 1962).

Pretibial myxedema is a finding unique to Graves' disease and occasionally


Hashimoto's thyroiditis. Like the exophthalmos, it may appear independently of thehyperthyroidism (Beierwaltes, 1954). The lesions begin as reddish-brown papules mostcommonly on the lateral anterior aspects of the lower shins. They enlarge and convergeto form irregular plaques several centimeters in diameter. Histologically they consist ofdermal deposits of mucopolysaccharides. Occasionally the ankles and legs may becompletely involved with non-pitting, brawny edema which is difficult to distinguishfrom elephantiasis. The presence of localized myxedema is better correlated withelevated LATS titers than hyperthyroidism and ophthalmopathy (Kriss et al., 1964).

NERVOUS, MUSCULAR AND SKELETAL SYSTEMS

Nervousness, irritability, restlessness, insomnia, increased fatiguability, tremor andmuscular weakness are common complaints. The hyperactivity is more apparent to thephysician than to the patient. It is common for the hyperthyroid patient to feel overlyoptimistic or even euphoric, but many are irritable, react quickly and inappropriatelywith excessive laughter or crying spells in response to trivial stimuli. They may appearquite agitated and emotionally unstable. Loss of concentrating ability leads toloquacious conversations which rush along without logical goal.

There may be great restlessness with rapidly performed, jerky movements, but unlikechorea they are purposeful and associated with a fine tremor of the hands. Cerebrationmay be quick. It is frequently difficult to perform simple mental tasks, and the patientmay show poor judgement. There may be clear failure of insight into the problem.Frank psychosis can be precipitated in the predisposed individual. Hyperthyroidismhas been implicated as a factor in the development of criminal behavior (Davis et al.,1971). Marked irritability, restlessness and insomnia may herald impending thyroidstorm. In elderly individuals delirium may occur even with slight hypermetabolicfeatures. After many years irreversible psychosis may occur (Dunlap and Moersch,1935).

Tremor is a fairly constant manifestation of hyperthyroidism. It is usually evident inthe outstretched hands and is accentuated by effort. While usually fine and rapid witheight 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 ofmuscles in response to deep tendon reflexes is increased.

Muscle weakness occurs quite early in the course of hyperthyroidism. Symptomsrange from mild to severe weakness and muscular atrophy (Thorn and Eder, 1946).Characteristically it is the proximal girdle muscles that are most affected. Patientscomplain of weakness particularly when rising from a chair, climbing stairs, or combingtheir hair. It may be brought out by having the patient step up on a stool. More distalinvolvement and actual muscle atrophy occur and occasionally must be differentiatedfrom progressive muscular atrophy (Ramsay, 1966).

Myasthenia gravis may mimic hyperthyroidism" clinically with muscle weaknessprogressing throughout the day, bulbar palsy, and falsely positive responses toneostigmine (Weikhardt and Redmond, 1960). However, 3 to 6 per cent of patientswith hyperthyroidism also have associated myasthenia gravis (Grob, 1958).

There is an association between hyperthyroidism and sporadic hypokalemic periodicparalysis which is particularly evident in Japanese and Chinese (Engel, 1961) andusually found during the course of active hyperthyroidism. The attacks often disappearonce the hyperthyroidism is controlled. Subachromial bursitis appears to be morecommon than in the general population (Skillern, 1952). Onset of muscle cramps andarthralgias during treatment should alert the clinician to the possible development ofhypothyroidism as arthralgias are a common and early sign of hypothyroidism and arenot associated with hyperthyroidism. Thyrotoxic acropachy with clubbing of the fingersand toes due to periosteal proliferation has been described in Graves' disease(Malkinson, 1963).

Increased bone resorption in hyperthyroidism leads to demineralization. The bonesof patients with long-standing disease may have decreased density on X-ray (Kranes,

Hyperthyroidism 411

1971). Hypercalcemia occurs in some hyperthyroid patients, but it is usually mild andasymptomatic. Although the incidence of hypercalcemia was reported to be 20 per centin one series of seventy-seven patients (Baxter and Bondy, 1966), we could not confirmthis high incidence. We found only one patient with hypercalcemia in a group ofseventy-one unselected consecutive hyperthyroid patients; the other seventy hadnormal serum calcium values. Serum calcium, if elevated, returns to normal withtherapy 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, eitherparoxysmal or continuous, is frequent in the elderly. The apex beat is forceful with abounding 'precordium. Cardiomegaly with the eventual development of congestivefailure may occur. Cardiac output is usually increased (DeGroot et al., 1960) andcirculation time is accelerated. Pulse pressure is increased with rise in systolic bloodpressure (Hurxthal, 1931). Loud arterial sounds can be heard with a stethoscope overthe uncompressed brachial artery. A pulmonic systolic scratch most audible on fullexpiration over the sternum in the second left interspace may be mistaken forpericardial rub (Means et al., 1963). The brachial arterial sounds and thepleuropericardial scratch disappear with return to euthyroidism.

It is often difficult to tell if there is coexistent heart disease in the thyrotoxic patientwith tachycardia, palpitations, systolic hypertension and congestive heart failure. Atrialfibrillation and congestive heart failure usually require larger than normal doses ofdigitalis for a beneficial response. Occasionally, dependent edema may be encounteredunrelated to localized myxedema. Its occurrence does not necessarily indicate the onsetof congestive failure (Means et al., 1963).

THE RETICULOENDOTHELIAL AND HEMIC SYSTEMS

Relative lymphocytosis is common. Lymphadenopathy associated with thymichyperplasia and elevated circulating concentrations of T-cell lyrnpholytes occur. Thesplenic 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 andmalabsorption due to diarrhea. Impaired utilization 'of iron has been found in anemichyperthyroid patients (Rivlin and Wagner, 1969).

GASTROINTESTINAL SYSTEM

Hyperthyroidism is characteristically associated with weight loss due to increasedcatabolism and increased gut peristalsis which causes diarrhea and occasionally leadsto overt malabsorption (Siurala et al., 1966). Patients tend to compensate for this byincreased food intake. Van Muller first called attention to the paradox of weight lossdespite excellent appetite (quoted by Sattler, 1952). Sometimes compensation issufficient to prevent weight loss, and especially in-peripubertal thyrotoxicosis, theremay be a sudden increase in weight. If anorexia develops, weight loss may beexcessive. Epigastric pain with vomiting has been described (Chapmen and Maloof,1956). Nausea and vomiting usually occur only in severe cases. The resulting caloricdeprivation and dehydration may precipitate thyroid storm.

Achlorhydria is often present (Brown et al., 1941) and histamine does not stimulategastric 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 beendescribed (Lamberg and Gordin, 1954), but clinical evidence of liver dysfunction israre. Mild hepatomegaly, with or without associated congestive failure, may occur.Frank jaundice is extremely rare without preexisting disorders of bilirubin metabolismor hepatic dysfunction.


GENITOURINARY SYSTEM

Aside from an increase in renal blood flow and glomerular filtration rate which maylead to mild polyuria, there are no urinary tract symptoms.

Changes in menstruation are very common in adult women. Oligomenorrhea is morefrequent than menometrorrhagia. The etiology of amenorrhea during hyperthyroidismis unclear. Proliferative endometria suggest a hypothalamic or pituitary disturbancewith 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 ofmiscarriage 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 ofhyperthyroid men. Mild degrees of gynecomastia are occasionally seen. This may bedue to the increased production of LH and elevated serum concentrations of freeestradiol (E;) seen in hyperthyroidism (Chopra and Tulchinsky, 1974),or it may resultfrom 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 hasobviated the need for retrospective diagnosis based on a clinical trial of therapy. Beforeundertaking therapy which could result in destruction of the thyroid, the diagnosisshould be documented by laboratory tests. In addition, the tests serve as a reference toevaluate the effectiveness of therapy. "

Measurement of serum thyroxine (serum T4) by competitive protein binding or.radioimmunoassay is probably the single best test to establish the diagnosis. Ameasurement of the saturation of the binding globulin such as the resin uptake oftriiodothyronine is useful to validate that the elevated serum T4 is due tohyperthyroidism in which the binding globulin"is relatively saturated. In rare instancesserum T4 is normal and the concentration of triiodothyronine in serum (serum T3) iselevated because of preferential hypersecretion of T3 , leading to Tj-inducedthyrotoxicosis. Therefore, a normal serum T4 does not exclude the diagnosis ofhyperthyroidism with. certainty. Elevation of serum 1'3 is a consistent finding and isprobably a more sensitive index of hyperthyroidism.

Measurements of thyroid uptake of radioiodine are less useful and should bereserved for special purposes. The thyroid uptake is necessary if the therapeutic doseof radioactive iodine is calculated on the basis of the uptake or biological half-life of theradioiodine. Radioiodine scans of the thyroid are necessary to establish the diagnosis ofhyperfunctioning nodules and to locate ectopic or metastatic hyperfunctioning thyroidtissue.

TREATMENT OF HYPERTHYROIDISM

GENERAL ASPECTS OF TREATMENT

Since the true etiology of Graves' disease is unclear, treatment cannot be directed atthe cause of the disorder; instead it is aimed mainly at controlling the excessivesecretion of thyroid hormone. There is no preventive therapy except avoidance of highintake of iodine in patients with goiter.

Treatment with long-term antithyroid medications temporarily controls theoverproduction of thyroid hormone until the disease undergoes spontaneous remission.The other modes of therapy, thyroidectomy and radioactive iodine, simply attempt toremove a portion of the gland and leave enough tissue to produce a normal amount ofthyroid hormone. That no therapy is universally acceptable reflects the fact that allhave significant risks.

General Indications

Hyperthyroidism

SURGERY

413

The role of surgery in the management of hyperthyroidism has decreased markedlyin the past 20 years. Less than 10 per cent of patients with Graves' disease are nowtreated by subtotal thyroidectomy at one large clinic which specialized in this form oftherapy (Sanfelippo et al., 1973). With increasing medical management there is now lessopportunity for surgeons to become proficient in thyroid surgery. This may have theeffect of diminishing the quality of surgery, increasing its complications, and makingmedical management even more attractive (Black, 1972). Despite advances in thenoninvasive management by drugs and radioactive iodine, surgery remains a safe andeffective alternative treatment when carried out by an experienced surgeon (Wool,1970). The indications for surgery will vary according to the clinical status of the patientand the decision of the patient's physicians. Few generalizations can be made that willnot be contradicted by others. There are some clinical situations where surgery shouldbe strongly considered. In the patient with hypersensitivity to antithyroid drugs or apatient in whom a trial of 1-2 years of antithyroid medication has failed to induce aremission, surgery represents a real alternative to radioactive iodine. A thyroidectomyscar is sometimes a reasonable cosmetic improvement for a patient who has had a hugegoiter for a long period of time. Surgery may be elected out of fear of radiation. This isparticularly true in prepubertal children for whom radiation may be a greater hazard.The older patient with a large multinodular goiter may prefer surgery since radioactiveiodine may control the hyperthyroidism without appreciably reducing the size of thethyroid gland. Surgery is the treatment of choice if there are symptoms of compression.

There are clinical situations where surgery is contraindicated. In the elderlydebilitated patient with significant cardiac, pulmonary, cerebrovascular, hepatic orrenal complications, surgery may be extremely hazardous. In patients who earn "theirliving by using their voices, post-surgical vocal cord paralysis may be catastrophic.Thyroidectomy should be avoided in patients who have had a previous thyroidectomybecause the complications are much greater with recurrent surgery.

Preoperative Considerations

All patients should be rendered euthyroid prior to the surgical procedure by the useof antithyroid drugs, such as propylthiouracil and methimazole, and inorganic iodine.The aims are to decrease circulating concentrations of thyroid hormones and todecrease the vascularity of the gland. Iodine decreases the size and vascularity of thethyroid gland when used in conjunction with the thiocarbamides. This decreases bloodloss 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 ofantithyroid drug with the addition of iodine during the final 1-2 weeks. Ideally, thecatabolism of hyperthyroidism is reversed; the patient should regain his weight andstrength, and have no resting tachycardia before surgery. Beta blocking agents havebeen 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 weeksnecessary for the salutary effects of the drugs to occur (Riddle and Schwartz, 1970).Addition- of propranolol to the ordinary drug program provides faster relief ofsymptoms.

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 enucleationalone. Details of the actual operative procedure have been reviewed in standardsurgical texts (Schwartz, 1969; Harrison, 1972). As generally practiced, the posteriorportion of the capsule is left along with 2-4 g of thyroid tissue from each lobe (Taylorand Painter, 1962; Plested and Pollock, 1967). It is important to recognize the difference


between true autonomous adenomata of the thyroid and 'hot' nodules belonging totoxic nodular goiter, since in the latter case subtotal thyroidectomy rather thannodulectomy must be performed. Total thyroidectomy has no place in the treatment ofhypermetabolism of thyrotoxicosis (Heimann, 1969).

COMPLICATIONS OF THYROIDECTOMY

Mortality

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

Early Postoperative Complications

Early postoperative complications include local edema and collections of bloodwhich may require local evacuation and occasionally reexploration of the wound.Respiratory obstruction due to hematoma may require a tracheostomy. Wound edemawas 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 patientis euthyroid prior to surgery (Hershman, 1966).

Wound infection, atelectasis, pneumonia, and pulmonary embolus have to beconsidered along with the morbidity which is peculiar to thyroid surgery (McDougalland Greig, 1971). Keloid formation or an ugly scar is an important post-operativecomplication in the young female. Rarely, damage to the cervical sympathetic nervesmay result in unilateral ptosis, enophthalmos, and miosis.

Vocal Cord Paralysis

Temporary paralysis of one or both vocal cords due to surgical trauma of therecurrent laryngeal nerves, edema and/or ecchymosis in the tissues of the neck is seenin about 10 per cent of patients (Bloomstedt, 1959). Unilateral paresis with hoarsenessmay be treated by rest and reassurance that a good speaking voice will return in severalweeks to months. Bilateral paralysis may 'result in aphonia if the cords do notapproximate. If they do, the speaking voice may be satisfactory, but there may bedyspnea and stridor. If permanent injury results in respiratory crowing and air hungerwith exertion, tracheostomy should be considered (Hawe and Lothian, 1960).Resuturing of the nerves has not been successful. Figures for objective persistentparalysis 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 ofexcessive amounts of parathyroid tissue or damage to the end-arteries supplying theglands may result in permanent hypoparathyroidism manifested by numbness andtingling of the hands, feet, lips and sides of the face, anxiety and depression, carpopedalspasm, and Trousseau's and Chvostek's signs. Without treatment there may beprogression to laryngeal spasm causing respiratory distress , anoxemia, delirium,generalized convulsions, and death. In many patients the symptoms of tetany disappearafter a few days even though the serum calcium concentration remains persistently low.Long-term complications of untreated hypoparathyroidism include impaired intellec-

Hyperthyroidism 415

tual ability, and cataracts (Lachmann, 1941). The frequency of tetany was reported tobe between 0.3 and 4 per cent in six series; hypocalcemia occurred in 1-6 per cent ofadults (Wade, 1960) and 2-7 per cent of children (Hayles et al., 1959; Bacon andLowrey, 1965). Permanent hypocalcemia due to hypoparathyroidism occurs in 2-4 percent of operated patients (Hurxthal, 1945; Cassidy, 1963; Wade, 1965; Heimann, 1%9).

The concept of partial parathyroid insufficiency following surgery or radioactiveiodine therapy has been debated in the literature (Jones and Fourman, 1963; Michie etal., 1966). Its prevalence and clinical significance are unknown. Its existence is based onthe demonstration of delay in recovery from hypocalcemia induced by infusion ofEDTA. Presumably damage to the parathyroid glands occurred during surgery leavingsufficient function to maintain a serum calcium in the normal range, but not sufficientreserve to maintain homeostasis during times of stress. This complication occurs in 24per cent of patients with thyroidectomy (Jones and Fourman, 1963). Its contribution topost-operative anxiety, depression and other non-specific complaints is unclear (Michieet al., 1966; Fourman et al., 1967).

Frank tetany must be treated promptly with parenteral calcium. A 10-20% solution ofcalcium gluconate in a dose of 10-20 ml may be given slowly, or 30-60 ml may be givenin 1000 ml of a 5% solution of glucose in water. The dose may be repeated as necessaryto 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 reliablepreparation, daily injections are required, and repeated doses result in allergicreactions. Vitamin D is given for the long-term control of calcium metabolism if .hypoparathyroidism is permanent. The present commercially available preparations ofergocalciferol (Vitamin D2) , cholecalciferol (Vitamin D3) and dihydrotachysterol areuseless for the immediate treatment of tetany since it takes days to weeks before theresponse.

Once tetany is controlled, chronic therapy should include large amounts of oralcalcium (about 1-2 g of calcium/day) together with ergocalciferol, 50,000 units per dayor dihydrotachysterol, 0.8-2.4 mg/day. The full effect of a change in the dose of vitaminD may not be seen for a month or so, and acute intoxication with hypercalcemia isdifficult to predict. Faster acting derivatives such as 1.25 dihydroxycholecalciferol arenot yet commercially' available. After one to two months, if serum calcium is normal,treatment should be stopped and serum calcium followed to see if hypoparathyroidismis permanent. Many patients do not require additional calcium supplementation. Theadvantage of maintaining calcium concentrations at slightly lower levels to stimulateresidual parathyroid tissue or prevent inadvertent vitamin D toxicity must be balancedagainst the risk of the long term complications. During pregnancy and lactation, serumcalcium 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 featureof recurrent hyperthyroidism following surgery is that it may occur over a wide timeinterval unlike treatment with anti-thyroid drugs where 70 per cent of relapses occurwithin a year (Hershman et al., 1966; Hausmann, 1972). McLarty (1969) found that halfof his ninety cases of recurrent hyperthyroidism occurred more than 5 years aftersurgery. Recurrent hyperthyroidism should not be treated by a second operation sincerate 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 stoppedafter 1 year to assess whether or not it is permanent. Hypothyroidism occurring 6months to 1 year after therapy is permanent with rare exceptions.


The incidence of hypothyroidism reported in the literature is quite variable. Thevariation in surgical results partially reflects differences in surgical techniques, butusually depends on the reason for thyroidectomy, the length of follow-up, the type ofpatients 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 thesubject have dealt adequately with this problem. Where long-term evaluation has beencarried out, the incidence of post-operative hypothyroidism has been reported to be5-43 per cent (Hershman, 1966; Nofal et al., 1966).Other surgical series reveal that withlong-term follow-up about 50 per cent of the patients will be receiving thyroidmedication even though the incidence of proven hypothyroidism is lower (Beahrs andSakulsky, 1968; Sawyers et al., 1972).

The incidence of hypothyroidism appears to increase slowly with time. It has beenstated that the incidence of this complication is less than that seen following radioactiveiodine. To a certain extent this may be due to patient selection, as the patients treatedsurgically tended to be younger and to have more nodular goiters-that is to berelatively more resistant to developing hypothyroidism after whatever form oftreatment is elected (Bronsky et al., 1968).

Iatrogenic hypothyroidism following treatment for hyperthyroidism is a public healthproblem of great magnitude. In the United States where the incidence ofhyperthyroidism is 20 per 100,000 people, we have calculated that treatment of thedisease will result in a pool of about a quarter of a million patients with hypothyroidismin 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 glandand the subsequent development of hypothyroidism (Green and Wilson, 1964; Beahrsand Sakulsky, 1968). Because of this, it is probably wise to treat such patients withthyroid replacement soon after surgery.

IMMUNOSUPPRESSIVE THERAPY,

If Graves' disease were due to autoimmunity, therapy with agents that suppress theimmune response might result in amelioration of the disease. The efficacious use ofhomologous serum in hyperthyroidism was reported by Bebe in 1900. Werner andPlatrnan (1965) treated five mildly to' moderately hyperthyroid patients with prednisonefor 1.5 to 2.5 months. They noted a decrease in goiter and a sustained remission in threeof the patients. During treatment there was an increase in nervousness and tachycardia.The acute administration of prednisone is known to increase BMR (Werner, 1950).Sideeffects included cushingoid features, slight growth of facial hair, euphoria and severeleg weakness. All patients were thought to be euthyroid at the end of therapy, and threepatients remained euthyroid for several months. The one patient with elevated LATShad progressive fall in titer. The use of prednisone in combination with radioactiveiodine or anti-thyroid drugs has been suggested without much clinical data to prove itsworth (Taka and Banos, 1971).

The appearance of hyperthyroidism during corticosteroid therapy has been describedin euthyroid patients with Hashimoto's thyroiditis (Singer, 1966), and in patients withno known thyroid disease (Brown and Lowman, 1964), as well as in patients given otherimmunosuppressive drugs (McDougall et al., 1971). It is probably wise to avoid givingcorticosteroids except as indicated for control of the ophthalmopathy.

SUMMARY

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

Hyperthyroidism 417

patients with nodular goiter, subacute thyroiditis, trophoblastic tumors producing molarthyrctropin.large differentiated thyroid carcinomas, struma ovarii, pituitary tumorsproducing thyrotropin, and taking excessive amounts of thyroid medication.

The clinical features of hyperthyroidism are described. Subtotal thyroidectomy iseffective treatment, but has the disadvantage of significant complications which includehypothyroidism, rare mortality, hypoparathyroidism, paralysis of vocal cords andaltered voice, recurrence of hyperthyroidism, rare thyroid crisis and morbidity from thewound.

ACKNOWLEDGEMENT

Supported in part by Veterans Administration Research Grant 3590 and USPHS Grant HD-7181.

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